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Abstract
Progress Toward the Total Synthesis of Ingenol
Haifeng Tang
Yale University
2002
Ingenol (1), a diterpene polyol initially isolated from the Euphorbia Ingens
species in 1968, is of considerable interest due to its structural complexity and
spectacular biological activities. Biologically, esters of ingenol have been shown to
possess potent tumor promoting, anti-leukemic, and anti-HIV properties. Structurally,
the unique ingenol framework featuring a rare example of “inside-outside” bicyclic
topological isomerism represents a formidable challenge to synthetic organic chemists.
Despite the efforts of many groups, ingenol did not yield to total synthesis until very
recently. Herein are described efforts toward the total synthesis of ingenol.
The complete carboskeleton of ingenol has been prepared in an efficient 13-step
sequence from known cycloheptenone 49, highlighted by the construction of the highly
strained “inside-outside” ingenol BC ring system via ring-closing metathesis (i.e.
127→128). The A ring of 128 has been functionalized in another 7 steps to furnish
highly advanced intermediate 136. Subsequent attempts to introduce the ingenol B ring
functionality via a singlet oxygen-ene reaction have yielded no success. Current work
stands only a few transformations away from a total synthesis of ingenol.
Progress Toward the Total Synthesis of Ingenol
A Dissertation
Presented to the Faculty of the Graduate School
of
Yale University
in Candidacy for the Degree of
Doctor of Philosophy
by
Haifeng Tang
Dissertation Director: Professor John Louis Wood
December, 2002
ii
© 2002 by Haifeng Tang
All rights reserved.
iii
To My Family
iv
Acknowledgements
First of all, I would like to thank my advisor, Professor John L. Wood for his
support and guidance. As an advisor, John always trusted me and gave me the time to
work things out, and for that I am very grateful. His passion for chemistry and love for
students have totally inspired me. From John, I have learned more than chemistry, and I
still have much more to learn.
I would also like to thank the members of my dissertation committee, Professor
Frederick E. Ziegler and Professor Andrew D. Hamilton, for their time and suggestions
and for their letters of support. I would like to extend my thanks to Professor Harry H.
Wassermann and Professor Jerome Berson for very helpful discussions.
To my parents I owe more than I can possibly repay in a lifetime. They have
literally devoted their lives to the future of their children, but never asked for anything.
They never questioned my decision to come to America, but supported me all the way
through. In times of uncertainty, their love and guidance always steered me in the right
direction. To my dear wife Shanshan, thank you for all your love and support. Life is
much more colorful with you around. I would also like to thank my dear friends, Hugh
and Jane Hedges, for their selfless devotion to international students at Yale. They taught
me to forgive and love, and they led me to the salvation of Jesus Christ. For the last four
and a half years, they have loved me like a son.
I must thank the members of the Wood group (W6), past and present, for creating
such a wonderful environment in which to learn and work. It has been a pleasure and a
privilege to work along side all of you. First of all, I would like to thank Team Ingenol.
Thanks to Andy Nickel for being my partner and material supplier. Thanks to Blake
Greene, who was a Yale undergrad working in our lab, for making a bunch of seven-
membered ring for me. Without the support from these two guys, I could not make so
much progress on this project.
I am grateful to Brad Shotwell and Andy Nickel for spending the time
proofreading my thesis and providing numerous corrections and suggestions that have
significantly improved its quality. I would like to thank Doug Fuerst for being a great
friend to me. I can always expect help from Doug whenever I need it. I have always
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enjoyed sharing ideas with Doug as well. Thanks to Roger for willingly helping me with
all my computer and NMR problems. Thanks to Pete L. Korakas for being my bench
neighbor and put up with me on a daily basis. I would also like to thank Jon Njardarson
for his super optimistic attitude and motivational ideas. Thanks to Stu for being the
party-organizer. Every time I drive by 188 Linden Street, I always remember the good
old days. I would like to thank Dave, who seems to know something about everything,
for always having time to explain something or discuss an idea. Thanks to Brian
Thompson for making all the suggestions for thesis writing, which made my job so much
easier. Thanks to George Moniz for his impressions, and to Jens Graeber for his years of
entertainment. I would also like to thank Joe Ready for all his insightful ideas. Thanks
to Gregg for being the nicest guy around and to Sarah Reisman for being the “sickest
girl” in the department. To the remainder of the crew: Ryan, Chee-Wah, Ivar, Ioana, Jay,
emelie, Masami, Takayuki, Makoto and Nobuaki: thanks for making the lab such a great
place to spend time.
I thank the Faller, Hamilton, Hartwig, Wasserman, and Ziegler groups for the use
of chemicals and equipment, as well as the many helpful discussions over the years. I
would also like to thank the Jorgensen group for advice on computational chemistry.
I would also like to thank Bessie, Dan, Ed, Jack, Karen, Rob, Brian, and Steve for
always keeping things in order here in the chemistry department and doing it with a
smile. Thanks to Sue, Karen, and the main office for taking care of all of us. I would
also like to acknowledge Dr. Ben Bangerter and Xiaoling Wu for their assistance on
NMR and Susan DeGala for crystal structure. I am also thankful to Virginia Harris who
has done so much for the entire the Wood group.
Finally, to the rest of my friends at Yale, thanks so much for making these past
five years so enjoyable and memorable. I wish all of you the best of everything in the
future.
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Table of Contents
Dedication .....................................................................................................................iii Acknowledgements....................................................................................................... iv Table of Contents .........................................................................................................vi List of Figures............................................................................................................... ix List of Schemes ............................................................................................................ xv List of Tables .............................................................................................................xvii List of Abbreviations................................................................................................xviii Chapter 1, Ingenol: A highly Oxygenated Tetracyclic Diterpene Polyol With
Interesting Biological Activities............................................................................1
1.1 Isolation.................................................................................................................1 1.2 Structure................................................................................................................2
1.2.1 A Highly Oxygenated Diterpene Polyol with Novel Structure .........................2 1.2.2 Inside-Outside Stereochemistry of Ingenol ......................................................3
1.3 Biological Activity ................................................................................................5 1.3.1 PKC Activation and Anti-Leukemic Properties ...............................................5 1.3.2 Anti-HIV Properties........................................................................................8
1.4 Related Natural Products .......................................................................................8
1.5 Synthetic Attempts Toward Ingenol.......................................................................9 1.5.1 Synthetic Efforts Prior to 1999........................................................................9 1.5.1.1 Paquette’s Synthesis of iso-Ingenol Analog ........................................ 10 1.5.1.2 Mehta’s Synthesis of the iso-Ingenol ABC Ring System..................... 11 1.5.1.3 Harmata’s Preparation of the iso-Ingenol ABC Ring System .............. 12 1.5.1.4 Rigby’s Efforts Toward the Ingenane ABC Ring Framework ............. 12 1.5.1.5 Funk’s Approach Toward the Ingenol Tetracyclic Skeleton ................ 14 1.5.1.6 Tanino and Kuwajima’s Synthesis of the Ingenol ABC Ring System.. 16 1.5.1.7 Winkler’s Efforts Toward the Ingenol Analogs................................... 17 1.5.2 Synthetic Efforts Since 1999 ......................................................................... 20 1.5.2.1 First Total Synthesis of Ingenol by Winkler........................................ 20 1.5.2.2 Kigoshi’s Approach Toward the Ingenol ABC Ring System............... 22
1.6 Conclusions ......................................................................................................... 23 1.7 Notes and References........................................................................................... 24
Chapter 2, Construction of the Complete Ingenol Carboskeleton ............................ 30
2.1 Initial Considerations........................................................................................... 30 2.1.1 Synthetic Strategy ......................................................................................... 30
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2.1.2 Ring-Closing Metathesis (RCM) ................................................................... 31 2.2 Toward the Ingenol BCD Ring System ................................................................ 34
2.2.1 Construction of the iso-Ingenol BCD Ring System........................................ 34 2.2.2 RCM Attempts Toward the Ingenol BCD Ring System................................. 36
2.3 Toward the Ingenol Tetracyclic Skeleton ............................................................. 38 2.3.1 Conformation Analysis of RCM Precursors................................................... 38 2.3.2 Revised Synthetic Plan.................................................................................. 38 2.3.3 Synthetic Efforts of the ROM-RCM Strategy ................................................ 39 2.3.3.1 Preparation of Exo-olefin 109 ............................................................. 39 2.3.3.2 Initial Attempts of Tandem ROM-RCM ............................................. 41 2.3.3.3 RCM Attempts of Triene 106 ............................................................. 42 2.3.4 Construction of the Ingenol Tetracyclic Skeleton via RCM ........................... 42 2.3.4.1 Modification of RCM Precursor ......................................................... 42 2.3.4.2 RCM of Modified Precursor 118......................................................... 43
2.4 Toward the Complete Ingenol Skeleton ............................................................... 44 2.4.1 Construction of the Complete Ingenol Skeleton via RCM.............................. 44 2.4.2 Investigation of the RCM Transformation ..................................................... 46
2.5 Conclusions ......................................................................................................... 49
2.6 Experimental Section........................................................................................... 51 2.6.1 Materials and Methods .................................................................................. 51 2.6.2 Preparative Procedures.................................................................................. 52
2.7 Notes and References........................................................................................... 91 Appendix 1, Spectra Relevant to Chapter 2 ............................................................... 96 Appendix 2, X-Ray Structure Reports Relevant to Chapter 2 ................................ 171
A.2.1 X-Ray Crystallography Report for Diol 104 ................................................... 172 A.2.1.1 Crystal Data ............................................................................................ 172 A.2.1.2 Intensity Measurements........................................................................... 173 A.2.1.3 Structure and Solution Refinements......................................................... 173 A.2.1.4 Atomic Coordinates and Biso/Beq.............................................................. 175
A.2.2 X-Ray Crystallography Report for Ketal 111c................................................ 178 A.2.2.1 Crystal Data ............................................................................................ 178 A.2.2.2 Intensity Measurements........................................................................... 179 A.2.2.3 Structure and Solution Refinements......................................................... 179 A.2.2.4 Atomic Coordinates and Biso/Beq.............................................................. 181
A.2.3 X-Ray Crystallography Report for Dibenzoate 121 ........................................ 183 A.2.3.1 Crystal Data ............................................................................................ 183 A.2.3.2 Intensity Measurements........................................................................... 184 A.2.3.3 Structure and Solution Refinements......................................................... 184 A.2.3.4 Atomic Coordinates and Biso/Beq.............................................................. 186
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A.2.4 X-Ray Crystallography Report for Compound 135......................................... 189 A.2.4.1 Crystal Data ............................................................................................ 189 A.2.4.2 Intensity Measurements........................................................................... 190 A.2.4.3 Structure and Solution Refinements......................................................... 190 A.2.4.4 Atomic Coordinates and Biso/Beq.............................................................. 192
Chapter 3, Introduction of the Ingenol Polyol Functionality .................................. 194
3.1 Retrosynthetic Analysis ..................................................................................... 194 3.2 Functionalization of the A Ring ......................................................................... 195
3.2.1 Preparation of Exo-olefin 138...................................................................... 195 3.2.2 Oxidation of the A Ring .............................................................................. 197 3.2.3 Introduction of the C(4) Hydroxyl............................................................... 198
3.3 Functionalization of the B Ring: Singlet Oxygen-Ene Strategy .......................... 199 3.3.1 Singlet Oxygen-Ene Reaction...................................................................... 199 3.3.2 Singlet Oxygen-Ene Reaction: Model Studies ............................................. 200 3.3.3 Singlet Oxygen-Ene Reaction of Allylic Alcohol 136.................................. 201 3.3.4 Singlet Oxygen-Ene Reaction: Substrate Modification ................................ 202
3.4 Alternative Approaches to Functionalize the B Ring .......................................... 208 3.4.1 Epoxide-Opening Approach........................................................................ 209 3.4.2 Intramolecular Cyclization Approach.......................................................... 213 3.4.3 Other Approaches Attempted ...................................................................... 215
3.5 Reexamination of the Singlet Oxygen-Ene Strategy........................................... 216 3.5.1 Computational Analysis of Singlet Oxygen Substrates ................................ 216 3.5.2 Toward the End-Game ................................................................................ 218
3.6 Conclusions ....................................................................................................... 219
3.7 Experimental Section......................................................................................... 220 3.7.1 Materials and Methods ................................................................................ 220 3.7.2 Preparative Procedures................................................................................ 221
3.8 Notes and References......................................................................................... 254 Appendix 3, Spectra Relevant to Chapter 3 ............................................................. 258 Appendix 4, Notebook Cross Reference ................................................................... 313 Bibliography .............................................................................................................. 317 Index .......................................................................................................................... 323 About the Author ...................................................................................................... 324
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List of Figures
Chapter 1
Figure 1.1 Ingenol ..........................................................................................................1 Figure 1.2 Ingenol Type Parent Alcohols........................................................................2 Figure 1.3 Ingenane and Ingenol.....................................................................................3 Figure 1.4 Inside-Outside Stereochemistry .....................................................................4 Figure 1.5 Natural Products with Inside-Outside Stereochemistry...................................5 Figure 1.6 Tumor Promoters...........................................................................................6 Figure 1.7 Three Point Model of Ingenol Esters..............................................................7 Figure 1.8 Phorbol and Tigiliane.....................................................................................9 Figure 1.9 Structural Relationship between Ingenane and Tigiliane ................................9 Chapter 2
Figure 2.1 Ring-Closing Metathesis Catalysts............................................................... 32 Figure 2.2 Olefin Metathesis and Ring-Closing Metathesis........................................... 33 Figure 2.3 Crystal Structure of Diol 104 ....................................................................... 36 Figure 2.4 Conformational Analyses of RCM Precursors.............................................. 38 Figure 2.5 Ortep Plot of Dibenzoate 121....................................................................... 44 Figure 2.6 Stabilized RCM Intermediate by Oxygen Chelation..................................... 47 Appendix 1 Figure A.1.1 1H NMR (500 MHz, C6D6) of Compound 100a........................................ 97 Figure A.1.2 FTIR Spectrum (thin film/NaCl) of Compound 100a ............................... 98 Figure A.1.3 13C NMR (500 MHz, C6D6) of Compound 100a....................................... 98 Figure A.1.4 1H NMR (400 MHz, CDCl3) of Compound 100b ..................................... 99 Figure A.1.5 FTIR Spectrum (thin film/NaCl) of Compound 100b ............................. 100 Figure A.1.6 13C NMR (400 MHz, CDCl3) of Compound 100b .................................. 100 Figure A.1.7 1H NMR (500 MHz, C6D6) of Compound 101........................................ 101 Figure A.1.8 FTIR Spectrum (thin film/NaCl) of Compound 101 ............................... 102 Figure A.1.9 13C NMR (400 MHz, C6D6) of Compound 101....................................... 102 Figure A.1.10 1H NMR (500 MHz, C6D6) of Compound 102...................................... 103 Figure A.1.11 FTIR Spectrum (thin film/NaCl) of Compound 102 ............................. 104 Figure A.1.12 13C NMR (400 MHz, C6D6) of Compound 102..................................... 104 Figure A.1.13 1H NMR (500 MHz, C6D6) of Compound 103...................................... 105 Figure A.1.14 FTIR Spectrum (thin film/NaCl) of Compound 103 ............................. 106 Figure A.1.15 13C NMR (400 MHz, C6D6) of Compound 103..................................... 106 Figure A.1.16 1H NMR (500 MHz, CD2Cl2) of Compound 104 .................................. 107
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Figure A.1.17 FTIR Spectrum (thin film/NaCl) of Compound 104 ............................. 108 Figure A.1.18 13C NMR (500 MHz, CD2Cl2) of Compound 104 ................................. 108 Figure A.1.19 1H NMR (500 MHz, C6D6) of Compound 91........................................ 109 Figure A.1.20 FTIR Spectrum (thin film/NaCl) of Compound 91 ............................... 110 Figure A.1.21 13C NMR (500 MHz, C6D6) of Compound 91....................................... 110 Figure A.1.22 1H NMR (500 MHz, CDCl3) of Compound 105 ................................... 111 Figure A.1.23 FTIR Spectrum (thin film/NaCl) of Compound 105 ............................. 112 Figure A.1.24 13C NMR (500 MHz, CDCl3) of Compound 105 .................................. 112 Figure A.1.25 1H NMR (500 MHz, C6D6) of Compound 112a.................................... 113 Figure A.1.26 FTIR Spectrum (thin film/NaCl) of Compound 112a ........................... 114 Figure A.1.27 13C NMR (400 MHz, C6D6) of Compound 112a................................... 114 Figure A.1.28 1H NMR (500 MHz, C6D6) of Compound 112b.................................... 115 Figure A.1.29 FTIR Spectrum (thin film/NaCl) of Compound 112b ........................... 116 Figure A.1.30 13C NMR (400 MHz, C6D6) of Compound 112b................................... 116 Figure A.1.31 1H NMR (500 MHz, C6D6) of Compound 112c .................................... 117 Figure A.1.32 FTIR Spectrum (thin film/NaCl) of Compound 112c............................ 118 Figure A.1.33 13C NMR (400 MHz, C6D6) of Compound 112c ................................... 118 Figure A.1.34 1H NMR (500 MHz, C6D6) of Compound 112d.................................... 119 Figure A.1.35 FTIR Spectrum (thin film/NaCl) of Compound 112d ........................... 120 Figure A.1.36 13C NMR (400 MHz, C6D6) of Compound 112d................................... 120 Figure A.1.37 1H NMR (500 MHz, C6D6) of Compound 113...................................... 121 Figure A.1.38 FTIR Spectrum (thin film/NaCl) of Compound 113 ............................. 122 Figure A.1.39 13C NMR (400 MHz, C6D6) of Compound 113..................................... 122 Figure A.1.40 1H NMR (500 MHz, C6D6) of Compound 114...................................... 123 Figure A.1.41 FTIR Spectrum (thin film/NaCl) of Compound 114 ............................. 124 Figure A.1.42 13C NMR (400 MHz, C6D6) of Compound 114..................................... 124 Figure A.1.43 1H NMR (500 MHz, C6D6) of Compound 109...................................... 125 Figure A.1.44 FTIR Spectrum (thin film/NaCl) of Compound 109 ............................. 126 Figure A.1.45 13C NMR (400 MHz, C6D6) of Compound 109..................................... 126 Figure A.1.46 1H NMR (500 MHz, C6D6) of Compound 115a.................................... 127 Figure A.1.47 FTIR Spectrum (thin film/NaCl) of Compound 115a ........................... 128 Figure A.1.48 13C NMR (400 MHz, C6D6) of Compound 115a................................... 128 Figure A.1.49 1H NMR (500 MHz, C6D6) of Compound 115b.................................... 129 Figure A.1.50 FTIR Spectrum (thin film/NaCl) of Compound 115b ........................... 130 Figure A.1.51 13C NMR (400 MHz, C6D6) of Compound 115b................................... 130 Figure A.1.52 1H NMR (500 MHz, C6D6) of Compound 115c .................................... 131 Figure A.1.53 FTIR Spectrum (thin film/NaCl) of Compound 115c............................ 132 Figure A.1.54 13C NMR (400 MHz, C6D6) of Compound 115c ................................... 132 Figure A.1.55 1H NMR (500 MHz, CDCl3) of Compound 108 ................................... 133 Figure A.1.56 FTIR Spectrum (thin film/NaCl) of Compound 108 ............................. 134 Figure A.1.57 13C NMR (400 MHz, CDCl3) of Compound 108 .................................. 134 Figure A.1.58 1H NMR (500 MHz, CDCl3) of Compound 106 ................................... 135 Figure A.1.59 FTIR Spectrum (thin film/NaCl) of Compound 106 ............................. 136 Figure A.1.60 13C NMR (400 MHz, CDCl3) of Compound 106 .................................. 136 Figure A.1.61 1H NMR (500 MHz, C6D6) of Compound 116...................................... 137 Figure A.1.62 FTIR Spectrum (thin film/NaCl) of Compound 116 ............................. 138
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Figure A.1.63 13C NMR (400 MHz, C6D6) of Compound 116..................................... 138 Figure A.1.64 1H NMR (500 MHz, C6D6) of Compound 117...................................... 139 Figure A.1.65 FTIR Spectrum (thin film/NaCl) of Compound 117 ............................. 140 Figure A.1.66 13C NMR (400 MHz, C6D6) of Compound 117..................................... 140 Figure A.1.67 1H NMR (500 MHz, C6D6) of Compound 118...................................... 141 Figure A.1.68 FTIR Spectrum (thin film/NaCl) of Compound 118 ............................. 142 Figure A.1.69 13C NMR (400 MHz, C6D6) of Compound 118..................................... 142 Figure A.1.70 1H NMR (500 MHz, C6D6, 60 °C) of Compound 119........................... 143 Figure A.1.71 FTIR Spectrum (thin film/NaCl) of Compound 119 ............................. 144 Figure A.1.72 13C NMR (400 MHz, C6D6, 60 °C) of Compound 119.......................... 144 Figure A.1.73 1H NMR (500 MHz, C6D6, 80 °C) of Compound 120........................... 145 Figure A.1.74 FTIR Spectrum (thin film/NaCl) of Compound 120 ............................. 146 Figure A.1.75 13C NMR (500 MHz, C6D6, 60 °C) of Compound 120.......................... 146 Figure A.1.76 1H NMR (500 MHz, C6D6, 80 °C) of Compound 121........................... 147 Figure A.1.77 FTIR Spectrum (thin film/NaCl) of Compound 121 ............................. 148 Figure A.1.78 13C NMR (500 MHz, C6D6, 80 °C) of Compound 121.......................... 148 Figure A.1.79 1H NMR (500 MHz, CDCl3) of Compound 122a ................................. 149 Figure A.1.80 FTIR Spectrum (thin film/NaCl) of Compound 122a ........................... 150 Figure A.1.81 13C NMR (500 MHz, CDCl3) of Compound 122a ................................ 150 Figure A.1.82 1H NMR (500 MHz, CDCl3) of Compound 122b ................................. 151 Figure A.1.83 FTIR Spectrum (thin film/NaCl) of Compound 122b ........................... 152 Figure A.1.84 13C NMR (500 MHz, CDCl3) of Compound 122b ................................ 152 Figure A.1.85 1H NMR (400 MHz, CDCl3) of Compound 123 ................................... 153 Figure A.1.86 FTIR Spectrum (thin film/NaCl) of Compound 123 ............................. 154 Figure A.1.87 13C NMR (400 MHz, CDCl3) of Compound 123 .................................. 154 Figure A.1.88 1H NMR (500 MHz, CDCl3) of Compound 124 ................................... 155 Figure A.1.89 FTIR Spectrum (thin film/NaCl) of Compound 124 ............................. 156 Figure A.1.90 13C NMR (500 MHz, CDCl3) of Compound 124 .................................. 156 Figure A.1.91 1H NMR (400 MHz, CDCl3) of Compound 125 ................................... 157 Figure A.1.92 FTIR Spectrum (thin film/NaCl) of Compound 125 ............................. 158 Figure A.1.93 13C NMR (400 MHz, CDCl3) of Compound 125 .................................. 158 Figure A.1.94 1H NMR (500 MHz, CDCl3) of Compound 127 ................................... 159 Figure A.1.95 FTIR Spectrum (thin film/NaCl) of Compound 127 ............................. 160 Figure A.1.96 13C NMR (500 MHz, CDCl3) of Compound 127 .................................. 160 Figure A.1.97 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 128......................... 161 Figure A.1.98 FTIR Spectrum (thin film/NaCl) of Compound 128 ............................. 162 Figure A.1.99 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 128 ....................... 162 Figure A.1.100 1H NMR (400 MHz, CDCl3) of Compound 129 ................................. 163 Figure A.1.101 FTIR Spectrum (thin film/NaCl) of Compound 129 ........................... 164 Figure A.1.102 13C NMR (400 MHz, CDCl3) of Compound 129 ................................ 164 Figure A.1.103 1H NMR (400 MHz, CDCl3, 50 °C) of Compound 132....................... 165 Figure A.1.104 FTIR Spectrum (thin film/NaCl) of Compound 132 ........................... 166 Figure A.1.105 13C NMR (400 MHz, CDCl3, 50 °C) of Compound 132...................... 166 Figure A.1.106 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 133....................... 167 Figure A.1.107 FTIR Spectrum (thin film/NaCl) of Compound 133 ........................... 168 Figure A.1.108 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 133...................... 168
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Figure A.1.109 1H NMR (500 MHz, CDCl3) of Compound 134 ................................. 169 Figure A.1.110 FTIR Spectrum (thin film/NaCl) of Compound 134 ........................... 170 Figure A.1.111 13C NMR (500 MHz, CDCl3) of Compound 134 ................................ 170 Appendix 2
Figure A.2.1 ORTEP Plot of Diol 104 ........................................................................ 172 Figure A.2.2 ORTEP Plot of Ketal 112c ..................................................................... 178 Figure A.2.3 ORTEP Plot of Dibenzoate 121.............................................................. 183 Figure A.2.4 ORTEP Plot of Compound 135 .............................................................. 189 Chapter 3 Figure 3.1 Singlet Oxygen-Ene Reaction .................................................................... 200 Figure 3.2 Computational Analysis of the Singlet Oxygen-Ene Reaction .................... 217 Appendix 3
Figure A.3.1 1H NMR (500 MHz, CDCl3) of Compound 140 ..................................... 259 Figure A.3.2 FTIR Spectrum (thin film/NaCl) of Compound 140 ............................... 260 Figure A.3.3 13C NMR (400 MHz, CDCl3) of Compound 140 .................................... 260 Figure A.3.4 1H NMR (500 MHz, CDCl3) of Compound 141 ..................................... 261 Figure A.3.5 FTIR Spectrum (thin film/NaCl) of Compound 141 ............................... 262 Figure A.3.6 13C NMR (400 MHz, CDCl3) of Compound 141 .................................... 262 Figure A.3.7 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 139 .......................... 263 Figure A.3.8 FTIR Spectrum (thin film/NaCl) of Compound 139 ............................... 264 Figure A.3.9 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 139 ......................... 264 Figure A.3.10 1H NMR (500 MHz, CDCl3, 50 °C) of Compound 138......................... 265 Figure A.3.11 FTIR Spectrum (thin film/NaCl) of Compound 138 ............................. 266 Figure A.3.12 13C NMR (500 MHz, CDCl3, 50 °C) of Compound 138 ....................... 266 Figure A.3.13 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 142......................... 267 Figure A.3.14 FTIR Spectrum (thin film/NaCl) of Compound 142 ............................. 268 Figure A.3.15 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 142 ....................... 268 Figure A.3.16 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 143......................... 269 Figure A.3.17 FTIR Spectrum (thin film/NaCl) of Compound 143 ............................. 270 Figure A.3.18 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 143 ....................... 270 Figure A.3.19 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 137......................... 271 Figure A.3.20 FTIR Spectrum (thin film/NaCl) of Compound 137 ............................. 272 Figure A.3.21 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 137 ....................... 272 Figure A.3.22 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 136......................... 273 Figure A.3.23 FTIR Spectrum (thin film/NaCl) of Compound 136 ............................. 274
xiii
Figure A.3.24 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 136 ....................... 274 Figure A.3.25 1H NMR (500 MHz, CDCl3, 50 °C) of Compound 147......................... 275 Figure A.3.26 FTIR Spectrum (thin film/NaCl) of Compound 147 ............................. 276 Figure A.3.27 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 147 ....................... 276 Figure A.3.28 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 148......................... 277 Figure A.3.29 FTIR Spectrum (thin film/NaCl) of Compound 148 ............................. 278 Figure A.3.30 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 148 ....................... 278 Figure A.3.31 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 149......................... 279 Figure A.3.32 FTIR Spectrum (thin film/NaCl) of Compound 149 ............................. 280 Figure A.3.33 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 149 ....................... 280 Figure A.3.34 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 154......................... 281 Figure A.3.35 FTIR Spectrum (thin film/NaCl) of Compound 154 ............................. 282 Figure A.3.36 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 154 ....................... 282 Figure A.3.37 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 155......................... 283 Figure A.3.38 FTIR Spectrum (thin film/NaCl) of Compound 155 ............................. 284 Figure A.3.39 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 155 ....................... 284 Figure A.3.40 1H NMR (400 MHz, CDCl3, 40 °C) of Compound 156......................... 285 Figure A.3.41 FTIR Spectrum (thin film/NaCl) of Compound 156 ............................. 286 Figure A.3.42 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 156 ....................... 286 Figure A.3.43 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 152......................... 287 Figure A.3.44 FTIR Spectrum (thin film/NaCl) of Compound 152 ............................. 288 Figure A.3.45 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 152 ....................... 288 Figure A.3.46 1H NMR (500 MHz, CDCl3, 50 °C) of Compound 158......................... 289 Figure A.3.47 FTIR Spectrum (thin film/NaCl) of Compound 158 ............................. 290 Figure A.3.48 13C NMR (500 MHz, CDCl3, 50 °C) of Compound 158 ....................... 290 Figure A.3.49 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 159......................... 291 Figure A.3.50 FTIR Spectrum (thin film/NaCl) of Compound 159 ............................. 292 Figure A.3.51 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 159 ....................... 292 Figure A.3.52 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 160......................... 293 Figure A.3.53 FTIR Spectrum (thin film/NaCl) of Compound 160 ............................. 294 Figure A.3.54 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 160 ....................... 294 Figure A.3.55 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 161......................... 295 Figure A.3.56 FTIR Spectrum (thin film/NaCl) of Compound 161 ............................. 296 Figure A.3.57 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 161 ....................... 296 Figure A.3.58 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 162......................... 297 Figure A.3.59 FTIR Spectrum (thin film/NaCl) of Compound 162 ............................. 298 Figure A.3.60 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 162 ....................... 298 Figure A.3.61 1H NMR (500 MHz, CDCl3, 50 °C) of Compound 163......................... 299 Figure A.3.62 FTIR Spectrum (thin film/NaCl) of Compound 163 ............................. 300 Figure A.3.63 13C NMR (400 MHz, CDCl3, 50 °C) of Compound 163 ....................... 300 Figure A.3.64 1H NMR (400 MHz, CDCl3, 40 °C) of Compound 165......................... 301 Figure A.3.65 FTIR Spectrum (thin film/NaCl) of Compound 165 ............................. 302 Figure A.3.66 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 165 ....................... 302 Figure A.3.67 1H NMR (500 MHz, CDCl3, 40 °C) of Compound 169......................... 303
xiv
Figure A.3.68 FTIR Spectrum (thin film/NaCl) of Compound 169 ............................. 304 Figure A.3.69 13C NMR (500 MHz, CDCl3, 40 °C) of Compound 169 ....................... 304 Figure A.3.70 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 170......................... 305 Figure A.3.71 FTIR Spectrum (thin film/NaCl) of Compound 170 ............................. 306 Figure A.3.72 13C NMR (400 MHz, CDCl3, 60 °C) of Compound 170 ....................... 306 Figure A.3.73 1H NMR (500 MHz, CDCl3, 60 °C) of Compound 172......................... 307 Figure A.3.74 FTIR Spectrum (thin film/NaCl) of Compound 172 ............................. 308 Figure A.3.75 13C NMR (500 MHz, CDCl3, 60 °C) of Compound 172 ....................... 308 Figure A.3.76 1H NMR (500 MHz, CDCl3, 65 °C) of Compound 173......................... 309 Figure A.3.77 FTIR Spectrum (thin film/NaCl) of Compound 173 ............................. 310 Figure A.3.78 13C NMR (400 MHz, CDCl3, 40 °C) of Compound 173 ....................... 310 Figure A.3.79 1H NMR (500 MHz, CDCl3, 50 °C) of Compound 175......................... 311 Figure A.3.80 FTIR Spectrum (thin film/NaCl) of Compound 175 ............................. 312 Figure A.3.81 13C NMR (500 MHz, CDCl3, 50 °C) of Compound 175 ....................... 312
xv
List of Schemes
Chapter 1 Scheme 1.5.1 Paquette: Synthesis of iso-Ingenol Analog 29.......................................... 11 Scheme 1.5.2 Mehta: Synthesis of the iso-Ingenol ABC Ring System........................... 11 Scheme 1.5.3 Harmata: Preparation of the iso-Ingenol ABC Ring System..................... 12 Scheme 1.5.4 Rigby: Synthesis of the iso-Ingenol Ring System .................................... 13 Scheme 1.5.5 Rigby: Synthesis of the Ingenane ABC Framework................................. 14 Scheme 1.5.6 Funk: Synthesis of the Ingenol BCD Ring System................................... 15 Scheme 1.5.7 Funk: Synthesis of the Ingenol Tetracyclic Skeleton................................ 16 Scheme 1.5.8 Tanino and Kuwajima: Synthesis of the Ingenol ABC Ring System ........ 17 Scheme 1.5.9 Winkler: Construction of the Ingenol ABC Ring System......................... 18 Scheme 1.5.10 Winkler: Synthesis of Ingenol Analog 76 .............................................. 19 Scheme 1.5.11 Winkler: Construction of the Ingenol Tetracyclic Skeleton.................... 21 Scheme 1.5.12 Winkler: The First Total Synthesis of Ingenol ....................................... 22 Scheme 1.5.11 Kigoshi: Preparation of the Ingenol ABC Ring System ......................... 23 Chapter 2 Scheme 2.1.1 First Generation Retrosynthetic Analysis................................................. 31 Scheme 2.1.2 Carbonyl Chelation in RCM.................................................................... 34 Scheme 2.2.1 Preparation of Cycloheptenone 49........................................................... 35 Scheme 2.2.2 Preparation of the iso-Ingenol BCD Ring System Using RCM ................ 36 Scheme 2.2.3 RCM Attempts Toward the Ingenol BCD Ring System........................... 37 Scheme 2.3.1 Revised Retrosynthesis: Tandem ROM-RCM Strategy............................ 39 Scheme 2.3.2 Preparation of Exo-Olefin 109................................................................. 40 Scheme 2.3.3 Initial Attempts on Tandem ROM-RCM ................................................. 41 Scheme 2.3.4 RCM of Triene 106 ................................................................................. 42 Scheme 2.3.5 Modification of RCM Precursor .............................................................. 43 Scheme 2.3.6 Construction of the Ingenol Tetracyclic Skeleton .................................... 44 Scheme 2.4.1 Preparation of RCM Product 125 ............................................................ 45 Scheme 2.4.2 Preparation of RCM Product 128 via Direct Alkylation........................... 46 Scheme 2.4.3 Comparison of the RCM Results ............................................................. 47 Scheme 2.4.4 Investigation of the RCM Transformation ............................................... 48 Scheme 2.4.5 RCM Attempts of Diene 134................................................................... 49 Scheme 2.5.1 Summary of Synthetic Progress............................................................... 50 Chapter 3 Scheme 3.1.1 Retrosynthetic Analysis......................................................................... 195
xvi
Scheme 3.2.1 RCM Attempts Toward Exo-olefin 138 ................................................. 196 Scheme 3.2.2 Preparation of Exo-olefin 138................................................................ 197 Scheme 3.2.3 Allylic Oxidation of the A Ring ............................................................ 198 Scheme 3.2.4 Introduction of the C(4) Hydroxyl......................................................... 199 Scheme 3.3.1 Singlet Oxygen-Ene Reaction: Model Studies ....................................... 201 Scheme 3.3.2 Attempts to Oxidize Allylic Alcohol 136 with 1O2 ................................ 202 Scheme 3.3.3 Modification of the Singlet Oxygen Substrate ....................................... 203 Scheme 3.3.4 Preparation of Exo-olefin 154................................................................ 204 Scheme 3.3.5 Preparation of Singlet Oxygen-Ene Substrate 152 ................................. 205 Scheme 3.3.6 Singlet Oxygen Attempts of Allylic Alcohol 152 .................................. 205 Scheme 3.3.7 Singlet Oxygen-Ene Reaction of Allylic Alcohol 158............................ 206 Scheme 3.3.8 Preparation of Exo-olefin 163................................................................ 207 Scheme 3.3.9 Singlet Oxygen Attempts of the Exo-olefin ........................................... 208 Scheme 3.4.1 Alternative Strategy to the Ingenol B Ring Functionality ...................... 209 Scheme 3.4.2 An Alternative Way Toward cis-Diol 150 ............................................. 210 Scheme 3.4.3 Epoxide Opening Attempts of Epoxide 170 .......................................... 211 Scheme 3.4.4 Epoxide Opening Attempts of Hydroxy-Epoxide 160............................ 212 Scheme 3.4.5 Epoxide Opening Attempts of 172 ........................................................ 213 Scheme 3.4.6 Electrophile Promoted Intramolecular Cyclization ................................ 214 Scheme 3.4.7 Synthetic Manipulation of Diol 175 ...................................................... 215 Scheme 3.4.8 Attempts to Eliminate Alcohol 148 ....................................................... 212 Scheme 3.5.1 Revised End-Game Strategy.................................................................. 218 Scheme 3.6.1 Summary of Synthetic Progress............................................................. 220
xvii
List of Tables
Appendix 2 Table A.2.1 Atomic Coordinates and Biso/Beq for Diol 104.......................................... 172 Table A.2.2 Atomic Coordinates and Biso/Beq for Ketal 112c ...................................... 181 Table A.2.3 Atomic Coordinates and Biso/Beq for Dibenzoate 121 ............................... 186 Table A.2.4 Atomic Coordinates and Biso/Beq for Compound 135 ............................... 135 Chapter 3 Table 3.1 Singlet Oxygen-Ene Conditions Screened for 136 ....................................... 202 Table 3.2 Singlet Oxygen-Ene Conditions Screened for 152 ....................................... 205 Table 3.3 Epoxide Opening Attempts of Epoxide 170................................................. 211 Table 3.4 Conditions Attempted to Open Hydroxy-Epoxide 160................................. 212 Table 3.5 Conditions Screened for Opening of Epoxide 172 ....................................... 213 Table 3.6 Conditions Attempted for Intramolecular Cyclization.................................. 214 Table 3.7 Conditions Attempted to Eliminate Alcohol 178.......................................... 216 Appendix 4
Table A.4.1 Compounds Appearing in Chapter 2 ........................................................ 313 Table A.4.2 Compounds Appearing in Chapter 3 ........................................................ 315
xviii
List of Abbreviations
AcOH acetic acid aq aqueous BF3
.OEt2 boron trifluoride diethyl etherate Bn benzyl br broad Bu butyl t-Bu tert-butyl BuLi butyllithium c concentration in g/ml C carbon °C degrees Celsius ca. approximately calc’d calculated CDCl3 chloroform-d CH3CN acetonitrile CHCl3 chloroform CH2Cl2 methylene chloride CI chemical ionization m-CPBA meta-chloroperoxybenzoic acid δ chemical shift in ppm downfield from Me4Si d doublet Δ heated to reflux DBU 1,8-diazabicyclo[5.4.0]undec-7-ene dd doublet of doublets ddd doublet of doublets of doublets DMAP 4-(dimethylamino)pyridine DMF dimethyl formamide DMSO dimethyl sulfoxide dt doublet of triplets ea. each ee enantiomeric excess EI electron impact equiv equivalent Et ethyl Et2O ethyl ether EtOAc ethyl acetate Et3N triethylamine FAB fast atom bombardment FTIR Fourier transform infrared g gram(s) h hour(s)
xix
H hydrogen hv light Hz hertz HCl hydrochloric acid HF hydrofluoric acid HPLC high performance liquid chromatography HRMS high resolution mass spectrum ICl iodine monochloride J coupling constant KHMDS potassium hexamethyldisilazide KOH potassium hydroxide L liter(s) LDA lithium diisopropylamide LDEA lithium diethylamide LiOH lithium hydroxide µ micro m milli, medium (FTIR), multiplet (NMR) M moles per liter MB methylene blue Me methyl MeOH methanol MgSO4 magnesium sulfate mp melting point MHz megahertz min minute(s) mol mole(s) m/z mass to charge ratio NH4Cl ammonium chloride NaCl sodium chloride NaH sodium hydride NaHCO3 sodium bicarbonate NaOH sodium hydroxide Na2SO4 sodium sulfate NBS N-bromosuccinimide NIS N-iodosuccinimide NMR nuclear magnetic resonance O oxygen [O] oxidation OAc acetate OsO4 osmium tetraoxide p para PCC pyridinium chlorochromate pH hydrogen ion concentration PhSeBr phenylselenium bromide PhSeCl phenylselenium chloride PPh3 triphenylphosphine
xx
ppm parts per million ppt precipitate PPTS pyridinium para-toluenesulfonic acid pTSA para-toluenesulfonic acid py pyridine q quartet quint. quintuplet RB rose bengal rt room temperature RuCl3 ruthenium(III) chloride s singlet (NMR), strong (FTIR) sat saturated soln solution t triplet td triplet of doublets TBAF tetrabutylammonium fluoride TBHP tert-butylhydroperoxide TBS tert-butyldimethylsilyl TFA trifluoroacetic acid THF tetrahydrofuran Ti(Oi-Pr)4 titanium iso-propoxide TLC thin layer chromatography TMS trimethylsilyl TMSE (trimethylsilyl)ethyl TMSI trimethylsilyl iodide TPP tetraphenyl porphine w weak
21
Chapter 1
Ingenol: A Highly Oxygenated Tetracyclic Diterpene Polyol
With Interesting Biological Activities
1.1 Isolation.
In 1968, researchers at the Biochemisches Institut am Deutschen
Krebsforschungszentrum reported the isolation of a new irritant and cocarcinogenic
hexadecanoic acid monoester with molecular formula C36H58O6 from the latex of
Euphorbia ingens and from the seed oil of Euphorbia lathyris.1 Mild base catalyzed
transesterification of the resinous ester yielded the biologically inactive resinous parent
diterpene alcohol with molecular formula C20H28O5, whose structure was determined by
single crystal X-ray analysis of its triacetate derivative in 1970.2 The diterpene parent
alcohol was named ingenol by Hecker and coworkers (1, Figure 1.1).
O
H
HOHO
HO OH
1
2
3 4
5 6
7
8910
11
12 13
14
15
16
17
18
19
20
Ingenol (1)
Figure 1.1 ingenol.
22
Since the identification of ingenol, diverse ingenol types with different oxidation
states at C(3), C(4), C(5), C(12), C(13), C(16) or C(20) have also been isolated.3 Some
of these compounds are shown in Figure 1.2. Less oxygenated diterpene alcohols 5-
deoxyingenol (2) and 20-deoxyingenol (3) were detected in E. myrsinites and in E.
Kansui, respectively.4 Diterpene alcohol 20-deoxy-16-hydroxyingenol (4) was isolated
from E. marginata Pursh. Diterpene parent alcohols more oxygenated than ingenol, such
as 13-hydroxyingenol (5) and 16-hydroxyingenol (6), have also been isolated.5 The
highest oxygenated parent alcohol to date, 16,19-dihydroxyingenol (7) was detected in E.
cyparissias.
O
H
HO HOOH
5-deoxyingenol (2)
E. myrsinites Latex
O
H
HO HOHO
20-deoxyingenol (3)
Euphorbia Kansui Liou
O
H
HO HO
HO
20-deoxy-16-hydroxyingenol (4)
Euphorbia marginata Pursh
O
H
HO HOHO OH
HO
13-hydroxyingenol (5)
Euphorbia Kansui Liou
O
H
HO HOHO OH
16-hydroxyingenol (6)
E. marginata Pursh
O
H
HO HOHO OH
HO
16,19-dihydroxyingenol (7)
Euphorbia cyparissias Latex
OH
OH OH
520 20
16
13
16 16
19
Figure 1.2 Ingenol Type Parent Alcohols.
1.2 Structure.
1.2.1 A Highly Oxygenated Diterpene Polyol with Novel Structure.
23
The isolation and characterization of ingenol alcohols revealed a novel class of
natural products to the scientific community. The diterpene ingenol alcohols all contain
the same ingenane tetracyclic skeleton 8 (Figure 1.3). Central to the novel structure of
ingenane skeleton is a highly strained trans-intrabridgehead bicyclo[4.4.1]undecane BC
ring system, colloquially referred to as an “inside-outside” ring system,6 to which the
cyclopentane A ring and dimethylcyclopropane D ring are cis fused. In addition to its
unique skeleton, the southern rim of ingenol is highly oxidized at C(3), C(4), C(5) and
C(20). Notably, the C(3), C(4) and C(5) alcohols form an unusual vicinal all cis-triol
array.
H
H
8 Ingenane
3 4
5
810
20
AB
C
D O
H
HO HOHO
cis-triol1
3 4
5
20
MM2 Picture of 1
OH
Figure 1.3 Ingenane and Ingenol.
1.2.2 Inside-Outside Stereochemistry of Ingenol.
Bridged bicyclic systems can exist as three different stereoisomers: an outside-
outside isomer 9, an inside-inside isomer 10 and an inside-outside isomer 11 as shown in
Figure 1.4.7 Usually the inside-inside isomer 10 is most unstable because of the severe
repulsive interaction between inside atoms A1 and A2. However, the energy difference
between inside-outside and outside-outside isomers varies depending on the system. For
24
example, the outside-outside isomer of bicyclo[4.4.4]tetradecane is less stable than the
inside-outside isomer by 12 kcal mol-1, presumably as a consequence of eclipsing
interactions along each of the three chains of the bridged bicyclic ring system. In the
ingenane ring system, the inside-outside isomer is generally more strained than the
outside-outside isomer.8 Inside-outside bicyclo[4.4.1]undecane 12 is more strained than
its outside-outside isomer 13 by 6.3 kcal mol-1, whereas the corresponding inside-outside
and outside-outside bicyclo[4.4.1]undecan-7-one conformers differ in strain energy by
3.3 kcal mol-1. Ingenol itself is more strained than its C(8) epimer, also known as iso-
ingenol, by 5.9 kcal mol-1.8
cA1 c A2 c A1 cA2
A1
A2
H
H
H
H
9 outside-outside 10 inside-inside
c
c
11 inside-outside
out
out
in
out
12 13
Figure 1.4 Inside-Outside Stereochemistry.
Only a few known natural products exhibit the phenomenon of inside-outside
isomerism, such as 3α-acetoxy-15β-hydroxy-7,6-secotrinervita-7,11-diene (14) and
secotrinerviten-2β,3α-diol (15) (Figure 1.5).6 The inside-outside intrabridgehead
25
stereochemical relationship in ingenol is depicted in the MM2 minimized three-
dimensional picture (Figure 1.3).
OH
H
AcO
H
HO OH
14 15
Figure 1.5 Natural Products with Inside-Outside Stereochemistry.
1.3 Biological Activity.
1.3.1 PKC Activation and Anti-Leukemic Properties.
Protein Kinase C (PKC) is a serine/threonine kinase that plays a central role in
cell growth, differentiation, and apoptosis.9 The enzyme is normally quiescent and
cytoplastic, but upon activation it becomes associated with the inner leaflet of plasma
membranes. Binding to the plasma membrane is transient, and is importantly regulated
by the association of hydrophobic (S)-diglycerides (16, DAGs, Figure 1.6) with the
enzyme. The simultaneous binding of the hydrophobic DAGs to PKC and the lipid
bilayer enhances the association of PKC to the membrane by hydrophobic interactions.10
The process of PKC activation is of substantial interest for chemists, given that activation
of the enzyme is caused not only by (S)-DAGs but also by the structurally diverse tumor
promoters including the phorbol esters (17), ingenol esters, aplysiatoxin (18) and
bryostatin 1 (19).11
26
O
O OO
H3CO
OH
H3CCH3
CH3
O
CH3
OCH3
OH
OH
CH3
Br
O
HO
OR
HO
H
OH
OR'
O
OH
O
O
R
O
R
O
OHO
O
O
H3C
H3CO2C
H O
O
OAcCH3
CH3
H
CO2CH3H3C CH3
OH
OH
CH3
HO
18 Aplysiatoxin
17 Phorbol esters16 DAGs
19 Bryostatin 1
Figure 1.6 Tumor-Promoters.
Although plants of the family Euphorbiaceae have been widely used in folk
medicine since 2000 years ago, little was known about their chemical and biological
nature until the late 1960s.12 In 1968, Hecker first identified that esters of ingenol
isolated from Euphorbia lathyris oil and Euphorbia ingens latex were responsible for
their irritant and tumor-promoting activities.1 Since then, numerous ingenol derivatives
have been identified as tumor-promoting activators of protein kinase C. The hydrophobic
acyl chains of ingenol esters seem to play a very important role in PKC activation by
translocating PKC to the plasma membrane from the cytoplasm via hydrophobic
interactions. In an assay to bind PKC-α, Ingenol 3-monobenzoate has yielded a Ki of
27
0.15 nM. Without the acyl chain, ingenol itself is only a weak PKC activator with a Ki of
30 µM.13
Based on their PKC binding studies of DAG derivatives and other activators,
Kishi and Rando proposed a “Three-Point Model” for PKC activation.11 This model
argues that molecules with three hydrophilic atoms separated by approximately 6 Å can
activate PKCs. In addition, a hydrophobic moiety is also required for membrane
docking. In the case of ingenol PKC activators, Kishi and Rando suggested that C(3)
acyl carbonyl, C(9) ketone carbonyl, and C(20) hydroxyl form the three points for PKC
binding (Figure 1.7). However, several ingenol derivatives that do not fit these criteria
do bind PKC, and simplified analogs that do contain the three points, but lack other
structural features, show little or no affinity at all.14
O
H
O HO
HO OH
R
O
3
9
20
Figure. 1.7 Three Point Model of Ingenol Esters.
Paradoxically, as long ago as 1976, there have been reports on ingenol derivatives
having anti-tumor properties.15,16 Of particular interest is ingenol 3-20-dibenzoate
(IDB). IDB exhibits only mild affinity for PKC in vitro, but potently inhibits P-388
lymphocytic leukemia in rodents.15 In recent studies on the biological activity of
ingenoids there have been clear separations between tumor-promotion and potentially
therapeutic activities, suggesting that there may be a mechanistic pathway independent of
28
PKC activation responsible for biological activity.17 To date, there is no conclusive
structure-activity-relationship (SAR) model to explain the divergent biological activity of
the various ingenoids.
1.3.2 Anti-HIV Properties.
Interest for ingenol as a scaffold for bioactivity was further heightened by recent
reports that ingenol derivatives affect HIV-1 replication. In acutely infected cells,
ingenol derivatives were shown to be powerful inhibitors of viral adsorption to the host
cells, greatly inhibiting viral replication.18,19 Interestingly, in latently infected host cells,
ingenol derivatives were later shown to enhance HIV-1 replication.20 A mechanism to
explain these results has not been elucidated, although evidence suggests that both PKC
dependent and PKC independent pathways are involved.
1.4 Related Natural Products.
In addition to the ingenol alcohols, the tigiliane alcohols have also been isolated
from the family Euphorbiaceae.1 Phorbol (20), isolated from the Euphorbiaceae Croton
tiglium oil by Hecker, is a diterpene polyol based on the tetracyclic tigiliane nucleus 21
(Figure 1.8). It consists of a five-membered ring A, a seven-membered ring B, a six-
membered ring C and a dimethylcyclopropane ring D. The only structural difference
between tigiliane and ingenane is that the tigiliane BC ring is trans fused at C(8)-C(9),
instead of the trans-bridgehead isomerism. Diverse tigiliane alcohols have also been
29
isolated. Biologically, phorbol esters have been shown to possess cocarcinogenic
activities similar to the ingenol esters.21
H
H
HA
B
C D
89
H
HO
OH
OHOH
OH
O
21 tigilianePhorbol (20)
H H
Figure 1.8 Phorbol and Tigiliane.
The structural relationship between ingenane and tigiliane has been demonstrated
by chemical means (Figure 1.9).3 When diacetonide 22 was treated under dissolving
metal conditions, the C(9) carbonyl group can be reduced to yield the corresponding
alcohols. The 9-R epimer 23 can be converted to the corresponding polyfunctional
diterpene 24 with the tigiliane skeleton by a Wagner-Meerwein type rearrangement.
O
H
O OO
O
Na
22 23
OH
H
O OO
O
24
O
O
H
OOEt2O/i-PrOH
MsCl
20
3 4
5
9
pyridine
Figure 1.9 Structural Relationship between Ingenane and Tigiliane.
1.5 Synthetic Attempts Toward Ingenol.
30
1.5.1 Synthetic Efforts Prior to 1999.
Since the 1980s, ingenol has attracted efforts from numerous synthetic groups.
While the high degree of oxygenation, notably the cis-triol, represents a significant
synthetic challenge, the most imposing obstacle is construction of the highly strained
trans-bridgehead BC ring system. Successful approaches to the BC ring junction have
generally relied upon fragmentation and rearrangement strategies, while attempts at direct
alkylations to construct the trans-bridgehead have all resulted in the cis-stereochemistry.
Despite a combined 20-year effort by over ten groups, ingenol had not yielded to total
synthesis prior to our initiation of this project in 1999.
1.5.1.1 Paquette’s Synthesis of iso-Ingenol Analog.
Paquette and co-workers have synthesized the less strained iso-ingenol analog 29,
which is epimeric with the natural product at C(8), possessing the fully functionalized AB
ring of ingenol (Scheme 1.5.1).14 The B and C rings of the ingenol skeleton were
generated by sequential inter- and intra-molecular alkylation of tetralone 25 with (Z)-1,4-
dichloro-2-butene yielding the cis-intrabridgehead stereochemistry instead of the
requisite trans relationship. The photo-induced isomerization of 27 led to the formation
of perhydroazulene 28, which was further elaborated to iso-ingenol analog 29. However,
subsequent testing indicated that iso-ingenol analog 29 was totally devoid of the
biological activity associated with the naturally occurring ingenol esters. These results
31
underscore the importance of the trans-intrabridgehead stereochemistry for the biological
activity of the ingenol esters.
Scheme 1.5.1 Paquette: Synthesis of iso-Ingenol Analog 29.
MeO
O
OR
H
OOH
O
H
MeO
H
ORHOHORO
O
O
OR
O
H
27 R = TBDMS
29 R = palmitate
1) KNH2, NH3
2) KH
hv 8 8
(7 steps)
25 26
28
(20 steps)
ClCl
1.5.1.2 Mehta’s Synthesis of the iso-Ingenol ABC Ring System.
Mehta has reported another synthesis of the iso-ingenol ABC ring framework.22
He employed a sequential titanium-catalyzed intramolecular variant of the Mukaiyama
reaction for the construction of the B ring, followed by base promoted aldol cyclization
for the formation of the A ring. This approach, however, did not provide the “inside-
outside” stereochemistry either (Scheme 1.5.2).
32
Scheme 1.5.2 Mehta: Synthesis of the iso-Ingenol ABC Ring System.
CO2MeO
O
CO2Me
O
Br OMe
OMe O
CO2MeH
MeO
O
CO2MeO
Br
2) LHMDS, TMSCl3) TiCl4
30 31
32 33
1) NaH 1) TMSCl2) PCC
3) LHMDS
1) PdCl2, CuCl2, O2
2) NaH
1.5.1.3 Harmata’s Preparation of the iso-Ingenol ABC Ring System.
Harmata has reported an approach utilizing an intramolecular [4+3] cycloaddition
between a cyclic oxyallyl cation and a tethered furan.23 Unfortunately, this approach also
led to the formation of the cis-intrabridgehead system (Scheme 1.5.3).
Scheme 1.5.3 Harmata: Preparation of the iso-Ingenol ABC Ring System.
OO OO
1) LDA
2) TfSO2Cl
3) LiClO4, TEA
+
-
7.3 : 1
O
HO
O
HO+
34 35 36 37
1.5.1.4 Rigby’s Efforts Toward the Ingenane ABC Ring Framework.
Rigby has reported the construction of cis-fused bicyclo[4.4.1]undecane using an
intermolecular [6π+4π] cycloaddition of tropone 38 to diene 39.24 He has also proved
33
that the iso-ingenol ABC framework 42 can be prepared from 41 using an intra-molecular
[6π+4π] cycloaddition (Scheme 1.5.4).25
Scheme 1.5.4 Rigby: Synthesis of the iso-Ingenol Ring System.
O
OAc O
AcO
H H
O
O
H
H
+
38 39 40
41 42
More recently, Rigby reported an elegant protocol for the conversion of the
“outside-outside” bicyclo[4.4.1]undecane system into the more strained “inside-outside”
stereoisomer by using an internal delivery approach for the establishment of the C(8)-β
bridgehead hydrogen stereochemistry (Scheme 1.5.5).26 Dienol 47, prepared from an
intramolecular [6π+4π] cycloaddition, underwent an alkoxide accelerated [1,5]-hydrogen
sigmatropic rearrangement to yield the “inside-outside” bicyclo[4.4.1]undecane 48.
34
Scheme 1.5.5 Rigby: Synthesis of the Ingenane ABC Framework.
Cr(CO)3
H
H
O O
O
LiNEt2
H
H
HO O
HOH
KH
H
H
O O
HO O
O
H
hv or 1) OsO4
mCPBA
18-Crown-6
2) (MeO)2CMe2
43 44 45
46 47 48
8
1.5.1.5 Funk’s Approach Toward the Ingenol Tetracyclic Skeleton.
Funk has reported a clever solution to the problem of the “inside-outside” ingenol
BC ring system.8 Starting from 3-carene, cycloheptenone 49 was prepared in four steps
employing an intramolecular Mukaiyama condensation strategy. Michael addition
followed by sequential alkylations gave rise to diester 50. It should be noted that the
crucial trans relationship of C(8) and C(10) was set in 50 by stereoselective alkylations.
In another three steps, diester 50 was advanced to 12-membered lactone 51, which, upon
treating with TIPSOTf, underwent an Ireland-Claisen rearrangement to furnish the more
strained trans-fused bicyclo[4.4.1]undecane ring system 53 (Scheme 1.5.6).
35
Scheme 1.5.6 Funk: Synthesis of the Ingenol BCD Ring System.
H O
O
OTIPS
E
O
MeO2C
H
OTBS
MeO
O
N Me
Cl
I
MeO
O O
O
H
O
TIPSO
MeO
O
H
O
OO
MeO
O
B
C
OTBSCl
TIPSOTf
C6H6 reflux
1) O3, Me2S2) HC(OMe)3,CeCl3
3) KH, (MeO)2CO4) TiCl4, CH2Cl2
1) LiMeCuCN2) LDA, THF
3) Triton-B
1) TBAF2) K2CO3
3)
3-carene 49
50 51
52 53
810
methyl acrolate
+
-
A subsequent approach using the same strategy delivered a more readily
elaborated Claisen product 56.27 The new version made use of an n to n-2 ring
contraction instead of an n to n-4 rearrangement, and led to the first synthesis of the
ingenol tetracyclic ring system 58 containing the “inside-outside” stereochemistry
(Scheme 1.5.7).
36
Scheme 1.5.7 Funk: Synthesis of the Ingenol Tetracyclic Skeleton.
HMeO2C
O
O
OTBSCl
O
H
O
H
MeO2C
OE
HO
H
OTBS
O
H
O
O
H
O
TBSO
H
MeO2CLHDMS
toluene
3) Et2MgBr, CuI4) NaOMe
1) HF2) (COCl)2, DMF
1) LHMDS2) DIBAL
3) NaOMe
H
54 55 56
57 58
1.5.1.6 Tanino and Kuwajima’s Synthesis of the Ingenol ABC Ring System.
More recently, Tanino and Kuwajima reported their approach to the “inside-
outside” BC ring system by a tandem cyclization-rearrangement sequence.28 Upon
treatment with Lewis acid, the dicobalt hexacarbonyl propargyl derivative 60 afforded the
tricyclic tertiary cation intermediate 61, which in turn, underwent rearrangement to yield
the ingenol ABC ring system 62 (Scheme 1.5.8).
37
Scheme 1.5.8 Tanino and Kuwajima: Synthesis of the Ingenol ABC Ring System.
OMe
OH
OH
OMe
OH
OAc
Co(CO)3
Co(CO)3
MeAl(OCOCF3)(OAr)
OMe
OHCo(CO)3
Co(CO)3
O
H
Co(CO)3
Co(CO)3
MeO
B
C
A
OMe
OHCo(CO)3
Co(CO)3
+
1) Ac2O, DMAP
2) Co2(CO)8
62 (77%) 63 (21%)
59 60
61
1.5.1.7 Winkler’s Efforts Toward the Ingenol Analogs.
Arguably, the Winkler group had done the most work towards the synthesis of
ingenol before 1999. They reported the first successful construction of trans-
bicyclo[4.4.1] BC ring system via the de Mayo reaction in 1987 (Scheme 1.5.9).29 Upon
irradiation, dioxenone 66 gave rise to [2+2] cycloaddition product 67. Subsequently
photo adduct 67 underwent base promoted retro aldol fragmentation to yield the “inside-
outside” ingenol ABC ring system 68.
38
Scheme 1.5.9 Winkler: Construction of the Ingenol ABC Ring System.
O
H
OO
O
O
H
KOHA
C
B
O
H
H
COOH
H
OO
OLi/NH3
5-hexenyl-1-iodide
1) cyanoformate
2) acetone, TFAA
(58% yield) (70% yield)
hv
(83% yield) (88% yield)
64 65 66
67 68
With a reliable approach toward the ingenol ABC ring system, the Winkler group
went on to install the ingenol polyol functionalities. In 1999, they reported construction
of fully functionalized ingenol analog 76 (Scheme 1.5.10).30 The southern rim of ester
70, which was prepared from dioxenone 69 via de Mayo reaction, was functionalized to
afford diene 71 in four steps. Epoxidation of diene 70 followed by dihydroxylation
delivered diol 72, which was transformed into sulfate 73 following a 6-step sequence.
The C(6)-C(7) unsaturation was installed by base (DBU) promoted sulfate elimination.
Ketone 74 was converted to diketone 75 after a 4-step manipulation. The cis-triol was
achieved by Luche reduction of the C(3) carbonyl from less hindered α-face. Subsequent
benzylation of the C(3) alcohol followed by deprotection gave rise to 3-monobenzoate
ingenol analog 76.
39
Scheme 1.5.10 Winkler: Synthesis of Ingenol Analog 76.
H
OO
O
MeOCOO
O
H
CO2Me
OHO
OH
O
H
OO
O
PMPH
OTBDPS
O
H
H
CO2MeMeOCOO
O
H
O
OO
HPMP
O
O2S
OTBDPS
O
H
OHHOHOPhCOO
O
H
CO2Me
O
H
OO
HPMP
HOOTBDPS
1) hv
2) p-TsOH
1) NBS, AIBN2) LiCl, DMF
3) MsCl4) DBU
1) mCPBA
(49% yield)
2) OsO4
(49% yield)
1) DBU2) H2SO4
(60% yield)
1) DDQ2) PMPCH(OMe)2
3) K2CO3
4) DMP
1) PhSeCl, H2O2
2) NaBH4, CeCl3
3) BzCl4) H3O+
1) CSA/H2O2) PMA-DMA3) LAH
4) TBDPSCl5) SOCl26) RuCl3, NaIO4
69 70
71 72
73 74
7675
6
7
33
The C(3) monobenzoate analog 76 was evaluated for its ability to interact with the
regulatory site on protein kinase C, and it yielded a Ki of 46±8nM. Compared to ingenol
3-monobenzoate, which has a Ki of 0.15±0.03nM, its activity is about 300 times lower.
The inhibition results indicate that the gem-dimethylcyclopropane D ring and the C(18),
C(19) methyl groups may play an important role in protein recognition, possibly by
controlling the conformation of ingenol.
40
1.5.2 Synthetic Efforts Since 1999.
Since our initiation of this project in 1999, there have been two other accounts of
synthetic efforts toward ingenol. Notably, the Winkler group reported the first total
synthesis of ingenol in 2002.31
1.5.2.1 First Total Synthesis of Ingenol by Winkler.
Following his de Mayo strategy leading to the ingenol ABC ring system, Winkler
was able to access 78 from dioxenone 77 in slightly lower yield. Compared to earlier de
Mayo product 68, 78 contains the C(11) α-methyl group and a chlorine atom at C(14),
which was subsequently eliminated to establish the C(13)-C(14) unsaturation. The
ingenol D ring was then installed by facial selective dibromocyclopropanation of olefin
79 followed by reductive methylation, and the ingenol tetracycle 80 was prepared from
64 in 18 steps (Scheme 1.5.11).
41
Scheme 1.5.11 Winkler: Construction of Ingenol Tetracyclic Skeleton.
O
H
HOTBS
O
H
Cl
OO
O
2) KOH
ClO
H
HCOOMe
H
HOTBS
O
11 steps 1) hv
1) LiAlH4
2) DBU
3) TBSCl
14
11
13
14
11
1) CHBr3, NaOH
2) MeLi, CuSCN
64 77 78
79 80
Although having secured access to the ingenol tetracyclic skeleton, installing the
ingenol polyol functionality was by no means an easy task. From tetracycle 80, Winkler
achieved the first total synthesis of ingenol in another 25 steps (Scheme 1.5.12). Like
their earlier approach, the ingenol southern rim was functionalized to afford diene 81 in a
7-step sequence. Diene 81 was converted into sulfate 82 by dihydroxylation and
protective manipulation. Again, the C(6)-C(7) unsaturation was installed by base (DBU)
promoted elimination of sulfate 82. Introduction of the C(2) methyl group and the C(1)-
C(2) olefin was achieved by carboxyallylation of 83, followed by methylation of the
derived β-ketoester and Pd(OAc)2 oxidation of the methylated ketoester to generate the
C(2) methylated enone. Finally, Luche reduction of the C(3) carbonyl followed by
deprotection accomplished the first total synthesis of 1 in 43 steps.
42
Scheme 1.5.12 Winkler: The First Total Synthesis of Ingenol.
H
HOTBS
O
H
O
OTBDPSO O
OPMP
H
H
HO
OH
O
OTBDPS
O
O
TESO
BzO
O2S
5) Ac2O, AcCl6) NBS7) LiCl, DMF
1) TBAF2) DMP3) t-BuBr4) LiCl, DMF
3 4
5 6
1) DIBAL-H2) OsO4 3) TBDPSCl4) TESOTf
5) OsO46) BzCl7) SOCl28) RuCl3, NaIO4
1) DBU2) H2SO4
3) TBAF
4) PMA-DMA5) K2CO3
6) DMP
1) LDACH2=CHCH2OCOCN2) MeI, K2CO3
3) Pd(OAc)2
4) NaBH4, CeCl35) HCl/MeOH6) TBAF
O
H
HO HOHO OH
80 81 82
83 1
6
71
23
1.5.2.2 Kigoshi’s Approach Toward the Ingenol ABC Ring System.
While our work was in progress, Kigoshi and Uemura published a similar RCM
approach toward the ingenol ABC ring system on a much-simplified substrate 88
(Scheme 1.5.13).32 Alkylation of cycloheptanone N,N-dimethylhydrazone with iodide 85
followed by hydrolysis with silica gel afforded ketone 86. Exposure of 86 to
concentrated HCl delivered the corresponding allyl chloride, which was treated with base
to afford spiroketone 87. Allylation of 87 provided RCM precursor 88. Refluxing diene
88 in toluene with the 1st generation Grubbs’s catalyst II gave rise to the ingenol ABC
ring system 89 in 20% yield.
43
Scheme 1.5.13: Kigoshi: Preparation of the Ingenol ABC Ring System.
NNMe2
I OTHP
O
HI
O
OTHP
Ru
PCy3
PCy3
ClCl Ph
(II)
H
H
O
O
1) n-BuLi, THF
2) silica gel
1) conc. HCl
toluene reflux
(20% yield)
84 86 87
88 89
(85)
2) t-BuOK
KHDMS, THF
1.6 Conclusions.
Due to its unique structural features as well as its interesting biological activities,
ingenol (1) has generated considerable interest from both the chemical and biological
communities. Although Winkler has accomplished the first total synthesis of 1 very
recently, an efficient and flexible synthesis has yet to be developed. It was with great
enthusiasm that this lab initiated a synthesis of 1 in 1999. The following chapters will
outline some of the work toward this end.
44
1.7 Notes and References.
(1) "Cocarcinogenic Prinicples From Seed Oil of Croton Tiglium and From Other
Euphorbiaceae", Hecker, E., Cancer Research 1968, 28, 2338-2349.
(2) "Structure Determination of New Tetracyclic Diterpene Ingenoltriacetate With
Triple Product Methods", Zecheist.K; Brandl, F.; Hoppe, W., Tetrahedron Letters 1970,
4075-4077.
(3) "New Toxic, Irritant and Cocarcinogenic Diterpene Esters From Euphorbiaceae
and From Thymelaeaceae", Hecker, E., Pure and Applied Chemistry 1977, 49, 1423-
1431.
(4) "Comparative Phytochemical Study of Diterpenes of Some Species of Genera
Euphorbia and Elaeophorbia (Euphorbiaceae)", Evans, F. J.; Kinghorn, A. D., Botanical
Journal of the Linnean Society 1977, 74, 23-35.
(5) "Toxic Substances of Euphorbiaceae", Hirata, Y., Pure and Applied Chemistry
1975, 41, 175-199.
(6) "In/out isomerism", Alder, R. W.; East, S. P., Chemical Reviews 1996, 96, 2097-
2111.
45
(7) "Approaches to the synthesis of ingenol", Kim, S.; Winkler, J. D., Chemical
Society Reviews 1997, 26, 387-399.
(8) "A Solution to the in,Out-Bicyclo[4.4.1]Undecan-7-One Problem Inherent in
Ingenane Total Synthesis", Funk, R. L.; Olmstead, T. A.; Parvez, M., Journal of the
American Chemical Society 1988, 110, 3298-3300.
(9) "Intracellular Signaling By Hydrolysis of Phospholipids and Activation of
Protein-Kinase-C", Nishizuka, Y., Science 1992, 258, 607-614.
(10) "Protein kinase C: Structural and spatial regulation by phosphorylation, cofactors,
and macromolecular interactions", Newton, A. C., Chemical Reviews 2001, 101, 2353-
2364.
(11) "Structural basis of protein kinase C activation by tumor promoters", Kishi, Y.;
Rando, R. R., Accounts of Chemical Research 1998, 31, 163-172.
(12) "Plants Used Against Cancer - a Survey", Hartwell, J. L., Lloydia 1969, 32, 153-
205.
(13) "Specific Binding to Protein-Kinase-C By Ingenol and Its Induction of Biological
Responses", Hasler, C. M.; Acs, G.; Blumberg, P. M., Cancer Research 1992, 52, 202-
208.
46
(14) "Stereocontrolled Construction of an Ingenol Prototype Having a Complete Array
of Oxygenated and Unsaturated Centers", Paquette, L. A.; Ross, R. J.; Springer, J. P.,
Journal of the American Chemical Society 1988, 110, 6192-6204.
(15) "Antileukemic Principles Isolated From Euphorbiaceae Plants", Kupchan, S. M.;
Uchida, I.; Branfman, A. R.; Dailey, R. G.; Fel, B. Y., Science 1976, 191, 571-572.
(16) "Antitumor Agents .119. Kansuiphorin-a and Kansuiphorin-B, 2 Novel
Antileukemic Diterpene Esters From Euphorbia-Kansui", Wu, T. S.; Lin, Y. M.; Haruna,
M.; Pan, D. J.; Shingu, T.; Chen, Y. P.; Hsu, H. Y.; Nakano, T.; Lee, K. H., Journal of
Natural Products 1991, 54, 823-829.
(17) "Ingenol esters induce apoptosis in Jurkat cells through an AP-1 and NF-kappa B
independent pathway", Blanco-Molina, M.; Tron, G. C.; Macho, A.; Lucena, C.; Calzado,
M. A.; Munoz, E.; Appendino, G., Chemistry & Biology 2001, 8, 767-778.
(18) "Ingenol derivatives are highly potent and selective inhibitors of HIV replication
in vitro", Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Wang, G. Y. S.; Uemura,
D.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M., Antiviral Chemistry & Chemotherapy
1996, 7, 230-236.
47
(19) "Mechanism of selective inhibition of human immunodeficiency virus by ingenol
triacetate", Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K.;
Wang, G. Y. S.; Uemura, D.; Yokota, T.; Baba, M., Antimicrobial Agents and
Chemotherapy 1996, 40, 271-273.
(20) "Upregulation of HIV-1 replication in chronically infected cells by ingenol
derivatives", Fujiwara, M.; Okamoto, M.; Ijichi, K.; Tokuhisa, K.; Hanasaki, Y.;
Katsuura, K.; Uemura, D.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M., Archives of
Virology 1998, 143, 2003-2010.
(21) "Tumor promoters in human carcinogenesis.", Boutwell, R. K., Important
Advances in Oncology 1985, 16-27.
(22) "Ingenane Synthesis - Construction of the Abc Framework", Mehta, G.; Pathak,
V. P., Journal of the Chemical Society-Chemical Communications 1987, 876-877.
(23) "Intramolecular [4+3]-Cycloadditions - Model Studies Toward the Synthesis of
Ingenanes", Harmata, M.; Elahmad, S.; Barnes, C. L., Tetrahedron Letters 1995, 36,
7158-7158.
(24) "Synthetic Studies On the Ingenane Diterpenes - Construction of a Tetracyclic 8-
Isoingenane Model", Rigby, J. H.; Cuisiat, S. V., Journal of Organic Chemistry 1993, 58,
6286-6291.
48
(25) "Studies on intramolecular higher-order cycloaddition reactions", Rigby, J. H.;
Rege, S. D.; Sandanayaka, V. P.; Kirova, M., Journal of Organic Chemistry 1996, 61,
842-850.
(26) "Synthetic studies on the ingenane diterpenes. Direct conversion of the out,out-
bicyclo[4.4.1]undecane system into a highly strained in,out stereoisomer", Rigby, J. H.;
deSainteClaire, V.; Cuisiat, S. V.; Heeg, M. J., Journal of Organic Chemistry 1996, 61,
7992-7993.
(27) "Stereoselective Construction of the Complete Ingenane Ring- System", Funk, R.
L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B., Journal of Organic Chemistry 1993, 58,
5873-5875.
(28) "A new approach for ingenol synthesis", Nakamura, T.; Matsui, T.; Tanino, K.;
Kuwajima, I., Journal of Organic Chemistry 1997, 62, 3032-3033.
(29) "Inside Outside Stereoisomerism .2. Synthesis of the Carbocyclic Ring-System of
the Ingenane Diterpenes Via the Intramolecular Dioxolenone Photocycloaddition",
Winkler, J. D.; Henegar, K. E.; Williard, P. G., Journal of the American Chemical Society
1987, 109, 2850-2851.
49
(30) "Synthesis and biological evaluation of highly functionalized analogues of
ingenol", Winkler, J. D.; Kim, S. H.; Harrison, S.; Lewin, N. E.; Blumberg, P. M.,
Journal of the American Chemical Society 1999, 121, 296-300.
(31) "The first total synthesis of (+/-)-ingenol", Winkler, J. D.; Rouse, M. B.; Greaney,
M. F.; Harrison, S. J.; Jeon, Y. T., Journal of the American Chemical Society 2002, 124,
9726-9728.
(32) "Synthetic studies of ingenol: synthesis of in,out- tricyclo[7.4.1.0(1,5)]tetradecan-
14-one", Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D., Tetrahedron Letters 2000, 41,
3927-3930.
30
Chapter 2
Construction of the Complete Ingenol Carboskeleton
2.1 Initial Considerations.
Inspired by its structural complexity as well as its interesting biological
properties, we started a research program directed toward a total synthesis of ingenol in
1999. Our initial focus was the construction of the ingenol carboskeleton, especially the
inside-outside ingenol BC ring system.
2.1.1 Synthetic Strategy.
In contemplating a synthesis of the ingenol BC ring system, we were intrigued by
the notion of establishing the trans relationship between C(8) and C(10) on a cyclic
precursor, and subsequently closing the B ring via a robust cyclization protocol.
Specifically, we were curious if application of a ring-closing metathesis (RCM)
protocol1,2 to diene 91 would furnish the inside-outside BC ring system 90 (Scheme
2.1.1). RCM precursor 91 could be derived from known cycloheptenone 49, which was
prepared from 3-carene in four steps by professor Funk.3
31
Scheme 2.1.1 First Generation Retrosynthetic Analysis.
RCMA
CO
H
HO HO
HO OH
B
1
MeO
O
D
O
H
O
MeO
O
H
O
MeO
O
91 49
90
3-carene
810
2.1.2 Ring-Closing Metathesis (RCM).
Historically, olefin metathesis has been studied extensively both from the
mechanistic standpoint and in the context of polymer synthesis.4 In contrast, its
application to the synthesis of complex organic molecules and natural products was
limited until the development of well-defined, single component metathesis catalysts. In
1990, Schrock and co-workers discovered highly reactive molybdenum-based catalyst
I,5,6 which was later shown to be an effective RCM catalyst (Figure 2.1).7 Although
catalyst I exhibits some level of functional group tolerance, the extreme sensitivity of the
system to air, water, and other polar functional groups, in addition to its difficult
preparation, prompted the development of ruthenium-based catalyst II by Grubbs.1
Catalyst II, also known as the first generation Grubbs’s catalyst, displays much improved
tolerance to air, water, and polar functional groups. Although less reactive than I, it has
been widely used since its discovery. In 1999, Grubbs reported preparation of a second
32
generation catalyst, III.8,9 Over the past three years, III has been demonstrated to exhibit
not only extraordinary reactivity and stability, but also increased ring-closing activity
toward sterically demanding olefins. Tri- and even tetra-substitute olefins can be
prepared using RCM catalyzed by III.8
Mo
N
i-Pr i-Pr
(F3C)2MeCO
(F3C)2MeCO
Ph
MeMe
Ru
PCy3
PCy3
Cl
Cl PhRu
PCy3
Cl
Cl Ph
NNMes Mes
I II III
Figure 2.1 Ring-Closing Metathesis Catalysts.
It is now accepted that olefin metathesis proceeds through a metallacyclobutane
mechanism.10 A [2+2] cycloaddition occurs between the metal alkylidene and the olefin
substrate to produce a metallacyclobutane intermediate (Figure 2.2). Subsequent
retrocycloaddition occurs to generate a new metal alkylidene and the olefin metathesis
product. When a suitable diene is treated under RCM conditions, an intramolecular [2+2]
cycloaddition can take place to afford metallacyclobutane 94, which can then undergo
retrocycloaddition to yield the cyclized olefin 95 and regenerate the alkylidene catalyst.
33
[M]R1
R2
R3
[M]
93
[M]
[M]R1
R2 R3
94
[M]
R2
[M]
R3
R1
95
[M]
++
++
92
Figure 2.2 Olefin Metathesis and Ring-Closing Metathesis.
The ring-closing metathesis reaction is emerging as powerful method for the
construction of cyclic olefins. The current empirical understanding for the ring-closing
metathesis reaction is that the formation of small rings (5, 6-membered) is generally
facile, and large rings (>9-membered) can be achieved under high dilution, while the
formation of medium rings (7, 8, 9-membered) is often difficult because of inherent ring
strain.11 Products can result from either ring-closing metathesis (RCM) or subsequent
ring-opening metathesis polymerization (ROMP).12 An attempt to access the highly
strained ingenol BC ring system by ring closure of the trans-bridgehead 7-membered
ingenol B ring affords a significant chance to extend the scope of RCM methodology.
Initial efforts focused on leaving the C(9) ketone in RCM precursor 91 unprotected, as
carbonyls can play a critical role in the ring-closing metathesis reaction.13 The C(9)
ketone might serve as a Lewis basic site to chelate with the catalyst and bias ring closure,
as in 96 90 (Scheme 2.1.2).
34
Scheme 2.1.2 Carbonyl Chelation in RCM.
O
HMeO
O
RCM
91
MeO
O O
H
[M]
96
H
O
MeO
O
90
9
2.2 Toward the Ingenol BCD Ring System.
2.2.1 Construction of the iso-Ingenol BCD Ring System
Following the procedure developed by Professor Funk, we have accessed over
200 grams of cycloheptenone 49.3,14 In the forward sense, ozonolysis of (±)-3-carene
($0.04/g from Aldrich) followed by reduction with dimethyl sulfide gave rise to aldehyde
97 in good yield. Refluxing 97 with ethylene glycol under acidic conditions delivered
dioxolane 98, which was subsequently converted to β-keto ester 99. Subjecting 99 to
Mukaiyama condensation conditions delivered cycloheptenone 49 in moderate yield
(Scheme 2.2.1).
35
Scheme 2.2.1 Preparation of Cycloheptenone 49.
O
O
(MeO)2CO
99
O
OO
O
OMe
97
1M TiCl4
CH2Cl2O
MeO
O
49
98
O
OO
(±)-3-carene
1) O3
2) DMS
NaH, THF
(70% yield) (90% yield)
(55% yield) (50% yield)
HO OH
p-TSA
Treatment of 49 with lithium dimethyl cuprate followed by trapping the resulting
enolate with allyl iodide gave rise to β-keto esters 100a and 100b as a 1:1.2 mixture of
diastereomers (Scheme 2.2.2). Uncertain of the relative stereochemistry present in 100a
and 100b, both esters were similarly advanced with the hope of obtaining this
information from later intermediates. Ester 100a was alkylated with allyl bromide to
provide enol ether 101, which upon heating smoothly underwent Claisen rearrangement
to furnish 102 as a single diastereomer. Heating a dichloromethane solution of 102 and
Grubbs’s catalyst II (10 mol%) to reflux provided ring-closed product 103 in good yield.
Reduction of 103 furnished diol 104, the structure of which was established by single-
crystal X-ray analysis (Figure 2.3). Inspection of the crystal structure revealed that 104
contained the undesired “outside-outside” stereochemistry; thus, rigorously establishing
the relative stereochemistry of 100a and 102.
36
Scheme 2.2.2 Preparation of iso-Ingenol BCD Ring System Using RCM.
OO
MeO1) Me2CuLi
KH, DMF
H
O
O
MeO
OO
MeO
I
Br
49
O
MeO
O
OO
MeO
OO
MeO
O
H
O
MeO
2)
LAH
200ºC
(95% yield)
(85% yield)
10 mol% II
(95% yield)
(99% yield)
(90% yield)
101 102
103
+
100a (1 : 1.2) 100b
100a
HO H
H
OH
104
Figure 2.3 Crystal Structure of Diol 104.
2.2.2 RCM Attempts Toward the Ingenol BCD Ring System.
Next, we focused our efforts on advancing the remaining diastereomer 100b.
Since studies of 3-component reactions on cyclic enones have shown that the electrophile
37
is typically trapped trans to the nucleophile, we were confident that compound 100b
possessed the correct stereochemistry to furnish the desired RCM precursor 91.15 Unlike
100a, alkylation of 100b gave rise exclusively to the C-alkylated product 91 (Scheme
2.2.3). The complete facial selectivity of this alkylation can be attributed to the steric
bias caused by the gem-dimethylcyclopropane D ring. It is worth noting that the ingenol
trans-bridgehead stereochemistry has been established at C(8) and C(10). Unfortunately,
all attempts to construct the BC ring system using RCM on substrate 91 were
unsuccessful. In an attempt to increase the flexibility of the C ring, diene 91 was reduced
with LiAlH4. Subsequent protection of the primary alcohol afforded TBS ether 105.
However, exposure modified precursor 105 to RCM conditions only resulted a mixture of
polymers.
Scheme 2.2.3 RCM Attempts Toward the Ingenol BCD Ring System.
OO
MeO
Br
KH, THF
O
H
O
MeO
100b
91
O
H
O
MeO
OH
H
TBSO
91
105
RCM
RCM
(85% yield)
polymers
1) LAH2) TBSCl
(95% yield)polymers
810
D
C
38
2.3 Toward the Ingenol Tetracyclic Skeleton.
2.3.1 Conformation Analyses of RCM Precursors.
Having established that diene 91 was not a suitable precursor to the ingenol BC
ring system, computational studies were performed to identify a more viable cyclization
substrate. Conformational searches of potential candidates using the Merck Molecular
Force Field (MMFF)16 suggested that inclusion of the A ring might facilitate construction
of the “inside-outside” BC ring system. A conformational search of precursor 91
illustrated that the two internal olefinic carbons are oriented 4.2 Å away from each other.
With the installation of the A ring, the C(4) olefin was rigidified. Moreover, the distance
between the two internal olefinic carbons was reduced to 3.8 Å (106, Figure 2.4).
H
OO
HMeO
O
91 106
3.8 Å4.2 Å
4A
A
4
Figure 2.4 Conformational Analyses of RCM Precursors.
2.3.2 Revised Synthetic Plan.
To explore this prediction, we initiated an approach to 106 wherein a Diels-Alder
reaction between exo-olefin 109 and cyclopentadiene (110) was envisioned to
simultaneously introduce the A ring and the functionality needed for the RCM chemistry
39
(Scheme 2.3.1). Thus, tandem ring-opening ring-closing metathesis (ROM-RCM) of 108
would furnish the tetracyclic ingenol skeleton 107.17
Scheme 2.3.1 Revised Retrosynthesis: Tandem ROM-RCM Strategy.
O
H
HOHO
HO OH
O
H RCM
O
ROM
O
H
107
108 109 110
H
O
106
+
1
A
2.3.3 Synthetic Efforts of the ROM-RCM Strategy.
2.3.3.1 Preparation of Exo-olefin 109.
Studies commenced with cycloheptenone 49; methyl cuprate addition gave rise to
all four possible diastereomers (Scheme 2.3.2).14 Although the diastereomers were
carefully separated at this stage, the separation was simplified following installation of a
ketal moiety. The reaction of β-keto ester 111 with ethylene glycol and catalytic p-TSA
in refluxing benzene under Dean-Stark conditions delivered the corresponding ketals,
which were separated by silica gel chromatography as 112a (18%), 112b (16%), 112c
(43%) and 112d (23%).18 Although both 112b and 112c contain the desired C(11) α-
40
methyl stereochemistry present in ingenol, only the major diastereomer 112c was
advanced due to the taxing separation of 112a and 112b. Reduction of 112c followed by
hydrolysis of the ketal delivered alcohol 113 in near quantitative yield. Acetylation of
the alcohol followed by subsequent elimination furnished exo-olefin 109.
Scheme 2.3.2 Preparation of Exo-olefin 109.
O
MeO
O
LiMeCuCN
O
MeO
O
HO OH
MeO
OO O
MeO
OO O
MeO
OO O
MeO
OO O
49 111
p-TSA, C6H6(95% yield)
(98% yield)
112a (18%) 112b (16%) 112c (43%) 112d (23%)
MeO
OO O
OAcO
112c
114
OHO
113
109
O
1) LAH, Et2O
(95% yield, two steps)
Ac2O, DMAP
(99% yield)
DBU, C6H6
(80% yield)
2) HCl, acetone
41
2.3.3.2 Initial Attempts of Tandem ROM-RCM.
With exo-olefin 109 in hand, attention was next focused on the incorporation of
the ingenol A ring. After considerable experimentation, it was found that boron
trifluoride diethyl etherate effectively catalyzed the Diels-Alder reaction between 109 and
cyclopentadiene (110) to provide a ternary mixture of diastereomers (115a, 115b, 115c)
in a ratio of 20:8:1, respectively.19 We were delighted to find that the major constituent
115a possessed the desired stereochemistry. Alkylation of 115a with allyl bromide
furnished 108, the precursor for the tandem ROM-RCM. However, upon exposure of
108 to ROM-RCM conditions under an atmosphere of ethylene, only ring-opening
metathesis was observed, thereby providing triene 106 in excellent yield (Scheme 2.3.3).
Scheme 2.3.3 Initial Attempts on Tandem ROM-RCM.
109
O
O
H
BF3 OEt2
(110)
108
O
H
O
106
Br
KH, THF
(59% yield)
.
115a
(76% yield)
3 mol% II, ethylene
(95% yield)
42
2.3.3.3 RCM Attempts of Triene 106.
Although initial ROM-RCM strategy did not yield success, the preparation of
triene 106 encouraged us to apply more forcing RCM conditions. However, further
exposure of triene 106 to RCM conditions did not result in the desired product, but rather
regenerated norbornene 108 as the only isolable product in 8% yield (Scheme 2.3.4).
This is the first report of the generation of norbornene via a RCM precursor. In fact,
many ring-opening polymerization processes take advantage of the highly strained
norbornene bicyclic skeleton.20
Scheme 2.3.4 RCM of Triene 106.
H
O
106 108
O
H60 mol% II
toluene reflux (8% yield)
2
2.3.4 Construction of the Ingenol Tetracyclic Skeleton via RCM.
2.3.4.1 Modification of RCM Precursor.
In an effort to prevent reversion to 108, efforts focused on masking the C(2)
olefin prior to attempted RCM. To this end, ring-opening metathesis of 115a under an
atmosphere of ethylene gave rise to diene 116 in excellent yield. Regio-selective
dihydroxylation of the C(2) olefin followed by oxidative cleavage provided the
43
corresponding aldehyde which was protected to afford acetal 117. Alkylation of 117
proceeded smoothly to afford RCM precursor 118 (Scheme 2.3.5).
Scheme 2.3.5 Modification of RCM Precursor.
O O
KH, THFH
OO
OO
O
O
HO OH
Br
116
117118
115a
1) OsO4/NMO2) NaIO4
(73% yield,three steps)
(92% yield)
(98% yield)
2 mol% II4
2
ethylene 3)
2.3.4.2 RCM of Modified Precursor 118.
Gratifyingly, following careful optimization, exposure of 118 to the first
generation Grubbs’s catalyst II (4 additions of 20 mol% II every 45 minutes) in refluxing
toluene led to the elusive “inside-outside” ring system 119 (Scheme 2.3.6). In contrast,
the second generation Grubbs’s catalyst III was also attempted to cyclize diene 118, but
only trace amounts of 119 were observed. To verify the RCM result, 119 was
dihydroxylated to furnish diol 120, which was esterified with p-bromobenzoyl chloride to
deliver dibenzoate 121. The structure of 121 was confirmed by single-crystal X-ray
analysis (Figure 2.5).
44
Scheme 2.3.6 Construction of the Ingenol Tetracyclic Skeleton.
H
O
O
O
118
O
H
O
O
OHHOH
C Br
O
120
O
H
O
O H
119
O
H
O
O
ORROH
121
80 mol% II
(45% yield)
OsO4/NMO
R =
(84% yield)
(82% yield)
p-BrC6H4COCl
Figure 2.5 Ortep Plot of Dibenzoate 121.
2.4 Toward the Complete Ingenol Skeleton.
2.4.1 Construction of the Complete Ingenol Skeleton via RCM.
Having achieved the formidable ring closure of the ingenol B ring, it was
envisioned that RCM could be used on a substrate containing the ingenol C(6)-C(20)
bond to access the complete ingenol skeleton. More advanced RCM precursor 124 was
45
prepared conveniently from 118 in four steps (Scheme 2.4.1). Diene 118 was
regioselectively dihydroxylated to deliver diol 122 as a pair of diastereomers. Selective
protection of the primary alcohol with TBSCl followed by Dess-Martin oxidation of the
secondary alcohol gave rise to ketone 123. Wittig olefin of 123 produced RCM precursor
124 in excellent yield. RCM attempts of 124 using the 1st generation Grubbs’s catalyst
II under various conditions yielded recovered starting material. Very surprisingly,
treating 124 with the 2nd generation Grubbs’s catalyst III (25 mol%) in refluxing
benzene gave rise to ring-closed product 125 in excellent yield!
Scheme 2.4.1 Preparation of RCM Product 125.
H
OO
O
OsO4, NMO
H
OO
OO
OTBS
1) TBSCl 2) DMP
H
OO
O OTBS
118
124
123
H
OO
OHO
OH
Ph3P=CH2
122
O
H
HOTBS
O
O
125
(60% yield)
(90% yield)(93% yield, two steps)
25 mol% III
(96% yield)6
20
46
In a parallel sequence, it was found that RCM precursor 127 could be prepared
from direct alkylation of 117 with allyl chloride 126.21 Similarly, treating 127 with 2nd
generation Grubbs’s catalyst III in refluxing benzene delivered RCM adduct 128 in
excellent yield, along with small amount of cross-metathesis product 129 (Scheme 2.4.2).
RCM products 125 and 128 both contain the complete ingenol carboskeleton.
Scheme 2.4.2 Preparation of RCM Product 128 via Direct Alkylation.
OO
O
OBn
Cl
O
H
HOBn
O
O
KH, THF
117
128 (92%)
H
OO
O OBn
H
OO
O OBn
Ph
127
129 (4%)
25 mol% III
(93% yield)
(126)
+C6H6 reflux
2.4.2 Investigation of the RCM Transformation.
Generally, trisubstituted olefins are much more difficult to access via RCM than
are their disubstituted counterparts.22 Unexpectedly, RCM of the more substituted
precursor 127 using III (25 mol%) gave rise to trisubstituted olefin 128 in excellent yield,
while treating diene 118 under identical conditions resulted in only trace amounts of the
corresponding disubstituted olefin 119 (Scheme 2.4.3). A moderate yield of disubstituted
47
olefin 119 can be achieved by refluxing diene 118 with II (80 mol%) in toluene. This
interesting result prompted further investigation of the ring-closure step. It was
anticipated that the neighboring C(20) ether oxygen of 127 might chelate to the
ruthenium center, forming a more stabilized alkylidene intermediate 130, analogous to
RCM catalyst 131 prepared by Hoveyda (Figure 2.6).23
Scheme 2.4.3 Comparison of the RCM Results.
O
H
HOBn
O
O
128
H
OO
O OBn
127
25 mol% III
C6H6 reflux
H
O
O
O
118
O
HO
O H
119
80 mol% II
(45% yield)
(92% yield)
toluene reflux
H
OO
O[Ru]
O
R
RuCl
Cl
NN MesMes
Oi-Pr
130 131
20
Figure 2.6 Stabilized RCM Intermediate by Oxygen Chelation.
48
Treating methyl substituted diene 132 under identical RCM conditions, however,
delivered the corresponding ring-closed product 133 in excellent yield, proving that
oxygen chelation is not necessary for this transformation (Scheme 2.4.4). Notably, upon
exposure of disubstituted RCM product 119 to the 2nd generation Grubbs’s catalyst III in
refluxing benzene, total material decomposition resulted. Clearly disubstituted olefin 119
was not stable under RCM conditions in the presence of III. The exceptional reactivity
of the 2nd generation Grubbs’s catalyst III, especially its increased ring-closing reactivity
toward sterically demanding olefins, enabled efficient access to trisubstituted olefin 128.
Scheme 2.4.4 Investigation of the RCM Transformation.
OO
O
117
C6H6 reflux
KH, THF
CH3
Cl
O
H
HCH3
O
O
133
H
OO
O
CH3
132
25 mol% III
(82% yield)
(93% yield)
With a robust RCM protocol in hand, the relative importance of an intact ingenol
A ring to the success of the reaction was explored via RCM attempts of diene 134, which
was prepared from alkylation of β-keto ester 100b. Upon exposure of 134 to the 2nd
generation Grubbs’s catalyst III, no desired ring-closure product was observed. This
49
again demonstrates the pivotal role of the ingenol A ring in the RCM reaction (Scheme
2.4.5).
Scheme 2.4.5 RCM Attempts of Diene 134.
OO
MeO
CH3
Cl
KH, THF
100b
O
H
O
MeO
CH3134
III
(97% yield)
polymers
2.5 Conclusions.
The carboskeleton of ingenol (1) was efficiently prepared in 13 steps from known
cycloheptenone 49, and in 17 steps from commercially available 3-carene (Scheme
2.5.1). The highlight of the sequence was construction of the ingenol inside-outside BC
ring system via ring-closing metathesis (i.e. 118 119 and 127 128). The ingenol A
ring was proved to be critical to the closure of ingenol B ring via this strategy. All
attempts to construct the ingenol BCD ring system in the absence of the A ring via RCM
did not yield success. With the incorporation of the ingenol A ring, RCM of diene 118
furnished the ingenol tetracyclic skeleton 119. Furthermore, RCM of 127 using the 2nd
generation Grubbs’s catalyst III delivered the complete ingenol skeleton 128 in excellent
yield.
50
Scheme 2.5.1 Summary of Synthetic Progress.
O
MeO
O
49
O
HMeO
O
91
H
O
O
O
H
O
O
OOBn
118
RCM
Ru
PCy3
PCy3
Cl
ClPh
MesMes
Ru
PCy3
Cl
ClPh
NN
127
H
O
MeO
O
90
O
HO
O H
O
H
HOBn
O
O
119
128
(2 steps)
(4 steps)
(92% yield)
(11 steps)
(45% yield)
(11 steps)
(±)-3-carene
A
A
51
2.6 Experimental Section.
2.6.1 Materials and Methods.
Unless stated otherwise, reactions were performed in flame dried glassware under
a nitrogen atmosphere using freshly distilled solvents. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were distilled from sodium/benzophenone ketyl. Methylene
chloride (CH2Cl2), benzene (PhH), toluene (PhMe), triethylamine (Et3N), pyridine, and
piperidine were distilled from calcium hydride. Methyl sulfoxide (DMSO) and N,N-
dimethylformamide (DMF) were either purchased from the Aldrich Chemical Company
in Sure/Seal™ containers and used as received or stored over molecular sieves. All other
commercially obtained reagents were used as received.
Unless stated otherwise, all reactions were magnetically stirred and monitored by
thin-layer chromatography (TLC) using E. Merck silica gel 60 F254 precoated plates (0.25
mm). Column or flash chromatography was performed with the indicated solvents using
silica gel (230-400 mesh) purchased from Bodman. In general, the chromatography
guidelines reported by Still, Kahn, and Mitra were followed. Concentration in vacuo
refers to the removal of solvent with a Buchi R-3000 rotary evaporator at normal
aspirator pressure followed by further evacuation with a two stage mechanical pump.
When reactions were adsorbed onto silica gel, the amount of silica gel used was equal to
two times the weight of the reagents.
All melting points were obtained on a Gallenkamp variable temperature capillary
melting point apparatus (model: MPD350.BM2.1) and are uncorrected. Infrared spectra
52
were recorded on a Midac M1200 FTIR. 1H and 13C NMR spectra were recorded on a
Bruker AM-500, Bruker Avance DPX-500, or Bruker Avance DPX-400 spectrometer.
Chemical shifts are reported relative to internal chloroform (1H, δ 7.27 ppm; 13C, δ 77.3
ppm), benzene (1H, δ 7.20 ppm; 13C, δ 128.4 ppm), or methylene chloride (1H, δ 5.32
ppm; 13C, δ 54.0 ppm). High resolution mass spectra were performed at the University of
Illinois Mass Spectrometry Center. High performance liquid chromatography (HPLC)
was performed on a Waters 510 solvent delivery system using a Rainin Microsorb 80-
199-C5 column, or a Rainin Dynamax SD-200 solvent delivery system using a Rainin
Microsorb 80-120-C5 column. Single crystal X-ray analyses were performed by Susan
DeGala of Yale University.
2.6.2 Preparative Procedures.
Preparation of β-keto Esters 100a and 100b.
O
MeO
O
1) Me2CuLi
49
OMeO
O
OMeO
O
2) allyl iodide
(95% yield)
+
100a (1 : 1.2) 100b
β-Keto Esters 100a and 100b. A solution of lithium dimethylcuprate in
anhydrous ether (12 mL) was prepared from CuI (481 mg, 2.5 mmol, 2.0 equiv) and 1.4
M MeLi solution in ether (3.6 mL, 5.0 mmol, 4.0 equiv). After stirring at 0 °C for 15
minutes, an ether (6 mL) solution of 49 (265 mg, 1.3 mmol, 1.0 equiv) was slowly added
into the reaction flask. The mixture was allowed to stir at 0 °C under N2 for 40 minutes.
53
A mixture of THF (4 mL) and HMPA (5 mL) was injected into the reaction solution,
followed by rapid addition of allyl iodide (3 mL, large excess). The reaction was kept
stirring at 0 °C for one more hour. The reaction mixture was poured into 10% NH4OH
solution, and the product was extracted with ether. The extraction was washed with
water and brine. After drying with MgSO4, the solvent was removed under reduced
pressure. The residue was purified by flash chromatography (40:1 Hexanes:EtOAc
eluent).
β-Keto Ester 100a. First to elute was 100a (285 mg, 43% yield): FTIR (thin
film/NaCl) 3075 (w), 2979 (m), 2948 (m), 1743 (m), 1711 (s), 1637 (w), 1459 (m), 1434
(m), 1377 (w), 1278 (w), 1232 (m), 1212 (s), 1170 (w), 1133 (w), 1119 (w), 1004 (w),
915 (w), 753 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 6.35 (dddd, J = 17, 11, 9, 5.0 Hz,
1H), 5.17-5.24 (m, 2H), 3.32 (s, 3H), 3.26 (ddt, J = 14, 5, 2 Hz, 1H), 2.70 (dd, J = 12, 6
Hz, 1H), 2.65 (dd, J = 14, 9 Hz, 1H), 2.61 (t, J = 11.5 Hz, 1H), 2.12 (dt, J = 15.5, 11 Hz,
1H), 1.96 (ddtd 11, J = 7.5, 7, 1.5 Hz, 1H), 1.72 (ddd, J = 15, 6, 1.5 Hz, 1H), 1.32 (d, J =
7 Hz, 3H), 1.07 (s, 3H), 0.99 (s, 3H), 0.72 (ddd, J = 11, 9, 6 Hz, 1H), 0.57 (ddd, J = 11,
9, 6 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 204.6, 172.3, 136.4, 118.1, 67.2, 51.9, 39.3,
39.2, 38.8, 30.6, 28.7, 27.8, 22.8, 22.0, 18.8, 15.7; HRMS (EI) m/z found: 264.1723
[calc'd for C16H24O3 (M+): 264.1725].
β-Keto Ester 100b. Second to elute was 100b (342 mg, 52% yield): FTIR (thin
film/NaCl) 3076 (w), 2947 (m), 1738 (s), 1703 (s), 1639 (w), 1457 (m), 1434 (m), 1379
(w), 1268 (w), 1210 (s), 1148 (w), 1130 (w), 1078 (w) cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.64 (ddt, J = 17, 10, 7.5 Hz, 1H), 5.03 (m, 2H), 3.67 (s, 3H), 2.67 (dd, J = 15,
8 Hz, 2H), 2.56 (dd, J = 14, 7.5 Hz, 1H), 2.24 (dd, J = 15, 9 Hz, 1H), 2.04 (td, J = 7, 5
54
Hz, 1H), 1.82 (dt, J = 15, 6.5 Hz, 1H), 1.42 (ddd, J = 15, 8.5, 5 Hz, 1H), 1.16 (d, J = 7
Hz, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.80 (td, J = 9, 6.5 Hz, 1H), 0.63 (q, J = 9 Hz, 1H);
13C NMR (400 MHz, CDCl3) δ 208.0, 171.9, 133.0, 118.3, 65.6, 51.4, 39.7, 37.6, 36.4,
28.5, 28.4, 22.9, 20.5, 20.2, 16.8, 15.0; HRMS (EI) m/z found: 264.1725 [calc'd for
C16H24O3 (M+): 264.1725].
Preparation of Enol Ether 101.
OMeO
OBr
KH, DMFMeO
O
O
101
(90% yield)
100a
Enol Ether 101. To a sealed 50 mL round bottom flask containing KH powder
(23 mg, 0.57 mmol, 1.5 equiv) was added a solution of 100a (102 mg, 0.38 mmol, 1.0
equiv) in DMF (10 mL). After stirring the mixture for 5 minutes, allyl bromide (100 uL,
1.0 mmol, 3.0 equiv) was injected into the reaction. The reaction was allowed to stir at
room temperature for half an hour. Several drops of methanol were added into the
reaction to quench excess KH. The crude product was diluted with ether and washed
with NH4Cl and brine. After drying with MgSO4, the solvent was evaporated under
reduced pressure. Flash chromatography (50:1 Hexanes:EtOAc eluent) of the yellow
residue afforded enol ether 101 (104 mg, 90% yield) as a light yellow oil.
Enol Ether 101: FTIR (thin film/NaCl) 3075 (w), 2976 (m), 2947 (m), 1663 (w),
1646 (w), 1456 (w), 1433 (w), 1375 (w), 1295 (w), 1220 (s), 1185 (m), 1172 (m), 1138
(m), 1079 (w), 996 (w), 915 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 6.15 (dtd, J = 17, 9,
55
5 Hz, 1H), 5.82 (ddt, J = 17, 11, 4.5 Hz, 1H), 5.37 (dq, J = 17, 2 Hz, 1H), 5.29 (m, 1H),
5.26 (m, 1H), 5.13 (qd, J = 11, 2 Hz, 1H), 4.90 (d, J = 2.5 Hz, 1H), 4.06 (m, 2H), 3.51 (s,
3H), 2.92 (dd, J = 14, 9 Hz, 1H), 3.36 (dtd, J = 15, 3.5, 1.5 Hz, 1H), 2.40 (ddd, J = 14, 9,
7 Hz, 1H), 2.30 (dt, J = 14, 5 Hz, 1H), 1.55 (dd, J = 14, 7 Hz, 1H), 1.30 (s, 3H), 1.18 (s,
3H), 1.07 (d, J = 7.0 Hz, 3H), 0.96-1.08 (m, 2H); 13C NMR (400 MHz, C6D6) δ 174.3,
155.6, 136.2, 134.6, 118.0, 116.0, 101.4, 68.8, 62.1, 51.6, 39.7, 35.6, 31.2, 28.6, 28.4,
22.3, 20.7, 19.1, 16.6; HRMS (EI) m/z found: 304.2037 [calc'd for C19H28O3 (M+):
304.2038].
Preparation of Diene 102 via Claisen Rearrangement.
MeO
O
O MeO
O
O
H200 ºC
(99% yield)
101 102
Diene 102. In a 2 dram Fisher brand vial, enol ether 101 (104 mg, 0.34 mmol, 1.0
equiv) was dissolved in xylene (2 mL). The vial was stoppered and sealed with Teflon
tape and heated in a 200°C sand bath for 1 hour. The vial was removed from the sand
bath and allowed to cool to room temperature. Flash chromatography (40:1
Hexanes:EtOAc eluent) of the crude product afforded diene 102 (103 mg, 99% yield) as a
light yellow oil.
Diene 102: FTIR (thin film/NaCl) 3075 (w), 2978 (m), 2948 (m), 1744 (w), 1910
(s), 1639 (w), 1457 (w), 1434 (w), 1376 (w), 1216 (s), 1211 (w), 1029 (w), 913 (m) cm-1;
1H NMR (500 MHz, C6D6) δ 6.41 (dddd, J = 17, 10.5, 9, 5.5 Hz, 1H), 5.89 (dddd, J =
56
17, 12.5, 7.5, 7.0 Hz, 1H), 5.04-5.24 (m, 4H), 3.35 (s, 3H), 3.23 (ddt, J = 14, 5.5, 1.5 Hz,
1H), 2.83 (dt, J = 13, 7 Hz, 1H), 2.65 (dd, J = 14, 9 Hz, 1H), 2.59 (dt, J = 10.5, 7 Hz,
1H), 2.48-2.54 (m, 1H), 2.15 (dt, J = 15.5, 11.5 Hz, 1H), 1.94 (dtd, J = 15, 7, 1.5 Hz,
1H), 1.75 (ddd, J = 15, 5.5, 1.5 Hz, 1H), 1.39 (d, J = 7 Hz, 3H), 1.08 (s, 3H), 1.01 (s,
3H), 0.56 (ddd, J = 12, 9, 6 Hz, 1H), 0.39 (dd, J = 10, 9 Hz, 1H); 13C NMR (400 MHz,
C6D6) δ 206.0, 172.1, 137.4, 136.5, 118.1, 116.5, 66.9, 51.7, 48.4, 39.7, 39.4, 36.9, 30.7,
29.3, 29.0, 27.5, 22.0, 18.7, 16.0; HRMS (EI) m/z found: 304.2045 [calc'd for C19H28O3
(M+): 304.2038].
Preparation of RCM Product 103.
MeO
O
O
H
MeO
O H
O
(85% yield)
10 mol% II
102 103
RCM Product 103. To a solution of diene 102 (136 mg, 0.45 mmol, 1.0 equiv)
in CH2Cl2 (60 mL) was added Grubbs’s catalyst (II) (37 mg, 0.05 mmol, 10 mol%). The
reaction was heated to reflux for 24 hours. Concentration in vacuo followed by flash
chromatography (20:1 Hexanes:EtOAc eluent) afforded RCM product 103 (105 mg, 85%
yield) as a light pink oil.
RCM Product 103: FTIR (thin film/NaCl) 3026 (w), 2949 (m), 1739 (s), 1682
(s), 1455 (m), 1376 (w), 1237 (m), 1181 (m), 1147 (w), 1046 (w), 998 (w), 808 (w), 779
(w), 686 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 5.80-5.91 (m, 2H), 2.58 (s, 3H), 3.21
(m, 1H), 3.13 (dd, J = 15.5, 7 Hz, 1H), 2.55 (dd, J = 16, 5.5 Hz, 1H), 2.39 (dqd, J = 17,
57
7, 2.5 Hz, 1H), 2.21-2.27 (m, 1H), 2.18 (dt, J = 16, 6 Hz, 1H), 1.78 (dt, J = 15.5, 10.5
Hz, 1H), 1.71 (ddd, J = 15.5, 7.5, 2 Hz, 1H), 1.07 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.58
(ddd, J = 11, 9, 7.5 Hz, 1H), 0.40 (dd, J = 9, 1.5 Hz, 1H); 13C NMR (400 MHz, C6D6) δ
211.1, 173.2, 131.5, 130.0, 71.7, 54.4, 51.9, 37.2, 34.2, 33.5, 30.8, 29.9, 29.2, 27.2, 21.3,
18.3, 16.3; HRMS (EI) m/z found: 276.1722 [calc'd for C17H24O3 (M+): 276.1725].
Preparation of Diol 104.
Diol 104. To a solution of 103 (60 mg, 0.22 mmol, 1.0 equiv) in ether (10 mL)
was added lithium aluminum hydride (17 mg, 0.44 mmol, 2.0 equiv). The mixture was
allowed to stir at room temperature for 1 hour. Saturated Na2SO4 aqueous solution (0.5
mL) was carefully added into the solution to quench excess LAH. The mixture was kept
stirring until the precipitates turned white. After adding MgSO4 to dry the solution, the
product was filtered. The solvent was removed under reduced pressure. Diol 104 was
collected as colorless crystals (50 mg, 95% yield).
Diol 104: m.p. 146.5-148.7°C; FTIR (thin film/NaCl) 3428 (m), 3329 (s broad),
3011 (w), 2984 (m), 2949 (m), 2891 (s), 2860 (s), 1478 (w), 1452 (w), 1441 (w), 1373
(w), 1090 (w), 1048 (s), 1015 (m), 895 (w), 846 (w) cm-1; 1H NMR (500 MHz, CD2Cl2)
δ 5.53 (m, 2H), 4.04 (s, 1H), 3.64 (d, J = 4.0 Hz, 2H), 3.14-3.20 (m, 1H), 2.74 (s broad,
1H), 2.47-2.54 (m, 1H), 2.29 (s broad, 1H), 2.24-2.28 (m, 1H), 2.15 (m, 1H), 2.01 (dt, J
58
= 14, 12 Hz, 1H), 1.74 (ddd, J = 14, 6, 4.5 Hz, 1H), 1.66 (m, 1H), 1.60 (dd, J = 16, 8 Hz,
1H), 1.12 (d, J = 7 Hz, 3H), 1.10 (s, 3H), 1.09 (s, 3H), 0.85 (ddd, J = 12, 9, 6 Hz, 1H),
0.55 (dd, J = 9.5, 4 Hz, 1H); 13C NMR (400 MHz, CD2Cl2) δ 129.2, 125.3, 80.0, 71.5,
48.4, 41.0, 40.6, 39.0, 34.6, 31.0, 30.7, 28.9, 27.5, 20.8, 19.9, 15.9; HRMS (EI) m/z
found: 250.1934 [calc'd for C16H26O2 (M+): 250.1933].
Preparation of Diene 91.
MeO
O
O
Br
KH, THFMeO
O
O
H
91
(85% yield)
100b
Diene 91. To a solution of 100b (125 mg, 0.47 mmol, 1.0 equiv) in dry THF (25
mL) was added KH powder (55 mg, 1.4 mmol, 3.0 equiv). The flask was then sealed
under N2. Allyl bromide (150 uL, 1.5 mmol, 3.0 equiv) was injected into the solution.
The reaction was allowed to reflux vigorously for 12 hours. The solution was cooled to
room temperature, and carefully quenched with methanol (0.5 mL). The crude product
was diluted with ether and washed with saturated NH4Cl and brine. After drying with
MgSO4, the solvent was removed under reduced pressure. Flash chromatography (40:1
Hexanes:EtOAc eluent) of the residue afforded diene 91 (121 mg, 85% yield) as a light
yellow oil.
Diene 91: FTIR (thin film/NaCl) 3077 (w), 2978 (m), 2948 (m), 2865 (m), 1735
(s), 1705 (s), 1640 (w), 1435 (m), 1379 (w), 1262 (m), 1213 (s), 1155 (w), 995 (m), 915
(m) cm-1; 1H NMR (500 MHz, C6D6) δ 5.90 (dddd, J = 17, 10, 7.5, 7 Hz, 1H), 5.81 (ddt,
59
J = 17, 10, 7.5 Hz, 1H), 5.07-5.21 (m, 4H), 3.52 (s, 3H), 2.89 (ddt, J = 14, 7.5, 1.5 Hz,
1H), 2.80 (ddt, J = 14, 8, 1.5 Hz, 1H), 2.69-2.76 (m, 1H), 2.57 (m, 1H), 2.43 (ddd, J =
10, 9, 5.5 Hz, 1H), 2.25 (m, 1H), 1.94 (ddd, J = 17, 10, 8 Hz, 1H), 1.60 (ddd, J = 17, 5.5,
4 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.78 (ddd, J = 9.5, 8.5, 5.5
Hz, 1H), 0.36 (t, J = 9.5 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 206.9, 172.2, 137.2,
133.5, 119.5, 117.0, 67.7, 51.9, 45.9, 40.3, 36.5, 35.0, 29.3, 29.1, 28.9, 23.6, 20.0, 17.2,
16.2; HRMS (EI) m/z found: 304.2044 [calc'd for C19H28O3 (M+): 304.2038].
Preparation of TBS Ether 105.
O
H
O
MeO
91
OH
H
TBSO
105
1) LAH2) TBSCl
(95% yield)
TBS Ether 105. To a solution of 91 (30 mg, 0.10 mmol) in ether (6 mL) was
added lithium aluminum hydride (15 mg, 0.40 mmol, 4.0 equiv). The mixture was
allowed to stir at room temperature for 1 hour. Saturated Na2SO4 aqueous solution (0.5
mL) was carefully added into the solution to quench excess LAH. The solution was
stirred until the precipitates turned white, dried with MgSO4, and filtered. Concentration
in vacuo afforded a colorless oil. After redissolving the crude diol in CH2Cl2 (5 mL),
TBSCl (16 mg, 0.11 mmol, 1.1 equiv) and imidazole (10 mg, 0.15 mmol, 1.5 equiv) were
added to the reaction at rt. The reaction mixture was stirred at rt for 5 h, diluted with
ether (25 mL), washed with brine (5 mL), dried over Na2SO4, and filtered. Concentration
60
in vacuo followed by flash chromatography (10:1 Hexanes:EtOAc eluent) afforded TBS
ether 105 (37 mg, 95% yield) as a colorless oil.
TBS Ether 105: FTIR (thin film/NaCl) 3617 (m), 3498 (br m), 3075 (m), 2955
(s), 2929 (s), 2859 (s), 2738 (w), 1638 (m), 1462 (m), 1388 (m), 1255 (s), 1095 (s), 1005
(m), 996 (m), 912 (s), 857 (s), 836 (s), 775 (s), 667 (m), 626 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.81-5.70 (m, 2H), 5.06-4.97 (m, 4H), 3.74 (d, J = 9.5 Hz, 1H), 3.64 (d,
J = 9.5 Hz, 1H), 3.57 (d, J = 8.0 Hz, 1H), 2.26-2.20 (m, 1H), 2.15 (dt, J = 14, 7.0 Hz,
1H), 2.04 (d, J = 7.5 Hz, 2H), 1.82 (d, J = 8.0 Hz, 1H), 1.78-1.72 (m, 1H), 1.66 (dt, J =
15, 6.0 Hz, 1H), 1.55 (dt, J = 9.5, 7.5 Hz, 1H), 1.45 (ddd, J = 16, 12, 1.5 Hz, 1H), 1.17
(d, J = 7.0 Hz, 3H), 1.06 (s, 3H), 1.03 (s, 3H), 0.91 (s, 9H), 0.76 (ddd, J = 11.5, 9.0, 6.0
Hz, 1H), 0.37 (dd, J = 10, 9.5 Hz, 1H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (400 MHz,
C6D6) δ 138.1, 135.5, 117.8, 115.9, 79.7, 65.1, 47.9, 40.6, 37.7, 36.4, 35.5, 29.6, 27.1,
26.8, 26.2, 22.8, 19.6, 18.5, 16.4, -5.2; HRMS (EI) m/z found: 392.3112 [calc'd for
C24H44O2Si (M+): 392.3111].
61
Preparation of Ketals 112a, 112b, 112c, 112d.
O
MeO
O
LiMeCuCN
O
MeO
O
HO OH
MeO
OO O
MeO
OO O
MeO
OO O
MeO
OO O
49 111
p-TSA, C6H6
(95% yield) (98% yield)
112a (18%) 112b (16%) 112c (43%) 112d (23%)
Ketals 112a, 112b, 112c, 112d. In a flame-dried 100 mL round bottom flask,
CuCN (600 mg, 6.6 mmol, 1.4 equiv) was stirred with anhydrous ether (30 mL). The
solution was chilled to –78°C before adding MeLi (1.4 M, 4.7 mL, 6.6 mmol, 1.4 equiv).
After the mixture was stirred for 30 minutes, a solution of 49 (998 mg, 4.7 mmol, 1.0
equiv) in ether (30 mL) was slowly added to the cuprate solution. The reaction was
allowed to stir at –78°C for 2 hours. After the reaction was warmed to room temperature,
it was diluted with ether and washed with 10% NH4OH solution, water and brine. After
drying with MgSO4, The solvent was evaporated under reduced pressure. The crude
product was then dissolved in benzene (50 mL), followed by addition of ethylene glycol
(1.3 ml, 23.5 mmol, 5.0 equiv) and catalytic pTSA (5 mg). The mixture was heated under
Dean-Stark conditions for 12 hours. The crude solution was then washed with saturated
NaHCO3 solution and brine. After drying with MgSO4, the solvent was removed. The
residue was purified by flash chromatography (25:1:1 Hexanes:EtOAc:CH2Cl2 eluent).
62
Ketal 112a. First to elute was 112a (186 mg, 15% yield from cycloheptenone
49): FTIR (thin film/NaCl) 2953 (m), 2932 (m), 2874 (m), 1732 (s), 1461 (w), 1368 (w),
1333 (w), 1308 (w), 1214 (m), 1148 (m), 1096 (m) cm-1; 1H NMR (500 MHz, C6D6) δ
3.58-3.74 (m, 4H), 3.50 (s, 3H), 3.11 (s, 1H), 2.94 (dd, J = 14, 12 Hz, 1H), 2.48 (m, 1H),
2.35 (td, J = 11, 7.5 Hz, 1H), 2.12 (ddd, J = 15, 6, 2 Hz, 1H), 1.61 (dd, J = 15, 6 Hz,
1H), 1.41 (s, 3H), 1.19 (s, 3H), 1.08 (d, J = 7 Hz, 3H), 0.99 (m, 1H), 0.85 (ddd, J = 10.5,
9, 6.5 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 172.7, 111.5, 65.1, 64.7, 59.6, 51.2, 33.4,
31.2, 29.3, 28.1, 28.0, 22.5, 22.1, 20.8, 16.3; HRMS (EI) m/z found: 268.1672 [calc'd for
C15H24O4 (M+): 268.1675].
Ketal 112b. Ketal 112b was eluted the second to deliver a colorless oil (165 mg,
13% yield from cycloheptenone 49): FTIR (thin film/NaCl) 2986 (m), 2951 (m), 2930
(m), 2875 (m), 1736 (s), 1459 (w), 1434 (w), 1378 (w), 1331 (w), 1306 (m), 1194 (m),
1173 (m), 1153 (m) cm-1; 1H NMR (500 MHz, C6D6) δ 3.54-3.70 (m, 4H), 3.52 (s, 3H),
3.12 (dd, J = 3, 1.5 Hz, 1H), 2.82 (dd, J = 15, 11 Hz, 1H), 2.22-2.32 (m, 2H), 2.13 (ddd,
J = 15, 6.5, 2 Hz, 1H), 1.78 (dt, J = 15, 6 Hz, 1H), 1.45 (d, J = 7 Hz, 3H), 1.35 (s, 3H),
1.17 (s, 3H), 0.88 (ddd, J = 10.5, 9, 6.5 Hz, 1H), 0.83 (ddt, J = 9.5, 5.5, 5.5 Hz, 1H); 13C
NMR (400 MHz, C6D6) δ 174.0, 112.7, 65.2, 64.5, 58.5, 51.6, 33.8, 32.4, 29.6, 26.3,
24.1, 21.6, 21.0, 20.0, 16.3; HRMS (EI) m/z found: 268.1675 [calc'd for C15H24O4 (M+):
268.1675].
Ketal 112c. Ketal 112c was eluted the third to furnish a white solid (444 mg,
35% yield from cycloheptenone 49): m.p. 92.6-94.7°C; FTIR (thin film/NaCl) 2952 (s),
2932 (s), 2875 (s), 1739 (s), 1455 (m), 1434 (m), 1379 (m), 1352 (w), 1310 (w), 1271
(w), 1195 (m), 1179 (m), 1131 (m) cm-1; 1H NMR (500 MHz, C6D6) δ 4.31 (q, J = 7.0
63
Hz, 1H), 3.86 (td, J = 7, 5 Hz, 1H), 3.77 (td, J = 7, 5 Hz, 1H), 3.59 (q, J = 7 Hz, 1H),
3.54 (s, 3H), 3.05 (d, J = 3.5 Hz, 1H), 2.40 (m, 1H), 2.06 (ddd, J = 14, 4, 2.5 Hz, 1H),
1.91 (dt, J = 14.5, 6 Hz, 1H), 1.63 (d, J = 7 Hz, 3H), 1.35-1.42 (m, 1H), 1.18-1.26 (m,
1H), 1.14 (s, 3H), 1.02 (s, 3H), 0.79-0.89 (m, 2H); 13C NMR (400 MHz, C6D6) δ 172.2,
112.8, 66.9, 64.3, 60.6, 51.1, 36.4, 34.1, 31.4, 29.6, 24.3, 21.8, 20.1, 16.0, 15.2; HRMS
(EI) m/z found: 268.1675 [calc'd for C15H24O4 (M+): 268.1675].
Ketal 112d. The last to elute was 112d (237 mg, 19% yield from cycloheptenone
49), which furnished a white solid: m.p. 53.2-54.0°C; FTIR (thin film/NaCl) 2953 (m),
1740 (s), 1460 (w), 1434 (w), 1353 (w), 1271 (w), 1208 (w), 1168 (w), 1140 (m), 1044
(m), 984 (w), 948 (w), 801 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 4.02 (m, 1H), 3.72
(m, 2H), 3.57-3.62 (m, 1H), 3.58 (s, 3H), 2.58-2.69 (m, 2H), 2.09 (dd, J = 14, 6 Hz, 1H),
1.73 (dd, J = 15, 6 Hz, 1H), 1.46 (dd, J = 14.5 Hz, 1H), 1.13 (s, 3H), 1.04 (d, J = 7 Hz,
3H), 1.02 (s, 3H), 0.97 (m, 1H), 0.89 (ddd, J = 11, 9, 6.5 Hz, 1H), 0.81 (ddd, J = 11, 9,
6.5 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 173.0, 111.7, 66.2, 65.1, 64.8, 51.3, 35.9,
34.5, 33.4, 29.5, 27.5, 22.72, 22.68, 20.2, 16.1; HRMS (EI) m/z found: 268.1674 [calc'd
for C15H24O4 (M+): 268.1675].
64
Preparation of Alcohol 113.
MeO
OO O
112c
OHO
113
1) LAH, Et2O2) HCl, acetone
(95% yield, two steps)
Alcohol 113. To a solution of 112c (1.2 g, 4.5 mmol, 1.0 equiv) in anhydrous
ether (100 mL) was added lithium aluminum hydride (342 mg, 9.0 mmol, 2.0 equiv).
The mixture was allowed to stir under N2 for two hours. Saturated Na2SO4 solution was
carefully added into the solution to quench excess LAH. The mixture was kept stirring
until the precipitates turned white. After adding MgSO4 to dry the solution, the product
was filtered. The solvent was removed under reduced pressure. The crude oil was
dissolved in acetone (20 mL), followed by addition of 1 M HCl (1.0 mL). The solution
was allowed to stir at room temperature for 30 minutes. Saturated sodium bicarbonate
solution (5 mL) was added to neutralize the acid. Organic solvent was removed under
reduced pressure. The aqueous phase was extracted with ether, and the extraction was
washed with brine. After drying with MgSO4, the solution was concentrated under
reduced pressure. Flash chromatography (3:1 Hexane:EtOAc eluent) of the crude oil
afforded alcohol 113 (0.84 g, 95% 2 steps) as a colorless oil.
Alcohol 113: FTIR (thin film/NaCl) 3430 (m broad), 2935 (s), 2877 (s), 1698 (s),
1455 (m), 1382 (m), 1289 (w), 1202 (w), 1155 (w), 1117 (w), 1025 (m), 984 (w), 940 (w)
cm-1; 1H NMR (500 MHz, C6D6) δ 4.23 (t, J = 10 Hz, 1H), 3.58 (m, 1H), 2.55 (dd, J =
11.5, 6.5 Hz, 1H), 2.48 (dt, J = 8, 4.5 Hz, 1H), 2.19 (s broad, 1H), 2.00 (m, 1H), 1.83 (m,
2H), 1.13 (ddd, J = 15, 11, 1.5 Hz, 1H), 1.00 (s, 3H), 0.94 (s, 3H), 0.88 (d, J = 7.0 Hz,
65
3H), 0.51-0.61 (m, 2H); 13C NMR (400 MHz, C6D6) δ 209.6, 62.54, 62.50, 41.2, 32.9,
30.9, 29.1, 24.2, 21.2, 20.8, 15.6, 14.0; HRMS (EI) m/z found: 196.1457 [calc'd for
C12H20O2 (M+): 196.1463].
Preparation of Acetate 114.
OHO
113
OAcO
114
Ac2O, DMAP
pyridine
(99% yield)
Acetate 114. To a solution of alcohol 113 (450 mg, 2.3 mmol) in pyridine (10
mL) was sequentially added acetic anhydride (1.1 mL, 12 mmol, 5.0 equiv) and catalytic
DMAP (2 mg). The mixture was allowed to stir at room temperature for half an hour.
Pyridine was removed from the reaction under reduced pressure. Flash chromatography
(20:1 Hexanes:EtOAc eluent) of the yellow residue afforded acetate 114 (526 mg, 96%
yield) as a colorless oil.
Acetate 114: FTIR (thin film/NaCl) 2937 (m), 1742 (s), 1703 (s), 1456 (m), 1368
(m), 1240 (s), 1203 (m), 1152 (w), 1031 (m), 983 (w) cm-1; 1H NMR (500 MHz, C6D6) δ
4.82 (dd, J = 11, 8 Hz, 1H), 4.29 (dd, J = 11, 6 Hz, 1H), 2.62 (ddd, J = 7.5, 6, 4.5 Hz,
1H), 2.51 (m, 1H), 2.05 (m, 1H), 1.83 (s, 3H), 1.80 (m, 2H), 1.10 (ddd, J = 15, 11, 1.5
Hz, 1H), 0.99 (s, 3H), 0.92 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H), 0.54 (m, 2H); 13C NMR
(400 MHz, C6D6) δ 206.1, 170.7, 63.9, 58.6, 40.8, 32.8, 30.6, 29.1, 24.0, 21.2, 21.1, 21.0,
15.6, 13.4; HRMS (EI) m/z found: 238.1563 [calc'd for C14H22O3 (M+): 238.1569].
66
Preparation of Exo-olefin 109.
OAcO
114 109
O
DBU, C6H6
(80% yield)
Exo-olefin 109. To a solution of 114 (500 mg, 2.1 mmol 1.0 equiv) in benzene
(150 mL), was added DBU (947 uL, 6.3 mmol, 3.0 equiv). The mixture was heated to
reflux for 10 hours. After cooling to room temperature, the crude product was washed
with saturated NH4Cl solution, brine, and then dried over anhydrous MgSO4.
Concentration under reduced pressure afforded a yellow oil, which was purified by flash
chromatography (60:1 Hexanes:Et2O eluent) to afford exo-olefin 109 (332 mg, 88%
yield) as a colorless oil.
Exo-olefin 109: FTIR (thin film/NaCl) 2959 (s), 1697 (s), 1608 (m), 1457 (m),
1377 (w), 1266 (m), 1138 (w), 940 (w), 770 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 6.07
(dd, J = 2.0, 0.5 Hz, 1H), 5.06 (dd, J = 2.0, 1.0 Hz, 1H), 2.69 (dd, J = 13, 7.0 Hz, 1H),
2.33 (h, J = 7.0 Hz, 1H), 2.18 (dd, J = 13, 11 Hz, 1H), 1.63 (m, 2H), 1.04 (d, J = 7.0 Hz,
3H), 0.97 (s, 3H), 0.86 (s, 3H), 0.66 (ddd, J = 11, 9.0, 7.0 Hz, 1H), 0.57 (td, J = 9.0, 7.0
Hz, 1H); 13C NMR (400 MHz, C6D6) δ 201.8, 155.0, 118.3, 38.3, 36.3, 32.5, 31.0, 29.0,
22.7, 20.5, 19.3, 15.3; HRMS (EI) m/z found: 178.1359 [calc'd for C17H24O (M+):
178.1358].
67
Preparation of Diels-Alder Products 115a, 115b, 115c.
O
BF3 OEt2
109 110
Otoluene, -78
oC
(86% yield)
+
115 a:b:c = 20:8:1
.
Diels-Alder Product 115a, 115b, 115c. In a flame-dried 100 mL round bottom
flask, exo-olefin 109 (400 mg, 2.25 mmol, 1.0 equiv) was dissolved in toluene (25 mL).
After the solution was chilled to –78°C in a dry ice bath, boron trifluoride diethyl etherate
(556 uL, 4.50 mmol, 2.0 equiv) was added into the flask. The mixture was allowed to stir
at –78°C for 15 minutes before adding newly cracked cyclopentadiene monomer (110)
(1.85 mL, 22.5 mmol, 10 equiv). The reaction mixture was allowed to stir at -78°C under
N2 for one hour. Water (2 mL) was injected into the flask to quench the reaction. The
reaction was allowed to warm to room temperature slowly. The reaction mixture was
diluted with ether, and the crude product was washed with 1 M NaOH, water and brine.
After drying with MgSO4, the solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography (150:1 hexanes: Et2O eluent).
Diels-Alder Product 115b. First to elute was product 115b to furnish a light
yellow solid (130 mg, 24% yield): m.p. 63.5-66.2°C; FTIR (thin film/NaCl) 3058 (w),
2944 (s), 2875 (m), 1693 (s), 1457 (m), 1380 (m), 1301 (w), 1240 (w), 1206 (w), 1191
(w), 1148 (w), 982 (w), 778 (w), 721 (m), 644 (w) cm-1; 1H NMR (500 MHz, C6D6) δ
6.22 (dd, J = 5.8, 3.0 Hz, 1H), 5.97 (dd, J = 5.0, 3.0 Hz, 1H), 3.18 (dd, J = 12, 4 Hz,
1H), 2.94 (d, J = 1.5 Hz, 1H), 2.72 (s, 1H), 2.62 (dd, J = 12, 7.0 Hz, 1H), 2.48 (dd, J =
7.0, 5.0 Hz, 1H), 1.79 (dt, J = 15, 6.0 Hz, 1H), 1.55 (m, 1H), 1.46 (m, 2H), 1.20 (d, J =
68
8.0 Hz, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 1.01 (d, J = 6.5 Hz, 3H), 0.77 (dd, J = 12, 2.5 Hz,
1H), 0.70 (m, 2H); 13C NMR (400 MHz, C6D6) δ 208.9, 141.3, 133.4, 67.9, 50.1, 48.4,
42.8, 40.4, 36.7, 33.5, 29.2, 27.1, 24.9, 21.9, 21.2, 16.2, 15.9; HRMS (EI) m/z found:
244.1826 [calc'd for C17H24O (M+): 244.1827].
Diels-Alder Product 115c. Product 115c was eluted the second to furnish a
colorless oil (16 mg, 3.0% yield): FTIR (thin film/NaCl) 3058 (w), 2959 (s), 2875 (s),
1694 (s), 1455 (m), 1379 (w), 1332 (w), 1253 (w), 1148 (w), 781 (w), 717 (m), 646 (m),
589 (m) cm-1; 1H NMR (500 MHz, C6D6) δ 6.70 (dd, J = 5.5, 3.0 Hz, 1H), 6.10 (dd, J =
5.5, 3.0 Hz, 1H), 3.40 (q, J = 1.5 Hz, 1H), 2.70 (s, 1H), 2.35 (dd, J = 11.8, 6.8 Hz, 1H),
2.10 (t, J = 11 Hz, 1H), 1.80 (m, 2H), 1.50 (m, 3H), 1.40 (m, 1H), 1.32 (d, J = 12 Hz,
1H), 1.12 (d, J = 6.5 Hz, 3H), 1.04 (s, 3H), 1.02 (s, 3H), 0.75 (ddd, J = 11, 10.5, 6.5 Hz,
1H), 0.66 (m, 1H); 13C NMR (400 MHz, C6D6) δ 209.2, 140.8, 136.4, 68.3, 46.9, 46.3,
42.8, 41.6, 38.6, 37.7, 29.2, 28.0, 23.6, 22.5, 21.8, 15.8, 14.9; HRMS (EI) m/z found:
244.1825 [calc'd for C17H24O (M+): 244.1827].
Diels-Alder Product 115a. Third to elute was product 115a (326 mg, 59%
yield): m.p. 62.1-64.2°C; FTIR (thin film/NaCl) 3056 (w), 2971 (s), 2877 (m), 1700 (s),
1457 (w), 1380 (w), 1336 (w), 1277 (w), 779 (w), 710 (m), 647 (w) cm-1; 1H NMR (500
MHz, C6D6) δ 6.19 (dd, J = 5.5, 3.0 Hz, 1H), 5.93 (dd, J = 5.5, 3.0 Hz, 1H), 2.82 (s, 1H),
2.72 (s, 1H), 2.66 (dd, J = 12, 3.0 Hz, 1H), 2.49 (dd, J = 12, 7.0 Hz, 1H), 2.18 (t, J = 11
Hz, 1H), 1.80 (m, 1H), 1.76 (m, 2H), 1.59 (dd, J = 14, 11 Hz, 1H), 1.48 (m, 1H), 1.44 (d,
J = 8.5 Hz, 1H), 1.36 (dd, J = 12, 4.0 Hz, 1H), 1.10 (d, J = 7.0 Hz, 3H), 1.08 (s, 3H),
1.06 (s, 3H), 0.70 (m, 2H); 13C NMR (400 MHz, C6D6) δ 206.8, 140.5, 133.9, 67.2, 48.9,
69
48.2, 43.8, 40.4, 38.1, 35.9, 29.2, 27.4, 24.2, 21.59, 21.56, 16.5, 16.1; HRMS (EI) m/z
found: 244.1827 [calc'd for C17H24O (M+): 244.1827].
Preparation of Diene 108.
KH, THF
115a
(76% yield)O
H
O
Br
108
Diene 108. To a 25ml round bottom flask containing a solution of 115a (25 mg,
0.10 mmol, 1.0 equiv) in THF (10 mL) was sequentially added KH powder (20 mg, 0.50
mmol, 5.0 equiv) and allyl bromide (100 uL, 1.0 mmol, 10 equiv). The reaction was
allowed to reflux vigorously for 12 hours. After the solution was cooled to room
temperature, methanol (0.5 mL) was carefully added to quench excess KH. The crude
product was diluted with ether. The solution was then washed with saturated NH4Cl and
brine. After drying with MgSO4, the crude product was concentrated. The residue was
purified by flash chromatography. Diene 108 was collected as a white solid (22 mg, 76%
yield).
Diene 108: m.p. 61.2-62.9 °C; FTIR (thin film/NaCl) 3063 (w), 2975 (s), 2878
(m), 1699 (s), 1640 (w), 1445 (w), 1381 (w), 1261 (w), 1088 (w), 994 (w), 909 (m), 864
(w), 712 (m), 680 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 6.15 (dd, J = 6, 3 Hz, 1H),
5.94 (dd, J = 6, 3 Hz, 1H), 5.75 (ddt, J = 17, 10, 7.5 Hz, 1H), 5.00-5.09 (m, 2H), 2.99 (s,
1H), 2.78 (s, 1H), 2.37 (m, 1H), 2.26 (td, J = 10, 4 Hz, 1H), 2.18 (m, 2H), 1.90 (m, 2H),
1.63 (m, 1H), 1.57 (d, J = 8.5 Hz, 1H), 1.42-1.46 (m, 1H), 1.40 (dd, J = 12, 4 Hz, 1H),
70
1.060 (s, 3H), 1.058 (s, 3H), 0.94 (d, J = 7 Hz, 3H), 0.70 (ddd, J = 11, 9, 6 Hz, 1H), 0.15
(t, J = 9 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 210.2, 139.9, 136.7, 133.1, 115.9, 66.4,
47.9, 47.4, 46.6, 42.8, 40.1, 36.1, 35.6, 28.8, 27.1, 26.7, 23.3, 21.0, 16.0, 15.6; HRMS
(EI) m/z found: 284.2140 [calc'd for C20H28O (M+): 284.2140].
Preparation of Triene 106 via ROM.
3 mol% II, ethylene
(95% yield)O
HH
O
108 106
Triene 106. To a solution of 108 (56 mg, 0.20 mmol, 1.0 equiv) in CH2Cl2 (50
mL) was added catalyst II (5.0 mg, 0.006 mmol, 3 mol%). The reaction was allowed to
stir under ethylene gas for 6 hours. Concentration under reduced pressure with
concomitant adsorption onto silica gel followed by flash chromatography (40:1
Hexanes:Et2O eluent) afforded triene 106 (59 mg, 95% yield) as a light pink oil.
Triene 106: FTIR (thin film/NaCl) 3075 (m), 2977 (s), 2954 (s), 2864 (m), 1694
(s), 1640 (w), 1453 (m), 1419 (w), 1378 (w), 1264 (w), 1164 (w), 996 (m), 909 (s) cm-1;
1H NMR (500 MHz, CDCl3) δ 5.82 (ddd, J = 17, 10, 7.5 Hz, 1H), 5.69 (ddt, J = 17, 10,
7 Hz, 1H), 5.59 (dt, J = 17, 10 Hz, 1H), 4.94-5.03 (m, 5H), 4.90 (dt, J = 10, 1.5 Hz, 1H),
2.75 (m, 1H), 2.54 (m, 1H), 2.20-2.37 (m, 3H), 2.16 (t, J = 9 Hz, 1H), 2.01 (dd, J = 14, 7
Hz, 1H), 1.95 (ddd, J = 14, 7, 2 Hz, 1H), 1.83 (m, 2H), 1.63 (ddd, J = 15, 10, 2 Hz, 1H),
1.36 (ddd, J = 13, 8, 4 Hz, 1H), 1.03 (s, 3H), 1.00 (s, 3H), 0.94 (d, J = 7 Hz, 3H), 0.69
(td, J = 9, 7 Hz, 1H), 0.15 (t, J = 9.5 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 212.1,
71
143.2, 140.9, 136.7, 115.6, 115.1, 112.7, 68.1, 50.1, 47.1, 39.8, 38.0, 35.9, 35.6, 34.9,
28.7, 27.4, 27.0, 22.7, 20.8, 15.9, 14.8; HRMS (EI) m/z found: 312.2444 [calc'd for
C22H32O (M+): 312.2453].
Preparation of Diene 108 via RCM.
60 mol% II, toluene
(8% yield) O
HH
O
108106
Diene 108. A solution of 106 (40 mg, 0.06 mmol, 1.0 equiv) in toluene (40 mL)
was heated to reflux for 3 hours. During this time, three portions of catalyst II (20 mg,
0.0024 mmol, 20 mol%) was added to the reaction every 60 minutes. Toluene was
removed under reduced pressure. Flash chromatography (30:1 Hexanes:Et2O eluent) of
the crude product afforded diene 108 (2.6 mg, 8% yield) as a light pink solid.
(Experimental data identical to the alkylation product)
Preparation of Diene 116.
115a
O(98% yield)
2 mol% II
Oethylene
116
72
Diene 116. To a solution of 115a (250 mg, 1.0 mmol, 1.0 equiv) in
dichloromethane (150 mL) was added II (16 mg, 0.020 mmol, 2.0 mol%). The solution
was allowed to stir at room temperature under ethylene gas for 12 hours. Concentration
under reduced pressure with concomitant adsorption onto silica gel followed by flash
chromatography (40:1 Hexanes:Et2O eluent) afforded diene 116 (266 mg, 98% yield) as a
white solid.
Diene 116: m.p.64.5-65.5°C; FTIR (thin film/NaCl) 3076 (w), 2975 (m), 2944
(m), 1696 (s), 1639 (w), 1457 (w), 1420 (w), 1378 (w), 1297 (w), 1272 (w), 1203 (w),
996 (m), 911 (m), 643 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 5.94 (ddd, J = 17, 10, 7.5
Hz, 1H), 5.69 (dt, J = 17, 10 Hz, 1H), 5.16 (ddd, J = 17, 2, 1 Hz, 1H), 5.06 (ddd, J = 10,
2, 1 Hz, 1H), 4.96 (ddd, J = 17, 2, 0.5 Hz, 1H), 4.91 (dd, J = 10, 2 Hz, 1H), 2.48-2.61
(m, 3H), 2.32 (dd, J = 12, 11 Hz, 1H), 2.20-2.27 (m, 2H), 2.16 (ddd, J = 13, 9, 8 Hz,
1H), 1.69-1.81 (m, 2H), 1.59 (ddd, J = 14.5, 9.5, 1.5 Hz, 1H), 1.50 (ddd, J = 14, 7.5, 4
Hz, 1H), 1.07 (s, 3H), 1.03 (s, 3H), 0.96 (d, J = 7 Hz, 3H), 0.70 (ddd, J = 10.5, 9, 6.5 Hz,
1H), 0.65 (td, J = 9, 6 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 209.1, 144.2, 141.9,
115.4, 113.5, 69.2, 50.9, 40.9, 39.6, 38.8, 36.9, 35.5, 29.1, 27.3, 23.5, 21.7, 21.4, 15.8,
15.5; HRMS (EI) m/z found: 272.2140 [calc'd for C19H28O (M+): 272.2140].
Preparation of Dioxolane 117.
1) OsO4/NMO
(73% yield)
2) NaIO4
3) ethylene glycolO O
O
O
116 117
73
Dioxolane 117. To a solution of diene 116 (794 mg, 3.0 mmol, 1.0 equiv) in
THF/H2O (4:1, 25 mL) was added 2.5 wt. % OsO4 solution in 2-methyl-2-propanol (940
uL, 0.08 mmol, 2.5 mol%) and NMO (386 mg, 3.3 mmol, 1.1 equiv). The mixture was
allowed to stir at room temperature for 8 hours. The crude solution was diluted with
ether. After washing with NaHCO3 and brine, the solution was filtered through a silica
gel pad. After drying with MgSO4, the solvent was evaporated under reduced pressure.
The residue was then dissolved in a solvent mixture of CH3OH/THF (4:1, 30 mL),
followed by addition of an aqueous solution of 0.5 M NaIO4 (18 mL, 9.0 mmol, 3.0
equiv). The mixture was allowed to stir at room temperature for 1 hour. The reaction
was diluted with water (20 mL), and the crude product was extracted with ether. After
drying with MgSO4, the solvent was rotavapored and the resultant colorless oil was then
dissolved in benzene (30 mL). To this solution was added ethylene glycol (0.85 mL, 15
mmol, 5.0 equiv) and catalytic PPTS (5 mg). The reaction was heated to reflux for 4
hours under Dean-Stark conditions. After the solution was cooled to room temperature,
the crude product was diluted with ether. The crude solution was washed with NaHCO3
and brine, and then dried over MgSO4. The solvent was removed under reduced
pressure. Purification of the residue by flash chromatography (10:1 Hexanes:EtOAc
eluent) afforded as dioxolane 117 (696 mg, 73% yield over 3 steps) as A colorless oil.
Dioxolane 117: FTIR (thin film/NaCl) 3073 (w), 2953 (m), 1696 (s), 1457 (w),
1380 (w), 1272 (w), 1156 (m), 1096 (m), 1077 (m), 995 (w), 940 (w), 913 (w) cm-1; 1H
NMR (500 MHz, C6D6) δ 5.91 (dt, J = 17, 10 Hz, 1H), 4.98 (dd, J = 17, 2 Hz, 1H), 4.94
(dd, J = 10, 2 Hz, 1H), 4.89 (d, J = 5 Hz, 1H), 3.68 (m, 2H), 3.52 (m, 2H), 2.62 (td, J =
9, 2.5 Hz, 1H), 2.57 (dd, J = 12, 6.5 Hz, 1H), 2.34-2.48 (m, 3H), 2.29 (dd, J = 12, 11 Hz,
74
1H), 2.22 (m, 1H), 1.72-1.82 (m, 2H), 1.70 (dt, J = 15, 6 Hz, 1H), 1.57 (ddd, J = 15, 10,
1 Hz, 1H), 1.06 (s, 3H), 1.02 (s, 3H), 0.98 (d, J = 7 Hz, 3H), 0.67 (m, 2H); 13C NMR
(400 MHz, C6D6) δ 209.0, 141.9, 115.2, 107.9, 69.5, 65.7, 65.6, 50.3, 40.2, 39.7, 35.2,
33.0, 31.8, 29.1, 26.9, 23.7, 21.6, 15.9, 15.3; HRMS (EI) m/z found: 318.2191 [calc'd for
C20H30O3 (M+): 318.2195].
Preparation of RCM Diene 118.
KH, THF
(92% yield)
H
OOO
O
O
O
Br
117 118
Diene 118. To a solution of 117 (580 mg, 1.8 mmol, 1.0 equiv) in dry THF (40
mL) was sequentially added KH powder (365 mg, 9.1 mmol, 5.0 equiv) and allyl bromide
(2.0 ml, 18.2 mmol, 10 equiv). The reaction was heated to reflux vigorously for 10 hours.
After cooling to room temperature, methanol was carefully added into the reaction to
quench excess KH. The crude product was extracted with ether, and the solution was
washed with NH4Cl and brine. After drying with MgSO4, the solvent was removed, and
flash chromatography (30:1 Hexanes:EtOAc eluent) afforded RCM diene 118 (592 mg,
92% yield) as a white solid.
Diene 118: m.p. 64.1-65.1°C; FTIR (thin film/NaCl) 3073 (w), 2975 (s), 2880 (s),
1694 (s), 1639 (w), 1454 (m), 1415 (w), 1379 (w), 1156 (m), 1094 (m), 1034 (m), 996
(m), 911 (m), 752 (w), 651 (w) cm-1; 1H NMR (500 MHz, C6D6) δ 5.63 (ddd, J = 17, 10,
7.5 Hz, 1H), 5.62 (ddd, J = 17, 10.5, 10 Hz, 1H), 4.91 (dd, J = 17, 2 Hz, 1H), 4.85 (dd, J
75
= 10, 2 Hz, 1H), 4.70 (dd, J = 17, 2.5 Hz, 1H), 4.67 (dd, J = 10, 2.5 Hz, 1H), 4.62 (d, J =
3 Hz, 1H), 3.41 (m, 2H), 3.24 (m, 2H), 2.51 (ddd, J = 13, 10, 8 Hz, 1H), 2.38 (m, 1H),
2.25 (ddd, J = 12.5, 7.5, 4 Hz, 1H), 2.11 (m, 4H), 1.95 (m, 1H), 1.40-1.50 (m, 3H), 1.28
(dd, J = 14, 11 Hz, 1H), 0.81 (s, 3H), 0.80 (s, 3H), 0.71 (d, J = 6.5 Hz, 3H), 0.41 (td, J =
10, 6 Hz, 1H), 0.00 (dd, J = 10, 9 Hz, 1H); 13C NMR (400 MHz, C6D6) δ 210.6, 142.1,
137.9, 116.2, 115.2, 107.8, 69.3, 65.7, 65.6, 50.1, 48.1, 39.9, 37.0, 35.2, 33.0, 32.1, 29.3,
27.9, 27.1, 23.6, 21.6, 16.8, 15.2; HRMS (EI) m/z found: 358.2503 [calc'd for C23H34O3
(M+): 358.2508].
Preparation of Tetracycle 119 via RCM.
80 mol% II
O
HH
OO
O
O
O H
(45% yield)
118 119
Tetracycle 119. A solution of 118 (50 mg, 0.14 mmol, 1.0 equiv) in dry toluene
(50 mL) was heated to reflux for 3 hours. During this time, four portions of catalyst II
(23 mg, 0.028 mmol, 20 mol%) were added to the solution every 45 minutes. After
cooling to room temperature, Pb(OAc)4 (101 mg, 0.28 mmol, 2.0 equiv), and the mixture
was allowed to stir for 24 hours. The crude solution was poured on a short silica gel
column (15:1 Hexanes:Et2O eluent), and the product was collected as a pink oil. The
RCM product was further purified by HPLC (20:1 Hexanes:Et2O eluent) to afford
tetracycle 119 (21 mg, 45% yield) as a colorless oil.
76
Tetracycle 119: FTIR (thin film/NaCl) 2999 (m), 2948 (m), 2876 (m), 1721 (s),
1457 (w), 1380 (w), 1160 (w), 1103 (w), 1036 (w), 960 (w) cm-1; 1H NMR (500 MHz,
80°C, C6D6) δ 5.50 (m, 2H), 4.82 (d, J = 5 Hz, 1H), 3.70 (m, 2H), 3.55 (m, 2H), 3.29 (td,
J = 13, 3.5 Hz, 1H), 3.06 (d, J = 3.5 Hz, 1H), 2.66 (m, 1H), 2.10-2.45 (m, 5H), 1.90 (m,
1H), 1.76 (dd, J = 7.5, 4.5 Hz, 2H), 1.70 (ddd, J = 12.5, 7, 4.5 Hz, 1H), 1.13 (s, 3H), 1.05
(d, J = 7 Hz, 3H), 1.04 (s, 3H), 0.91 (dd, J = 12, 9 Hz, 1H), 0.70 (q, J = 8 Hz, 1H); 13C
NMR (400 MHz, 80°C, C6D6) δ 210.5, 138.4, 131.2, 108.0, 72.4, 66.7, 46.3, 46.1, 43.3,
37.5, 35.9, 32.6, 31.2, 30.3, 29.8, 29.3, 25.1, 24.7, 23.5, 16.3, 15.7; HRMS (EI) m/z
found: 330.2187 [calc'd for C21H30O3 (M+ 330.2195].
Preparation of Diol 120.
OsO4/NMO
(82% yield)
O
H
O
O
O
H
O
O
HO OHH H
119 120
Diol 120. To a solution of tetracycle 119 (66 mg, 0.20 mol) in THF/H2O (4:1 15
mL) was added 2.5 wt. % OsO4 solution in 2-methyl-2-propanol (50 uL, 0.004 mmol, 2
mol%) and NMO (117 mg, 1.0 mmol, 5.0 equiv). The mixture was allowed to stir at
room temperature for 12 hours. The crude product was extracted with ether. The
solution was washed with brine. After drying over MgSO4, solvent was removed under
reduced pressure. Flash chromatography (2:1 Hexanes:EtOAc eluent) afforded diol 120
(60 mg, 82% yield) as a colorless oil.
77
Diol 120: FTIR (thin film/NaCl) 3454 (br m), 2926 (s), 2883 (s), 1713 (s), 1453
(w), 1220 (w), 1159 (w), 1034 (m), 940 (w) cm-1; 1H NMR (500 MHz, 80°C, C6D6) δ
4.82 (d, J = 4 Hz, 1H), 4.00 (s broad, 1H), 3.70 (m, 2H), 3.55 (m, 2H), 3.34 (d, J = 8 Hz,
1H), 3.25 (td, J = 14, 2 Hz, 1H), 2.66 (q, J = 7 Hz, 1H), 2.43 (m, 1H), 2.35 (broad, 1H),
2.20 (m, 2H), 2.14 (td, J = 6.5, 2.5 Hz, 1H), 2.08 (dd, J = 14, 7 Hz, 1H), 1.97 (t, J = 7.5
Hz, 2H), 1.87 (ddd, J = 13, 7.5, 2.5 Hz, 1H), 1.78 (m, 2H), 1.50 (broad, 1H), 1.32 (s,
3H), 1.06 (s, 3H), 1.03 (d, J = 7 Hz, 3H), 0.90 (dd, J = 11.5, 8.5 Hz, 1H), 0.67 (q, J = 8.5
Hz, 1H); 13C NMR (400 MHz, 80°C, C6D6) δ 212.4, 107.9, 77.4, 75.2, 68.8, 65.8, 65.6,
47.9, 42.4, 42.2, 37.6, 34.0, 30.9, 29.6, 28.1, 27.9, 25.8, 25.2, 23.7, 17.0, 15.4; HRMS
(EI) m/z found: 364.2248 [calc'd for C21H32O5 (M+): 364.2250].
Preparation of Dibenzoate 121.
O
H
O
OHO OHH
BrC6H4COCl
O
H
O
OORRO
HC
O
Br(84% yield) R =
120 121
Dibenzoate 121. To a solution of diol 120 (30 mg, 0.08 mmol, 1.0 equiv) in
dichloromethane (10 mL) was sequentially added para-bromobenzoic chloride (88 mg,
0.40 mmol, 5.0 equiv) and DMAP (25 mg, 0.20 mmol, 2.5 equiv). The flask was then
sealed under N2. Triethyl amine (110 uL, 0.80 mmol, 10 equiv) was injected into the
reaction. The reaction was allowed to stir at room temperature for 8 hours.
Concentration under reduced pressure with concomitant adsorption onto silica gel
78
followed by flash chromatography (4:1 Hexanes:EtOAc eluent) afforded dibenzoate 121
(51 mg, 84% yield) as a crystalline solid.
Dibenzoate 121: m.p. 183.6-184.8°C; FTIR (thin film/NaCl) 2955 (w), 2883 (w),
1723 (s), 1590 (m), 1484 (w), 1398 (w), 1272 (s), 1173 (w), 1113 (m), 1100 (m), 1012
(m), 923 (w), 847 (w), 754 (m), 737 (w), 682 (w) cm-1; 1H NMR (500 MHz, 80°C,
C6D6) δ 7.88 (dd, J = 8.5, 7 Hz, 4H), 7.34 (m, 4H), 5.88 (t, J = 4.5 Hz, 1H), 5.69 (s
broad, 1H), 4.77 (d, J = 5.5 Hz, 1H), 3.67 (m, 2H), 3.59 (t, J = 10 Hz, 1H), 3.51 (m, 2H),
2.89 (d, J = 6 Hz, 1H), 2.70 (t, J = 13 Hz, 1H), 2.56 (dt, J = 13, 5 Hz, 1H), 2.37 (m, 1H),
2.31 (m, 1H), 2.21 (dt, J = 14, J = 7 Hz, 1H), 1.85-2.00 (m, 4H), 1.75 (ddd, J = 16, 9, 7
Hz, 1H), 1.50 (broad, 1H), 1.23 (s, 3H), 1.02 (s, 3H), 0.96 (d, J = 7 Hz, 3H), 0.65 (ddd, J
= 8.5, 6.5, 4.5 Hz, 1H); 13C NMR (400 MHz, 80°C, C6D6) δ 210.4, 165.4, 165.2, 132.6,
131.9, 131.8, 130.4, 130.3, 107.6, 79.3, 74.8, 68.1, 65.7, 50.1, 43.3, 41.5, 41.3, 39.6, 32.1,
31.4, 31.0, 29.4, 27.1, 26.5, 25.4, 22.9, 17.1, 15.8; HRMS (EI) m/z found: 730.0952
[calc'd for C35H38 Br2O7 (M+): 730.0964].
Preparation of Diol 122a and 122b.
H
OO
O
OsO4, NMO
118
H
OO
OHO
OH
122
(60% yield)
Diol 122a and 122b. To a solution of diene 118 (240 mg, 0.68 mmol) in
THF/H2O (4:1 40 mL) was added 4 wt. % OsO4 aqueous solution (108 uL, 0.017 mmol,
2.5 mol%) and NMO (80 mg, 0.68 mmol, 1.0 equiv) at rt. The mixture was stirred at rt
79
for 12 hours, extracted with ether (250 mL), washed with brine (20 mL), dried over
MgSO4, and filtered. After evaporation of solvent under reduced pressure, the residue
was purified by flash chromatography (2:1 Hexanes:EtOAc eluent).
Diol 122a. First to eluent was diol 122a (82 mg, 31% yield) to furnish a white
solid: m.p. 95.8-96.9 °C; FTIR (thin film/NaCl) 3461 (br m), 2953 (s), 2918 (s), 1688 (s),
1638 (w), 1455 (m), 1380 (m), 1298 (w), 1269 (w), 1221 (w), 1152 (m), 1096 (m), 1070
(m), 1035 (m), 997 (m), 919 (m), 873 (w), 733 (s), 648 (w) cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.65 (dt, J = 17, 10 Hz, 1H), 5.06 (dd, J = 17, 2.0 Hz, 1H), 4.99 (dd, J = 10,
1.5 Hz, 1H), 4.80 (d, J = 5.0 Hz, 1H), 4.00-3.92 (m, 2H), 3.89-3.84 (m, 2H), 3.68-3.61
(m, 2H), 3.43 (dd, J = 10.5, 7.5 Hz, 1H), 2.80 (dd, J = 9.5, 7.5 Hz, 1H), 2.58 (dt, J = 3.5,
10 Hz, 1H), 2.22-2.13 (m, 2H), 2.01-1.83 (m, 6H), 1.72-1.64 (m, 2H), 1.52-1.44 (m, 2H),
1.12 (s, 3H), 1.07 (s, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.71 (dt, J = 6.5, 9.5 Hz, 1H), 0.06 (t,
J = 10 Hz, 1H); 13C NMR (500 MHz, CDCl3) δ 213.1, 140.6, 116.1, 107.6, 67.0, 68.1,
65.4, 65.4, 49.6, 43.7, 39.5, 35.2, 34.7, 32.5, 31.1, 29.2, 27.8, 27.2, 22.9, 21.3, 16.1, 15.2,
14.4; HRMS (CI) m/z found: 393.2639 [calc'd for C23H37O5 (M+H): 393.2641].
Diol 122b. Second to eluent was diol 122b (77 mg, 29% yield) to furnish a light
yellow solid: m.p. 114.2-116.0 °C; FTIR (thin film/NaCl) 3407 (br m), 2990 (s), 2922 (s),
2874 (s), 1685 (s), 1452 (m), 1395 (w), 1295 (w), 1263 (m), 1154 (m), 1098 (s), 1071 (s),
1036 (s), 999 (w), 931 (m), 866 (w), 732 (s), 692 (w) cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.66 (dt, J = 17, 10 Hz, 1H), 5.00 (dd, J = 17, 1.5 Hz, 1H), 4.95 (dd, J = 10, 1.5 Hz,
1H), 4.80 (d, J = 4.5 Hz, 1H), 3.98-3.92 (m, 2H), 3.87-3.82 (m, 2H), 3.73 (ddd, J = 12,
7.0, 3.5 Hz, 1H), 3.57 (dd, J = 11, 3.0 Hz, 1H), 3.38 (dd, J = 11, 6.5 Hz, 1H), 2.78-2.73
(m, 1H), 2.46 (dt, J = 11, 5.5 Hz, 1H), 2.21-2.10 (m, 2H), 1.98 (dd, J = 14, 7.0 Hz, 1H),
80
1.95 (dd, J = 13.5, 6.5 Hz, 1H), 1.92-1.84 (m, 2H), 1.70-1.64 (m, 2H), 1.62 (dd, J = 8.0,
5.0 Hz, 1H), 1.53 (ddd, J = 15, 6.0, 4.0, 1H), 1.48 (dd, J = 7.0, 3.0 Hz, 1H), 1.079 (s,
3H), 1.076 (s, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.75 (dd, J = 7.0, 6.0 Hz, 1H), 0.36 (t, J =
10.5 Hz, 1H); 13C NMR (500 MHz, CDCl3) δ 214.5, 141.1, 115.6, 107.3, 69.2, 68.4, 67.6,
65.6, 65.5, 50.0, 45.0, 39.3, 35.1, 34.5, 32.8, 31.2, 29.0, 26.6, 25.6, 23.4, 21.7, 15.5, 15.0;
HRMS (CI) m/z found: 393.2639 [calc'd for C23H37O5 (M+H): 393.2641].
Preparation of Ketone 123.
H
OO
OO
OTBS
1) TBSCl 2) DMP
123
H
OO
OHO
OH
122
(93% yield, two steps)
Ketone 123. To a solution of diol 122a and 122b (150 mg, 0.38 mmol) in
CH2Cl2 (20 mL) was added TBSCl (69 mg, 0.46 mmol, 1.2 equiv) and imidazole (39 mg,
0.57 mmol, 1.5 equiv) at rt. The reaction mixture was stirred under N2 for 12 h, diluted
with ether (200 mL), washed with brine (20 mL), dried over Na2SO4, and filtered. After
passing the crude product through a silica gel pad, solvent was evaporated under reduced
pressure. The resulting oil was redissolved in CH2Cl2 (20 mL), and Dess-Martin reagent
(193 mg, 0.46 mmol, 1.2 equiv) was added to the solution at rt. The reaction mixture was
heated to reflux for 2 h. After the solution was cooled to rt, Na2S2O3 (20 ml, 10 wt%
aqueous solution) to work up the reaction. The reaction mixture was allowed to stir until
the two layers were clear. The crude product was extracted with ether (150 mL), washed
with NaHCO3 (20 mL, sat. aqueous solution) and brine (20 mL), dried over MgSO4, and
81
filtered. Concentration in vacuo followed by flash chromatography (20:1
Hexanes:EtOAc eluent) afforded ketone 123 (178 mg, 93% yield over two steps) as a
white solid.
Ketone 123: m.p. 91.8-93.0 °C; FTIR (thin film/NaCl) 2954 (s), 2929 (s), 2859
(s), 1733 (m), 1694 (s), 1460 (m), 1380 (w), 1255 (m), 1099 (m), 1038 (w), 1003 (w),
939 (w), 839 (s), 780 (m), 734 (w), 699 (w) cm-1; 1H NMR (400 MHz, CDCl3) δ 5.64
(dt, J = 16.8, 10.4 Hz, 1H), 5.09 (dd, J = 17.2, 1.6 Hz, 1H), 4.94 (dd, J = 10.4, 1.6 Hz,
1H), 4.78 (d, J = 4.8 Hz, 1H), 4.20 (d, J = 17.6 Hz, 1H), 4.14 (d, J = 17.6 Hz, 1H), 4.00-
3.91 (m, 2H), 3.88-3.82 (m, 2H), 2.83 (dd, J = 14.4, 9.6 Hz, 1H), 2.76 (dd, J = 10, 2.8
Hz, 1H), 2.78-2.72 (m, 1H), 2.32 (dd, J = 15.2, 3.2 Hz, 1H), 2.22-2.03 (m, 2H), 1.99-1.89
(m, 3H), 1.83 (dd, J = 15.2, 6.8 Hz, 1H), 1.68 (ddd, J = 14.8, 10, 1.6 Hz, 1H), 1.50 (ddd,
J = 12.8, 6.0, 3.6 Hz, 1H), 1.00 (s, 3H), 0.98 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.91 (s,
9H), 0.68 (dt, J = 6.4, 9.6 Hz, 1H), 0.15 (t, J = 9.6 Hz, 1H), 0.08 (s, 6H); 13C NMR (400
MHz, CDCl3) δ 211.3, 208.5, 140.0, 116.4, 107.5, 70.3, 68.9, 65.5, 65.4, 50.0, 43.6, 39.8,
39.6, 35.0, 32.3, 31.3, 29.7, 27.6, 27.1, 26.2, 23.3, 21.7, 18.8, 15.8, 15.4, -4.99, -5.00;
HRMS (CI) m/z found: 505.3351 [calc'd for C29H49O5Si (M+H): 505.3349].
Preparation of Diene 124.
H
OO
OO
OTBS
H
OO
O OTBS
124123
Ph3P=CH2
(90% yield)
82
Diene 124. To a suspension of Ph3PCH3I (240 mg, 0.60 mmol, 2.0 equiv) in THF
(8 mL) under N2 was added n-BuLi (0.24 mL 2.5 M solution in hexanes, 0.60 mmol, 2.0
equiv) at 0 °C. The resulting Wittig Ylide solution was allowed to stir for 1 h at 0 °C.
At that point, ketone 123 (150 mg, 0.30 mmol) was dissolved in THF (5 mL). After
cooling the ketone solution to 0 °C, a solution of the Wittig Ylide (4 mL, 0.30 mmol, 1.0
equiv) was added over two minutes to the reaction flask by syringe. After stirring the
reaction mixture at 0 °C for 30 minutes under N2, more Wittig solution (2 mL, 0.15
mmol, 0.5 equiv) was syringed to the reaction. The mixture was allowed to stir for
another 15 minutes at 0 °C before a third portion of Wittig Ylide solution (2 mL, 0.15
mmol, 0.5 equiv) was added. The reaction mixture was stirred at 0 °C for another 30
minutes, neutralized with NH4Cl (5 mL sat. aqueous solution), extracted with ether (200
mL), washed with brine (30 mL), dried over Na2SO4, and filtered. Concentration in
vacuo followed by flash chromatography (20:1 Hexanes:EtOAc eluent) afforded diene
124 (136 mg, 90% yield) as a colorless oil.
Diene 124: FTIR (thin film/NaCl) 3071 (w), 2953 (s), 2930 (s), 2859 (s), 1692
(s), 1653 (w), 1459 (m), 1388 (m), 1360 (w), 1255 (m), 1102 (s), 1036 (w), 997 (w), 939
(w), 913 (w), 898 (w), 838 (s), 777 (m), 734 (w), 668 (w) cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.64 (dt, J = 17, 10 Hz, 1H), 5.12 (dd, J = 3.5, 2.0 Hz, 1H), 5.04 (dd, J = 15,
1.5 Hz, 1H), 4.99 (dd, J = 10, 1.5 Hz, 1H), 4.82 (s, 1H), 4.79 (d, J = 4.5 Hz, 1H), 3.99-
3.90 (m, 4H), 3.89-3.83 (m, 2H), 2.79-2.73 (m, 1H), 2.34 (dt, J = 3.0, 10 Hz, 1H), 2.25
(dd, J = 13, 11 Hz, 1H), 2.20-2.11 (m, 2H), 2.08 (dd, J = 13, 2.5 Hz, 1H), 1.98 (dd, J =
14, 7.0 Hz, 1H), 1.96-1.86 (m, 2H), 1.83 (dt, J = 15.5, 6.5 Hz, 1H), 1.63 (ddd, J = 15, 10,
1.5 Hz, 1H), 1.52-1.45 (m, 1H), 0.98 (s, 3H), 0.93 (d, J = 7 Hz, 1H), 0.92 (s, 3H), 0.91 (s,
83
9H), 0.65 (dt, J = 6.5, 9.5 Hz, 1H), 0.11 (t, J = 10 Hz, 1H), 0.05 (s, 3H), 0.04 (s, 3H); 13C
NMR (500 MHz, CDCl3) δ 212.3, 146.4, 141.0, 115.6, 110.7, 107.8, 107.6, 68.7, 65.8,
65.5, 65.4, 49.8, 47.3, 39.6, 34.9, 34.6, 32.8, 31.2, 29.8, 29.0, 28.2, 27.2, 26.3, 23.0, 21.4,
18.7, 16.1, 15.1, -4.98, -5.00; HRMS (CI) m/z found: 503.3557 [calc'd for C30H51O4Si
(M+H): 503.3557].
Preparation of RCM Product 125.
H
OO
O OTBS
124
O
H
HOTBS
O
O
125
25 mol% III
(96% yield)
RCM Product 125. To a solution of diene 124 (140 mg, 0.28 mmol) in benzene
(40 mL) was added 2nd generation Grubbs’s catalyst III (59 mg, 0.07 mmol, 25 mol%) at
rt. The reaction mixture was heated to reflux for 24 h. Concentration under reduced
pressure with concomitant adsorption onto silica gel followed by flash chromatography
(16:1 Hexanes:EtOAc eluent) afforded 125 (127 mg, 96% yield) as a pink oil.
RCM Product 125: FTIR (thin film/NaCl) 2953 (s), 2929 (s), 2859 (s), 1722 (s),
1693 (w), 1461 (m), 1382 (m), 1339 (w), 1255 (m), 1210 (w), 1140 (m), 1093 (s), 1073
(s), 1007 (w), 940 (w), 839 (s), 777 (s), 733 (m), 699 (w), 648 (w) cm-1; 1H NMR (400
MHz, CDCl3) δ 5.39 (s, 1H), 4.69 (d, J = 5.2 Hz, 1H), 4.00-3.90 (m, 4H), 3.87-3.81 (m,
2H), 3.27-3.14 (m, 2H), 2.36-2.16 (m, 3H), 2.12 (dd, J = 16, 1.2 Hz, 1H), 2.08-2.00 (m,
1H), 1.92-1.84 (m, 3H), 1.77 (dd, J = 13.6, 11.2 Hz, 1H), 1.52-1.46 (m, 1H), 1.13 (s,
3H), 1.05 (s, 3H), 1.00 (d, J = 7.2 Hz, 3H), 0.73-0.65 (m, 2H), 0.05 (s, 6H); 13C NMR
84
(400 MHz, CDCl3) δ 212.0, 140.9, 132.0, 107.6, 68.9, 65.4, 65.3, 45.4, 44.8, 42.4, 36.9,
35.3, 32.0, 30.7, 29.8, 29.0, 28.9, 26.2, 24.3, 24.1, 23.3, 18.6, 15.9, 15.4, -4.95, -5.00;
HRMS (FAB) m/z found: 473.3087 [calc'd for C28H45O4Si (M-H): 473.3087].
Preparation of Diene 127.
OO
O
OBn
Cl
KH, THF
117
H
OO
O OBn
127
(93% yield)
(126)
Diene 127. To a solution of dioxolane 117 (120 mg, 0.38 mmol) in THF (20 mL)
was added KH powder (large excess, freshly washed with pentane) at rt. The mixture
was heated to reflux under N2 for 15 minutes before allyl chloride 126 (370 uL, 1.88
mmol, 5.0 equiv) was injected. After refluxing the reaction for another 30 minutes, a
little more KH powder (~10 mg) was added to the reaction from the top of the condenser.
The reaction mixture was allowed to reflux for another 4 h. The reaction was then cooled
to rt. Methanol (2 mL) was carefully added to the solution to quench excess KH. The
solution was then neutralized with NH4Cl (5 mL sat. aqueous solution), extracted with
ether (150 mL), washed with brine (30 mL), dried over MgSO4, and filtered.
Concentration in vacuo followed by flash chromatography (12:1 Hexanes:EtOAc eluent)
afforded diene 127 (169 mg, 93% yield) as a white solid.
Diene 127: m.p. 99.6-101.0 °C; FTIR (thin film/NaCl) 3066 (w), 3029 (w), 2954
(s), 2920 (s), 2857 (s), 1726 (w), 1692 (m), 1650 (w), 1453 (m), 1378 (w), 1260 (w),
1096 (s), 1029 (m), 996 (w), 912 (w), 736 (m), 697 (m) cm-1; 1H NMR (500 MHz,
85
CDCl3) δ 7.33-7.24 (m, 5H), 5.60 (dt, J = 17, 10 Hz, 1H), 5.12 (d, J = 2.0 Hz, 1H), 4.96
(dd, J = 17, 2.0 Hz, 1H), 4.92-4.89 (m, 2H), 4.76 (d, J = 4.5 Hz, 1H), 4.48 (d, J = 12 Hz,
1H), 4.45 (d, J = 12 Hz, 1H), 3.98-3.92 (m, 2H), 3.86-3.80 (m, 4H), 2.74-2.69 (m, 1H),
2.35 (dt, J = 3.0 10 Hz, 1H), 2.29 (t, J = 11.5 Hz, 1H), 2.20-2.08 (m, 3H), 1.96 (dd, J =
13.5, 7.0 Hz, 1H), 1.92-1.77 (m, 3H), 1.60 (dd, J = 15, 9 Hz, 1H), 1.51-1.44 (m, 1H),
0.93 (s, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.88 (s, 3H), 0.63 (dt, J = 6.5, 9.0 Hz, 1H), 0.10 (t,
J = 10 Hz, 1H); 13C NMR (500 MHz, CDCl3) δ 212.2, 144.0, 140.8, 138.8, 128.7, 128.0,
127.9, 115.8, 113.8, 107.6, 73.1, 72.5, 68.7, 65.5, 65.4, 49.8, 47.1, 39.6, 34.8, 32.8, 31.2,
29.0, 28.1, 27.3, 23.0, 21.3, 16.2, 15.2; HRMS (CI) m/z found: 479.3161 [calc'd for
C31H43O4 (M+H): 479.3161].
Preparation of RCM Product 128 and C-M Product 129.
O
H
HOBn
O
O
128
H
OO
O OBn
H
OO
O OBn
Ph
127
129
25 mol% III
(92% yield)
+
RCM Product 128 and C-M Product 129. To a solution of diene 127 (150 mg,
0.31 mmol) in benzene (45 mL) was added 2nd generation Grubbs’s catalyst III (67 mg,
86
0.078 mmol, 25 mol%) at rt. The reaction mixture was heated to reflux for 36 h.
Concentration under reduced pressure with concomitant adsorption onto silica gel
followed by flash chromatography (12:1 Hexanes:EtOAc eluent) afforded RCM product
128 (130 mg, 92% yield) as a colorless oil and C-M product 129 (7 mg, 4% yield) as a
white solid.
RCM Product 128: FTIR (thin film/NaCl) 3029 (w), 2948 (s), 2876 (s), 1720
(s), 1680 (w), 1454 (m), 1381 (m), 1352 (w), 1209 (w), 1161 (m), 1090 (s), 1071 (s),
1031 (m), 948 (m), 920 (m), 735 (s), 699 (m), 647 (w) cm-1; 1H NMR (500 MHz, CDCl3,
60 °C) δ 7.34-7.25 (m, 5H), 5.42 (s, 1H), 4.71 (d, J = 5 Hz, 1H), 4.42 (d, J = 12 Hz, 1H),
4.38 (d, J = 12 Hz, 1H), 3.98-3.91 (m, 2H), 3.90-3.80 (m, 4H), 3.30-3.23 (m, 1H), 3.21
(br s, 1H), 2.44 (t, J = 15 Hz, 1H), 2.30-2.19 (m, 3H), 2.08-2.02 (m, 1H), 1.93-1.78 (m,
4H), 1.50 (ddd, J = 18, 11, 4.5 Hz, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 1.02 (d, J = 7.5 Hz,
3H), 0.75-0.68 (m, 2H); 13C NMR (500 MHz, CDCl3, 60 °C) δ 212.0, 139.1, 139.0,
135.6, 128.7, 128.2, 127.9, 107.6, 77.6, 76.7, 72.0, 65.5, 65.4, 45.7, 45.0, 42.5, 37.0, 35.3,
32.6, 29.9, 29.1, 29.0, 24.4, 24.2, 23.4, 16.0, 15.5; HRMS (EI) m/z found: 451.2849
[calc'd for C29H39O4 (M+H): 451.2848].
C-M Product 129: m.p. 152.2-154.0 °C; FTIR (thin film/NaCl) 3024 (w), 2992
(m), 2953 (m), 2919 (m), 2871 (m), 1725 (w), 1681 (s), 1650 (w), 1494 (w), 1451 (m),
1377 (w), 1258 (w), 1116 (w), 1098 (m), 986 (m), 948 (w), 906 (w), 750 (m), 734 (m),
694 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.36-7.16 (m, 10H), 6.34 (d, J = 15.5 Hz,
1H), 6.04 (dd, J = 15.5, 10 Hz, 1H), 5.04 (d, J = 1.5 Hz, 1H), 4.82 (d, J = 10 Hz, 1H),
4.73 (s, 1H), 4.31 (d, J = 12 Hz, 1H), 4.10 (d, J = 12 Hz, 1H), 4.01-3.94 (m, 2H), 3.90-
3.86 (m, 2H), 3.67 (d, J = 9.0 Hz, 1H), 3.35 (d, J = 13.5 Hz, 1H), 2.92 (m, 1H), 2.39 (dt,
87
J = 3.0, 11 Hz, 1H), 2.31 (t, J = 12 Hz, 1H), 2.27-2.19 (m, 2H), 2.10-1.95 (m, 3H), 1.93-
1.83 (m, 2H), 1.65 (dd, J = 14.5, 12 Hz, 1H), 1.59 (dd, J = 7.0, 4.0 Hz, 1H), 0.97 (d, J =
7.0 Hz, 3H), 0.95 (s, 3H), 0.91 (s, 3H), 0.67 (q, J = 8.5 Hz, 1H), 0.10 (t, J = 9.0 Hz, 1H);
13C NMR (400 MHz, CDCl3, 40 °C) δ 212.2, 143.7, 139.0, 137.4, 132.3, 131.0, 129.0,
128.9, 128.7, 128.6, 127.8, 127.78, 127.73, 126.6, 112.5, 107.6, 72.9, 72.6, 65.5, 65.4,
49.1, 47.5, 39.8, 35.0, 34.9, 33.3, 31.5, 30.8, 29.0, 28.3, 27.4, 23.0, 21.3, 16.1, 15.3;
HRMS (CI) m/z found: 555.3480 [calc'd for C37H47O4 (M+H): 555.3474].
Preparation of Diene 132.
OO
O
117
KH, THF
CH3
Cl H
OO
O
CH3
132
(93% yield)
Diene 132. To a solution of dioxolane 117 (80 mg, 0.25 mmol) in THF (15 mL)
was added KH powder (large excess, freshly washed with pentane) at rt. The mixture
was heated to reflux under N2 for 15 minutes before 3-chloro-2-methyl-propene (110 uL,
1.25 mmol, 5.0 equiv) was injected. The reaction mixture was allowed to reflux for 4 h.
After cooling the reaction to rt, methanol (2 mL) was carefully added to quench excess
KH. The solution was then neutralized with NH4Cl (5 mL sat. aqueous solution),
extracted with ether (150 mL), washed with brine (30 mL), dried over MgSO4, and
filtered. Concentration in vacuo followed by flash chromatography (25:1
Hexanes:EtOAc eluent) afforded diene 132 (86 mg, 93% yield) as a colorless oil.
88
Diene 132: FTIR (thin film/NaCl) 3070 (w), 2994 (s), 2955 (s), 2886 (s), 1685
(s), 1647 (w), 1449 (m), 1337 (m), 1293 (w), 1166 (w), 1139 (m), 1089 (w), 1048 (m),
931 (s), 883 (m), 745 (w), 723 (w) cm-1; 1H NMR (400 MHz, CDCl3, 50 °C) δ 5.67 (dt, J
= 17.6, 10 Hz, 1H), 5.06 (dd, J = 16.8, 1.2 Hz, 1H), 4.99 (dd, J = 10, 2.0 Hz, 1H), 4.81
(d, J = 4.8 Hz, 1H), 4.77-4.75 (m, 1H), 4.69 (br s, 1H), 4.01-3.94 (m, 2H), 3.89-3.83 (m,
2H), 2.81-2.75 (m, 1H), 2.43 (dt, J = 3.2, 10.4 Hz, 1H), 2.30 (dd, J = 12.8, 10.4 Hz, 1H),
2.22-2.10 (m, 3H), 2.05-1.90 (m, 3H), 1.84 (dt, J = 15.2, 6.8 Hz, 1H), 1.71-1.63 (m, 1H),
1.67 (s, 3H), 1.54 (ddd, J = 12, 10.4, 4.0 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 3H), 0.95 (d, J =
7.2 Hz, 3H), 0.67 (dt, J = 6.8, 9.2 Hz, 1H), 0.14 (t, J = 9.6 Hz, 1H); 13C NMR (400 MHz,
CDCl3, 50 °C) δ 210.9, 142.5, 139.6, 114.3, 111.3, 106.4, 67.3, 64.2, 64.1, 48.6, 45.4,
38.6, 38.5, 33.6, 31.7, 29.9, 27.7, 27.3, 26.2, 22.1, 21.9, 19.9, 14.9, 13.9; HRMS (CI) m/z
found: 373.2743 [calc'd for C24H37O3 (M+H): 373.2743].
Preparation of RCM Product 133.
C6H6 reflux
O
H
HCH3
O
O
133
H
OO
O
CH3
132
25 mol% III
(82% yield)
RCM Product 133. To a solution of diene 132 (85 mg, 0.23 mmol) in benzene
(30 mL) was added 2nd generation Grubbs’s catalyst III (48 mg, 0.057 mmol, 25 mol%)
at rt. The reaction mixture was heated to reflux for 24 h. Concentration under reduced
pressure with concomitant adsorption onto silica gel followed by flash chromatography
89
(20:1 Hexanes:EtOAc eluent) afforded RCM product 133 (65 mg, 82% yield) as a
colorless oil.
RCM Product 133: FTIR (thin film/NaCl) 2953 (s), 2878 (s), 1722 (s), 1447
(m), 1380 (m), 1339 (w), 1210 (w), 1163 (w), 1129 (w), 1090 (m), 1070 (w), 1035 (w),
958 (w) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C) δ 5.08 (s, 1H), 4.70 (d, J = 4.5 Hz,
1H), 3.99-3.92 (m, 2H), 3.88-3.82 (m, 2H), 3.26-3.20 (m, 1H), 3.17 (br s, 1H), 2.33 (t, J
= 14 Hz, 1H), 2.28-2.16 (m, 2H), 2.06 (d, J = 17 Hz, 1H), 2.04-1.98 (m, 1H), 1.94-1.80
(m, 3H), 1.75 (dd, J = 13.5, 11 Hz, 1H), 1.66 (s, 3H), 1.48-1.41 (m, 1H), 1.13 (s, 3H),
1.04 (s, 3H), 0.99 (d, J = 7.0 Hz, 1H), 0.69 (dt, J = 6.5, 8.5 Hz, 1H), 0.65 (dd, J = 11, 8.5
Hz, 1H); 13C NMR (400 MHz, CDCl3, 40 °C) δ 212.7, 138.4, 132.9, 107.8, 77.7, 65.4,
65.3, 45.5, 45.3, 42.4 36.6, 36.3, 35.5, 30.1, 29.7, 29.1, 26.7, 24.2, 24.0, 23.4, 16.0, 15.5;
HRMS (EI) m/z found: 344.2351 [calc'd for C22H32O3 (M+): 344.2351].
Preparation of Diene 134.
OO
MeOKH, THF
100b
O
H
O
MeO
CH3134
(97% yield)
CH3
Cl
Diene 134. To a solution of β-keto ester 100b (32 mg, 0.12 mmol) in THF (8
mL) was added KH powder (large excess, freshly washed with pentane) and 3-chloro-2-
methyl-propene (53 uL, 0.60 mmol, 5.0 equiv) at rt. The reaction mixture was heated to
reflux for 1 h. After cooling the reaction to rt, methanol (1 mL) was carefully added to
quench excess KH. The solution was then neutralized with NH4Cl (5 mL sat. aqueous
90
solution), extracted with ether (100 mL), washed with brine (20 mL), dried over MgSO4,
and filtered. Concentration in vacuo followed by flash chromatography (30:1
Hexanes:Et2O eluent) afforded diene 134 (37 mg, 97% yield) as a colorless oil.
Diene 134: FTIR (thin film/NaCl) 3075 (w), 2948 (s), 2864 (m), 1737 (s), 1706
(s), 1648 (w), 1442 (m), 1378 (m), 1259 (w), 1213 (s), 1154 (w), 995 (w), 921 (w), 887
(w) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.68-5.59 (m, 1H), 5.11-5.06 (m, 2H), 4.78 (s,
1H), 4.71 (s, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.48 (ddd, J = 9.5, 8.5, 5.0 Hz, 1H),
2.39 (dd, J = 13, 5.0 Hz, 1H), 2.24-2.16 (m, 2H), 1.93 (ddd, J = 15.5, 10, 8.5 Hz, 1H),
1.70 (s, 3H), 1.64 (ddd, J = 15, 5.5, 4.0 Hz, 1H), 1.01 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H),
0.97 (s, 3H), 0.73 (dt, J = 5.5, 9.0 Hz, 1H), 0.28 (t, J = 9.5 Hz, 1H); 13C NMR (400 MHz,
CDCl3, 40 °C) δ 208.2, 172.2, 143.4, 132.6, 119.5, 113.0, 67.5, 52.1, 44.5, 39.8, 39.7,
34.7, 29.0, 28.9, 23.2, 23.0, 19.9, 16.9, 15.9; HRMS (EI) m/z found: 318.2197 [calc'd for
C20H30O3 (M+): 318.2195].
91
2.7 Notes and References.
(1) "A Series of Well-Defined Metathesis Catalysts - Synthesis of
[RuCl2(=CHR')(Pr(3))(2)] and Its Reactions", Schwab, P.; France, M. B.; Ziller, J. W.;
Grubbs, R. H., Angewandte Chemie-International Edition in English 1995, 34, 2039-
2041.
(2) "The Application of Catalytic Ring-Closing Olefin Metathesis to the Synthesis of
Unsaturated Oxygen Heterocycles", Fu, G. C.; Grubbs, R. H., Journal of the American
Chemical Society 1992, 114, 5426-5427.
(3) "Titanium-Mediated Cyclizations of Beta-Keto-Esters With Acetals - a
Convenient Route to 2-Carbalkoxycycloalkenones", Funk, R. L.; Fitzgerald, J. F.;
Olmstead, T. A.; Para, K. S.; Wos, J. A., Journal of the American Chemical Society 1993,
115, 8849-8850.
(4) "Polymer Synthesis and Organotransition Metal Chemistry", Grubbs, R. H.;
Tumas, W., Science 1989, 243, 907-915.
(5) "Living Ring-Opening Metathesis Polymerization of 2,3- Difunctionalized
Norbornadienes By Mo(Ch-Tert-Bu)(N-2,6-C6h3- Iso-Pr2)(O-Tert-Bu)2", Bazan, G. C.;
Khosravi, E.; Schrock, R. R.; Feast, W. J.; Gibson, V. C.; Oregan, M. B.; Thomas, J. K.;
Davis, W. M., Journal of the American Chemical Society 1990, 112, 8378-8387.
92
(6) "Synthesis of Molybdenum Imido Alkylidene Complexes and Some Reactions
Involving Acyclic Olefins", Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
Dimare, M.; Oregan, M., Journal of the American Chemical Society 1990, 112, 3875-
3886.
(7) "Ring-Closing Metathesis and Related Processes in Organic- Synthesis", Grubbs,
R. H.; Miller, S. J.; Fu, G. C., Accounts of Chemical Research 1995, 28, 446-452.
(8) "Synthesis and Activity of a New Generation of Ruthenium-Based Olefin
Metathesis Catalysts Coordinated with 1,3-Dimesityl-4,5-dihydroimidazol-2-ylidene
Ligand", Scholl, m.; Ding, S.; Lee, C. W.; Grubbs, R. H., Organic Letters 1999, 1, 953-
956.
(9) "Increased ring closing metathesis activity of ruthenium-based olefin metathesis
catalysts coordinated with imidazolin-2- ylidene ligands", Scholl, M.; Trnka, T. M.;
Morgan, J. P.; Grubbs, R. H., Tetrahedron Letters 1999, 40, 2247-2250.
(10) "Olefin metathesis and beyond", Furstner, A., Angewandte Chemie-International
Edition 2000, 39, 3013-3043.
(11) "Synthesis of medium-sized rings by the ring-closing metathesis reaction", Maier,
M. E., Angewandte Chemie-International Edition 2000, 39, 2073-2077.
93
(12) "Tandem ring opening ring closing metathesis of cyclic olefins", Zuercher, W. J.;
Hashimoto, M.; Grubbs, R. H., Journal of the American Chemical Society 1996, 118,
6634-6640.
(13) "Macrocycles by ring-closing metathesis", Furstner, A.; Langemann, K.,
Synthesis-Stuttgart 1997, 792-803.
(14) "A Solution to the In,Out-Bicyclo[4.4.1]Undecan-7-One Problem Inherent in
Ingenane Total Synthesis", Funk, R. L.; Olmstead, T. A.; Parvez, M., Journal of the
American Chemical Society 1988, 110, 3298-3300.
(15) "Regiospecific Alkylation of Organocopper Enolates", Boeckman, R. K. J.,
Journal of Organic Chemistry 1973, 38, 4450-4452.
(16) Calculations were performed using Spartan Version 5.1 Wavefunction Inc. 18401
Von Karman Ave. Suite 370, Irvine, CA 92612. For a reference, see: Halgren, T. A. J.
Computational Chem. 1996, 17, 490-519.
(17) "Domino metathesis - A combined ring opening-, ring closing- and cross
metathesis", Stragies, R.; Blechert, S., Synlett 1998, 169-170.
94
(18) The stereochemistry of 112c was unambiguously determined by single crystal X-
ray crystallography (Appendix 2.2).
(19) Ozonolysis of the major diastereomer 115a gave rise to a crystalline compound
135, the structure of which was established by X-ray crystallography (Appendix 2.4).
For spectral data pertaining to 115b and 115c, see Appendix One.
(20) "Ring-Opening Polymerization of Norbornene By a Living Tungsten Alkylidene
Complex", Schrock, R. R.; Feldman, J.; Cannizzo, L. F.; Grubbs, R. H., Macromolecules
1987, 20, 1169-1172.
(21) "Beta-Lactam Antifungals II Enantiocontrolled Synthesis of (2r,5s)-2-
Hydroxymethyl-1-Carbapenam, the Carba-Analog of a Clavam Antifungal", Konosu, T.;
95
Furukawa, Y.; Hata, T.; Oida, S., Chemical & Pharmaceutical Bulletin 1991, 39, 2813-
2818.
(22) "Effects of olefin substitution on the ring-closing metathesis of dienes", Kirkland,
T. A.; Grubbs, R. H., Journal of Organic Chemistry 1997, 62, 7310-7318.
(23) "Efficient and recyclable monomeric and dendritic Ru-based metathesis
catalysts", Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H., Journal of the
American Chemical Society 2000, 122, 8168-8179.
96
Appendix One: Spectra Relevant
To Chapter Two
171
Appendix Two: X-ray Structures Relevant
To Chapter Two
172
X-Ray Crystallography Report for Diol 104
HO H
H
OH
104
Figure A.2.1 Ortep Plot of Diol 104.
A.2.1.1 Crystal Data.
Empirical Formula C32H52O4
Formula Weight 500.76
Crystal Color, Habit colorless, plate
Crystal Dimensions 0.05 X 0.12 X 0.19
mm
Crystal System monoclinic
Lattice Type Primitive
Lattice Parameters a = 9.7381(2)Å
b = 13.3319(4) Å
c = 11.5709(3) Å
β = 101.424(2)o
V = 1472.46(6) Å3
Space Group P21 (#4)
Z value 2
Dcalc 1.129 g/cm3
F000 552.00
µ(MoKα) 0.72 cm-1
173
A.2.1.2 Intensity Measurements.
Diffractometer Nonius KappaCCD
Radiation MoKα (λ = 0.71069
Å)
graphite
monochromated
Take-off Angle 2.8o
Crystal to Detector Distance 33 mm
Temperature -90.0oC
Scan Type ω
Scan Rate 180s/frame
Scan Width 2.0o/frame
2θmax 50.0o
No. of Reflections Measured Total: 4748
Corrections Lorentz-polarization
A.2.1.3 Structure Solution and Refinement.
Structure Solution Direct Methods
(SIR92)
Refinement Full-matrix least-
squares
Function Minimized Σ w (|Fo| - |Fc|)2
Least Squares Weights 1/σ2(Fo)
p-factor 0.0100
Anomalous Dispersion All non-hydrogen
atoms
174
No. Observations (I>3.00σ(I)) 2171
No. Variables 340
Reflection/Parameter Ratio 6.39
Residuals: R; Rw 0.041; 0.043
Goodness of Fit Indicator 1.99
Max Shift/Error in Final Cycle 0.00
Maximum peak in Final Diff. Map 0.15 e-/Å3
Minimum peak in Final Diff. Map -0.16 e-/Å3
175
Table A.2.1 Atomic coordinates and Biso/Beq for Diol 104.
atom x y z Beq
------------------------------------------------------------------------------------------
O(1) 0.8727(2) 0.7035 -0.0938(2) 3.03(5)
O(2) 0.6094(2) 0.7626(3) -0.0948(2) 3.52(5)
O(3) 0.6482(2) 0.2768(2) 0.2293(2) 3.37(5)
O(4) 0.9070(2) 0.2409(3) 0.1965(2) 3.83(5)
C(1) 0.8100(3) 0.6123(3) -0.0612(2) 2.58(6)
C(2) 0.9193(3) 0.5272(3) -0.0414(3) 3.22(7)
C(3) 0.8480(4) 0.4334(4) -0.1027(4) 5.9(1)
C(4) 0.7099(5) 0.4051(4) -0.0701(5) 6.8(1)
C(5) 0.6423(4) 0.4468(4) 0.0031(5) 6.4(1)
C(6) 0.6866(3) 0.5307(4) 0.0869(3) 4.61(9)
C(7) 0.7279(2) 0.6329(3) 0.0370(2) 2.74(7)
C(8) 0.5871(3) 0.6803(3) -0.0209(3) 3.43(7)
C(9) 0.8098(3) 0.6980(3) 0.1400(3) 3.55(7)
C(10) 0.7822(4) 0.8108(4) 0.1310(3) 5.01(9)
C(11) 0.9694(3) 0.6817(3) 0.1636(3) 3.31(7)
C(12) 1.0170(3) 0.5754(3) 0.1845(2) 3.11(7)
C(13) 0.9925(3) 0.5014(3) 0.0839(3) 3.20(7)
C(14) 1.1409(3) 0.5336(3) 0.1406(3) 3.03(7)
C(15) 1.2247(3) 0.5985(3) 0.0729(3) 4.04(8)
C(16) 1.2305(3) 0.4584(3) 0.2187(3) 4.48(8)
C(17) 0.7344(3) 0.3145(3) 0.3356(2) 2.57(6)
C(18) 0.6395(3) 0.3603(3) 0.4150(3) 3.09(7)
C(19) 0.7038(4) 0.4617(4) 0.4584(4) 5.5(1)
C(20) 0.8556(5) 0.4573(4) 0.5173(4) 6.5(1)
C(21) 0.9425(4) 0.3811(5) 0.5379(3) 5.9(1)
C(22) 0.9152(3) 0.2713(4) 0.5162(3) 4.25(8)
C(23) 0.8434(2) 0.2372(3) 0.3905(2) 2.67(6)
176
C(24) 0.9619(2) 0.2403(3) 0.3199(2) 3.42(7)
C(25) 0.7846(3) 0.1290(3) 0.3974(3) 3.24(7)
C(26) 0.7867(3) 0.0608(3) 0.2915(3) 4.59(9)
C(27) 0.6343(3) 0.1264(3) 0.4215(3) 3.41(8)
C(28) 0.6094(3) 0.1871(3) 0.5249(3) 3.30(7)
C(29) 0.6125(3) 0.3003(3) 0.5192(3) 3.29(7)
C(30) 0.4765(3) 0.2459(3) 0.5234(3) 3.58(7)
C(31) 0.3605(3) 0.2440(4) 0.4178(3) 4.83(9)
C(32) 0.4241(4) 0.2516(4) 0.6385(3) 5.7(1)
H(1) 0.7421 0.5933 -0.1284 3.0971
H(2) 0.9906 0.5456 -0.0827 3.8645
H(3) 0.8315 0.4446 -0.1853 7.1147
H(4) 0.9105 0.3785 -0.0832 7.1147
H(5) 0.6658 0.3477 -0.1097 8.1492
H(6) 0.5519 0.4200 0.0032 7.6580
H(7) 0.6112 0.5438 0.1258 5.5324
H(8) 0.7655 0.5081 0.1427 5.5324
H(9) 0.5408 0.7040 0.0388 4.1220
H(10) 0.5305 0.6312 -0.0672 4.1220
H(11) 0.7797 0.6763 0.2092 4.2635
H(12) 0.6880 0.8238 0.1370 6.0125
H(13) 0.8438 0.8442 0.1931 6.0125
H(14) 0.7978 0.8346 0.0573 6.0125
H(15) 1.0031 0.7059 0.0972 3.9746
H(16) 1.0096 0.7197 0.2313 3.9746
H(17) 1.0046 0.5484 0.2577 3.7370
H(18) 0.9699 0.4362 0.1074 3.8398
H(19) 1.2601 0.5584 0.0176 4.8438
H(20) 1.3005 0.6282 0.1262 4.8438
H(21) 1.1662 0.6496 0.0325 4.8438
H(22) 1.2964 0.4928 0.2768 5.3774
177
H(23) 1.1728 0.4172 0.2562 5.3774
H(24) 1.2789 0.4178 0.1723 5.3774
H(25) 0.533(3) 0.775(3) -0.141(3) 5.1(9)
H(26) 0.806(3) 0.743(3) -0.119(3) 4.7(9)
H(27) 0.7855 0.3690 0.3123 3.0803
H(28) 0.5511 0.3736 0.3659 3.7028
H(29) 0.6950 0.5054 0.3925 6.6400
H(30) 0.6525 0.4882 0.5133 6.6400
H(31) 0.8955 0.5202 0.5441 7.8454
H(32) 1.0366 0.3980 0.5716 7.1244
H(33) 1.0031 0.2381 0.5350 5.1058
H(34) 0.8575 0.2498 0.5687 5.1058
H(35) 1.0198 0.1829 0.3391 4.1072
H(36) 1.0160 0.2993 0.3405 4.1072
H(37) 0.8427 0.0977 0.4632 3.8892
H(38) 0.7280 0.0883 0.2235 5.5052
H(39) 0.7535 -0.0039 0.3067 5.5052
H(40) 0.8798 0.0556 0.2786 5.5052
H(41) 0.5728 0.1507 0.3531 4.0865
H(42) 0.6120 0.0585 0.4348 4.0865
H(43) 0.6504 0.1599 0.5996 3.9596
H(44) 0.6535 0.3299 0.5926 3.9475
H(45) 0.3983 0.2493 0.3484 5.7996
H(46) 0.2990 0.2987 0.4214 5.7996
H(47) 0.3102 0.1828 0.4164 5.7996
H(48) 0.3674 0.1947 0.6452 6.8856
H(49) 0.5018 0.2526 0.7028 6.8856
H(50) 0.3704 0.3109 0.6395 6.8856
H(51) 0.705(3) 0.256(3) 0.186(3) 5.2(9)
H(52) 0.981(3) 0.231(3) 0.161(3) 4.1(7)
178
X-Ray Crystallography Report for Ketal 112c
Figure A.2.2 Ortep Plot of Ketal 112c.
A.2.2.1 Crystal Data.
Empirical Formula C15H24O4
Formula Weight 268.35
Crystal Color, Habit colorless, plates
Crystal Dimensions 0.05 X 0.20 X 0.24
mm
Crystal System orthorhombic
Lattice Type Primitive
Lattice Parameters a = 5.8792(2)Å
b = 7.0770(3) Å
c = 34.695(1) Å
V = 1443.56(8) Å3
Space Group P212121 (#19)
Z value 4
Dcalc 1.235 g/cm3
F000 584.00
µ(MoKα) 0.88 cm-1
179
A.2.2.2 Intensity Measurements.
Diffractometer Nonius KappaCCD
Radiation MoKα (λ = 0.71069
Å)
graphite
monochromated
Take-off Angle 2.8o
Crystal to Detector Distance 45 mm
Temperature -90.0oC
Scan Rate 48s/frame
Scan Width 0.8o/frame
2θmax 55.0o
No. of Reflections Measured Total: 3333
Corrections Lorentz-polarization
A.2.2.3 Structure Solution and Refinement.
Structure Solution Direct Methods
(SIR92)
Refinement Full-matrix least-
squares
Function Minimized Σ w (|Fo| - |Fc|)2
Least Squares Weights 1/σ 2(Fo)
p-factor 0.0100
Anomalous Dispersion All non-hydrogen
atoms
No. Observations (I>3.00σ(I)) 1188
No. Variables 172
180
Reflection/Parameter Ratio 6.91
Residuals: R; Rw 0.052; 0.055
Goodness of Fit Indicator 2.38
Max Shift/Error in Final Cycle 0.00
Maximum peak in Final Diff. Map 0.24 e-/Å3
Minimum peak in Final Diff. Map -0.25 e-/Å3
181
Table A.2.2 Atomic coordinates and Biso/Beq for Ketal 112c.
atom x y z Beq
------------------------------------------------------------------------------------------
O(1) -0.2389(4) 0.3153(4) 0.30847(6) 2.64(6)
O(2) 0.0588(4) 0.2579(4) 0.34940(6) 2.73(6)
O(3) -0.1105(5) -0.1129(5) 0.30737(8) 4.06(8)
O(4) -0.4884(5) -0.1143(4) 0.31139(7) 3.53(7)
C(1) -0.1803(7) 0.2690(6) 0.34778(10) 2.39(10)
C(2) -0.2662(7) 0.4256(5) 0.37406(9) 2.61(10)
C(3) -0.1656(7) 0.4216(6) 0.41410(10) 2.27(9)
C(4) -0.1968(6) 0.2540(6) 0.44089(10) 2.50(9)
C(5) -0.3312(8) 0.0812(6) 0.4293(1) 3.2(1)
C(6) -0.2409(8) -0.0256(6) 0.3944(1) 3.0(1)
C(7) -0.3001(7) 0.0763(6) 0.35590(10) 2.59(9)
C(8) -0.0354(8) 0.3767(7) 0.2904(1) 3.7(1)
C(9) 0.1476(8) 0.309(1) 0.3136(1) 7.1(2)
C(10) -0.3009(7) 0.4429(6) 0.45099(10) 2.59(10)
C(11) -0.1923(7) 0.5503(6) 0.4835(1) 3.28(10)
C(12) -0.5556(7) 0.4692(7) 0.4494(1) 3.9(1)
C(13) 0.0099(8) -0.0777(6) 0.3987(1) 3.3(1)
C(14) -0.2833(8) -0.0548(7) 0.3226(1) 2.9(1)
C(15) -0.4967(7) -0.2452(6) 0.2802(1) 4.0(1)
H(1) -0.2298 0.5437 0.3626 3.1314
H(2) -0.4267 0.4140 0.3762 3.1314
H(3) -0.0181 0.4761 0.4155 2.7192
H(4) -0.0648 0.2253 0.4555 2.9956
H(5) -0.3326 -0.0033 0.4506 3.8970
H(6) -0.4822 0.1203 0.4237 3.8970
H(7) -0.3213 -0.1420 0.3938 3.5754
H(8) -0.4572 0.1060 0.3579 3.1086
182
H(9) -0.0250 0.3255 0.2651 4.4920
H(10) -0.0319 0.5107 0.2890 4.4920
H(11) 0.2579 0.4061 0.3168 8.5283
H(12) 0.2162 0.2027 0.3017 8.5283
H(13) -0.0315 0.5442 0.4810 3.9361
H(14) -0.2368 0.4961 0.5073 3.9361
H(15) -0.2399 0.6785 0.4826 3.9361
H(16) -0.6228 0.4163 0.4718 4.6729
H(17) -0.5900 0.6002 0.4481 4.6729
H(18) -0.6142 0.4077 0.4271 4.6729
H(19) 0.0575 -0.1488 0.3769 3.9954
H(20) 0.0300 -0.1510 0.4214 3.9954
H(21) 0.0983 0.0344 0.4005 3.9954
H(22) -0.4978 -0.1782 0.2565 4.8259
H(23) -0.6308 -0.3195 0.2822 4.8259
H(24) -0.3671 -0.3253 0.2812 4.8259
183
X-Ray Crystallography Report for Dibenzoate 121
Figure A.2.3 Ortep Plot of Dibenzoate 121.
A.2.3.1 Crystal Data.
Empirical Formula C35H38O7Br2
Formula Weight 730.49
Crystal Color, Habit colorless, needle
Crystal Dimensions 0.05 X 0.05 X 0.16
mm
Crystal System orthorhombic
Lattice Type Primitive
Lattice Parameters a = 7.0834(3) Å
b = 12.7467(4) Å
c = 36.377(1) Å
V = 3284.4(2) Å3
Space Group P212121 (#19)
Z value 4
Dcalc 1.477 g/cm3
F000 1496.00
µ(MoKα) 25.23 cm-1
184
A.2.3.2 Intensity Measurements.
Diffractometer Nonius KappaCCD
Radiation MoKα (λ = 0.71069
Å)
graphite
monochromated
Take-off Angle 2.8o
Crystal to Detector Distance 50 mm
Temperature -90.0oC
Scan Rate 81s/frame
Scan Width 0.9o/frame
2θmax 50.1o
No. of Reflections Measured Total: 5842
Unique: 3378 (Rint = 0.112)
Corrections Lorentz-polarization
Secondary Extinction
(coefficient:
6.99826e-08)
Absorption:
SORTAV
A.2.3.3 Structure Solution and Refinement.
Structure Solution Direct Methods
(SIR92)
Refinement Full-matrix least-
squares
185
Function Minimized Σ w (|Fo| - |Fc|)2
Least Squares Weights 1/σ 2(Fo)
p-factor 0.0200
Anomalous Dispersion All non-hydrogen
atoms
No. Observations (I>3.00σ(I)) 1514
No. Variables 397
Reflection/Parameter Ratio 3.81
Residuals: R; Rw 0.040; 0.034
Goodness of Fit Indicator 1.34
Max Shift/Error in Final Cycle 0.00
Maximum peak in Final Diff. Map 0.34 e-/Å3
Minimum peak in Final Diff. Map -0.38 e-/Å3
186
Table A.2.3 Atomic coordinates and Biso/Beq for Dibenzoate 121.
atom x y z Beq
-----------------------------------------------------------------------------------------
Br(1) -0.4058(2) -0.09229(8) 0.59808(3) 4.37(3)
Br(2) 0.5498(3) 0.03313(10) 0.49628(3) 8.26(5)
O(1) 0.0951(9) 0.3186(4) 0.6682(1) 2.0(1)
O(2) 0.339(1) 0.2107(5) 0.6535(2) 3.7(2)
O(3) 0.2547(9) 0.4174(5) 0.6115(2) 2.4(2)
O(4) 0.568(1) 0.4444(5) 0.6178(2) 3.5(2)
O(5) 0.375(1) 0.6719(5) 0.5804(2) 3.6(2)
O(6) 0.1633(9) 0.7095(5) 0.5361(2) 3.3(2)
O(7) 0.1976(10) 0.6703(5) 0.7125(2) 3.0(2)
C(1) 0.194(1) 0.4397(7) 0.7154(2) 2.1(2)
C(2) 0.233(1) 0.4022(7) 0.6763(2) 2.1(2)
C(3) 0.214(1) 0.4815(7) 0.6438(2) 1.9(3)
C(4) 0.020(1) 0.5342(7) 0.6361(2) 1.9(2)
C(5) -0.006(1) 0.6371(7) 0.6609(2) 1.6(2)
C(6) 0.084(2) 0.6141(7) 0.6976(2) 1.8(3)
C(7) 0.023(1) 0.5107(7) 0.7141(2) 1.5(2)
C(8) 0.172(2) 0.2295(8) 0.6551(3) 2.4(3)
C(9) 0.026(2) 0.1538(8) 0.6420(3) 2.2(3)
C(10) -0.162(2) 0.1634(8) 0.6508(3) 2.9(3)
C(11) -0.292(1) 0.0895(9) 0.6373(3) 3.3(3)
C(12) -0.227(2) 0.0095(8) 0.6158(2) 2.5(3)
C(13) -0.042(2) -0.0006(7) 0.6062(3) 2.8(3)
C(14) 0.082(2) 0.0705(8) 0.6204(3) 3.3(3)
C(15) 0.439(2) 0.3999(8) 0.6034(3) 2.4(3)
C(16) 0.463(2) 0.3162(8) 0.5752(2) 2.5(3)
C(17) 0.309(2) 0.2644(8) 0.5610(3) 3.9(3)
C(18) 0.333(2) 0.180(1) 0.5379(3) 5.0(4)
187
C(19) 0.511(3) 0.1499(9) 0.5277(3) 4.9(4)
C(20) 0.667(2) 0.199(1) 0.5412(3) 6.4(5)
C(21) 0.644(2) 0.2863(9) 0.5651(3) 4.0(4)
C(22) 0.002(1) 0.5785(6) 0.5970(2) 2.2(2)
C(23) 0.053(1) 0.6966(6) 0.5983(2) 1.9(2)
C(24) 0.099(2) 0.7189(6) 0.6389(2) 2.0(2)
C(25) 0.211(2) 0.7281(8) 0.5728(3) 2.8(3)
C(26) 0.468(2) 0.6527(8) 0.5460(3) 4.8(3)
C(27) 0.343(2) 0.7065(8) 0.5178(2) 4.0(3)
C(28) -0.218(2) 0.6633(7) 0.6693(2) 2.4(3)
C(29) -0.337(1) 0.5869(7) 0.6923(2) 1.8(2)
C(30) -0.294(1) 0.5786(7) 0.7336(2) 2.0(2)
C(31) -0.103(2) 0.5366(7) 0.7465(2) 2.3(2)
C(32) -0.233(1) 0.7739(6) 0.6865(2) 3.5(3)
C(33) -0.280(2) 0.4734(7) 0.7533(2) 2.3(3)
C(34) -0.350(1) 0.4731(7) 0.7927(2) 3.5(3)
C(35) -0.313(1) 0.3690(8) 0.7343(2) 3.0(3)
H(1) 0.2998 0.4773 0.7246 2.4670
H(2) 0.1691 0.3813 0.7309 2.4670
H(3) 0.3562 0.3727 0.6756 2.5762
H(4) 0.3077 0.5342 0.6462 2.3383
H(5) -0.0790 0.4859 0.6408 2.2444
H(6) -0.0581 0.4800 0.6963 1.7760
H(7) -0.2040 0.2197 0.6658 3.5054
H(8) -0.4221 0.0951 0.6430 3.9384
H(9) -0.0004 -0.0550 0.5902 3.3720
H(10) 0.2122 0.0624 0.6152 4.0002
H(11) 0.1850 0.2868 0.5670 4.7119
H(12) 0.2272 0.1424 0.5290 5.9753
H(13) 0.7897 0.1760 0.5347 7.6458
H(14) 0.7510 0.3236 0.5740 4.8455
188
H(15) -0.1234 0.5699 0.5885 2.6213
H(16) 0.0867 0.5428 0.5810 2.6213
H(17) -0.0564 0.7356 0.5918 2.2817
H(18) 0.2306 0.7132 0.6431 2.4223
H(19) 0.0572 0.7872 0.6455 2.4223
H(20) 0.2356 0.8008 0.5759 3.3312
H(21) 0.4754 0.5795 0.5413 5.7604
H(22) 0.5908 0.6821 0.5460 5.7604
H(23) 0.3871 0.7751 0.5125 4.8360
H(24) 0.3361 0.6669 0.4957 4.8360
H(25) -0.2786 0.6678 0.6461 2.8602
H(26) -0.3205 0.5189 0.6821 2.1550
H(27) -0.4649 0.6076 0.6899 2.1550
H(28) -0.3435 0.6342 0.7481 2.4168
H(29) -0.0456 0.5698 0.7671 2.8144
H(30) -0.2227 0.8254 0.6678 4.1554
H(31) -0.3517 0.7808 0.6985 4.1554
H(32) -0.1346 0.7833 0.7039 4.1554
H(33) -0.4233 0.5343 0.7970 4.1477
H(34) -0.2452 0.4723 0.8090 4.1477
H(35) -0.4254 0.4126 0.7968 4.1477
H(36) -0.2561 0.3145 0.7482 3.6318
H(37) -0.2578 0.3708 0.7104 3.6318
H(38) -0.4444 0.3566 0.7322 3.6318
189
X-Ray Crystallography Report for Compound 135
Figure A.2.4 Ortep Plot of Compound 135.
A.2.4.1 Crystal Data.
Empirical Formula C18H26O4
Formula Weight 306.40
Crystal Color, Habit colorless, plate
Crystal Dimensions 0.07 X 0.17 X 0.19
mm
Crystal System orthorhombic
Lattice Type Primitive
Lattice Parameters a = 6.0539(2)Å
b = 12.3425(3) Å
c = 23.046(1) Å
V = 1722.03(9) Å3
Space Group P212121 (#19)
Z value 4
Dcalc 1.182 g/cm3
F000 664.00
µ(MoKα) 0.82 cm-1
190
A.2.4.2 Intensity Measurements.
Diffractometer Nonius KappaCCD
Radiation MoKα (λ = 0.71069
Å)
graphite
monochromated
Take-off Angle 2.8o
Crystal to Detector Distance 35 mm
Temperature -90.0oC
Scan Rate 84s/frame
Scan Width 1.4o/frame
2θmax 50.1o
No. of Reflections Measured Total: 3072
Corrections Lorentz-polarization
A.2.4.3 Structure Solution and Refinement.
Structure Solution Direct Methods
(SIR92)
Refinement Full-matrix least-
squares
Function Minimized Σ w (|Fo| - |Fc|)2
Least Squares Weights 1/σ 2(Fo)
p-factor 0.0200
Anomalous Dispersion All non-hydrogen
atoms
No. Observations (I>3.00σ(I)) 1422
No. Variables 303
191
Reflection/Parameter Ratio 4.69
Residuals: R; Rw 0.036; 0.036
Goodness of Fit Indicator 1.88
Max Shift/Error in Final Cycle 0.00
Maximum peak in Final Diff. Map 0.19 e-/Å3
Minimum peak in Final Diff. Map -0.19 e-/Å3
192
Table A.2.4 Atomic coordinates and Biso/Beq for Compound 135.
atom x y z Beq
-----------------------------------------------------------------------------------------
O(1) -0.0465(3) -0.0325(1) 0.29639(7) 3.31(4)
O(2) 0.3870(3) 0.0385(1) 0.22267(8) 3.83(4)
O(3) 0.3276(4) -0.2450(2) 0.08171(8) 6.48(7)
O(4) -0.0163(3) -0.2703(2) 0.11030(7) 3.93(5)
C(1) 0.2376(4) -0.1603(2) 0.2739(1) 2.25(5)
C(2) 0.2414(4) -0.2585(2) 0.3175(1) 2.57(5)
C(3) 0.3728(5) -0.2385(2) 0.3737(1) 2.94(6)
C(4) 0.2532(5) -0.1720(2) 0.4192(1) 2.92(6)
C(5) 0.2106(5) -0.0531(2) 0.4080(1) 2.81(6)
C(6) 0.2814(5) -0.0058(2) 0.3506(1) 2.60(6)
C(7) 0.1454(4) -0.0608(2) 0.3045(1) 2.46(6)
C(8) 0.0112(6) -0.3022(3) 0.3309(1) 3.81(7)
C(9) 0.3642(5) -0.0858(2) 0.4563(1) 3.48(6)
C(10) 0.2734(7) -0.0731(3) 0.5174(1) 4.60(9)
C(11) 0.6091(5) -0.0652(3) 0.4520(2) 4.41(9)
C(12) 0.4717(4) -0.1461(2) 0.2477(1) 2.33(5)
C(13) 0.4873(5) -0.2330(2) 0.1993(1) 2.75(6)
C(14) 0.2479(4) -0.2638(2) 0.18382(10) 2.40(5)
C(15) 0.1024(5) -0.1865(2) 0.2193(1) 2.66(6)
C(16) 0.5131(5) -0.0367(2) 0.2214(1) 3.02(6)
C(17) 0.1980(5) -0.2583(2) 0.1200(1) 2.92(6)
C(18) -0.0904(7) -0.2672(4) 0.0506(1) 4.48(9)
H(1) 0.317(4) -0.312(2) 0.296(1) 3.0(6)
H(2) 0.404(5) -0.314(2) 0.389(1) 4.4(6)
H(3) 0.522(5) -0.209(2) 0.3644(10) 2.6(5)
H(4) 0.136(5) -0.208(2) 0.438(1) 3.4(6)
H(5) 0.071(4) -0.026(2) 0.4189(9) 1.3(4)
193
H(6) 0.254(5) 0.076(2) 0.349(1) 3.9(5)
H(7) 0.436(4) -0.016(2) 0.3452(9) 1.9(5)
H(8) -0.081(4) -0.246(2) 0.349(1) 3.1(6)
H(9) -0.057(5) -0.338(2) 0.295(1) 4.2(6)
H(10) 0.026(5) -0.363(2) 0.360(1) 3.9(6)
H(11) 0.301(5) 0.002(2) 0.532(1) 4.6(7)
H(12) 0.102(7) -0.088(2) 0.517(1) 5.7(8)
H(13) 0.340(5) -0.126(2) 0.543(1) 5.2(7)
H(14) 0.675(5) -0.079(2) 0.412(1) 4.7(7)
H(15) 0.681(7) -0.116(3) 0.479(2) 7.0(10)
H(16) 0.646(5) 0.005(2) 0.466(1) 5.0(7)
H(17) 0.589(4) -0.152(2) 0.2750(10) 1.9(5)
H(18) 0.560(5) -0.211(2) 0.164(1) 3.8(6)
H(19) 0.571(4) -0.297(2) 0.211(1) 3.4(6)
H(20) 0.222(4) -0.341(2) 0.1955(9) 2.7(5)
H(21) -0.041(5) -0.219(2) 0.227(1) 2.8(5)
H(22) 0.088(4) -0.117(2) 0.195(1) 3.2(5)
H(23) 0.657(5) -0.031(2) 0.201(1) 3.6(6)
H(24) -0.048(6) -0.200(3) 0.036(1) 5.4(8)
H(25) -0.016(7) -0.326(3) 0.028(2) 7.2(9)
H(26) -0.249(6) -0.265(2) 0.052(1) 5.4(8)
194
Chapter 3
Introduction of the Ingenol Polyol Functionality
With an efficient, highly optimized route to the complete ingenol carboskeleton
128 in place, efforts were shifted to the introduction of the ingenol polyol functionality.
Conventional alcohol manipulations usually require tedious protective chemistry. In
order to achieve a concise synthesis of 1, it was necessary to devise an end-game strategy
that would minimize the use of protecting groups.
3.1 Retrosynthetic Analysis.
Retrosynthetically, the cis-triol functionality of 1 was envisioned to arise from α-
hydroxyketone 136 via a singlet oxygen-ene reaction1 followed by a chelation-controlled
reduction of the C(3) ketone. In turn, α-hydroxyketone 136 can be derived from
cyclopentenone 137, which was projected to arise from exo-olefin 138 via an allylic
oxidation strategy.2 Finally, exo-olefin 138 can be prepared by RCM of 139. The RCM
precursor 139 can be derived from diene 116 (Scheme 3.1.1).
195
Scheme 3.1.1 Retrosynthetic Analysis.
O
H
HO HOHO OH
O
H
OBnO H
H
O
OBn
139
137
O
H
HOOBn
O
O
H
OBnH
O
136
138
116
[O]
RCM
1
43
3.2 Functionalization of the A Ring.
3.2.1 Preparation of Exo-olefin 138.
In the forward sense, RCM precursor 139 was prepared from diene 116 in five
steps without incident. The C(2) olefin of diene 116 was regioselectively dihydroxylated
and cleaved with sodium periodate. Reduction of the resulting aldehyde gave rise to
alcohol 140 in good yield. Alcohol 140 was dehydrated using the Grieco protocol3 to
furnish exo-olefin 141, which was alkylated with allyl chloride 126 to deliver RCM
precursor 139 in excellent yield. The C(2) exo-olefin was not anticipated to interfere
196
with the desired RCM as Grubbs’s catalyst exhibits a reactivity preference for terminal
olefins over geminally disubstituted olefins.4 However, RCM attempts on triene 139
only gave rise to the desired product 138 in about 10% yield, accompanied by
unidentified side products (Scheme 3.2.1).
Scheme 3.2.1 RCM Attempts Toward Exo-olefin 138.
O
NO2
SeCN
116
H
O
OBn
139
O
141
OBn
Cl
OHO
O
H
OBnH
138
140
(126)
1) OsO4, NMO2) NaIO4
KH, THF
24
PBu3, mCPBA
3) NaBH4
(65% yield,three steps)
(98% yield)(70% yield)
C6H6, reflux
(10% yield)
2
50 mol% III
Although RCM of 139 did not afford satisfying results, an alternative approach
from RCM adduct 128 was utilized to access 138. The dioxolane moiety of 128 was
cleaved by acid catalyzed hydrolysis. Reduction of the resulting aldehyde followed by
Grieco dehydration delivered 138 in good yield (Scheme 3.2.2).
197
Scheme 3.2.2 Preparation of Exo-olefin 138.
H
HOBn
O
O
O
128
O
H
OBnH
138
1) HCl, acetone2) NaBH4, EtOH
3)
(70% yield, 3 steps)
3NO2
SeCN
3.2.2 Oxidation of the A Ring.
With 138 in hand, the stage was set for introduction of the ingenol A ring
functionality using the proposed allylic oxidation strategy. Initially, the proposed
regioselectivity of the allylic oxidation appears questionable. However, allylic oxidations
with selenium dioxide have been shown to be sensitive to subtle steric effects.5,6 Thus,
C(3) is anticipated to be the most reactive allylic site of 138. After much
experimentation, it was found that Sharpless catalytic allylic oxidation conditions gave
rise to 142 as a single product.2 Conditions using stoichiometric selenium dioxide or
other oxidants were less successful. Allylic alcohol 142 was then oxidized with Dess-
Martin periodate to deliver exo-enone 143 in nearly quantitative yield. Following
Disanayaka’s procedure, exo-enone 143 was isomerized to furnish cyclopentenone 137 in
excellent yield (Scheme 3.2.3).7
198
Scheme 3.2.3 Allylic Oxidation of the A Ring.
O
H
OBnH
SeO2, TBHP
O
H
OBnO H
RhCl3 3H2O
138
143
O
H
OBnO H
137
O
H
OBnHO H
142
DMP
.
(65% yield) (96% yield)
(91% yield)3
3
3.2.3 Introduction of the C(4) Hydroxyl.
With the C(3) carbonyl in place, efforts were focused on introduction of the C(4)
tertiary hydroxyl. After careful optimization, we were delighted to find that the C(4)
position can be oxidized by deprotonation of 137 with potassium tert-butoxide in THF/t-
BuOH (5:1) under an atmosphere of oxygen. In situ reduction of the resulting peroxide
144 with trimethyl phosphite delivered alcohol 136 in good yield.8 Careful choice of
solvent proved critical in this instance, as oxidations in THF gave only decomposition.
The reaction temperature was also carefully maintained to be around -20°C. Elevation of
the reaction temperature also led to material decomposition. With 136, possessing a fully
oxygenated A ring in hand, focus was shifted toward installation of the B ring
functionality (Scheme 3.2.4).
199
Scheme 3.2.4 Introduction of the C(4) Hydroxyl.
O
H
OBnO H
O
H
OBnO HO
136
137
O
H
OBnO O
HO144
t-BuOK, O2 P(OMe)3, -20°C
THF: t-BuOH (5:1)
(75% yield)4
3.3 Functionalization of the B Ring: Singlet Oxygen-Ene Strategy.
3.3.1 Singlet Oxygen-Ene Reaction.
Discovered by Schenck in 1953, the singlet oxygen-ene reaction has attracted
remarkable attention because of its controversial mechanism and synthetic aspects.9 It is
now generally accepted that singlet oxygen-ene reactions proceed through a perepoxide
intermediate 145 as shown in Figure 3.1. Subsequent suprafacial hydrogen abstraction
produces allylic hydroperoxide 146 with a shifted double bond. The overall change is
similar to that of other ene reactions. In the reaction of 1O2 with trisubstituted olefins, the
more reactive side of the double bond is the more substituted. This surprising selectivity
is referred to as the “cis-effect”.10
200
HO
O
145
HOO
146
1O2
+
-
Figure 3.1 Singlet Oxygen-Ene Reaction.
3.3.2 Singlet Oxygen-Ene Reaction: Model Studies.
The ingenol B ring functionality was expected to be introduced via a one step
singlet oxygen-ene reaction. RCM adducts 125 and 128 were utilized as model substrates
for the proposed singlet oxygen-ene reaction. Oxidation of benzyl ether 128 gave rise to
allylic alcohol 147 in moderate yield. Presumably, the quasi-axial C(4) hydrogen is more
suitably oriented than the quasi-equatorial C(7)-β hydrogen, thereby displaying higher
reactivity toward 1O2. Although 147 is the undesired regio-isomer, isolation of 147
remained encouraging. With the C(4) methine proton replaced by a hydroxyl group,
singlet oxygen-ene reaction of 136 would deliver the desired product. Treating TBS
ether 125 under similar conditions gave rise to a mixture of two products in a 10:1 ratio.
Again, the major product 148 possesses the undesired regiochemistry. More
encouragingly, the minor product 149 contains the desired regiochemistry, thereby
exhibiting a fully functionalized ingenol B ring (Scheme 3.3.1).
201
Scheme 3.3.1 Singlet Oxygen-Ene Reaction: Model Studies.
O
H
HOBn
O
O
O
H
HOTBS
O
O
O
H
OTBS
O
O
HO
128
125 148
O
H
OBn
O
O
HO
147
O
H
HOTBS
O
O
HO
149
2) PPh3+
(10:1)
(88% yield)
1) O2, RB, hv
2) PPh3
(45% yield)
1) O2, RB, hv
47
3.3.3 Singlet Oxygen-Ene Reaction of Allylic Alcohol 136.
With the singlet oxygen-ene reaction established as a promising method to
introduce the ingenol B ring functionality, efforts were directed toward oxidation of
allylic alcohol 136. It was anticipated that the C(4) hydroxyl of 136 would not require
protection, since singlet oxygen reactions generally tolerate a wide variety of
functionalities including free alcohols. Moreover, it has been demonstrated that
hydrogen bonding of allylic alcohols to singlet oxygen can be successfully utilized to
control the facial and diastereo-selectivity of ene reactions.11,12 In this case, the C(4)
hydroxyl would deliver singlet oxygen from the desired β-face, which, after reduction of
the resulting peroxide, should furnish cis-diol 150. Due to the electron poor nature of the
C(1)-C(2) olefin, it should not interfere with singlet oxygen reaction at C(5)-C(6)
olefin.10 However, upon exposure of 136 to singlet oxygen-ene reaction conditions, no
reaction was observed. In general, singlet oxygen reactions are highly substrate
202
dependent. The ease of such reactions is influenced only slightly by solvent.1 Thus, a
variety of solvents and photo sensitizers were screened, but only starting material was
recovered from these reactions (Table 3.1).
Scheme 3.3.2 Attempts to Oxidize Allylic Alcohol 136 with 1O2.
O
H
HOOBn
O
136
O
H
HOOBn
OHO
150
12
5 6
4
1) O2, solvent, hv, sensitizer
2) PPh3
Table 3.1 Singlet Oxygen-Ene Conditions Screened for 136.
Entry Solvent Photo Sensitizer Additive 1 CH3CN Rose Bengal X 2 CH3OH Rose Bengal X 3 CH3OH Rose Bengal NaOMe 4 CH3CN Methylene Blue X 5 CCl4 Tetraphenyl Porphine X 6 C6H6 Tetraphenyl Porphine X 7 CS2 Tetraphenyl Porphine X
3.3.4 Singlet Oxygen-Ene Reaction: Substrate Modification.
Having established that alcohol 136 was not a viable candidate for the singlet
oxygen-ene reaction, efforts were focused on substrate optimization. Literature reports
indicate that allylic oxygens can inductively reduce olefin reactivity toward 1O2.13
Therefore, the two allylic oxygen atoms of alcohol 136 might deactivate the C(5)-C(6)
olefin significantly. Removal of the C(20) benzyl ether functionality would deliver 152,
the C(5)-C(6) olefin of which should be more reactive toward 1O2. Allylic alcohol 152
203
can also be derive from RCM adduct 133 following the earlier developed procedure
(Scheme 3.3.3).
Scheme 3.3.3 Modification of Singlet Oxygen Substrate.
O
H
HO HO
HO OH
O
H
HOOBn
O
O
H
HOCH3
O
1
152
136
O
H
HCH3
O
O
O
H
HOO
HO OH
151
133
or
20
5 6
To access allylic alcohol 152, hydrogenation conditions were attempted to cleave
C(20) benzyl ether of 136, but only complicated reduction mixtures were detected. Thus,
RCM adduct 133 was advanced to allylic alcohol 152. Acid catalyzed hydrolysis of the
dioxolane followed by reduction of the resulting aldehyde furnished alcohol 153.
Surprisingly, dehydration using the Grieco protocol only yielded the starting alcohol.
Eventually, alcohol 153 was successfully converted to exo-olefin 154 via a two-step
sequence. Exposure of alcohol 153 to MsCl and Et3N afforded the corresponding
204
mesylate, which, after in situ formation of the iodide, was eliminated to furnish 154 in
good yield over four steps (Scheme 3.3.4).
Scheme 3.3.4 Preparation of Exo-olefin 154.
O
H
HCH3
O
O
133
154
O
H
CH3
H
153
O
H
HCH3
HO
1) HCl, acetone
(75% yield, 4 steps)
2) NaI/DBU, DMF
2) NaBH4, EtOH
1) MsCl, Et3N
Following the earlier developed procedure, exo-olefin 154 was advanced to allylic
alcohol 152 in four steps. Regio-selective allylic oxidation at C(3) position was achieved
under carefully controlled reaction conditions to deliver alcohol 155. Dess-Martin
oxidation of alcohol 155 followed by rhodium (III) catalyzed olefin isomerization gave
rise to cyclopentenone 156 in excellent yield. The C(4) hydroxyl was introduced using
the same reaction conditions to produce singlet oxygen-ene substrate 152 (Scheme 3.3.5).
205
Scheme 3.3.5 Preparation of Singlet Oxygen-Ene Substrate 152.
O
H
CH3
H
154
O
H
CH3
HO
156
O
H
CH3
HHO
155
O
H
CH3
HOO
152
2) RhCl3 3H2O.SeO2, TBHP
CH2Cl2, 0°C
(55% yield)
1) Dess-Martin
(92% yield, two steps)
t-BuOK, O2
P(OMe)3, -20°C
(79% yield)
THF: t-BuOH (5:1)
3
4
With allylic alcohol 152 in hand, efforts were again focused on the singlet
oxygen-ene reaction. A number of reaction conditions were screened, but only resulted
starting material recovery (Table 3.2). To this end, it was clear that modification at C(20)
would not affect the outcome of the singlet oxygen-ene reaction (Scheme 3.3.6).
Scheme 3.3.6 Singlet Oxygen Attempts of Allylic Alcohol 152.
O
H
HOCH3
O
152
O
H
HOCH3
OHO
157
1) O2, solvent, hv, sensitizer
2) PPh3
4
Table 3.2 Singlet Oxygen-Ene Conditions Screened for 152.
Entry Solvent Photo Sensitizer 1 CH3CN Rose Bengal 2 CH3OH Rose Bengal 3 CCl4 Tetraphenyl Porphine 4 C6H6 Tetraphenyl Porphine
206
To probe possible interference from allylic hydroxyls, RCM adduct 125 was
deprotected to deliver allylic alcohol 158. Oxidation of 158 delivered diol 159 in good
yield, confirming that an allylic hydroxyl can be tolerated in singlet oxygen reactions
(Scheme 3.3.7).
Scheme 3.3.7 Singlet Oxygen-Ene Reaction of Allylic Alcohol 158.
O
H
HOTBS
O
O
125
TBAF
HO
O
H
OH
O
O
159
O
H
HOH
O
O
158
2) PPh3
(98% yield)
(80% yield)
1) O2, RB, hv
In an effort to further probe the singlet oxygen-ene reaction, exo-olefin 163 was
prepared from allylic alcohol 158 in four steps (Scheme 3.3.8). Epoxidation of 158
followed by protection of the primary alcohol gave mesylate 161 in good yield.14
Subsequent treatment of mesylate 161 with NaI in DMF afforded iodide 162, which was
subjected to reductive elimination conditions to furnish exo-olefin 163.
207
Scheme 3.3.8 Preparation of Exo-olefin 163.
With the preparation of exo-olefin 163, singlet oxygen-ene reaction conditions
were attempted once again. Unfortunately, only starting material was recovered from the
reaction (Scheme 3.3.9). The C(5) alcohol of 163 was then protected to furnish TBS
ether 165. In contrast to other substrates, consumption of material was observed upon
exposure of 165 to singlet oxygen-ene conditions.15 Protected allylic alcohol 165
remains a promising substrate deserving of future study.
O
O
OHH
H
O
O
O
O
OMsH
H
O
O
O
O
IH
H
O
158
161
162
O
O
H
H
O
HO
O
H
HOH
O
O
O
163
160
VO(acac)2, TBHP
(93% yield)
MsCl, Et3N
(97% yield)
NaI, DMF
(85% yield)
Zn, HOAc
(77% yield)
208
Scheme 3.3.9 Singlet Oxygen Attempts of the Exo-olefin.
O
O
H
H
O
HO
O
O
H
H
O
HO
TBSOTf
163
163
O
O
H
H
O
TBSO
O
O
H
H
O
HO OH
165
164
2) PPh3
(92% yield)
1) O2, CH3CN
RB, hv
2,6-lutidine5
3.4 Alternative Approaches to Functionalize the B Ring.
In addition to the singlet oxygen strategy, alternative approaches were
investigated to functionalize the ingenol B ring. Research efforts were focused on the
introduction of the C(6)-C(7) olefin of the ingenol B ring (Scheme 3.4.1). It was
envisioned that the C(6)-C(7) olefin could be derived from E2 elimination of 166,
providing that a suitable leaving group is introduced at C(6). For instance, Winkler
furnished the unsaturation using a four-step sulfate elimination strategy (Scheme
1.5.12).16 The C(6)-C(7) olefin can also arise from E1 elimination of tertiary cation 167.
It is worth noting that pinacol type rearrangement is not likely to occur here, because the
highly strained ingenol B ring is unlikely to contract in size.
209
Scheme 3.4.1 Alternative Strategy to the Ingenol B Ring Functionality.
O
H
HOR
O
O
*O
H
LG
O
H
H
OR
O
O
*O
H
-B
167
166
O
H
H
OR
O
O
HO
168
6
6
7
E1
E2
B
3.4.1 Epoxide-Opening Approach.
The C(5)-C(6) olefin of allylic alcohol 136 can be epoxidized to give rise to
epoxide 169 in excellent yield. Thus, epoxide-opening of 169 could deliver the cis-diol
150 in an alternative way (Scheme 3.4.2).
210
Scheme 3.4.2 An Alternative Way Toward cis-Diol 150.
O
H
HOOOBn
O
H
HOOHO OBn
136
150
169
O
H
HOOOBnO
VO(acac)2, TBHP
(82% yield)5 6
epoxide opening
To explore the possibility of the epoxide-opening approach, epoxide 170 was
prepared from RCM adduct 128 as a model substrate (Scheme 2.4.3). Exposure of 128 to
mCPBA delivered epoxide 170 as a single diastereomer in moderate yield. Epoxide 170
was treated with various Lewis acids in hope of promoting E1 elimination to produce
171, but no desired product was observed.17 Forcing reaction conditions only led to
material decomposition. Basic conditions were also investigated, but most resulted only
in the recovery of starting material.18 Attempts using combinations of bases and Lewis
acids to open epoxide 170 yielded no success as well (Table 3.3).
211
Scheme 3.4.3 Epoxide Opening Attempts of Epoxide 170.
O
H
HOBn
O
O
O
H
HOBn
O
O
HO
128
171
O
H
HOBn
O
O
O
170
mCPBA
NaHCO3, CH2Cl2
(65% yield)
Lewis acid
and/or base
Table 3.3 Conditions Attempted to Open Epoxide 170.
Entry Acid Base Solvent Additive 1 BF3 OEt2 X Et2O X 2 PPTS X C6H6 X 3 Al(Oi-Pr)3 X iso-PrOH X 4 TMSI X CH2Cl2 X 5 HOAc X THF-H2O X 6 X LDEA THF X 7 X LDEA Et2O DBU 8 X LDA THF X 9 X LDA THF HMPA
10 BF3 OEt2 LDEA Et2O X 11 BF3 OEt2 LDA THF X 12 MgCl2 LDEA THF X
The inertness of epoxide 170 could be attributed to its congested surroundings.
To reduce steric hindrance, hydrogenation of 170 afforded alcohol 160 in excellent yield.
Alternatively, hydroxy-epoxide 160 can be prepared from TBS ether 125 using the two-
step sequence illustrated in Scheme 3.4.4. Hydroxy-epoxide 160 furnished no promising
products when exposed to a variety of similar conditions (Table 3.4). Either recovered
212
starting material or complicated product mixture resulted from these experiments
(Scheme 3.4.4).19
Scheme 3.4.4 Epoxide Opening Attempts of Hydroxy-Epoxide 160.
O
H
HOBn
O
O
O
O
H
HOTBS
O
O
170
125
O
H
HOH
O
O
HO
164
O
H
HOH
O
O
O
160
(98% yield)
Lewis acid
base
Pd/C, H2
1) TBAF2) VO(acac)2, TBHP
(90% yield)
Table 3.4 Conditions Attempted to Open Hydroxy-Epoxide 160.
Entry Lewis Acid Base Solvent Additive 1 Al(Oi-Pr)3 X C6H6 X 2 Ti(Oi-Pr)4 X toluene X 3 X n-BuLi pentane X 4 X LDEA Et2O DBU 5 X LDEA Et2O X 6 X LDA THF DBU 7 X LDA THF X 8 MgCl2 n-BuLi THF X 9 MgCl2 LDA THF X
213
To further optimize the substrate, epoxide 172 was prepared from alcohol 163
(Scheme 3.4.5). Once again, epoxide 172 was subjected to various epoxide-opening
conditions, but no desired product was observed (Table 3.5).
Scheme 3.4.5 Epoxide Opening Attempts of 172.
O
H
H
O
O
HO
163
O
H
HOH
O
O
HO
164
O
H
H
O
O
HOO
172
Lewis acid
and/or base
VO(acac)2, TBHP
(84% yield)
Table 3.5 Conditions Screened for Opening of Epoxide 172.
Entry Lewis Acid Base Solvent Additive 1 pTSA X CHCl3 X 2 HOAc X iso-PrOH X 3 Al(Oi-Pr)3 X C6D6 X 4 X LDEA THF X 5 X LDEA Et2O X 6 X LDEA THF DBU 7 MgCl2 LDEA THF X
3.4.2 Intramolecular Cyclization Approach.
In an effort to introduce a better leaving group envisioned at the C(6) position, an
intramolecular cyclization approach was investigated. Treatment of alcohol 158 with
214
BOC anhydride furnished carbonate 173 in excellent yield. Carbonate 173 was exposed
to a number of electrophiles with hopes of triggering an intramolecular 6-endo
cyclization (Scheme 3.4.6). However, no desired cyclization was detected. Heating or
prolonged reaction only led to decomposition of the dioxolane (Table 3.6).
Scheme 3.4.6 Electrophile Promoted Intramolecular Cyclization.
O
H
H
O
O
OH
158
O
H
H
O
O
O
O
O
E
174
O
H
H
O
O
O
O
O
173
(95% yield)
BOC2O, DMAP
E+
electrophile
solvent
Table 3.6 Conditions Attempted for Intramolecular Cyclization.
Entry Electrophile Solvent
1 PhSeCl CHCl3 2 PhSeBr CHCl3 3 NBS/NaHCO3 CHCl3 4 ICl CCl4 5 NIS/NaHCO3 CHCl3
215
3.4.3 Other Approaches Attempted.
The C(5)-C(6) olefin of RCM adduct 128 can be dihydroxylated to deliver diol
175 in good yield. Exposure of diol 175 to Lewis acids in hope of promoting elimination
of the C(6) tertiary hydroxyl only led to total material decomposition (Scheme 3.4.7). In
an effort to mask the C(5) hydroxyl, treating 175 under oxidation conditions yielded
material decomposition as well.
Scheme 3.4.7 Synthetic Manipulation of Diol 175.
O
H
HOBn
O
O
128
O
H
HOBn
O
O
HO
176
O
H
HOBn
O
O
HO HO
175
O
H
HOBn
O
O
HOO
[O]
177
1) OsO4, py2) Na2S
(86% yield)
LA
5 6
The singlet oxygen adduct 148 was also treated under a number of elimination
conditions in hope of producing diene 178. Unfortunately, only complicated product
mixtures were generated from these reactions (Scheme 3.4.8).
216
Scheme 3.4.8 Attempts to Eliminate Alcohol 148.
O
H
OTBS
O
O
HO
148
O
H
OTBS
O
O
178
Table 3.7 Conditions Attempted to Eliminate Alcohol 178.
Entry Reagent Solvent
1 HOAc CH2Cl2 2 PPTS CHCl3 3 BF3 OEt2 Et2O 4 MsCl/pyridine CH2Cl2
3.5 Reexamination of the Singlet Oxygen-Ene Strategy.
3.5.1 Computational Analysis of Singlet Oxygen Substrates.
Unable to install the ingenol B ring functionality, the singlet oxygen-ene strategy
was re-examined. The perepoxide of 163 can exist as conformer 179 and 180. Because
of the hydrogen bonding between singlet oxygen and C(5) hydroxyl, conformer 180
represents an unfavorable conformation for the ene reaction, while conformer 179 would
allow the ene reaction to occur. Geometry optimization using semi-empirical method
(PM3) indicated that conformer 180 is 5.1 kcal mol-1 more stable than 179.20 Hence, the
equilibrium favoring 180 could prohibit the singlet oxygen-ene reaction from taking
place. In the case of 136, geometry optimization indicated strong hydrogen bonding from
the C(4) hydroxyl (181, Figure 3.2). Although the oxygen anion is only 2.6 Å away from
217
the C(7)-β hydrogen, strong hydrogen bonding could still inhibit the perepoxide to
establish the proper orbital orientation for the ene reaction. In addition, hydrogen
bonding would reduce the basicity of the perepoxide. In comparison, geometry
optimization of 182 indicated much weaker preference for hydrogen bonding, thereby
allowing 158 to undergo the singlet oxygen-ene reaction effectively.21 Although the
above analysis is not irrefutable, it is likely that the C(4) allylic hydroxyl of 136 could
have impeded the proposed singlet oxygen-ene reaction.
O
O
H
H
O
OO OH
H
O
H
HOH
O
O
179
O
O
H
H
O
HO163
158
O
O
H
H
O
OO
OH
H
O
H
HOH
O
OO
O
180
182
OBn
O
H
HOO
181
136
O
H
OOO
HO
OBn
H
HO
O
H
OH
O
O
159
4
+-
2) PPh3
(80% yield)
1) O2, hv
+
-
+-
7
2.6 Å
54
1O21O2
20 +-
Figure 3.2 Computational Analysis of the Singlet Oxygen-Ene Reaction.
218
3.5.2 Toward the End-Game.
In order to achieve the singlet oxygen-ene transformation, it is necessary to
protect the C(4) hydroxyl in 136. Arguably, the acetal protection in 183 is the best choice
considering minimizing steric hindrance (Scheme 3.5.1). The cis-diol functionality could
be derived from reduction of α-hydroxy ketone 136. Exposure of acetal 183 to singlet
oxygen-ene conditions would furnish the ingenol B ring functionality. Although the
neighboring acetal group represents considerable steric hindrance to the olefin, the singlet
oxygen-ene reaction should still take place from the desired β-face as the ingneol β-face
is much more accessible than the α-face. In addition, the C(5)-C(6) olefin would be
expected to be more reactive than the sterically congested C(1)-C(2) olefin.22 Final
deprotection of 184 would complete a total synthesis of 1.
Scheme 3.5.1 Revised End-game Strategy.
O
H
HOOOBn
O
H
OOOBnHO
136
184
O
H
HO HOHO OH
O
H
OOOBn
183
1
2) PPh3
4
1) TBSOTf
3) TBAF
4) (CH2O)n
1) O2, hv
1) H2, Pd/C
2) HCl
12
18
5 6
2) NaBH4
B
219
3.6 Conclusion.
In conclusion, allylic alcohol 136 was prepared from RCM adduct 128 in
7 steps, 20 total steps from known cycloheptenone 49 (Scheme 3.6.1). Allylic alcohol
136 represents the most advanced intermediate along the sequence, containing the
complete carboskeleton and the fully oxygenated ingenol A ring. Although singlet
oxygen-ene oxidation of TBS ether 125 furnished the ingenol B ring functionality with
limited success, initial attempts to oxidize allylic alcohol 136 using singlet oxygen-ene
reaction have yielded no success. Alternative approaches to functionalize the ingenol B
ring were also investigated with little success. Current work stands only a few
transformations away from the total synthesis.
Scheme 3.6.1 Summary of Synthetic Progress.
MeO
O O
49
O
H
H
O
O
OBn
128
O
H
HOOBn
O
136
4
(13 steps) (7 steps)
Substrate modification and computational analysis suggested that the C(4)
hydroxyl of 136 could have impeded the proposed singlet oxygen-ene reaction. Thus,
protection of the C(4) hydroxyl followed by singlet oxygen-ene oxidation would furnish
the ingenol B ring functionality. Further protective manipulation would complete a
synthesis of 1.
220
3.7 Experimental Section.
3.7.1 Materials and Methods.
Unless stated otherwise, reactions were performed in flame-dried glassware under
a nitrogen atmosphere using freshly distilled solvents. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were distilled from sodium/benzophenone ketyl. Methylene
chloride (CH2Cl2), benzene (PhH), toluene (PhMe), triethylamine (Et3N), pyridine,
diisopropylamine, and piperidine were distilled from calcium hydride. Methyl sulfoxide
(DMSO) and N,N-dimethylformamide (DMF) were either purchased from the Aldrich
Chemical Company in Sure/Seal™ containers and used as received or stored over
molecular sieves. All other commercially obtained reagents were used as received.
Unless stated otherwise, all reactions were magnetically stirred and monitored by
thin-layer chromatography (TLC) using E. Merck silica gel 60 F254 precoated plates (0.25
mm). Column or flash chromatography was performed with the indicated solvents using
silica gel (230-400 mesh) purchased from Bodman. In general, the chromatography
guidelines reported by Still, Kahn, and Mitra were followed.20 Reversed-phase
preparative TLC was performed with the indicated solvents using E. Merk RP-18 F254
precoated plates (0.25 mm). Concentration in vacuo refers to the removal of solvent with
a Buchi R-3000 rotary evaporator at normal aspirator pressure followed by further
evacuation with a two stage mechanical pump. When reactions were adsorbed onto silica
gel, the amount of silica gel used was equal to two times the weight of the reagents.
221
All melting points were obtained on a Gallenkamp variable temperature capillary
melting point apparatus (model: MPD350.BM2.1) and are uncorrected. Infrared spectra
were recorded on a Midac M1200 FTIR. 1H and 13C NMR spectra were recorded on a
Bruker AM-500, Bruker Avance DPX-500, or Bruker Avance DPX-400 spectrometer.
Chemical shifts are reported relative to internal chloroform (1H, δ 7.27 ppm; 13C, δ 77.3
ppm), benzene (1H, δ 7.20 ppm; 13C, δ 128.4 ppm), or methylene chloride (1H, δ 5.32
ppm; 13C, δ 54.0 ppm). High resolution mass spectra were performed at the University of
Illinois Mass Spectrometry Center. High performance liquid chromatography (HPLC)
was performed on a Waters 510 solvent delivery system using a Rainin Microsorb 80-
199-C5 column, or a Rainin Dynamax SD-200 solvent delivery system using a Rainin
Microsorb 80-120-C5 column. Reversed-phase HPLC was performed on a Rainin
Dynamax SD-200 solvent delivery system using a Rainin Dynamax 82-223-C8 column.
3.7.2 Preparative Procedures.
Preparation of Alcohol 140.
O
116
OHO
140
1) OsO4, NMO2) NaIO4
3) NaBH4
(65% yield,three steps)
Alcohol 140. To a stirred solution of 116 (0.30 g, 1.1 mmol) in THF/H2O (3:1,
30 ml) at 0 °C was added OsO4 (4% aqueous solution, 180 ul, 2.5 mol%) and NMO (120
mg, 4.4 mmol, 1.0 equiv). The reaction mixture was allowed to warm to rt slowly. After
222
stirring the reaction for 12 hours, water (10 ml) was added to dilute the solution. The
reaction mixture was then cooled back to 0 °C, and NaIO4 powder (706 mg) was added to
cleave the diol. The reaction mixture was stirred at 0 °C until there was no change on
TLC. The crude product was extracted with EtOAc. After washing with NaHSO3,
NaHCO3 and brine, the solution was dried over Na2SO4, the crude solution was
concentrated in vacuo, and the crude aldehyde was redissolved in anhydrous ethanol (20
ml). After cooling the solution to 0 °C, NaBH4 (31 mg, 4.0 equiv of hydride) was added
to the reaction. TLC showed the reduction went to completion in 5 minutes, and NH4Cl
(sat.) solution was added to quench the reaction. The reaction was extracted with EtOAc.
After the crude solution was washed with brine and dried over MgSO4, solvent was
evaporated under reduced pressure and the residue was flash chromatographed (4:1
hexanes:EtOAc eluent) to afford alcohol 140 (197 mg, 65% overall yield) as a colorless
oil.
Alcohol 140. FTIR (thin film/NaCl) 3422 (br m), 3074 (m), 2978 (s), 2733 (w),
1686 (s), 1636 (m), 1457 (s), 1378 (m), 1345 (w), 1322 (w), 1296 (m), 1270 (m), 1239
(w), 1204 (m), 1163 (m), 1069 (w), 1047 (m), 996 (m), 913 (m), 869 (w), 848 (w), 736
(w), 686 (w), 647 (m) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C) δ 5.57 (dt, J = 10.0, 16.5
Hz, 1H), 4.99 (dd, J = 17.0, 1.0 Hz, 1H), 4.92 (dd, J = 10.5, 2.0 Hz, 1H), 3.67 (t, J = 7.0
Hz, 1H), 2.70 (dt, J = 8.5, 4.5 Hz, 1H), 2.30 (dd, J = 12, 7.0 Hz, 1H), 2.25-2.18 (m, 2H),
1.92-2.05 (m, 3H), 1.84 (dt, J = 15.5, 6.5Hz, 1H), 1.73-1.62 (m, 4H), 1.23 (ddd, J = 12.5,
7.0, 5.0 Hz, 1H) 1.07 (s, 3H), 1.06 (s, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.67 (dt, J = 6.5, 9.0
Hz, 1H), 0.57 (ddd, J = 7.0, 9.0, 9.5 Hz, 1H); 13C NMR (400 MHz, CDCl3, 40 °C)
δ211.6, 141.3, 115.3, 68.8, 62.5, 50.4, 40.3, 39.2, 38.2, 36.1, 35.2, 32.6, 29.0, 27.0, 23.1,
223
21.2, 15.5, 15.2; HRMS (FAB) m/z found: 275.2021 [calc'd for C18H27O2 (M-H):
275.2011].
Preparation of Diene 141.
OHO
NO2
SeCN
140
O
141
PBu3, mCPBA
(70% yield)
Diene 141. To a 25 ml pear-shaped flask containing alcohol 140 (190 mg, 0.69
mmol) was added the Grieco reagent (314 mg, 1.38 mmol, 2.0 equiv). The flask was
then sealed under nitrogen. After dissolving the mixture in THF (4 mL), PBu3 (290 uL,
1.45 mmol, 2.1 equiv) was added to the reaction over two minutes at rt. The reaction was
allowed to stir at rt until all the starting material was consumed. The reaction was
concentrated in vacuo, and the residue was redissolved in CH2Cl2 (6 mL). After cooling
the solution to -10 °C in NaCl ice bath, mCPBA (237 mg, 1.38 mmol, 2.0 equiv) was
added to the reaction. The reaction mixture was allowed to stir at -10 °C for 1 h before i-
Pr2NH (500 uL, 3.45 mmol, 5.0 equiv) was added. The reaction mixture was heated to
reflux for 2 h. After cooling to rt, the reaction mixture was concentrated in vacuo and
flash chromatographed (6:1 hexanes:CH2Cl2 followed by 50:1 hexanes:ether eluent) to
afford diene 141 (125 mg, 70% yield) as a light yellow solid.
Diene 141: m.p. 70.2-71.5 °C; FTIR (thin film/NaCl) 3070 (m), 3029 (w), 2988
(s), 2957 (s), 2926 (s), 2872 (s), 1689 (s), 1459 (m), 1438 (m), 1392 (w), 1375 (m), 1275
(w), 1156 (w), 999 (m), 982 (w), 935 (m), 915 (w), 875 (m), 779 (w) cm-1; 1H NMR (400
224
MHz, CDCl3) δ 5.64 (dt, J = 13, 10 Hz, 1H), 5.04 (dd, J = 13.0, 1.2 Hz, 1H), 4.97 (dd, J
= 10, 1.2 Hz, 1H), 4.95 (br s, 1H), 4.82 (br s, 1H), 2.82 (t, J = 8.8 Hz, 1H), 2.77-2.67 (m,
2H), 2.47 (d, J = 17.0 Hz, 1H), 2.32 (dd, J = 12.0, 7.0 Hz, 1H), 2.24 (m, 1H), 2.19 (t, J =
1.6 Hz, 1H), 1.90-1.83 (m, 2H), 1.70-1.62 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.92 (d, J =
7.0 Hz, 3H), 0.72 (ddd, J = 11.2, 9.2, 6.0 Hz, 1H), 0.55 (ddd, J = 11.2, 8.8, 6.4 Hz, 1H);
13C NMR (400 MHz, CDCl3) δ 210.8, 148.6, 139.7, 116.2, 107.4, 68.2, 48.8, 39.2, 37.4,
37.1, 34.6, 29.0, 25.9, 23.4, 21.6, 20.6, 15.7, 14.9; HRMS (CI) m/z found: 259.2061
[calc'd for C18H27O (M+H): 259.2062].
Preparation of Tiene 139.
O
OBn
Cl (126)
141 139
H
O
OBn
KH, THF
(98% yield)
RCM Triene 139. To a solution of 141 (9 mg, 0.035 mmol) in THF (4 mL) was
added KH powder (large excess). The mixture was heated to reflux for 15 minutes before
allyl chloride 126 (60 uL, 0.35 mmol, 10 equiv) was injected into the reaction. A little
more KH was added to the reaction after another 15 minutes. The reaction was allowed
to reflux for 2 hours. After the solution was cooled to rt, methanol was carefully dropped
into the reaction to quench excess KH. The solution was neutralized with NH4Cl (sat.)
solution, and the crude product was extracted with ether, washed with brine, dried over
Na2SO4, and filtered. The crude solution was concentrated in vacuo, and flash
225
chromatography (10:1 hexanes:EtOAc eluent) afforded triene 139 (14 mg, 98% yield) as
a white solid.
Triene 139: m.p. 71.5-73.1 °C; FTIR (thin solid film/NaCl) 3075 (m), 2987 (m),
2963 (s), 2921 (s), 2857 (s), 1729 (m), 1883 (s), 1652 (m), 1494 (w), 1453 (s), 1374 (w),
1362 (w), 1259 (m), 1205 (w), 1081 (s), 1026 (w), 1013 (w), 996 (m), 935 (m), 901 (m),
891 (m), 801 (w), 751 (m), 699 (m) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C) δ 7.29-7.19
(m, 5H), 5.59 (dt, J = 17.0, 13.5 Hz, 1H), 5.09 (dd, J = 3.0, 1.5 Hz, 1H), 4.97 (dd, J =
17.0, 1.0 Hz, 1H), 4.91 (dd, J = 10, 1.5 Hz, 2H), 4.88 (s, 2H), 4.75 (s, 1H), 4.43 (dd, J =
14.5, 12.0 Hz, 2H), 3.80 (s, 2H), 2.78 (t, J = 9.0 Hz, 1H), 2.66-2.60 (m, 2H), 2.44 (d, J =
17 Hz, 1H), 2.35-2.27 (m, 1H), 2.27 (t, J = 10 Hz, 1H), 2.20-2.15 (m, 2H), 1.85-1.81 (m,
1H), 1.77 (dt, J = 15, 6.5 Hz, 1H), 1.55 (dd, J = 14.5, 10.5 Hz, 1H), 0.92 (s, 3H), 0.87 (s,
3H), 0.84 (d, J = 7.0 Hz, 3H), 0.66-0.61 (m, 1H), 0.07 (t, J = 9.5 Hz, 1H); 13C NMR (400
MHz, CDCl3, 40 °C) δ 211.6, 148.5, 144.1, 140.1, 138.9, 128.7, 128.0, 127.9, 116.4,
113.9,107.2, 73.3, 72.5, 68.0, 48.8, 47.3, 38.0, 37.5, 35.0, 34.9, 29.1, 27.9, 26.5, 23.4,
21.6, 16.3, 15.0; HRMS (CI) m/z 419.2949 [calc’d for C29H39O2 (M+H) 419.2950].
Preparation Exo-olefin 138.
H
O
OBn
RuCl
Cl
NN MesMes
PCy3Ph
(III)
139
O
H
OBnH
138
C6H6, reflux
(10% yield)
Exo-olefin 138. To a solution of triene 139 (21 mg, 50 umol) in C6H6 (10 mL)
was added Grubbs’s catalyst (III, 21 mg, 25 umol, 50 mol%) at rt. The reaction mixture
226
was heated to reflux for 12 h. After concentration in vacuo, flash chromatography (30:1
hexanes:Et2O eluent) afforded exo-olefin 138 (2 mg, ~10% yield) as a pink oil.
H
HOBn
O
O
O
128
O
H
OBnH
138
1) HCl, acetone2) NaBH4, EtOH
3)
(70% yield, 3 steps)
NO2
SeCN
Exo-olefin 138. To a stirred solution of RCM adduct 128 (80 mg, 0.18 mmol) in
acetone (15 mL) was added catalytic HCl (1M aqueous solution, 1 mL). The reaction
was heated to reflux for 2 hours. The acidic solution was neutralized with NaHCO3, and
the crude product was extracted with ether. After the crude solution was washed with
brine and dried over MgSO4, solvent was evaporated under reduced pressure. The
resultant oil was dissolved in anhydrous ethanol. The solution was cooled to 0 °C before
addition of NaBH4 (5 mg, 4.0 equiv of hydride). After stirring the solution at 0 °C for 30
minutes, the reaction was quenched by adding NH4Cl (sat.) solution. The crude product
was extracted with EtOAc, washed with brine, dried over MaSO4, and concentrated in
vacuo. The crude alcohol was passed through a silica gel pad, and transferred into a 15
mL pear-shaped flask. After addition of the Grieco reagent (82 mg, 0.36 mmol, 2.0
equiv), the reaction flask was sealed under nitrogen. After dissolving the mixture in THF
(2 mL), PBu3 (75 uL, 0.38 mmol, 2.1 equiv) was injected to the reaction over two
minutes at rt. The reaction was allowed to stir at rt until all the starting material was
consumed. After removal of solvent under reduced pressure, the residue was redissolved
in CH2Cl2 (3 mL). The solution was cooled to -10 °C in NaCl ice bath before adding
227
mCPBA (62 mg, 0.36 mmol, 2.0 equiv) to the reaction. The reaction mixture was
allowed to stir at -10 °C for 1 h before i-Pr2NH (130 uL, 0.90 mmol, 5.0 equiv) was
added. The reaction mixture was heated to reflux for 2 h. After cooling to rt, the reaction
mixture was concentrated in vacuo and flash chromatographed (6:1 hexanes:CH2Cl2
followed by 30:1 hexanes:ether eluent) to afford exo-olefin 138 (49 mg, 70% yield over
three steps ) as a light yellow oil.
Exo-olefin 138. FTIR (thin film/NaCl) 3076 (w), 2921 (s), 2871 (s), 1724 (s),
1662 (w), 1455 (m), 1377 (w), 1277 (w), 1204 (w), 1074 (m), 991 (w), 926 (w), 877 (m),
741 (m), 698 (m) cm-1; 1H NMR (500 MHz, CDCl3, 50 °C) δ 7.35-7.25 (m, 5H), 5.29 (s,
1H), 4.83 (s, 1H), 4.81 (s, 1H), 4.37 (dd, J = 10.5, 7.0 Hz, 2H), 3.82 (dd, J = 17, 12 Hz,
2H), 3.32-3.27 (m, 2H), 2.77 (dd, J = 17, 1.0 Hz, 1H), 2.68 (dd, J = 15, 8.0 Hz, 1H), 2.44
(dt, J = 2.0, 15 Hz, 1H), 2.33 (d, J = 17 Hz, 1H), 2.25 (dd, J = 17, 1.5 Hz, 1H), 2.18 (d, J
= 15.5 Hz, 1H), 2.04-2.01 (m, 1H), 1.92 (dt, J = 15, 5.0 Hz, 1H), 1.84 (ddd, J = 14.5,
9.0, 1.5 Hz, 1H), 1.15 (s, 3H), 1.07 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.76-0.67 (m, 2H);
13C NMR (500 MHz, CDCl3, 50 °C) δ 211.4, 150.5, 140.9, 138.8, 134.9, 128.7, 128.3,
127.9, 106.3, 76.4, 72.2, 72.0, 45.0, 44.6, 40.9, 37.4, 34.4, 32.8, 29.4, 29.0, 24.1, 23.9,
23.5, 15.8, 15.6; HRMS (CI) m/z 391.2632 [calc’d for C27H35O2 (M+H) 391.2637].
Preparation of Allylic Alcohol 142.
O
H
OBnH
SeO2, TBHP
138
O
H
OBnHO H
142
(65% yield)
228
Allylic Alcohol 142. To a suspension of SeO2 (3.5 mg, 0.031 mmol, 30 mol%) in
CH2CH2 (4 mL) was added TBHP (5~6 M aqueous solution, 60 uL, ~3 equiv). After
stirring the mixture at rt for 20 minutes, the suspension was cooled to 0 °C, and a solution
of exo-olefin 138 (40 mg, 0.103 mmol) in CH2Cl2 (2 mL) was added to the reaction. The
reaction mixture was stirred vigorously at 0 °C for 6 h, concentrated in vacuo, and flash
chromatographed (6:1 hexanes:EtOAc eluent) to afford allylic alcohol 142 (27 mg, 65%
yield) as a colorless oil.
Allylic Alcohol 142. FTIR (thin film/NaCl) 3480 (br s), 3062 (w), 2923 (s), 2853
(s), 1718 (s), 1486 (w), 1455 (m), 1380 (m), 1266 (m), 1210 (w), 1190 (w), 1114 (m),
1019 (w), 933 (w), 902 (w), 867 (w), 841 (w), 824 (w), 737 (m), 699 (m) cm-1; 1H NMR
(500 MHz, CDCl3, 40 °C) δ 7.35-7.27 (m, 5H), 5.24 (s, 1H), 5.09 (s, 1H), 5.01 (s, 1H),
4.37 (q, J = 6.5 Hz, 2H), 4.21 (s, 1H), 3.82 (s, 2H), 3.24-3.18 (m, 2H), 2.90-2.86 (m, 1H),
2.56-2.53 (m, 1H), 2.50 (d, J = 17 Hz, 1H), 2.46-2.39 (m, 1H), 2.23 (dd, J = 16.5, 2.0
Hz), 1.95-1.84 (m, 2H), 1.69 (br s, 1H), 1.15 (s, 3H), 1.06 (s, 3H), 0.98 (d, J = 7.0 Hz,
3H), 0.73 (dt, J = 6.5, 9.0 Hz, 1H), 0.68 (dd, J = 11.5, 8.5 Hz, 1H); 13C NMR (500 MHz,
CDCl3, 40 °C) δ 210.8, 153.3, 141.4, 138.6, 129.9, 128.7, 128.3, 128.0,109.7, 83.5, 76.2,
72.0, 71.1, 52.7, 45.2, 38.2, 32.8, 32.5, 29.1, 29.0, 24.0, 23.6, 23.3, 15.9, 15.5; HRMS
(CI) m/z 407.2586 [calc’d for C27H35O3 (M+H) 407.2586].
229
Preparation of Exo-enone 143.
O
H
OBnO H
143
O
H
OBnHO H
142
DMP
(96% yield)
Exo-enone 143. To a stirred solution of allylic alcohol 142 (25 mg, 62 umol) in
CH2Cl2 (10 mL) was added Dess-Martin periodate (39 mg, 92 umol, 1.5 equiv) at rt.
After stirring the reaction mixture at rt for 1 h, the reaction was quenched with Na2S2O3
(10% aqueous solution, 10 mL). The mixture was stirred vigorously until the two layers
were clear. The crude product was extracted with CH2Cl2, washed with brine, dried over
Na2SO4, and filtered. Concentration followed by flash chromatography (15:1
hexanes:EtOAc eluent) afforded exo-enone 143 (24 mg, 96% yield) as a light yellow oil.
Exo-enone 143. FTIR (thin film/NaCl) 3030 (w), 2922 (m), 2866 (m), 1725 (s),
1641 (m), 1495 (w), 1455 (m), 1434 (w), 1380 (m), 1275 (w), 1251 (w), 1112 (m), 1090
(m), 992 (w), 940 (w), 857 (w), 738 (m), 699 (m) cm-1; 1H NMR (500 MHz, CDCl3, 40
°C) δ 7.35-7.25 (m, 5H), 6.05 (s, 1H), 5.43 (s, 1H), 5.39 (s, 1H), 4.39 (dd, J = 18.5, 11.5
Hz, 2H), 3.86 (dd, J = 13, 13 Hz, 2H), 3.47 (s, 1H), 3.14 (dt, J = 3.0, 12 Hz, 1H), 3.00-
2.86 (m, 2H), 2.49 (t, J = 13.5 Hz, 1H), 2.29 (d, J = 16.5 Hz, 1H), 2.02-2.00 (m, 1H),
1.94 (dt, J = 15, 5.0 Hz, 1H), 1.80 (dd, J = 14, 7.0 Hz, 1H), 1.14 (s, 3H), 1.07 (s, 3H),
1.06 (d, J = 7.0 Hz, 3H), 0.80-0.72 (m, 2H); 13C NMR (500 MHz, CDCl3, 40 °C) δ
210.9, 205.6, 144.6, 144.0, 138.5, 128.8, 128.2, 128.0, 124.2, 119.3, 76.1, 72.3, 65.5,
56.0, 45.6, 37.1, 32.5, 31.7, 29.2, 29.0, 24.2, 23.81, 23.78, 16.0, 15.5; HRMS (CI) m/z
405.2436 [calc’d for C27H33O3 (M+H) 405.2430].
230
Preparation of Cyclopentenone 137.
O
H
OBnO H
RhCl3 3H2O
143
O
H
OBnO H
137
.
(91% yield)
Cyclopentenone 137. To a stirred solution of exo-enone 143 (24 mg, 59 umol) in
ethanol (6 mL) was added RhCl3.3H2O (3 mg, 12 umol, 20 mol%). The reaction mixture
was heated to reflux for 2 h. After the solution was cooled to rt, it was filtered through a
celite pad. Concentration in vacuo followed by flash chromatography (15:1
hexanes:EtOAc eluent) afforded cyclopentenone 137 (22 mg, 91% yield) as a colorless
oil.
Cyclopentenone 137. FTIR (thin film/NaCl) 3026 (w), 2922 (m), 2867 (m),
1711 (s), 1642 (w), 1495 (w), 1453 (m), 1381 (m), 1332 (w), 1208 (w), 1179 (w), 1073
(m), 1001 (w), 935 (w), 738 (m), 699 (m); 1H NMR (500 MHz, CDCl3, 40 °C) δ 7.59 (d,
J = 1.5 Hz, 1H), 7.35-7.26 (m, 5H), 5.50 (s, 1H), 4.38 (dd, J = 12, 12 Hz, 2H), 3.87 (s,
2H), 3.27 (d, J = 1.5 Hz, 1H), 3.12-3.06 (m, 1H), 2.47-2.39 (m, 1H), 2.30-2.26 (m, 1H),
2.03-1.89 (m, 3H), 1.81 (d, J = 2.0 Hz, 3H), 1.16 (s, 3H), 1.08 (s, 3H), 1.06 (d, J = 7.0
Hz, 3H), 0.83-0.76 (m, 2H); 13C NMR (500 MHz, CDCl3, 40 °C) δ 209.1, 207.0, 158.1,
142.2, 141.0, 138.5, 128.7, 128.2, 128.0, 125.9, 76.6, 72.3, 70.5, 54.4, 45.6, 43.0, 31.7,
31.3, 29.1, 24.3, 24.0, 23.4, 17.1, 15.4, 10.8; HRMS (CI) m/z 405.2431 [calc’d for
C27H33O3 (M+H) 405.2430].
231
Preparation of Alcohol 136.
O
H
OBnO H
P(OMe)3
O
H
OBnO HO
136137
t-BuOK, O2, -20°CTHF: t-BuOH (5:1),
(75% yield)
Alcohol 136. To a stirred solution of cyclopentenone 137 (20 mg, 50 umol) in
THF/t-BuOH (5:1, 6 mL total) was added P(OMe)3 (40 uL, 250 umol, 5.0 equiv) via
syringe. The solution was cooled down to –20 °C with a CaCl2 bath. After bubbling O2
through the solution for 5 minutes, a solution of t-BuOK (1 mL 0.1 M solution in t-
BuOH, 100 umol, 2.0 equiv) was injected into the reaction. The reaction mixture was
allowed to stir at –20 °C for 2 h. The reaction was then neutralized with NH4Cl,
extracted with Et2O, washed with brine, and dried over Na2SO4. Concentration in vacuo
followed by flash chromatography (10:1 hexanes:EtOAc eluent) afforded alcohol 136 (16
mg, 75% yield) as a colorless oil.
Alcohol 136. FTIR (thin film/NaCl) 3428 (br m), 3064 (w), 3029 (w), 2956 (s),
2923 (s), 2856 (s), 1718 (s), 1637 (w), 1496 (w), 1455 (m), 1382 (m), 1339 (w), 1192
(w), 1160 (w), 1091 (m), 1072 (m), 1029 (m), 968 (w), 901 (w), 854 (w), 788 (m), 757
(m), 699 (m) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C) δ 7.68 (s, 1H), 7.36-7.28 (m, 5H),
5.46 (s, 1H), 4.39 (dd, J = 18, 11.5 Hz, 2H), 3.83 (s, 2H), 3.51-3.46 (m, 1H), 3.08 (s,
1H), 2.45 (dd, J = 17.5, 13 Hz, 2H), 2.32 (d, J = 17 Hz, 1H), 2.19-2.16 (m, 1H), 1.86 (s,
3H), 1.85-1.81 (m, 1H), 1.17 (s, 3H), 1.09 (d, J = 6.0 Hz, 3H), 1.08 (s, 3H), 0.78-0.74 (m,
2H); 13C NMR (400 MHz, CDCl3, 40 °C) δ 209.0, 208.4, 158.8, 146.6, 138.3, 138.0,
232
128.8, 128.5, 128.2, 128.1, 79.5, 75.8, 72.6, 72.5, 44.1, 40.0, 32.6, 31.0, 29.0, 24.5, 24.3,
23.4, 17.7, 15.5, 11.0; HRMS (EI) m/z 420.2299 [calc’d for C27H32O4 (M+) 420.2301].
Preparation of Alcohol 147.
O
H
HOBn
O
O
128
O
H
OBn
O
O
HO
147
1) 1O2, RB
CH3CN
2) PPh3
(45% yield)
Alcohol 147. To a 20 cm glass tube containing Rose Bengal (5 mg) was added a
solution of benzyl ether 128 (50 mg, 0.11 mmol) in CH3CN (15 mL). The bottom of the
reaction tube was placed 1 cm into an ice bath with the rest of the tube exposed to the
light bulb. With O2 bubbling steadily through the solution, the reaction mixture was
irradiated with a tungsten-halogen lamp (600W) for 6 h. The oxygen line was then
removed, and PPh3 (144 mg, 0.55 mmol, 5.0 equiv) was added to the crude solution. The
reaction mixture was stirred at rt for half an hour, diluted with EtOAc (50 ml), washed
with NaHCO3 and brine, dried over MgSO4 and filtered. Concentration in vacuo
followed by flash chromatography (8:1 hexanes:EtOAc eluent) afforded alcohol 147 (12
mg, 45% yield BORSM 50%) as a colorless oil along with recovered starting material
128 (25 mg, 50% recovery). This preparation represents a general procedure for the
singlet oxygen-ene reaction.
Alcohol 147. FTIR (thin film/NaCl) 3472 (br m), 3087 (w), 3062 (w), 2925 (s),
2887 (s), 1725 (s), 1621 (w), 1496 (w), 1453 (m), 1382 (m), 1340 (w), 1207 (w), 1121
(s), 1072 (s), 1029 (m), 971 (m), 921 (m), 802 (w), 735 (m), 699 (m) cm-1; 1H NMR (500
233
MHz, CDCl3, 50 °C) δ 7.37-7.29 (m, 5H), 5.40 (s, 1H), 4.64 (d, J = 5.5 Hz, 1H), 4.56 (s,
2H), 3.97-3.91 (m, 2H), 3.85-3.80 (m, 2H), 3.59 (dt, J = 1.5, 11.5 Hz, 1H), 3.29 (dd, J =
9.5, 10.5 Hz, 2H), 2.85 (ddd, J = 16, 11, 2.5 Hz, 1H), 2.56 (s, 1H), 2.53 (ddd, J = 15, 8.0,
5.0 Hz, 1H), 2.38-2.29 (m, 1H), 2.21 (dd, J = 17, 5.0 Hz, 1H), 2.11 (dd, J = 13.5, 12.5
Hz, 1H), 2.07 (dd, J = 14, 9.5 Hz, 1H), 1.86-1.79 (m, 4H), 1.22 (s, 3H), 1.05 (d, J = 6.5
Hz, 3H), 1.02 (s, 3H), 0.80 (dd, J = 11.5, 8.5 Hz, 1H), 0.64 (dt, J = 9.0, 5.5 Hz, 1H); 13C
NMR (500 MHz, CDCl3, 50 °C) δ 211.1, 147.7, 138.4, 128.8, 128.1, 128.0, 126.8, 107.6,
78.9, 76.5, 74.0, 70.2, 65.5, 65.3, 42.4, 39.3, 38.7, 37.4, 36.7, 32.6, 29.3, 27.3, 25.2, 25.1,
22.8, 18.7, 15.1; HRMS (EI) m/z 466.2711 [calc’d for C30H38O5 (M+) 466.2719].
Preparation of Alcohol 148 and 149.
O
H
HOTBS
O
O
O
H
OTBS
O
O
HO
125 148
O
H
HOTBS
O
O
HO
149
1) 1O2, RB
CH3CN
2) PPh3+
(10:1)
(88% yield)
Alcohol 148 and 149. To a 20 cm glass tube containing Rose Bengal (5 mg) was
added a solution of TBS ether 125 (80 mg, 0.17 mmol) in CH3CN (20 mL). The bottom
of the reaction tube was placed 1 cm into an ice bath with the rest of the tube exposed to
the light bulb. With O2 bubbling steadily through the solution, the reaction mixture was
irradiated with a tungsten-halogen lamp (600W) for 2.5 h. TLC showed all the material
was consumed at that point. The oxygen line was then removed, and PPh3 (222 mg, 0.85
mmol, 5.0 equiv) was added to the crude solution. The reaction mixture was stirred at rt
for 0.5 h, diluted with EtOAc (50 ml), washed with NaHCO3 and brine, dried over
234
MgSO4 and filtered. Concentration in vacuo followed by flash chromatography (8:1
hexanes:EtOAc eluent) afforded alcohol 148 (66 mg, 80% yield) as a light yellow solid
and alcohol 149 (7 mg, 8% yield) as a colorless oil.
Alcohol 148: m.p. 98.0-99.8 °C; FTIR (thin film/NaCl) 3488 (br m), 2953 (s),
2926 (s), 2856 (s), 1727 (m), 1463 (m), 1382 (w), 1255 (m), 1120 (m), 1082 (m), 839
(m), 778 (m), 669 (w) cm-1; 1H NMR (500 MHz, CDCl3, 60 °C) δ 5.36 (s, 1H), 4.65 (d, J
= 5.5 Hz, 1H), 4.00-3.91 (m, 2H), 3.85-3.80 (m, 2H), 3.58 (dt, J = 1.5, 11.5 Hz, 1H),
3.35 (dd, J = 10, 10.5 Hz, 2H), 2.86 (ddd, J = 16.5, 11, 2.5 Hz, 1H), 2.68 (s, 1H), 2.55-
2.49 (m, 1H), 2.37-2.29 (m, 1H), 2.20 (dd, J = 16.5, 4.5 Hz, 1H), 2.08-2.02 (m, 2H),
1.86-1.81 (m, 3H), 1.72 (d, J = 13.5 Hz, 1H), 1.13 (s, 3H), 1.06 (d, J = 7.0 Hz, 3H), 1.03
(s, 3H), 0.93 (s, 9H), 0.80 (dd, J = 11.5, 0.90 Hz, 1H), 0.64 (dt, J = 8.5, 6.0 Hz, 1H),
0.086 (s, 3H), 0.081 (s, 3H); 13C NMR (500 MHz, CDCl3, 60 °C) δ 211.0, 147.3, 127.0,
125.8, 107.7, 76.8, 71.5, 70.2, 65.4, 65.3, 42.6, 39.3, 38.6, 37.0, 36.7, 32.6, 30.7, 29.3,
27.5, 26.2, 25.2, 25.1, 22.7, 18.6, 15.1, -5.12, -5.18; HRMS (EI) m/z 490.3119 [calc’d for
C28H46O5Si (M+) 490.3115].
Alcohol 149. FTIR (thin film/NaCl) 3361 (br m), 2953 (s), 2926 (s), 2855 (s),
1720 (m), 1698 (s), 1644 (w), 1461 (m), 1379 (w), 1318 (w), 1256 (m), 1142 (w), 1087
(m), 1037 (m), 997 (w), 963 (w), 838 (m), 776 (m), 730 (w) cm-1; 1H NMR (500 MHz,
CDCl3, 40 °C) δ 5.98 (d, J = 6.0 Hz, 1H), 4.80 (d, J = 5.0 Hz, 1H), 4.22 (d, J = 7.5 Hz,
1H), 4.14 (s, 2H), 4.11 (d, J = 5.5 Hz, 1H), 3.99-3.95 (m, 2H), 3.88-3.84 (m, 2H), 3.32 (s,
1H), 2.63 (dt, J = 5.5, 13 Hz, 1H), 2.36-2.27 (m, 2H), 2.03 (ddd, J = 14, 9.5, 7.0 Hz, 1H),
1.92-1.85 (m, 2H), 1.80 (dd, J = 7.0, 5.5 Hz, 2H), 1.69 (ddd, J = 14, 8.0, 5.5 Hz, 1H),
1.12 (s, 3H), 1.06 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.96 (dd, J = 12, 9.0 Hz, 1H), 0.91 (s,
235
3H), 0.69 (dd, J = 16, 7.0 Hz, 1H), 0.09 (s, 6H); 13C NMR (500 MHz, CDCl3, 40 °C) δ
208.8, 141.6, 127.4, 107.4, 76.6, 68.7, 68.4, 65.5, 52.6, 44.4, 41.1, 36.2, 30.6, 29.8, 26.7,
26.3, 24.5, 23.9, 23.3, 23.1, 18.6, 16.2, 15.7, -4.92, -5.03; HRMS (CI) m/z 491.3194
[calc’d for C28H47O5Si (M+H) 491.3193].
Preparation of Exo-olefin 154.
O
H
HCH3
O
O
133
154
O
H
CH3
H
153
O
H
HCH3
HO
1) HCl, acetone
(75% yield, 4 steps)
2) NaI/DBU, DMF
2) NaBH4, EtOH
1) MsCl, Et3N
Exo-olefin 154. To a stirred solution of dioxolane 133 (120 mg, 0.35 mmol) in
acetone (25 mL) was added catalytic HCl (1M aqueous solution, 1 mL). The reaction
mixture was heated to reflux for 2 hours. The acidic solution was neutralized with
NaHCO3, and the crude product was extracted with ether. After washing the crude
solution with brine and dried over MgSO4, solvent was evaporated under reduced
pressure. The resultant oil was dissolved in anhydrous ethanol (10 mL). The solution
was cooled to 0 °C before addition of NaBH4 (10 mg, 4.0 equiv of hydride). After
stirring the solution at 0 °C for 30 minutes, the reaction was quenched by adding NH4Cl
(sat.) solution. The crude product was extracted with EtOAc, washed with brine, dried
236
over MaSO4, and concentrated in vacuo. The resulting oil was dissolved in CH2Cl2 (10
mL). To the solution was injected MsCl (47 uL, 0.70 mmol, 2.0 equiv) and Et3N (190
uL, 1.40 mmol, 4.0 equiv) by syringe at rt. The reaction was allowed to stir at rt for 2
hrs, diluted with ether, washed with brine (10 mL), dried over Na2SO4, and filtered.
After evaporating solvent under reduced pressure, the crude oil was dissolved in DMF (5
mL), and the solution was transferred into a 15 pear-shaped flask containing flame-dried
NaI (262 mg, 1.75 mmol, 5.0 equiv) by cannula. After adding DBU (261 uL, 1.75 mmol,
5.0 equiv) to the reaction by syringe, the mixture was heated to 100 °C for 5 h. The
reaction was cooled to rt, extracted with EtOAc, washed with NH4Cl and brine. After
drying over MaSO4 and filtration, solvent was evaporated under reduced pressure.
Flashing chromatography (50:1 hexanes:Et2O eluent) of the residue afforded exo-olefin
154 (75 mg, 75% yield over three steps) as a colorless oil.
Exo-olefin 154. FTIR (thin film/NaCl) 3071 (w), 2913 (m), 1724 (s), 1661 (w),
1455 (m), 1432 (m), 1380 (m), 1367 (m), 1337 (w), 1139 (w), 985 (w), 925 (w), 876 (m),
849 (w) cm-1; 1H NMR (400 MHz, CDCl3, 40 °C) δ 4.97 (s, 1H), 4.81 (s, 1H), 4.78 (s,
1H), 3.31-3.24 (m, 2H), 2.74 (dd, J = 15.2, 2.0 Hz, 1H), 2.67-2.61 (m, 1H), 2.36-2.28 (m,
2H), 2.14-2.09 (m, 2H), 2.00-1.96 (m, 1H), 1.90 (ddd, J = 15.2, 6.0, 4.4 Hz, 1H), 1.82
(ddd, J = 16.4, 9.2, 2.0 Hz, 1H), 1.64 (s, 3H), 1.14 (s, 3H), 1.05 (s, 3H), 0.96 (d, J = 6.8
Hz, 3H), 0.71 (dt, J = 6.4, 8.4 Hz, 1H), 0.65 (dd, J = 11.2, 8.4 Hz, 1H); 13C NMR (400
MHz, CDCl3, 40 °C) δ 211.9, 150.9, 140.1, 132.0, 72.1, 45.2, 44.5, 40.9, 37.2, 36.4, 34.3,
30.7, 29.3, 29.0, 26.4, 24.0, 23.8, 23.4, 15.8, 15.6; HRMS (EI) m/z 284.2139 [calc’d for
C20H28O (M+) 284.2140].
237
Preparation of Allylic Alcohol 155.
O
H
CH3
H
154
O
H
CH3
HHO
155
SeO2, TBHP
CH2Cl2, 0°C
(55% yield)
Allylic Alcohol 155. To a suspension of SeO2 (3.0 mg, 0.026 mmol, 30 mol%) in
CH2CH2 (2 mL) was added TBHP (5~6 M aqueous solution, 50 uL, ~3 equiv). After
stirring the mixture at rt for 20 minutes, the suspension was cooled to 0 °C, and a solution
of exo-olefin 154 (25 mg, 0.088 mmol) in CH2Cl2 (2 mL) was added to the reaction. The
reaction mixture was stirred vigorously at 0 °C for 6 h, concentrated in vacuo, and flash
chromatographed (10:1 hexanes:EtOAc eluent) to afford allylic alcohol 155 (15 mg, 55%
yield) as a colorless oil.
Allylic Alcohol 155. FTIR (thin film/NaCl) 3433 (br m), 2916 (s), 1713 (s), 1455
(m), 1381 (m), 1338 (w), 1150 (w), 1047 (m), 991 (w), 895 (m), 732 (m), 679 (m) cm-1;
1H NMR (400 MHz, CDCl3, 40 °C) δ 5.09 (s, 1H), 5.00 (s, 1H), 4.91 (s, 1H), 4.17 (s,
1H), 3.22-3.15 (m, 2H), 2.86 (dt, J = 16.8, 2.0 Hz, 1H), 2.54-2.47 (m, 2H), 2.33 (t, J =
14.4 Hz, 1H), 2.10 (d, J = 15.6 Hz, 1H), 1.90 (ddd, J = 15.6, 7.2, 3.6 Hz, 1,), 1.86 (ddd, J
= 15.6, 9.2, 2.8 Hz, 1H), 1.66 (s, 3H), 1.61 (br s, 1H), 1.14 (s, 3H), 1.05 (s, 3H), 0.96 (d,
J = 6.8 Hz, 3H), 0.71 (dt, J = 6.8, 8.4 Hz, 1H), 0.63 (dd, J = 11.2, 8.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3, 40 °C) δ 211.1, 153.6, 140.8, 127.2, 109.6, 83.7, 71.2, 52.8, 45.4,
38.0, 36.5, 32.5, 29.0, 26.5, 24.0, 23.6, 23.2, 15.8, 15.5; HRMS (EI) m/z 483.2095
[calc’d for C20H28O2 (M+) 300.2089].
238
Preparation of Cyclopentenone 156.
O
H
CH3
HO
156
O
H
CH3
HHO
155
2) RhCl3 3H2O.1) Dess-Martin
(92% yield, two steps)
Cyclopentenone 156. To a stirred solution of allylic alcohol 155 (15 mg, 0.050
umol) in CH2Cl2 (5 mL) was added Dess-Martin reagent (32 mg, 75 umol, 1.5 equiv) at
rt. After stirring the reaction mixture at rt for 1 h, the reaction was quenched with
Na2S2O3 (10% aqueous solution, 10 mL). The mixture was stirred vigorously until the
two layers were clear. The crude product was extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and filtered. After evaporation of solvent under reduced pressure, the
resulting oil was redissolved in ethanol (4 mL). To the solution was added RhCl3.3H2O
(4 mg, 15 mmol, 30 mol%). The reaction mixture was heated to reflux for 2 h. After the
solution was cooled to rt, it was filtered through a celite pad. Concentration in vacuo
followed by flash chromatography (20:1 hexanes:EtOAc eluent) afforded cyclopentenone
156 (14 mg, 92% yield) as a colorless oil.
Cyclopentenone 156. FTIR (thin film/NaCl) 3022 (w), 2998 (m), 2948 (m),
2921 (m), 2861 (w), 1718 (s), 1706 (s), 1638 (w), 1446 (m), 1387 (m), 1335 (m), 1216
(w), 1179 (w), 1090 (w), 1040 (w), 986 (w), 934 (w), 892 (w), 854 (w), 783 (w), 727 (w),
682 (w), 655 (w) cm-1; 1H NMR (400 MHz, CDCl3, 40 °C) δ 7.59 (s, 1H), 5.16 (s, 1H),
3.23 (s, 1H), 3.11-3.04 (m, 1H), 2.34 (t, J = 14 Hz, 1H), 2.07 (d, J = 16.8 Hz, 1H), 1.96-
1.90 (m, 3H), 1.80 (d, J = 1.6 Hz, 3H), 1.71 (s, 3H), 1.15 (s, 3H), 1.07 (s, 3H), 1.06 (d, J
= 6.8 Hz, 3H), 0.79-0.74 (m, 2H); 13C NMR (400 MHz, CDCl3, 40 °C) δ 209.3, 207.7,
239
158.0, 141.6, 140.9, 123.1, 70.8, 54.7, 45.9, 43.0, 35.5, 31.2, 29.1, 26.6, 24.1, 23.8, 23.4,
17.0, 15.4, 10.8; HRMS (EI) m/z 298.1936 [calc’d for C20H26O2 (M+) 298.1933].
Preparation of Allylic Alcohol 152.
O
H
CH3
HO
156
O
H
CH3
HOO
152
t-BuOK, O2
P(OMe)3, -20°C
(79% yield)
THF: t-BuOH (5:1)
Allylic Alcohol 152. To a stirred solution of enone 156 (12 mg, 0.040 mmol) in
THF/t-BuOH (5:1, 4 mL total) was added P(OMe)3 (32 uL, 0.20 mol, 5.0 equiv) via
syringe. The solution was cooled down to –20 °C with a CaCl2 bath. After bubbling O2
through the solution for 5 minutes, a solution of t-BuOK (0.8 mL 0.1 M solution in t-
BuOH, 0.080 mmol, 2.0 equiv) was injected into the reaction. The reaction mixture was
allowed to stir at –20 °C for 2 h. The reaction was then neutralized with NH4Cl,
extracted with Et2O, washed with brine, and dried over Na2SO4. Concentration in vacuo
followed by flash chromatography (12:1 hexanes:EtOAc eluent) afforded alcohol 152 (10
mg, 79% yield) as a white solid.
Allylic Alcohol 152: m.p. 168.3-169.9 °C; FTIR (thin film/NaCl) 3435 (br m),
2956 (s), 2923 (s), 2870 (s), 1717 (s), 1645 (m), 1459 (m), 1381 (w), 1365 (w), 1338 (w),
1281 (w), 1191 (w), 1162 (w), 1073 (w), 1029 (m), 968 (w), 936 (w), 910 (w), 899 (w),
882 (w), 841 (w), 732 (m) cm-1; 1H NMR (500 MHz, CDCl3, 50 °C) δ 7.66 (q, J = 1.5
Hz, 1H), 5.19 (q, J = 1.5 Hz, 1H), 3.51-3.44 (m, 1H), 3.01 (br s, 1H), 2.48-2.40 (m, 1H),
2.39 (ddd, J = 17, 13, 1.0 Hz, 1H), 2.22-2.13 (m, 2H), 1.85 (d, J = 1.0 Hz, 3H), 1.72 (d, J
240
= 0.5 Hz, 3H), 1.17 (s, 3H), 1.081 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H), 0.75 (dd, J = 9.0, 6.0
Hz, 1H), 0.72 (dd, J = 8.0, 3.0 Hz); 13C NMR (500 MHz, CDCl3, 40 °C) δ 209.2, 208.6,
158.5, 146.7, 138.0, 127.3, 79.8, 72.9, 44.4, 40.0, 36.5, 31.0, 29.0, 26.8, 24.6, 24.3, 23.3,
17.7, 15.5, 11.0; HRMS (EI) m/z 314.1880 [calc’d for C20H26O3 (M+) 314.1882]
Preparation of Allylic alcohol 158.
O
H
HOTBS
O
O
125
TBAF
O
H
HOH
O
O
158
(98% yield)
Allylic alcohol 158. To a stirred solution of TBS ether 125 (65 mg, 0.137 mmol)
in THF (5 mL) was added TBAF (0.274 mL, 1 M solution in THF, 0.274 mmol, 2.0
equiv) by syringe at 0 °C. The resulting reaction mixture was stirred at rt for 1 h, then
diluted with Et2O (50 mL), washed with NH4Cl (10 mL), brine (10 mL), dried over
Na2SO4, and filtered. Concentration in vacuo followed by flash chromatography (2:1
hexanes:EtOAc eluent) afforded allylic alcohol 158 (48 mg, 98% yield) as a light yellow
oil.
Allylic alcohol 158. FTIR (thin film/NaCl) 3461 (br m), 2956 (s), 2924 (s), 2874
(s), 1719 (s), 1653 (w), 1459 (m), 1380 (m), 1339 (w), 1275 (w), 1209 (w), 1190 (w),
1160 (w), 1091 (w), 1069 (w), 1035 (w), 953 (w), 920 (w), 858 (w), 733 (m), 686 (w),
647 (w) cm-1; 1H NMR (500 MHz, CDCl3, 50 °C) δ 5.40 (s, 1H), 4.71 (d, J = 5.0 Hz,
1H), 3.97-3.94 (m, 4H), 3.86-3.82 (m, 2H), 3.27-3.21 (m, 1H), 3.19 (s, 1H), 2.42 (t, J =
241
14 Hz, 1H), 2.30-2.17 (m, 3H), 2.08-2.02 (m, 1H), 1.92-1.81 (m, 3H), 1.77 (t, J = 12 Hz,
1H), 1.56 (br s, 1H), 1.50 (dd, J = 12, 6.0 Hz, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 1.01 (d, J =
7.0 Hz, 3H), 0.74-0.66 (m, 2H); 13C NMR (400 MHz, CDCl3, 50 °C) δ 212.3, 141.5,
133.7, 107.5, 71.9, 69.3, 65.5, 65.4, 45.4, 44.9, 42.4, 36.9, 35.3, 32.2, 29.8, 29.1, 29.0,
24.2, 24.1, 23.4, 16.1, 15.5; HRMS (CI) m/z 361.2378 [calc’d for C22H33O4 (M+H)
361.2379].
Preparation of Diol 159.
HO
O
H
OH
O
O
159
O
H
HOH
O
O
158
2) PPh3
1) 1O2, RB
CH3CN
(80% yield)
Diol 159. To a 20 cm glass tube containing Rose Bengal (3 mg) was added a
solution of allylic alcohol 158 (25 mg, 0.069 mmol) in CH3CN (10 mL). The bottom of
the reaction tube was placed 1 cm into an ice bath with the rest of the tube exposed to the
light bulb. With O2 bubbling steadily through the solution, the reaction mixture was
irradiated with a tungsten-halogen lamp (600W) for 3 h. The oxygen line was then
removed, and PPh3 (91 mg, 0.35 mmol, 5.0 equiv) was added to the crude solution. The
reaction mixture was stirred at rt for 0.5 h, diluted with EtOAc (25 ml), washed with
NaHCO3 and brine, dried over MgSO4 and filtered. Concentration in vacuo followed by
flash chromatography (1:1 hexanes:EtOAc eluent) afforded diol 159 (19 mg, 80% yield)
as a white solid.
242
Diol 159: m.p. 146.0-147.5 °C; FTIR (thin film/NaCl) 3435 (br s), 3052 (w), 2927
(s), 2886 (s), 2766 (w), 1723 (s), 1621 (w), 1452 (m), 1382 (m), 1340 (w), 1269 (w),
1225 (w), 1192 (w), 1124 (m), 1070 (m), 972 (w), 952 (w), 922 (w), 880 (w), 799 (w),
735 (m), 702 (w) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C) δ 5.38 (s, 1H), 4.72 (d, J =
5.0 Hz, 1H), 3.99-3.92 (m, 2H), 3.87-3.81 (m, 2H), 3.48 (dt, J = 2.0, 12 Hz, 1H), 3.35 (s,
2H), 2.84 (ddd, J = 16, 12, 2.0 Hz, 1H) 2.50-2.45 (m, 1H), 2.43-2.37 (m, 1H), 2.36 (s,
1H), 2.20 (dd, J = 16, 3.0 Hz, 2H), 2.06 (t, J = 13 Hz, 1H), 1.98 (dd, J = 14, 9.0 Hz, 1H),
1.88-1.78 (m, 3H), 1.73 (dd, J = 13, 2.0 Hz, 1H), 1.19 (s, 3H), 1.05 (d, J = 7.0 Hz, 3H),
1.03 (s, 3H), 0.76 (dd, J = 11.5, 8.5 Hz, 1H), 0.67 (dt, J = 8.5, 6.0 Hz, 1H); 13C NMR
(500 MHz, CDCl3, 40 °C) δ 211.2, 148.1, 127.9, 107.4, 77.7, 72.0, 70.7, 65.5, 65.3, 43.4,
38.3, 38.2, 36.3, 35.9, 32.0, 29.2, 26.7, 25.0, 24.6, 23.0, 18.1, 15.3; HRMS (EI) m/z
376.2252 [calc’d for C22H32O5 (M+) 376.2250].
Preparation of Epoxy-Alcohol 160.
O
O
OHH
H
O
158
O
H
HOH
O
O
O
160
VO(acac)2, TBHP
(93% yield)
Epoxy-Alcohol 160. To a stirred solution of allylic alcohol 158 (40 mg, 0.11
mmol) in C6H6 (5 mL) was added catalytic VO(acac)2 (4 mg) and TBHP (56 uL 5~6 M
solution, 0.28 mmol, 2.5 equiv) at rt. The reaction mixture was stirred until all of the
starting material was consumed on TLC (ca. 5 h), at which point it was diluted with Et2O
(50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in
243
vacuo. The resulting oil was purified by flash chromatography (3:1 hexanes:EtOAc
eluent) afforded Epoxy-Alcohol 160 (39 mg, 93% yield) as a colorless oil.
O
H
HOBn
O
O
O
170
O
H
HOH
O
O
O
160
(98% yield)
Pd/C, H2
Epoxy-Alochol 160. To a stirred solution of 170 (10 mg, 0.021 mmol) in
methanol (2 mL) was added Pd/C (5 mg) at rt. The reaction mixture was stirred under an
atmosphere of H2 for 1 h, filtered through celite, concentration in vacuo followed by flash
chromatography (4:1 hexanes:EtOAc eluent) afforded epoxy-alcohol 160 (8 mg, 98%
yield) as a light yellow oil.
Epoxy-Alcohol 160. FTIR (thin film/NaCl) 3510 (br m), 2924 (s), 2876 (s), 2741
(w), 2606 (w), 1918 (s), 1459 (m), 1382 (m), 1341 (w), 1306 (w), 1269 (w), 1228 (w),
1193 (w), 1169 (w), 1147 (m), 1090 (m), 1048 (m), 943 (m), 924 (m), 866 (w), 801 (w),
736 (m), 704 (m) cm-1; 1H NMR (500 MHz, CDCl3, 60 °C) δ 4.77 (d, J = 4.5 Hz, 1H),
3.97-3.94 (m, 2H), 3.86-3.83 (m, 2H), 3.53 (d, J = 12 Hz, 1H), 3.47 (d, J = 12 Hz, 1H),
2.96 (d, J = 2.5 Hz, 1H), 2.60-2.57 (m, 1H), 2.51 (dt, J = 3.0, 13 Hz, 1H), 2.35-2.26 (m,
2H), 2.21 (t, J = 13.5 Hz, 1H), 2.05-1.99 (m, 1H), 1.93-1.81 (m, 4H), 1.76 (dd, J = 8.5,
2.5 Hz, 1H), 1.74-1.67 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.67
(dt, J = 6.0, 8.5 Hz, 1H), 0.61 (dd, J = 11, 8.5 Hz, 1H); 13C NMR (500 MHz, CDCl3, 60
°C) δ 211.3, 106.8, 70.6, 67.8, 66.1, 65.8, 65.5, 65.4, 47.6, 42.3, 41.9, 36.9, 32.8, 29.6,
244
29.4, 28.95, 28.86, 24.0, 23.7, 23.3, 15.6, 15.1; HRMS (EI) m/z 376.2253 [calc’d for
C22H32O5 (M+) 376.2250].
Preparation of Mesylate 161.
O
O
O
OMsH
H
O
161
O
H
HOH
O
O
O
160
MsCl, Et3N
(97% yield)
Mesylate 161. To a stirred solution of epoxy alcohol 160 (35 mg, 0.093 mmol) in
CH2Cl2 (10 mL) was added Et3N (63 uL, 0.47 mmol, 5.0 equiv) and MsCl (15 uL, 0.23
mmol, 2.5 equiv) at rt. The reaction mixture was stirred at rt for 2 hr, diluted Et2O (50
mL), washed with brine (10 mL), dried over Na2SO4 and filtered. Concentration in vacuo
followed by flash chromatography (3:1 hexanes:EtOAc eluent) afforded mesylate 161 (41
mg, 97% yield) as a colorless oil.
Mesylate 161. FTIR (thin film/NaCl) 2951 (s), 2879 (s), 1718 (s), 1457 (m),
1381 (m), 1358 (s), 1213 (w), 1176 (s), 1149 (w), 1129 (w), 1093 (w), 1066 (w), 1034
(w), 963 (m), 836 (m), 733 (m) cm-1; 1H NMR (500 MHz, CDCl3, 60 °C) δ 4.78 (d, J =
4.5 Hz, 1H), 4.12 (d, J = 11.5 Hz, 1H), 3.98-3.94 (m, 3H), 3.88-3.83 (m, 2H), 3.05 (s,
3H), 2.90 (d, J = 3.0 Hz, 1H), 2.58 (dt, J = 8.0, 3.5 Hz, 1H), 2.43 (dt, J = 2.5, 13.5 Hz,
1H), 2.41-2.32 (m, 2H), 2.27 (ddd, J = 14, 9.5, 8.5 Hz, 1H), 2.02-1.98 (m, 2H), 1.90-1.82
(m, 3H), 1.75-1.69 (m, 2H), 1.09 (s, 3H), 1.04 (s, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.68 (dt,
J = 5.5, 9.0 Hz, 1H), 0.61 (dd, J = 8.5, 11 Hz, 1H); 13C NMR (500 MHz, CDCl3, 60 °C)
δ 210.8, 106.5, 73.5, 70.9, 69.3, 65.53, 65.49, 63.1, 47.5, 42.1, 41.9, 38.2, 36.8, 32.4,
245
29.4, 29.3, 28.9, 28.7, 23.9, 23.6, 23.4, 15.5, 15.0; HRMS (EI) m/z 454.2026 [calc’d for
C23H34O7S (M+) 454.2025].
Preparation of Iodide 162.
O
O
O
OMsH
H
O
O
O
O
IH
H
O
161 162
NaI, DMF
(85% yield)
Iodide 162. A solution of mesylate 161 (38 mg, 0.084 mmol) in DMF (4 mL)
was syringed into a 15 ml pear-shaped flask containing flame-dried NaI (63 mg, 0.42
mmol, 5.0 equiv) at rt. The reaction mixture was heated to 80 °C for 0.5 h. The reaction
mixture was then diluted with Et2O (50 mL), washed with sat. NaHCO3 (10 mL), brine (5
mL), dried over Na2SO4, and filtered. Concentration in vacuo followed by flash
chromatography (4:1 hexanes:EtOAc eluent) afforded iodide 162 (35 mg, 85% yield) as a
light yellow oil.
Iodide 162. FTIR (thin film/NaCl) 2950 (s), 2876 (s), 2747 (w), 1719 (s), 1458
(m), 1381 (m), 1309 (w), 1216 (w), 1191 (w), 1169 (m), 1148 (m), 1064 (m), 1009 (w),
942 (w), 926 (w), 887 (w), 865 (w), 837 (w), 735 (m), 705 (w) cm-1; 1H NMR (500
MHz, CDCl3, 60 °C) δ 4.80 (d, J = 4.5 Hz, 1H), 4.00-3.93 (m, 2H), 3.89-3.83 (m, 2H),
3.12 (d, J = 10 Hz, 1H), 3.03 (d, J = 10 Hz, 1H), 2.87 (d, J = 2.0 Hz, 1H), 2.53 (dt, J =
8.5, 4.0 Hz, 1H), 2.41-2.31 (m, 3H), 2.26 (ddd, J = 14, 9.5, 8.5 Hz, 1H), 2.15-2.08 (m,
1H), 2.01-1.95 (m, 1H), 1.93-1.88 (m, 2H), 1.83 (dt, J = 16, 5.5 Hz, 1H), 1.73-1.67 (m,
2H), 1.08 (s, 3H), 1.03 (s, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.66 (dt, J = 6.0, 8.5 Hz, 1H),
246
0.61 (dt, J = 2.5, 8.5 Hz, 1H); 13C NMR (500 MHz, CDCl3, 60 °C) δ 210.7, 106.6, 74.5,
70.7, 65.5, 64.8, 48.3, 42.1, 42.0, 36.7, 32.6, 31.7, 29.3, 28.9, 28.7, 23.9, 23.7, 23.3, 15.5,
15.1, 13.9; HRMS (EI) m/z 486.1259 [calc’d for C22H31O5I (M+) 486.1267].
Preparation of Exo-olefin 163.
O
O
O
IH
H
O
162
O
O
H
H
O
HO
163
Zn, HOAc
(77% yield)
MeOH
Exo-olefin 163. To a stirred solution of iodide 162 (30 mg, 0.062 mmol) in
HOAc (2 mL) and MeOH (1 mL) was added Zinc metal (large excess) at rt. After the
mixture was stirred vigorously at rt for 12 h, the reaction was diluted with ether (50 mL),
neutralized with NaHCO3, washed with brine (5 mL), dried over Na2SO4 and filtered.
Concentration in vacuo followed by flash chromatograph (6:1 hexanes:EtOAc eluent)
afforded exo-olefin 163 (17 mg, 77% yield) as a colorless oil.
Exo-olefin 163. FTIR (thin film/NaCl) 3379 (br s), 3066 (w), 2959 (s), 2894 (s),
1696 (s), 1640 (s), 1454 (m), 1438 (m), 1398 (m), 1325 (w), 1253 (w), 1220 (w), 1193
(w), 1158 (m), 1102 (m), 1057 (m), 1034 (m), 1014 (w), 934 (w), 912 (m), 882 (w), 828
(w), 734 (m) cm-1; 1H NMR (500 MHz, CDCl3, 50 °C) δ 4.96 (s, 1H), 4.87 (s, 1H), 4.69
(d, J = 6.0 Hz, 1H), 4.45 (d, J = 3.0 Hz, 1H), 3.99-3.91 (m, 3H), 3.88-3.81 (m, 2H), 2.62-
2.56 (m, 1H), 2.48 (t, J = 14 Hz, 1H), 2.40-2.34 (m, 2H), 2.33 (dd, J = 13.5, 10.5 Hz,
1H), 2.02-1.93 (m, 1H), 1.86 (br s, 1H), 1.83 (dt, J = 16, 2.5 Hz, 1H), 1.66 (dt, J = 12,
5.5 Hz, 1H), 1.61-1.54 (m, 2H), 1.19 (s, 3H), 1.07 (q, J = 12 Hz, 1H), 1.01 (s, 3H), 0.98
247
(d, J = 7.0 Hz, 3H), 0.80 (dd, J = 11, 9.0 Hz, 1H), 0.57 (ddd, J = 8.5, 7.0, 2.0 Hz, 1H);
13C NMR (400 MHz, CDCl3, 50 °C) δ 212.2, 146.1, 116.3, 108.0, 81.0, 66.3, 65.33,
65.31, 53.4, 42.2, 39.8, 38.5, 32.4, 32.3, 32.0, 29.5, 26.0, 25.3, 24.8, 21.7, 17.1, 15.2;
HRMS (EI) m/z 360.2308 [calc’d for C22H32O4 (M+) 360.2301].
Preparation of TBS Ether 165.
O
O
H
H
O
HO
TBSOTf
163
O
O
H
H
O
TBSO
165
(92% yield)
TBS Ether 165. To a stirred solution of 163 (10 mg, 0.028 mmol) in CH2Cl2 (2
mL) was added TBSOTf (15 uL, 0.056 mmol, 2.0 equiv) and 2,6-lutidine (8 uL, 0.07
mmol, 2.5 equiv) at 0 °C. The resulting yellow reaction mixture was stirred at 0 °C for 2
h, then diluted with Et2O (25 mL), washed with brine (5 mL), dried over Na2SO4, and
filtered. Concentration in vacuo followed by flash chromatography (20:1 hexanes:EtOAc
eluent) afforded TBS ether 165 (12 mg, 92% yield) as a light yellow oil.
TBS Ether 165. FTIR (thin film/NaCl) 3071 (w), 2953 (s), 2930 (s), 2884 (s),
2858 (s), 1720 (s), 1637 (w), 1471 (m), 1463 (m), 1432 (w), 1360 (w), 1346 (w), 1251
(m), 1185 (w), 1158 (m), 1091 (s), 1062 (s), 1005 (w), 965 (w), 938 (w), 905 (w), 861 (s),
837 (s), 777 (s), 734 (w), 672 (w) cm-1; 1H NMR (400 MHz, CDCl3, 40 °C) δ 4.90 (s,
1H), 4.73 (s, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 2.4 Hz, 1H), 4.07 (dt, J = 5.2,
11.6 Hz, 1H), 4.00-3.91 (m, 2H), 3.88-3.81 (m, 2H), 2.66 (ddt, J = 6.4, 2.4, 13.2 Hz, 1H),
2.41 (t, J = 12.8 Hz, 1H), 2.38-2.30 (m, 2H), 2.27 (ddd, J = 14, 5.2, 2.4 Hz, 1H), 1.95-
248
1.83 (m, 1H), 1.80 (dd, J = 15.6, 1.6 Hz, 1H), 1.60-1.47 (m, 4H), 1.17 (s, 3H), 0.99 (s,
3H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.79 (dd, J = 10.4, 9.2 Hz, 1H), 0.53 (t, J =
8.0 Hz, 1H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (400 MHz, CDCl3, 40 °C) δ 212.3,
145.9, 115.9, 108.2, 82.0, 65.9, 65.34, 65.27, 54.2, 42.2, 39.0, 38.4, 32.6, 32.5, 31.9, 29.4,
26.2, 26.1, 25.1, 25.6, 21.5, 28.6, 16.7, 15.6, -4.62; HRMS (EI) m/z 474.3165 [calc’d for
C28H46O4Si (M+) 474.3165].
Preparation of Epoxide 169.
O
H
HOOOBn
136 169
O
H
HOOOBnO
VO(acac)2, TBHP
(82% yield)
Epoxide 169. To a stirred solution of 136 (6 mg, 0.014 mmol) in C6H6 (2 mL)
was added catalytic VO(acac)2 (1 mg) and TBHP (11 uL 5~6 M solution, 0.056 mmol,
5.0 equiv) at rt. The reaction mixture was stirred until all of the starting material was
consumed on TLC (ca. 5 h), at which point it was diluted with Et2O (20 mL), washed
with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting
oil was purified by flash chromatography (10:1 hexanes:EtOAc eluent) afforded epoxide
169 (5 mg, 82% yield) as a colorless oil.
Epoxide 169. FTIR (thin film/NaCl) 3426 (br m), 3063 (w), 3029 (w), 2955 (s),
2855 (s), 1719 (s), 1636 (w), 1496 (w), 1455 (m), 1382 (m), 1333 (w), 1311 (w), 1269
(w), 1200 (m), 1168 (w), 1118 (m), 1076 (w), 1029 (w), 971 (w), 920 (w), 904 (w), 868
(w), 826 (w), 737 (m), 699 (m), 656 (w) cm-1; 1H NMR (500 MHz, CDCl3, 40 °C)
249
δ 7.70 (s, 1H), 7.35-7.23 (m, 5H), 4.47 (d, J = 12 Hz, 1H), 4.43 (d, J = 12 Hz, 1H), 3.37
(d, J = 11 Hz, 1H), 3.33 (s, 1H), 3.27 (d, J = 11 Hz, 1H), 2.80 (s, 1H), 2.66 (ddd, J = 15,
11.5, 3.5 Hz, 1H), 2.38 (t, J = 14 Hz, 1H), 2.33 (ddd, J = 15.5, 10, 2.0 Hz, 1H), 2.19-2.16
(m, 1H), 2.10 (dd, J = 14, 3.0 Hz, 1H), 1.88 (d, J = 0.5 Hz, 3H), 1.78 (ddd, J = 16, 6.0,
4.5 Hz, 1H), 1.12 (s, 3H), 1.06 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.71 (dt, J = 6.0, 9.0 Hz,
1H), 0.64 (dd, J = 11.5, 8.5 Hz, 1H); 13C NMR (400 MHz, CDCl3, 40 °C) δ 208.4, 206.5,
158.8, 138.6, 138.0, 128.8, 128.2, 128.1, 78.7, 73.70, 73.67, 71.6, 69.0, 65.9, 41.5, 40.0,
30.4, 29.6, 28.9, 24.1, 23.4, 17.4, 15.3, 11.1; HRMS (EI) m/z 436.2255 [calc’d for
C27H32O5 (M+) 436.2250].
Preparation of Epoxide 170.
O
H
HOBn
O
O
128
O
H
HOBn
O
O
O
170
mCPBA
NaHCO3, CH2Cl2
(65% yield)
Epoxide 170. To a solution of 128 (28 mg, 0.062 mmol) in CH2Cl2 (5 mL) was
added mCPBA (21 mg, 0.124 mmol, 2.0 equiv) and NaHCO3 powder (20 mg) at rt. The
reaction mixture was stirred at rt for 6 hours, diluted with ether (25 mL), washed with
brine (5 mL), dried over Na2SO4, and filtered. Concentration in vacuo followed by flash
chromatography (16:1 hexanes:EtOAc eluent) afforded epoxide 170 (19 mg, 65% yield)
as a colorless oil.
Epoxide 170. FTIR (thin film/NaCl) 3087 (w), 3062 (w), 3030 (w), 2924 (s),
2875 (s), 1719 (s), 1496 (w), 1454 (m), 1381 (m), 1370 (w), 1341 (w), 1308 (w), 1270
250
(w), 1212 (w), 1148 (m), 1096 (m), 1072 (m), 1029 (m), 994 (w), 940 (w), 867 (w), 809
(w), 735 (m), 699 (m), 647 (w) cm-1; 1H NMR (500 MHz, CDCl3, 60 °C) δ 7.35-7.27 (m,
5H), 4.77 (d, J = 4.5 Hz, 1H), 4.52 (d, J = 12 Hz, 1H), 4.48 (d, J = 12 Hz, 1H), 3.96-3.90
(m, 2H), 3.89-3.81 (m, 2H), 3.41 (d, J = 11 Hz, 1H), 3.34 (d, J = 11 Hz, 1H), 2.85 (d, J =
2.0 Hz, 1H), 2.60 (dt, J = 8.0, 4.0 Hz, 1H), 2.50 (t, J = 13 Hz, 1H), 2.38 (t, J = 13.5 Hz,
1H), 2.35-2.30 (m, 1H), 2.26 (dt, J = 13.5, 9.0 Hz, 1H), 2.06-2.00 (m, 1H), 1.96 (dd, J =
13.5, 2.5 Hz, 1H), 1.90 (d, J = 9.5 Hz, 2H), 1.84 (dt, J = 16, 6.0 Hz, 1H), 1.78-1.66 (m,
2H), 1.10 (s, 3H), 1.04 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.66 (dt, J = 6.5, 8.0 Hz, 1H),
0.62 (dd, J = 10.5, 8.5 Hz, 1H); 13C NMR (500 MHz, CDCl3, 60 °C) δ 211.3, 138.6,
128.7, 128.0, 127.9, 106.8, 75.1, 73.5, 68.7, 65.49, 65.46, 65.1, 47.6, 42.3, 41.81, 41.76,
36.9, 32.8, 29.6, 29.5, 29.0, 28.9, 23.94, 23.90, 23.2, 15.6, 15.1; HRMS (EI) m/z
466.2725 [calc’d for C29H38O5 (M+) 466.2719].
Preparation of Epoxide 172.
O
H
H
O
O
HO
163
O
H
H
O
O
HOO
172
VO(acac)2, TBHP
(84% yield)
Epoxide 172. To a stirred solution of 163 (8 mg, 0.022 mmol) in C6H6 (2 mL)
was added catalytic VO(acac)2 (1 mg) and TBHP (18 uL 5~6 M solution, 0.088 mmol,
4.0 equiv) at rt. The reaction mixture was stirred at rt until all of the starting material was
consumed on TLC (ca. 5 h), at which point it was diluted with Et2O (25 mL), washed
with brine (5 mL), dried over Na2SO4, and filtered. Concentrated in vacuo followed by
251
flash chromatography (10:1 hexanes:EtOAc eluent) afforded epoxide 172 (7 mg, 84%
yield) as a white solid.
Epoxide 172: m.p. 142.0-143.9 °C; FTIR (thin film/NaCl) 3452 (br m), 2953 (s),
2884 (s), 1715 (s), 1454 (m), 1379 (m), 1346 (m), 1303 (w), 1218 (w), 1187 (w), 1157
(m), 1087 (m), 1061 (m), 1027 (m), 984 (w), 952 (w), 938 (w), 888 (w), 862 (w), 732 (s),
670 (w), 647 (w) cm-1; 1H NMR (500 MHz, CDCl3, 60 °C) δ 4.76 (d, J = 4.5 Hz, 1H),
3.98-3.96 (m, 2H), 3.87-3.84 (m, 2H), 3.52 (dt, J = 3.5, 11 Hz, 1H), 3.39 (s, 1H), 2.91 (d,
J = 4.5 Hz, 1H), 2.64 (d, J = 5.0 Hz, 1H), 2.51-2.46 (m, 1H), 2.44-2.40 (m, 1H), 2.26 (d,
J = 4.0 Hz, 1H), 2.17-2.10 (m, 2H), 2.04 (t, J = 13 Hz, 1H), 1.87 (ddd, J = 16, 5.0, 3.0
Hz, 1H), 1.84-1.70 (m, 4H), 1.55-1.48 (m, 1H), 1.19 (s, 3H), 1.03 (s, 3H), 1.01 (d, J = 6.5
Hz, 3H), 0.73 (dd, J = 11, 9.0 Hz, 1H), 0.63 (ddd, J = 9.0, 6.5, 5.0 Hz, 1H); 13C NMR
(500 MHz, CDCl3, 60 °C) δ 212.6, 107.4, 78.4, 67.7, 65.44, 65.40, 61.3, 54.2, 52.9, 42.0,
41.2, 37.7, 33.1, 31.3, 30.3, 29.3, 25.8, 25.4, 24.6, 22.6, 16.8, 15.1; HRMS (EI) m/z
376.2248 [calc’d for C22H32O5 (M+) 376.2250].
Preparation of Carbonate 173.
O
H
H
O
O
OH
158
O
H
H
O
O
O
O
O
173
(95% yield)
BOC2O, DMAP
Carbonate 173. To a stirred solution of 158 (10 mg, 0.028 mmol) in CH2Cl2 (2
mL) was added BOC2O (15 mg, 0.069 mmol, 2.5 equiv), Et3N (19 uL, 0.14 mmol, 5.0
252
equiv) and catalytic DMAP (1 mg) at rt. The reaction mixture was stirred at rt for 4 h,
diluted with ether (20 mL), washed with brine, dried over Na2SO4, and filtered.
Concentration in vacuo followed by flash chromatography (10:1 hexanes:EtOAc eluent)
afforded carbonate 173 (12 mg, 95% yield) as a white solid.
Carbonate 173: m.p. 136.6-138.0 °C; FTIR (thin film/NaCl) 2954 (s), 2878 (s),
1939 (s), 1458 (m), 1394 (m), 1369 (s), 1339 (w), 1277 (s), 1254 (s), 1209 (w), 1163 (s),
1090 (m), 1035 (m), 961 (w), 857 (m), 794 (w), 736 (w), 703 (w), 686 (w), 615 (w) cm-1;
1H NMR (500 MHz, CDCl3, 65 °C) δ 5.46 (s, 1H), 4.70 (d, J = 5.5 Hz, 1H), 4.40 (d, J =
12 Hz, 1H), 4.36 (d, J = 12 Hz, 1H), 3.97-3.92 (m, 2H), 3.85-3.80 (m, 2H), 3.25-3.17 (m,
2H), 2.42 (t, J = 14 Hz, 1H), 2.29-2.18 (m, 3H), 2.09-2.03 (m, 1H), 1.92-1.88 (m, 4H),
1.54-1.48 (m, 1H), 1.50 (s, 9H), 1.14 (s, 3H), 1.06 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.73
(dd, J = 8.0, 4.0 Hz, 1H), 0.70 (dd, J = 9.0, 7.0 Hz, 1H); 13C NMR (400 MHz, CDCl3, 40
°C) δ 210.3, 151.8, 135.6, 134.7, 105.5, 80.5, 71.3, 70.0, 63.6, 63.5, 43.7, 42.9, 40.4,
35.0, 33.3, 30.6, 27.0, 27.1, 27.0, 26.3, 22.2, 22.1, 21,5, 14.1, 13.6; HRMS (EI) m/z
460.2819 [calc’d for C27H40O6 (M+) 460.2825].
Preparation of Diol 175.
O
H
HOBn
O
O
128
O
H
HOBn
O
O
HO HO
175
1) OsO4, py2) Na2S
(86% yield)
Diol 175. To a stirred solution of 128 (16 mg, 0.036 mmol) in pyridine (4 mL)
was added OsO4 (276 uL, 0.043 mmol, 1.2 equiv) at 0 °C. The reaction mixture was
253
stirred at 0 °C for 1 h. After removing pyridine under reduced pressure, the residue was
redissolved in THF (5 mL) and H2O (5 mL). To the brownish solution was added Na2S
(200 mg, large excess) at rt. The mixture was stirred at rt for 2 h, extracted with Et2O (50
mL), washed with brine (5 mL), dried over Na2SO4, and filtered. Concentrated in vacuo
followed by flash chromatography (3:1 hexanes:EtOAc eluent) afforded diol 175 (15 mg,
86% yield) as a colorless oil.
Diol 175. FTIR (thin film/NaCl) 3451 (br m), 3087 (w), 3062 (w), 2951 (s), 2824
(s), 2879 (s), 1715 (s), 1496 (w), 1453 (m), 1382 (m), 1341 (w), 1209 (w), 1163 (w),
1974 (s), 1010 (m), 946 (m), 912 (m), 869 (w), 734 (s), 699 (m), 647 (w) cm-1; 1H NMR
(500 MHz, CDCl3, 50 °C) δ 7.37-7.28 (m, 5H), 4.77 (d, J=4.5 Hz, 1H), 4.57 (d, J=12 Hz,
1H), 4.52 (d, J=12 Hz, 1H), 3.99-3.91 (m, 2H), 3.87-3.82 (m, 2H), 3.59 (d, J=9.5 Hz,
1H), 3.44 (d, J=9.5 Hz, 1H), 3.39 (d, J=5.0 Hz, 1H), 3.19 (dd, J=10, 5.0 Hz, 1H), 2.98 (t,
J=12 Hz, 1H), 2.68 (dt, J=2.5, 9.0 Hz, 1H), 2.65 (s, 1H), 2.38-2.30 (m, 1H), 2.13 (ddd,
J=14, 7.0, 3.0 Hz, 1H), 2.05 (ddd, J=15, 6.5, 3.0 Hz, 1H), 2.00-1.85 (m, 5H), 1.69 (dd,
J=14, 11 Hz, 1H), 1.08 (s, 3H), 1.03 (s, 3H), 1.01 (d, J=7.0 Hz, 3H), 0.67 (dd, J=15, 8.0
Hz, 1H), 0.61 (dd, J=11.5, 8.5 Hz, 1H); 13C NMR (500 MHz, CDCl3, 50 °C) δ 214.1,
138.0, 128.8, 128.2, 128.0, 107.4, 78.5, 78.3, 74.2, 68.2, 65.5, 65.4, 48.1, 42.5, 40.8, 37.0,
36.1, 29.6, 29.1, 27.7, 26.3, 24.3, 24.1, 23.8, 16.5, 15.1; HRMS (EI) m/z 484.2818
[calc’d for C29H40O6 (M+) 484.2825].
254
3.8 Notes and References.
(1) "Sensitized photooxygenation of olefins", Denny, R. W.; Nickon, A., Organic
Reactions 1973, 20, 133-336.
(2) "Allylic Oxidation of Olefins By Catalytic and Stoichiometric Selenium Dioxide
With tert-Butyl Hydroperoxide", Umbreit, M. A.; Sharpless, K. B., Journal of the
American Chemical Society 1977, 99, 5526-5528.
(3) "Organoselenium Chemistry - Facile One-Step Synthesis of Alkyl Aryl Selenides
From Alcohols", Grieco, P. A.; Gilman, S.; Nishizawa, M., Journal of Organic Chemistry
1976, 41, 1485-1486.
(4) "Effects of olefin substitution on the ring-closing metathesis of dienes", Kirkland,
T. A.; Grubbs, R. H., Journal of Organic Chemistry 1997, 62, 7310-7318.
(5) "Mechanism of Allylic Hydroxylation By Selenium Dioxide", Stephenson, L. M.;
Speth, D. R., Journal of Organic Chemistry 1979, 44, 4683-4689.
(6) "Selenium Dioxide Oxidation of Olefins - Evidence For Intermediacy of
Allylseleninic Acids", Sharples.K. B.; Lauer, R. F., Journal of the American Chemical
Society 1972, 94, 7154-7155.
255
(7) "A Convenient Synthesis of 2-Methyl-2-Cyclopenten-1-One", Disanayaka, B. W.;
Weedon, A. C., Synthesis-Stuttgart 1983, 952-952.
(8) "Anthracyclines I the Synthesis of Racemic Daunomycinone and Some Related
Tetrahydronaphthacenequinones", Broadhurst, M. J.; Hassall, C. H., Journal of the
Chemical Society-Perkin Transactions 1 1982, 2227-2238.
(9) "*Photochemische Reaktionen III Uber Die Bildung Von Hydroperoxyden Bei
Photosensibilisierten Reaktionen Von O-2 Mit Geeigneten Akzeptoren, Insbesondere Mit
Alpha-Pinen Und Beta- Pinen", Schenck, G. O.; Eggert, H.; Denk, W., Annalen Der
Chemie-Justus Liebig 1953, 584, 177-198.
(10) "Regioselectivity in the ene reaction of singlet oxygen with alkenes", Stratakis,
M.; Orfanopoulos, M., Tetrahedron 2000, 56, 1595-1615.
(11) "Hydroxy group directivity in the epoxidation of chiral allylic alcohols: Control of
diastereoselectivity through allylic strain and hydrogen bonding", Adam, W.; Wirth, T.,
Accounts of Chemical Research 1999, 32, 703-710.
(12) "The Schenck ene reaction: Diastereoselective oxyfunctionalization with singlet
oxygen in synthetic applications", Prein, M.; Adam, W., Angewandte Chemie-
International Edition in English 1996, 35, 477-494.
256
(13) "Reactivity and Geometry in Allylic Systems VI Stereospecific Conversion of
Allylic Alcohols to Alpha,Beta-Epoxy Ketones By Photosensitized Oxygenation",
Nickon, A.; Mendelso.Wl, Journal of the American Chemical Society 1965, 87, 3921-
3928.
(14) "Stereoselective Epoxidations of Acyclic Allylic Alcohols By Transition Metal-
Hydroperoxide Reagents - Synthesis of Dl-C18 Cecropia Juvenile-Hormone From
Farnesol", Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharples.K. B.; Michaels.R. C.;
Cutting, J. D., Journal of the American Chemical Society 1974, 96, 5254-5255.
(15) Exposure of exo-olefin 165 to singlet oxygen-ene conditions resulted a promising
new spot on TLC consistently. Unfortunately, the reaction was extremely slow possibly
caused by the demanding size of TBS protection. The new compound has not been
characterized yet.
(16) "The first total synthesis of (+/-)-ingenol", Winkler, J. D.; Rouse, M. B.; Greaney,
M. F.; Harrison, S. J.; Jeon, Y. T., Journal of the American Chemical Society 2002, 124,
9726-9728.
(17) "Stereoselective reductive rearrangement of alpha-hydroxy epoxides: A new
method for synthesis of 1,3-diols", Tu, Y. Q.; Sun, L. D.; Wang, P. Z., Journal of
Organic Chemistry 1999, 64, 629-633.
257
(18) "Base-Induced Rearrangement of Epoxides to Allylic Alcohols III
Alkylidenecycloalkane Oxides", Thummel, R. P.; Rickborn, B., Journal of Organic
Chemistry 1971, 36, 1365-1368.
(19) For an example of base promoted ring-opening of hydroxy-epoxide, see:
"Remarkably chemoselective indium-mediated coupling en route to the C21-C40 acyclic
portion of the azaspiracids", Hao, J. L.; Aiguade, J.; Forsyth, C. J., Tetrahedron Letters
2001, 42, 821-824.
(20) Calculations were performed using Spartan Version 5.1 Wavefunction Inc. 18401
Von Karman Ave. Suite 370, Irvine, CA 92612. For a reference, see: Halgren, T. A. J.
Computational Chem. 1996, 17, 490-519.
(21) Geometry optimization using semi-empirical method (PM3) suggested perepoxide
182 was only stabilized by 2.3 kcal mol-1 from hydrogen bonding.
(22) Geometry optimization of 183:
O
H
OO
OBn
183
258
Appendix Three: Spectra Relevant
To Chapter Three
324
Appendix 4
Notebook Cross Reference.
The following notebook cross reference has been included to facilitate access to
the original spectroscopic data obtained for the compounds presented in this work. For
each compound a folder name is given (e.g. WHT(III)-236) which corresponds to an
archived characterization folder hard copy and folders stored on a CD. For each folder a
characterization notebook number and page number (e.g. (III)-236) is given and for each
spectrum a code (i.e. H-nmr for 1H NMR, C-nmr for 13C NMR, and .spc for FTIR) is
given. The characterization notebook, spectral data, and discs are stored in the Wood
Group archives.
Table A.4.1 Compounds Appearing in Chapter 2.
Compound Folder 1H NMR 13C NMR FTIR
91 WHT(III)-236 H-nmr C-nmr Wht(iii)-236.spc
100a WHT(III)-234A H-nmr C-nmr Wht(iii)-234a.spc
100b WHT(III)-234B H-nmr C-nmr Wht(iii)-234b.spc
101 WHT(III)-193 H-nmr C-nmr Wht(iii)-193.spc
102 WHT(III)-194 H-nmr C-nmr Wht(iii)-194.spc
103 WHT(III)-195 H-nmr C-nmr Wht(iii)-195.spc
104 WHT(III)-196 H-nmr C-nmr Wht(iii)-196.spc
105 WHT(II)-242 H-nmr C-nmr Wht(ii)-242.spc
106 WHT(III)-244 H-nmr C-nmr Wht(iii)-244.spc
108 WHT(III)-243 H-nmr C-nmr Wht(iii)-243.spc
325
Table A.4.1 Compounds Appearing in Chapter 2 (Continued).
109 WHT(III)-102 H-nmr C-nmr Wht(iii)-102.spc
112a WHT(III)-78A H-nmr C-nmr Wht(iii)-78a.spc
112b WHT(III)-78B H-nmr C-nmr Wht(iii)-78b.spc
112c WHT(III)-78C H-nmr C-nmr Wht(iii)-78c.spc
112d WHT(III)-78D H-nmr C-nmr Wht(iii)-78d.spc
113 WHT(III)-81 H-nmr C-nmr Wht(iii)-81.spc
114 WHT(III)-101 H-nmr C-nmr Wht(iii)-101.spc
115a WHT(II)-236A H-nmr C-nmr Wht(ii)-236a.spc
115b WHT(II)-236B H-nmr C-nmr Wht(ii)-236b.spc
115c WHT(II)-236C H-nmr C-nmr Wht(ii)-236c.spc
116 WHT(III)-92 H-nmr C-nmr Wht(iii)-92.spc
117 WHT(III)-164 H-nmr C-nmr Wht(iii)-164.spc
118 WHT(III)-168 H-nmr C-nmr Wht(iii)-168.spc
119 WHT(III)-172 H-nmr C-nmr Wht(iii)-172.spc
120 WHT(III)-174 H-nmr C-nmr Wht(iii)-174.spc
121 WHT(III)-227 H-nmr C-nmr Wht(iii)-227.spc
122a WHT(V)-67A H-nmr C-nmr Wht(v)-67a.spc
122b WHT(V)-67B H-nmr C-nmr Wht(v)-67b.spc
123 WHT(V)-77 H-nmr C-nmr Wht(v)-77.spc
124 WHT(V)-137 H-nmr C-nmr Wht(v)-137.spc
125 WHT(V)-144 H-nmr C-nmr Wht(v)-144.spc
127 WHT(VI)-139 H-nmr C-nmr Wht(vi)-139.spc
128 WHT(VI)-141 H-nmr C-nmr Wht(vi)-141.spc
129 WHT(VI)-141B H-nmr C-nmr Wht(vi)-141b.spc
132 WHT(VII)-53 H-nmr C-nmr Wht(vii)-53.spc
326
133 WHT(VII)-55 H-nmr C-nmr Wht(vii)-55.spc
Table A.4.1 Compounds Appearing in Chapter 2 (Continued).
134 WHT(VII)-159 H-nmr C-nmr Wht(vii)-159.spc
Table A.4.2 Compounds Appearing in Chapter 3.
Compound Folder 1H NMR 13C NMR FTIR
136 WHT(VI)-237 H-nmr C-nmr Wht(vi)-237.spc
137 WHT(VI)-189 H-nmr C-nmr Wht(vi)-189.spc
138 WHT(VI)-157 H-nmr C-nmr Wht(vi)-157.spc
139 WHT(VI)-129 H-nmr C-nmr Wht(vi)-129.spc
140 WHT(IV)-241 H-nmr C-nmr Wht(iv)-241.spc
141 WHT(IV)-266 H-nmr C-nmr Wht(iv)-266.spc
142 WHT(VI)-161 H-nmr C-nmr Wht(vi)-161.spc
143 WHT(VI)-163 H-nmr C-nmr Wht(vi)-163.spc
147 WHT(VI)-191 H-nmr C-nmr Wht(vi)-191.spc
148 WHT(V)-215 H-nmr C-nmr Wht(v)-215.spc
149 WHT(VI)-223B H-nmr C-nmr Wht(vi)-223b.spc
152 WHT(VII)-191 H-nmr C-nmr Wht(vii)-191.spc
154 WHT(VII)-183 H-nmr C-nmr Wht(vii)-183.spc
155 WHT(VII)-185 H-nmr C-nmr Wht(vii)-185.spc
156 WHT(VII)-189 H-nmr C-nmr Wht(vii)-189.spc
158 WHT(V)-253 H-nmr C-nmr Wht(v)-253.spc
159 WHT(VI)-209 H-nmr C-nmr Wht(vi)-209.spc
160 WHT(VI)-295 H-nmr C-nmr Wht(vi)-295.spc
327
161 WHT(VII)-63 H-nmr C-nmr Wht(vii)-63.spc
162 WHT(VII)-109 H-nmr C-nmr Wht(vii)-109.spc
Table A.4.2 Compounds Appearing in Chapter 3 (Continued).
163 WHT(VII)-110 H-nmr C-nmr Wht(vii)-110.spc
165 WHT(VII)-129 H-nmr C-nmr Wht(vii)-129.spc
169 WHT(VI)-293 H-nmr C-nmr Wht(vi)-293.spc
170 WHT(VI)-159 H-nmr C-nmr Wht(vi)-159.spc
172 WHT(VII)-171 H-nmr C-nmr Wht(vii)-171.spc
173 WHT(VII)-97 H-nmr C-nmr Wht(vii)-97.spc
175 WHT(VII)-141 H-nmr C-nmr Wht(vii)-141.spc
328
Bibliography
Adam, W.; Wirth, T., Accounts of Chemical Research 1999, 32, 703.
Alder, R. W.; East, S. P., Chemical Reviews 1996, 96, 2097.
Bazan, G. C.; Khosravi, E.; Schrock, R. R.; Feast, W. J.; Gibson, V. C.; Oregan, M. B.;
Thomas, J. K.; Davis, W. M., Journal of the American Chemical Society 1990, 112,
8378.
Blanco-Molina, M.; Tron, G. C.; Macho, A.; Lucena, C.; Calzado, M. A.; Munoz, E.;
Appendino, G., Chemistry & Biology 2001, 8, 767.
Boeckman, R. K. J., Journal of Organic Chemistry 1973, 38, 4450.
Boutwell, R. K., Important Advances in Oncology 1985, 16.
Broadhurst, M. J.; Hassall, C. H., Journal of the Chemical Society-Perkin Transactions 1
1982, 2227.
Denny, R. W.; Nickon, A., Organic Reactions 1973, 20, 133.
Disanayaka, B. W.; Weedon, A. C., Synthesis-Stuttgart 1983, 952.
Evans, F. J.; Kinghorn, A. D., Botanical Journal of the Linnean Society 1977, 74, 23.
Fu, G. C.; Grubbs, R. H., Journal of the American Chemical Society 1992, 114, 5426.
329
Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Wang, G. Y. S.; Uemura, D.;
Shigeta, S.; Konno, K.; Yokota, T.; Baba, M., Antiviral Chemistry & Chemotherapy
1996, 7, 230.
Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K.; Wang, G. Y.
S.; Uemura, D.; Yokota, T.; Baba, M., Antimicrobial Agents and Chemotherapy 1996, 40,
271.
Fujiwara, M.; Okamoto, M.; Ijichi, K.; Tokuhisa, K.; Hanasaki, Y.; Katsuura, K.;
Uemura, D.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M., Archives of Virology 1998,
143, 2003.
Funk, R. L.; Olmstead, T. A.; Parvez, M., Journal of the American Chemical Society
1988, 110, 3298.
Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B., Journal of Organic Chemistry
1993, 58, 5873.
Funk, R. L.; Fitzgerald, J. F.; Olmstead, T. A.; Para, K. S.; Wos, J. A., Journal of the
American Chemical Society 1993, 115, 8849.
Furstner, A.; Langemann, K., Synthesis-Stuttgart 1997, 792.
Furstner, A., Angewandte Chemie-International Edition 2000, 39, 3013.
Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H., Journal of the American
Chemical Society 2000, 122, 8168.
Grieco, P. A.; Gilman, S.; Nishizawa, M., Journal of Organic Chemistry 1976, 41, 1485.
Grubbs, R. H.; Tumas, W., Science 1989, 243, 907.
330
Grubbs, R. H.; Miller, S. J.; Fu, G. C., Accounts of Chemical Research 1995, 28, 446.
Halgren, T. A., Journal of Computational Chemistry 1996, 17, 490.
Hao, J. L.; Aiguade, J.; Forsyth, C. J., Tetrahedron Letters 2001, 42, 821.
Harmata, M.; Elahmad, S.; Barnes, C. L., Tetrahedron Letters 1995, 36, 7158.
Hartwell, J. L., Lloydia 1969, 32, 153.
Hasler, C. M.; Acs, G.; Blumberg, P. M., Cancer Research 1992, 52, 202.
Hecker, E., Cancer Research 1968, 28, 2338.
Hecker, E., Pure and Applied Chemistry 1977, 49, 1423.
Hirata, Y., Pure and Applied Chemistry 1975, 41, 175.
Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D., Tetrahedron Letters 2000, 41, 3927.
Kim, S.; Winkler, J. D., Chemical Society Reviews 1997, 26, 387.
Kirkland, T. A.; Grubbs, R. H., Journal of Organic Chemistry 1997, 62, 7310.
Kishi, Y.; Rando, R. R., Accounts of Chemical Research 1998, 31, 163.
Konosu, T.; Furukawa, Y.; Hata, T.; Oida, S., Chemical & Pharmaceutical Bulletin 1991,
39, 2813.
331
Kupchan, S. M.; Uchida, I.; Branfman, A. R.; Dailey, R. G.; Fel, B. Y., Science 1976,
191, 571.
Maier, M. E., Angewandte Chemie-International Edition 2000, 39, 2073.
Mehta, G.; Pathak, V. P., Journal of the Chemical Society-Chemical Communications
1987, 876.
Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I., Journal of Organic Chemistry 1997,
62, 3032.
Newton, A. C., Chemical Reviews 2001, 101, 2353.
Nickon, A.; Mendelso.Wl, Journal of the American Chemical Society 1965, 87, 3921.
Nishizuka, Y., Science 1992, 258, 607.
Paquette, L. A.; Ross, R. J.; Springer, J. P., Journal of the American Chemical Society
1988, 110, 6192.
Prein, M.; Adam, W., Angewandte Chemie-International Edition in English 1996, 35,
477.
Rigby, J. H.; Cuisiat, S. V., Journal of Organic Chemistry 1993, 58, 6286.
Rigby, J. H.; deSainteClaire, V.; Cuisiat, S. V.; Heeg, M. J., Journal of Organic
Chemistry 1996, 61, 7992.
Rigby, J. H.; Rege, S. D.; Sandanayaka, V. P.; Kirova, M., Journal of Organic Chemistry
1996, 61, 842.
332
Schenck, G. O.; Eggert, H.; Denk, W., Annalen Der Chemie-Justus Liebig 1953, 584,
177.
Scholl, m.; Ding, S.; Lee, C. W.; Grubbs, R. H., Organic Letters 1999, 1, 953.
Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H., Tetrahedron Letters 1999, 40,
2247.
Schrock, R. R.; Feldman, J.; Cannizzo, L. F.; Grubbs, R. H., Macromolecules 1987, 20,
1169.
Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare, M.; Oregan, M.,
Journal of the American Chemical Society 1990, 112, 3875.
Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H., Angewandte Chemie-
International Edition in English 1995, 34, 2039.
Sharples.Kb; Lauer, R. F., Journal of the American Chemical Society 1972, 94, 7154.
Stephenson, L. M.; Speth, D. R., Journal of Organic Chemistry 1979, 44, 4683.
Stragies, R.; Blechert, S., Synlett 1998, 169.
Stratakis, M.; Orfanopoulos, M., Tetrahedron 2000, 56, 1595.
Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharples.Kb; Michaels.Rc; Cutting, J. D.,
Journal of the American Chemical Society 1974, 96, 5254.
Thummel, R. P.; Rickborn, B., Journal of Organic Chemistry 1971, 36, 1365.
Tu, Y. Q.; Sun, L. D.; Wang, P. Z., Journal of Organic Chemistry 1999, 64, 629.
333
Umbreit, M. A.; Sharpless, K. B., Journal of the American Chemical Society 1977, 99,
5526.
Winkler, J. D.; Henegar, K. E.; Williard, P. G., Journal of the American Chemical Society
1987, 109, 2850.
Winkler, J. D.; Kim, S. H.; Harrison, S.; Lewin, N. E.; Blumberg, P. M., Journal of the
American Chemical Society 1999, 121, 296.
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T., Journal of the
American Chemical Society 2002, 124, 9726.
Wu, T. S.; Lin, Y. M.; Haruna, M.; Pan, D. J.; Shingu, T.; Chen, Y. P.; Hsu, H. Y.;
Nakano, T.; Lee, K. H., Journal of Natural Products 1991, 54, 823.
Zecheist.K; Brandl, F.; Hoppe, W., Tetrahedron Letters 1970, 4075.
Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H., Journal of the American Chemical
Society 1996, 118, 6634.
334
Index
Error! No index entries found.
324
ABOUT THE AUTHOR
Haifeng Tang (Wayne) was born on September 12, 1975, the first child of
Haoxing Tang and Fengjuan Shi. Wayne was raised along with his sister Yanfeng in
Wuxi, a small city in eastern China along the Yangzi River. He attended the Liu Village
Elementary School for 6 years. After elementary graduation, he then attended Yanqiao
Junior High School for 3 years where he was an active member of the school science
team. After passing the high school entrance examination in 1991, Wayne was admitted
to Wuxi No. 1 Middle School where his interest in science and nature found a foothold in
chemistry. After two years at Wuxi No. 1 High School, Wayne moved to Beijing to
attend the Chemistry Class organized by the Chinese Chemical Society as a prospective
chemist. In 1994, he was selected to participate in the 26th Chemistry Olympiad in Oslo,
Norway, where he won a silver medal.
In the fall of 1994, Wayne began his undergraduate studies at the University of
Science and Technology of China (USTC), majoring in chemistry and biology.
Discourage by the bland memorization of biology, Wayne shifted his focus to organic
chemistry. Inspired by the pharmaceutical applications of organic chemistry, he decided
to pursue a career in the pharmaceutical industry and seeking research experience.
Wayne approached Professor Qingxiang Guo, his instructor for first-semester organic
chemistry, for a position in his research group. Wayne spent an enjoyable year at the
Guo group working on the preparation of gene carriers. During that time, he decided to
go to the United States to study for a Ph.D. degree in Chemistry. In the fall of 1998,
325
Wayne began graduate studies at Yale University. He received his Master’s Degree in
2000 and his Doctorate in 2002 under the direction of Professor John L. Wood.
Wayne will move to Massachusetts Institute of Technology where he has accepted a post-
doctoral position with Professor Gregory C. Fu starting in January 2003.
![for · 1. The type of isomerism shown by the complex [CoCl 2 (en) 2] is (1) Geometrical isomerism (2) Linkage isomerism (3) Ionization isomerism (4) Coordination isomerism Answer](https://img.dokumen.tips/doc/110x75/5ea5e4a5a62be97117265dc3/for-1-the-type-of-isomerism-shown-by-the-complex-cocl-2-en-2-is-1-geometrical.jpg)
