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Ring Expansion/Contraction ReactionsLecture Notes
General Reviews:L. F. Silva, Tetrahedron 2002, 58, 9137.
Wagner-Meerwein Rearrangements/Carbocations:X. Criery, Chem. Rev. 1991, 91, 1625.
Grob Fragmentations:C. A. Grob, P. W. Schiess, Angew. Chem. Int. Ed. 1967, 6, 1.
Pinacol Rearrangements:Z.-L. Song, C.-A. Fan, Y.-Q. Tu, Chem. Rev. 2011, 111, 7523.
Wolff Rearrangements:W. Kirmse, Eur. J. Org. Chem. 2002, 2193
Ring Contractions/Expansions: Why Bother?
D. L. Boger, C. M. Baldino, J. Am. Chem. Soc. 1993, 115, 11418.
N N
NN
CO2MeCO2Me
MeOMeO
MeO2C
MeO2C
NH
NH
CO2MeMeOMeO
CO2Me
CO2Me
MeO2C
-[NH3](68%)
HN N
NNH
CO2MeCO2Me
MeOMeO
MeO2C
MeO2C
H2N NH
NHNH2
CO2MeCO2Me
MeOMeO
MeO2C
MeO2C
N
N
CO2HMeOMeO
CO2H
CO2H
HO2C
NaH, MeI, DMF
Me
MeN
N
CO2MeMeOMeO
CO2Me
CO2Me
MeO2C
Me
Me
(100%)LiOH
Reductivecleavage
Zn,HOAc
Enamine-Iminecondensation
(98%)
22 °C,24 h
Electrocyclization Cascades:Black's Hypothesis for the Biosynthesis of the Endiandric Acids
OO
OMeMe
OPMB
XX
OTBS
D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.
CO2H
HO2C
Ph
CO2H
PhCO2H
Ph
Ph
HO2CPh
HH
H
CO2H
HH
HPh
endiandric acid D
endiandric acid E
Diels-Alderreaction
A = conrotatory 8πelectrocyclization
B = disrotatory 6πelectrocyclization
A
A
B
B
HH
PhH
HH
endiandric acid A
CO2H
4π-Electrocyclic Reactions:Part of a Total Synthesis of Periplanone B
OO
OMeMe
OPMB
XX
OTBS
S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038.For a review, see: Classics in Total Synthesis I, Chapter 21
OH
Me
Me
OH
Me
Me
O
Me
Me
H
Me
Me
175 °C, toluene
O
Me
Me
hν
O
Me
Me
O
O
O
periplanone B
Oxy-Coperearrangement
4π-conrotatoryelectrocyclicring opening
KH,18-Crown-6
OO
OO
O
O
18-crown-6
(75%)
(82%)
Olefin isomerization
+
6π-Electrocyclic Reactions:Erasure of the Ring-Opened Product
OO
OMeMe
OPMB
XX
OTBS
E. J. Corey, A. G. Hortmann, J. Am. Chem. Soc. 1965, 87, 5736.
OO
MeMe
Me
dihydrocostunolide
H
OO
MeMe
H
Me
HO
Br
OO
MeMe
H
Me
HOO
O
MeMe
H
Me
HHO
OO
MeMe
H
Me
HOO
MeMe
Me H hν, MeOH,-18 °C
Al(Oi-Pr)3,i-PrOH, Δ
Al2O3,pyridine,
220 °C
LiBr,DMF,
120 °C
What is the name reaction in the second step?
H2,Raney NiMeOH,-18 °C
6π-conrotatoryelectrocyclicring opening
25 °C
OO
MeMe
H
Me
H
6π-disrotatoryelectrocyclization
6π-Electrocyclic Reactions:One of Three Pericyclic Reactions in a Colchicine Total Synthesis
OO
OMeMe
OPMB
XX
OTBS
A. Eschenmoser and co-workers, Helv. Chim. Acta 1961, 44, 540.
O
O
MeO
MeOMeO
O
O
O
Cl
Diels-Alderreaction
MeO
MeOMeO
OH
O
O
Cl
O O
MeO
MeOMeO
OH
O
O
Cl
MeO
MeOMeO
CO2Me
CO2Me
H
ClMeO
MeOMeO
CO2Me
CO2Me
norcaradiene derivative
MeO
MeOMeO
CO2Me
CO2Me
colchicine
RetroDiels-Alder
reaction
-[CO2]
t-BuOK
1. MeOH, H2SO42. CH2N2
6π-disrotatory electrocyclic ring openings are often referred to as norcaradiene rearrangements
6π-dis-
rotatoryopening
25 °C
Oxidative Ring Expansions
P. A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976.
OH
Me
OAc
OBn
OOTBS
OOOAc
OTBS
Me
OAc
OBn
OOOH
OTBS
Me
OAc
OBn
OH
Me
OAc
OBn
OOTBS
OOH
Me
OAc
OBn
OOTBS
OH
O
Me
OAc
OBn
OOH
OTBS
mCPBA,THF,
0→25 °C,12 h
Ac2O,4-DMAP,
(96%)
py, 0 °C,10 min
[Ketalization](100%)
-[H ]
Ring Contractions/Expansions: Why Bother?
K. Iida and co-workers, FEBS 2007, 274, 3475.
NH HN
NNH
MeCO2H
CO2Me
CO2H
CO2MeMeO2C
HO2CMe
MeHO2C
MeO2C
precorrin core
NH N
NN
MeCONH2
CONH2
Me
CONH2RHNOC
H2NOC
MeH2NOC
H2NOC
Me
Me
H
MeMe
Me
vitamin B12
Ring Contractions/Expansions: Why Bother?
T. Narender and co-workers, J. Nat. Prod. 2010, 73, 747.
BzOH OAcO
OHAcOMe
O
O
NH
O
Ph
Ph
OH
O
HOTaxolTM
H
OAcAcOMe
AcO
AcO
HOAc
H
OAcAcOMe
AcO
HOAc
H
OAcAcOMe
AcO
OAcH
BF3•OEt2
(70%)
abeotaxane frameworktaxane framework
Progesterone: A Critical Steroid
Me
HMe
OH H
OMeH
progesterone
Progesterone: A Critical Steroid
Me
HMe
OH H
OMe
H
progesterone
Me OH
Me
MeMe
MeMe
Me
MeO O
O
ClClTFA, 0 °C
Me
HMe
H H
OMe
H
Me
(72%)
Progesterone: A Critical Steroid
Me
HMe
OH H
OMe
H
progesterone
Me OH
Me
MeMe
MeMe
Me
MeO O
O
ClClTFA, 0 °C
Me
HMe
H H
OMe
H
Me
(72%)
Drugs of the Future?
with A. P. Brucks, D. S. Treitler, I. Moga, J. Am. Chem. Soc. 2012, 134, 17714.
NHNNH
NH2 HN
NHNH2N
•H2SO4
Octaporphyrin[30 electron system, n = 7]
O
HNH
H
HOH H
H
Cyclopamine
Drugs of the Future?
with A. P. Brucks, D. S. Treitler, I. Moga, J. Am. Chem. Soc. 2012, 134, 17714.
NHNNH
NH2 HN
NHNH2N
•H2SO4
Octaporphyrin[30 electron system, n = 7]
O
HNH
H
HOH H
H
Cyclopamine
Ring Contractions/Expansions: Why Bother?
A. Giannis and co-workers, J. Am. Chem. Soc. 2010, 132, 9968.
OH
HO O
HHBnO
N
NTf Tf
Cl
O
O
HBnO
O
O
HBnO
H
H
+
74% 22%
HO
H
O
H HMeO
H
O
H HMeO
N
NTf Tf
Cl
HMeO
H H
O
HH
39% 41%
+
Ring Contractions/Expansions: Why Bother?
A. Giannis and co-workers, J. Am. Chem. Soc. 2010, 132, 9968.
OH
HO O
HHBnO
N
NTf Tf
Cl
O
O
HBnO
O
O
HBnO
H
H
+
74% 22%
HO
H
O
H HMeO
H
O
H HMeO
N
NTf Tf
Cl
HMeO
H H
O
HH
39% 41%
+
Ring Contractions/Expansions: Why Bother?
H.-G. Schmalz and co-workers, Org. Lett. 2012, 14, 3692.
O
H
AcO
H
H
OH
O
H
AcO
H
H
O
H
AcO
H
H
OMe
What other productscould have formed?
BF3•OEt2
MeOH,CH2Cl2
(93%)
Ring Contractions/Expansions: Why Bother?
E. M. Carreira and co-workers, J. Am. Chem. Soc. 2002, 124, 14826.
NH
N
MeNHNO
H HHO
strychnofoline
NH
OBnO
MgI2
NH
OBnO
IN OTBDPS
NH
N
OH H
OTBDPS
BnO(55%)
Wagner-Meerwein Rearrangements
E. M. Carreira and co-workers, J. Am. Chem. Soc. 2002, 124, 14826.
OH[1,2-alkyl
shift]
OCHOO
Can you devisea mechanism
for the openingoperations?
(51%)
45 oC
HCO2H
O
O
Wagner-Meerwein Rearrangements
A. B. Smith and co-workers, J. Org. Chem. 1984, 49, 4094.
O
THF,50 oC
H2SO4
OHO
OHO
OOO
O
quadrone
[1,2-alkylshift]
(85%)
Pinacol Rearrangements for Ring Contractions and Expansions
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
H2SO4
conc.H2SO4
40%H2SO4
Ph
OPh
PhH
O
Ph
PhPh
OHHO O
Original discovery [R. Fittig, 1860]
Controlling product distribution [S. Danilov, 1917]
OHHO
PhPh
HPh
Key mechanistic consideration: diol/epoxide equilibrium
OHHO
RR
RR
OH
RR
RR
R
OR
RR
RR
RR
O
protic acid or Lewis acid conditions
Pinacol Rearrangements for Ring Contractions and Expansions
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
H2SO4
conc.H2SO4
40%H2SO4
Ph
OPh
PhH
O
Ph
PhPh
OHHO O
Original discovery [R. Fittig, 1860]
Controlling product distribution [S. Danilov, 1917]
OHHO
PhPh
HPh
Key mechanistic consideration: diol/epoxide equilibrium
OHHO
RR
RR
OH
RR
RR
R
OR
RR
RR
RR
O
protic acid or Lewis acid conditions
Pinacol Rearrangements for Ring Contractions and Expansions
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
OHOHOH
OH
OHOHOHOH
O
O(93%) (7%)
O
O(97%) (3%)
aq.HClO4
aq.HClO4
Pinacol Rearrangements for Ring Contractions and Expansions
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
OHOHOH
OH
OHOHOHOH
O
O(93%) (7%)
O
O(97%) (3%)
aq.HClO4
aq.HClO4
Pinacol Rearrangements for Ring Contraction
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
originally proposed structure of diazonamide AHO
O
N
MeMe
ON
ON Cl
NH
Cl
OOH
NH2N
Me Me
O
H H
revised structure of diazonamide A
O
O
N
MeMe
ON
ON Cl
NH
Cl
NH
N
Me Me
O
H H
HO
+
BnO
O
N
MeMe
ON
O
CBzHNH
BrO
Br
CN
BnO
O
N
MeMe
ONBocHN
H
BrO
Br
CN
OHOH
H
HOBnO
OH2ArO
Br
Br+1. p-TsOH
(3.0 equiv), toluene, 95 oC, 40 min2. N-(benzyloxy- carbonyloxy)- succinimide
(54%overall)
Pinacol Rearrangements for Ring Expansion
P. S. Baran and co-workers, Science 2013, 341, 878.
OTMS
Me
MeMeHO
OOO Me
OTBSH
Me
Me
Me
Me
H
Me
OHMe
H
Me
MeH
Me
OHMe
HOO
OHOH
OH phorbol
Me
HOHOOH
O
MeMeMe
H
HO ingenol putative intermediate
BF3•OEt2(10 equiv),
CH2Cl2-78 oC to
-40 oC, 30 min(80%)
Me
HOHOOH
O
MeMeMe
H
HO ingenol
Me
Me
O
MeMeMe
H
OTBSOOO
Pinacol Rearrangements for Ring Expansion
P. S. Baran and co-workers, Science 2013, 341, 878.
OTMS
Me
MeMeHO
OOO Me
OTBSH
Me
Me
Me
Me
H
Me
OHMe
H
Me
MeH
Me
OHMe
HOO
OHOH
OH phorbol
Me
HOHOOH
O
MeMeMe
H
HO ingenol putative intermediate
BF3•OEt2(10 equiv),
CH2Cl2-78 oC to
-40 oC, 30 min(80%)
Me
HOHOOH
O
MeMeMe
H
HO ingenol
Me
Me
O
MeMeMe
H
OTBSOOO
Semi-Pinacol Rearrangements for Ring Contractions and Expansions
P. G. Harran and co-workers, Angew. Chem. Int. Ed. 2001, 40, 4765.
R RHO RM
XX = OMs, OTs, Cl, Br, I,
N2+, SR, SeR, etc.
Bronsted acid or baseR R
O
RM
RR2
R1
O RM
X
H
nO σ*C-C (app)σC-C σ*C-X (app)
R
HO RMR
O
R RM
R
E RE
RR
R
R
ORM
RR
REH
Electrophiles for intramolecular cases:oxocarbeniums, thiocabeniums, iminiums
Electrophiles for intermolecular cases:haloniums, seleniums, proton, Lewis acids
Pinacol Rearrangements for Ring Expansion/Contraction
J. K. Cha and co-workers, Angew. Chem. Int. Ed. 2005, 44, 121.Tanino and co-workers, J. Am. Chem. Soc. 2003, 125, 1498.
AlMe3,CH2Cl2
-78 to 0 oC
MeH
H
OAl
H
OH
H
(82%)89
10
114
8910
11
4
H
O
MeMeMe
HHOMe
MeH
Me
OH
HO
O
AlMe3,CH2Cl2
(76%over
2 steps)
HMe
O
H HOR
OH
OMe
AlR = TIPS
MeO
O
MeMeMe
HHO
OTIPS
MeMeMe
HOH
OTIPS
O
OMe
Pinacol Rearrangements for Ring Expansion/Contraction
J. K. Cha and co-workers, Angew. Chem. Int. Ed. 2005, 44, 121.Tanino and co-workers, J. Am. Chem. Soc. 2003, 125, 1498.
AlMe3,CH2Cl2
-78 to 0 oC
MeH
H
OAl
H
OH
H
(82%)89
10
114
8910
11
4
H
O
MeMeMe
HHOMe
MeH
Me
OH
HO
O
AlMe3,CH2Cl2
(76%over
2 steps)
HMe
O
H HOR
OH
OMe
AlR = TIPS
MeO
O
MeMeMe
HHO
OTIPS
MeMeMe
HOH
OTIPS
O
OMe
Pinacol Rearrangements for Ring Expansion
J. S. Kingsbury and E. J. Corey, J. Am. Chem. Soc. 2005, 127, 13813.
HO
OMTM
O
O
AlMe3,toluene,CH2Cl2,
4 oC(90%)
O
O
OOO
O
OCH2SMe
AlHMe3
OHH
β-araneosene
OHOH
MsCl,CH2Cl2,
-30 to 4 oC
(98%)
Pinacol Rearrangements for Ring Expansion
J. S. Kingsbury and E. J. Corey, J. Am. Chem. Soc. 2005, 127, 13813.
HO
OMTM
O
O
AlMe3,toluene,CH2Cl2,
4 oC(90%)
O
O
OOO
O
OCH2SMe
AlHMe3
OHH
β-araneosene
OHOH
MsCl,CH2Cl2,
-30 to 4 oC
(98%)
Pinacol Rearrangements for Ring Contraction
Y. Kita and co-workers, J. Am. Chem. Soc. 2001, 123, 3214.
N
CpO2COMeOMe
O
BF3•Et2OCH2Cl2, 0 oC
N
CpO2COMeOMe
OBF3
(94%) N
OMeOMe
O
CpO2C
Cp = (1S)-(_)-camphanic acid
O
O
O
R
O
BF3
RCOO
H
O
RCOO1
23
1
2
3HN
HOO
O
O
HO
OH
O
O OMe
fredericamycin A
Pinacol Rearrangements for Ring Expansion
H. Nemoto and co-workers, J. Chem. Soc. Perkin Trans. 1 2000, 16, 2629.
MeOH
OH Pd(OAc)2,HMPA/
THF (1:4)
MeOH
O HX2Pd
MeOH
OX2Pd
MeOH
O
MeOH
O
+
(60%)(2.7:1 A:B)
HOH
O
equilenin A B
Semi-Pinacol Rearrangements for Ring Expansion
F. D. Toste and co-workers, Org. Lett. 2008, 10, 4315.
HO AuPPh3Cl (3 mol %),AgSbF6 (3 mol %),
CH2Cl2, 25 oC
H
H
OMePdCl2(CH3CN)2
DDQ, THF(70%)
H
H
O
H
H (±)-ventricosene
OHH
Au
OHH
Au
(87%)
H
H
O
OHH
AuH
Grob Fragmentations
C. A. Grob, P. W. Schiess, Angew. Chem. Int. Ed. Engl. 1967, 6, 1.
a b c d x
electrofuge nucleofuge
a b c d x+ +
OH
OH
OTsH
HTsO
NaHO
OTsH
O
O
Grob Fragmentations
C. A. Grob, P. W. Schiess, Angew. Chem. Int. Ed. Engl. 1967, 6, 1.
a b c d x
electrofuge nucleofuge
a b c d x+ +
OH
OH
OTsH
HTsO
NaHO
OTsH
O
O
Grob Fragmentations for Ring Expansion
E. J. Corey and co-workers, J. Am. Chem. Soc. 1964, 86, 485
MeMe
MeOTs
HO
MeMe
O
MeNaH
[Grobfrag-
mentation]
MeMe MeH H H
H H H
caryophyllene
Grob Fragmentations
L. A. Paquette and co-workers, J. Am. Chem. Soc. 2002, 124, 6542.
OH
MeBnO
Me
Me
HO
H
MeMe
1. MsCl
2. KOt-Bu
Me
Me
BnO
O
MeMeMe
H(98%)
Me
Me O
MeMeMe
H
O
Ojatrophatrione
Grob Fragmentations
J. D. Winkler and co-workers, Org. Lett. 2003, 5, 1805.
H
H OH
O O
O
O
HO
H
H O
O O
OK2CO3
DMF,75 oC
H
H
OO
OH
OH
H
H
OO
OMe
OH MeI,Ag2O
(68%)
(76%)
core of eleutherobin
Benzylic Acid Rearrangements in Total Synthesis
K. Gademann and co-workers, Chem. Eur. J. 2010, 16, 7692.
R
OH OO
R
O
OO
OO
O
R R
Otaiwaniaquinoid framework
LiHMDSTHF,
-15 oC
R = OMe6%
R = H65%
Benzylic Acid Rearrangements in Total Synthesis
K. Gademann and co-workers, Chem. Eur. J. 2010, 16, 7692.
R
OH OO
R
O
OO
OO
O
R R
Otaiwaniaquinoid framework
LiHMDSTHF,
-15 oC
R = OMe6%
R = H65%
Favorskii Rearrangements in Synthesis
H. O. House and co-workers, J. Org. Chem. 1965, 30, 2948.
Cl
H
O
H
O
H
O OMe
H
O OMe
NaOMe
MeOH
Favorskii Rearrangements in Synthesis
H. Takeshita and co-workers, J. Org. Chem. 1994, 59, 6490.
ClO O
OH
KOH;acid
(88%)
"Quasi-Favorskii" Rearrangement for Ring Contraction
M. Harmata and S. Wcharasindhu, Org. Lett. 2005, 7, 2563.
O
BrMeMe
LiOBr +
THF,-78 oC
Me
Me-30 oC
(90%) O
MeMe
(from [4+3]reaction)
O
H
AcO
H
O
Me Me
O
H
AcOCO2Me
OAc
tricycloclavulone
Ring Contraction of Cross-Conjugated Dienones
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2001, 40, 3679.
OO
Osantonin
isophotosantoniclactone
OO
OO
O
O
OO
O
H2O
O
O
O
HOH
Dozensof
natural products
(33%)
hν
AcOH/H2O
Ring Contraction of Cross-Conjugated Dienones
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2001, 40, 3679.
OO
Osantonin
isophotosantoniclactone
OO
OO
O
O
OO
O
H2O
O
O
O
HOH
Dozensof
natural products
(33%)
hν
AcOH/H2O
Norrish Type-1 Cleavage Pathways
K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2001, 40, 3679.
Me
MeO OO
H
Me
MeO O
H
Me
MeO OO
H
Me
MeO O
H
hν
(90%)
Wolff Rearrangements
L. Wolff, Liebigs Ann. Chem. 1902, 325, 129.
ON2
ON N Ag2O,
H2O
O
OH
[or hv, H2O]
ON N O
O• O
O
[1,2]
Ag2O or hνH2O
Wolff Rearrangements
L. Wolff, Liebigs Ann. Chem. 1902, 325, 129.
ON2
ON N Ag2O,
H2O
O
OH
[or hv, H2O]
ON N O
O• O
O
[1,2]
Ag2O or hνH2O
The Wolff Photochemical Rearrangement
V. Mascitti, E. J. Corey, J. Am. Chem. Soc. 2004, 126, 15664.For a review, see: W. Kirmse, Eur. J. Org. Chem. 2002, 2193.
O
N2•O
O
CO2MeCO2H
pentacycloanemmoxic acid
hν
MeOH
MeOH, 2 h
(72%)
O O
Wolff Rearrangements
P. A. Grieco and co-workers, J. Am. Chem. Soc. 1999, 122, 9891.L. N. Mander and co-workers, J. Am. Chem. Soc. 1997, 120, 3828.
O
O
OMe
MeOMOM
BnO
H H
H O OMe
MeOMOM
BnO
H H
H
MeO2C
1. NaH, HCO2Et2. TsN3
3. hν, MeOH(48%)
HO
ON2
BnO2C H
hν, MeOH O O
HO
BnO2C H CO2Me(79%)
O O
Wolff Rearrangements
P. A. Grieco and co-workers, J. Am. Chem. Soc. 1999, 122, 9891.L. N. Mander and co-workers, J. Am. Chem. Soc. 1997, 120, 3828.
O
O
OMe
MeOMOM
BnO
H H
H O OMe
MeOMOM
BnO
H H
H
MeO2C
1. NaH, HCO2Et2. TsN3
3. hν, MeOH(48%)
HO
ON2
BnO2C H
hν, MeOH O O
HO
BnO2C H CO2Me(79%)
Wolff Rearrangement Strategy to Access Dolabellatrienone
Me
Me
Me
H O
Me
Me
Me
H
CO2Me
Me
Me
Me
H
Me
Me
Me
H
O
Me
Me
Me
H O
N2
Me
Me
Me
H
O
MeMe
OHCO2Me
dolabellatrienone
[Wolffrearrangement]
Wolff Rearrangement Strategy to Access Dolabellatrienone
Me
Me
Me
H O
Me
Me
Me
H
CO2Me
Me
Me
Me
H
Me
Me
Me
H
O
LDA, -78 °C, THF;O2, P(OEt)3
2. NaIO4 on silica gel
1. NaHMDS, -78 °C, THF; HCO2Et, -78→0 °C
(82% overall)
Me
Me
Me
H O
N2
hν, 450 W,MeOH,
25 °C, 2 h2. TsN3, Et3N CH2Cl2
(80%)
Me
Me
Me
H
O
MeMe (86% overall)
1. LiAlH4
(73%)
OHCO2Me
dolabellatrienone
[Wolffrearrangement]
New Wolff Rearrangement Strategy to Access Dolabellanes
Me
Me
Me
H O
Me
Me
Me
H
Me
Me
Me
H O ON2
New Wolff Rearrangement Strategy to Access Dolabellanes
Me
Me
Me
H O
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H O
[Wolffrearrange-
ment]
ON2
CO2MeCO2Me
severalnatural
products
Wolff Rearrangement Strategy to Access Dolabellatrienone
Me
Me
Me
H O
Me
Me
Me
H
Me
Me
Me
H O(79%)
ON2
LiHMDS,-78 °C, THF;
TMSCl;IBX•MPO,
DMSO, 25 °C(79%)
Trisyl azide,BnEt3NCl,
18-Crown-6.benzene/
66% aq.KOH,45 °C, 48 h
N
OMe
OMPO
OI
O
OHO
IBX
K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. Int. Ed. 2002, 41, 993.L. Lombardo, L. N. Mander, Synthesis 1980, 368.
Wolff Rearrangement Strategy to Access Dolabellatrienone
Me
Me
Me
H O
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H O
hν, 450 W,MeOH,
25 °C, 2 h
(79%)[Wolff
rearrange-ment]
ON2
CO2Me
LiHMDS,-78 °C, THF;
TMSCl;IBX•MPO,
DMSO, 25 °C(79%)
Trisyl azide,BnEt3NCl,
18-Crown-6.benzene/
66% aq.KOH,45 °C, 48 h
N
OMe
OMPO
OI
O
OHO
IBX
K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. Int. Ed. 2002, 41, 993.L. Lombardo, L. N. Mander, Synthesis 1980, 368.
Wolff Rearrangement Strategy to Access Dolabellatrienone
Me
Me
Me
H O
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H O
hν, 450 W,MeOH,
25 °C, 2 h
(79%)[Wolff
rearrange-ment]
ON2
CO2MeCO2Me
LiHMDS,-78 °C, THF;
TMSCl;IBX•MPO,
DMSO, 25 °C(79%)
Trisyl azide,BnEt3NCl,
18-Crown-6.benzene/
66% aq.KOH,45 °C, 48 h
N
OMe
OMPO
OI
O
OHO
IBX
DBU,115 °C, 18 h
(68%)
K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. Int. Ed. 2002, 41, 993.L. Lombardo, L. N. Mander, Synthesis 1980, 368.
Wolff Rearrangement Strategy to Access Dolabellanes
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H(67%)
CO2Me
E. J. Corey, R. S. Kania, Tetrahedron Lett. 1998, 39, 741.J. S. Kingsbury, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 13813.
MeMe
OHpalominol
O
Me Me
dolabellatrienone
MeLi,THF, -20°C
PDC,4 A M.S.
CH2Cl2, 25°C(92%)
Wolff Rearrangement Strategy to Access Dolabellanes
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H(67%)
CO2Me
E. J. Corey, R. S. Kania, Tetrahedron Lett. 1998, 39, 741.J. S. Kingsbury, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 13813.
MeMe
OHpalominol
O
Me Me
dolabellatrienone
Me
Me
Me
H O
1. L-Selectride2. LDA, O23. LiAlH4, NaIO4
(51%overall)
MeLi,THF, -20°C
PDC,4 A M.S.
CH2Cl2, 25°C(92%)
Wolff Rearrangement Strategy to Access Dolabellanes
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
H(67%)
CO2Me
E. J. Corey, R. S. Kania, Tetrahedron Lett. 1998, 39, 741.J. S. Kingsbury, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 13813.
MeMe
OHpalominol
O
Me Me
dolabellatrienone
Me
Me
Me
H
Me
Me
Me
HMe MeO
1. L-Selectride2. LDA, O23. LiAlH4, NaIO4
(51%overall)
1. MOMI, i-Pr2NEt, THF, Δ, 12 h2. Li/NH3
Me
Li
β-araneoseneisoedunol
Me
Me
Me
HMe
OH
MeLi,THF, -20°C
PDC,4 A M.S.
CH2Cl2, 25°C(92%)
Et2O, -78°C(82%) (92% overall)
Planned Synthetic Approach to Presilperfolan-8-ol
with P. Hu, J. Am. Chem. Soc. 2017, 139, 5007.
O
MeMe
Me
Me
H LDA,Br
(90%)(5:1 dr)
[6 gram scale]
O
MeMe
Me
Me
H KHMDS; Comins'reagent(86%)(5:1 rr)
[7 gram scale]
MeMeMe
H
Me
OTf
H
Me
MeMe
MeH
Me O
MeMe
MeOH
presilphiperfolan-8-ol
[RingContraction]Me
Me
MeH
Me
HOH
Pd(OAc)2 (10 mol %),DPEPhos (20 mol %),
Et3N (2 equiv), toluene, 0.1 M, 110 °C
[2 gramscale]
3 steps
[gram scale]
(28% over4 steps)
13 step total synthesis of moleculeFirst 10 steps performed on gram scale
[1 step from(R)-pulegone]
H
Use of the Wolff Rearrangement to Afford a trans-Fused [3.3.0]-Bicyclooctane
with P. Hu, J. Am. Chem. Soc. 2017, 139, 5007.
MeMe
MeH
Me O
HOH p-ABSA,DBU Me
Me
MeH
Me O
HOR N2
presilphiperfolan-8-ol
MeMe
MeH
Me
HOR
CO2Me*MeMe
MeH
Me
HOR
CHOMeMe
MeH
Me
HOH
(95% over2 steps)
MeMe
MeH
Me O
HORTMSOTf,Et3N
R = TMS
>800 mg prepared
[Wolffrearrange-ment]
Use of the Wolff Rearrangement to Afford a trans-Fused [3.3.0]-Bicyclooctane
with P. Hu, J. Am. Chem. Soc. 2017, 139, 5007.
MeMe
MeH
Me O
HOH p-ABSA,DBU Me
Me
MeH
Me O
HOR N2
presilphiperfolan-8-ol
MeMe
MeH
Me
HOR
CO2Me*MeMe
MeH
Me
HOR
CHOMeMe
MeH
Me
HOH
(95% over2 steps)
(83%)
MeMe
MeH
Me O
HORTMSOTf,Et3N
R = TMS125 W Hg UV-lamp,
MeOH
>800 mg prepared
[Wolffrearrange-ment]
Use of the Wolff Rearrangement to Afford a trans-Fused [3.3.0]-Bicyclooctane
with P. Hu, J. Am. Chem. Soc. 2017, 139, 5007.
MeMe
MeH
Me O
HOH p-ABSA,DBU Me
Me
MeH
Me O
HOR N2
presilphiperfolan-8-ol
DIBAL-H;t-BuOH,
Dess-Martinperiodinane Me
Me
MeH
Me
HOR
CO2Me*MeMe
MeH
Me
HOR
CHOMeMe
MeH
Me
HOH
(95% over2 steps)
(83%)
(93%)
MeMe
MeH
Me O
HORTMSOTf,Et3N
R = TMS125 W Hg UV-lamp,
MeOH
>800 mg prepared
[Wolffrearrange-ment]
Use of the Wolff Rearrangement to Afford a trans-Fused [3.3.0]-Bicyclooctane
with P. Hu, J. Am. Chem. Soc. 2017, 139, 5007.
MeMe
MeH
Me O
HOH p-ABSA,DBU Me
Me
MeH
Me O
HOR N2
presilphiperfolan-8-ol
DIBAL-H;t-BuOH,
Dess-Martinperiodinane
1. Rh(PPh3)3Cl2. TBAF Me
Me
MeH
Me
HOR
CO2Me*MeMe
MeH
Me
HOR
CHOMeMe
MeH
Me
HOH
(95% over2 steps)
(83%)
(93%)(40% over2 steps)
MeMe
MeH
Me O
HORTMSOTf,Et3N
R = TMS125 W Hg UV-lamp,
MeOH
>800 mg prepared
[Wolffrearrange-ment]
Ring Contractions/Expansions: Take-Home Challenge
H.-G. Schmalz and co-workers, Org. Lett. 2012, 14, 3692.
?????
The Laurencia Family of Haloethers:An Open Biogenetic Question for their Formation
OBr
Me OAc
HOBr
Me
HOO
H
laurefucinlaurencin
O
Br
H
O
H
HBr
laurallene
H
Me
Fujiwara, K. “Total Synthesis of Medium-Ring Ethers from Laurencia Red Algae” in Topics in Heterocyclic Chemistry (Vol. 5), Kiyota, H. (Ed.), Springer-Verlag: Berlin, 2006, pp. 97-148.
laureoxanyne
OBr
MeH
BrO
First member isolated in 1965 by IrieOver 150 members total
Largest subset (>50 members) have 8-membered bromoetherTotal and Formal Syntheses of Laurencin: Murai, Overman, Palenzuela, Holmes,
Hoffmann, Crimmins, Yamamoto, Kim, Fujiwara, Pansare, OrtegaOther Syntheses: Overman, Crimmins, Fujiwara, Boeckman, Hoshi, Kim, Takeda
The Laurencia Family of Haloethers:An Open Biogenetic Question for their Formation
OBr
Me OAc
H
laurencin
Fujiwara, K. “Total Synthesis of Medium-Ring Ethers from Laurencia Red Algae” in Topics in Heterocyclic Chemistry (Vol. 5), Kiyota, H. (Ed.), Springer-Verlag: Berlin, 2006, pp. 97-148.
O
HO
HO OPivO
O OPiv
O
(92%)
Pb(OAc)4
Murai and co-workers, Tetrahedron Lett. 1992, 33, 4345.
Overman and co-workers, J. Am. Chem. Soc. 1995, 117, 5958.
Crimmins and co-workers, J. Am. Chem. Soc. 1999, 121, 5653.
33 linearsteps total
OAcO
Me
OMe
OPiv
PhS
OAcO
Me OPiv
SPh
OBr
Me OAc
H
laurencin
23 linearsteps total
BF3•OEt2,t-BuOMe
(57%)
OAcO
AcO OTBDPSOBr
Me OAc
H
laurencin
OAcO
AcO OTBDPS(97%)
24 linearsteps totalGrubbs 1
The Laurencia Family of Haloethers:An Open Biogenetic Question for their Formation
Murai, A. “Biosynthesis of Cyclic Bromoethers from Red Algae” in Comprehensive NaturalProducts Chemistry (Vol. 1), Sankawa, U. (Ed), Elsevier: New York, 1999, pp. 303-324.
OBr
Me OH
HHO
MeOH
crudebromo-
peroxidase
0.015%(0.085%brsm)
laurediol deacetyllaurencin
Murai and co-workers, Chem. Lett. 1994, 2307
HOMe
OHlaurediol
O
Me
Br
HO
H O
Me
Br
HO
HBr
"Br " * 8-memberedbromoether
naturalproducts
"Br "
Our alternative hypothesis:
The Laurencia Family of Haloethers:An Open Biogenetic Question for their Formation
Murai, A. “Biosynthesis of Cyclic Bromoethers from Red Algae” in Comprehensive NaturalProducts Chemistry (Vol. 1), Sankawa, U. (Ed), Elsevier: New York, 1999, pp. 303-324.
OBr
Me OH
HHO
MeOH
crudebromo-
peroxidase
0.015%(0.085%brsm)
laurediol deacetyllaurencin
Murai and co-workers, Chem. Lett. 1994, 2307
HOMe
OHlaurediol
O
Me
Br
HO
H O
Me
Br
HO
HBr
"Br " * 8-memberedbromoether
naturalproducts
"Br "
Our alternative hypothesis:
Value and Challenges of a Bis-Oxonium Biosynthetic Intermediate
with D. S. Treitler, A. P. Brucks, W. Sattler, J. Am. Chem. Soc. 2011, 133, 15898.
OBr
Me
HOO
H
laurefucin
OBr
MeH
deacyllaurencinOH
HOMe OH
laurediolMe OH
O H
Br
OH
O H
Br
Me
Br
"Br " "Br "
[loss of Br ]
Value and Challenges of a Bis-Oxonium Biosynthetic Intermediate
with D. S. Treitler, A. P. Brucks, W. Sattler, J. Am. Chem. Soc. 2011, 133, 15898.
OBr
Me
HOO
H
laurefucin
OBr
MeH
deacyllaurencinOH
HOMe OH
laurediolMe OH
O H
Br
OH
O H
Br
Me
Br
"Br " "Br "
[loss of Br ]
Value and Challenges of a Bis-Oxonium Biosynthetic Intermediate
with D. S. Treitler, A. P. Brucks, W. Sattler, J. Am. Chem. Soc. 2011, 133, 15898.
OBr
Me
HOO
H
laurefucin
OBr
MeH
deacyllaurencinOH
OBr
Me
O
H
Br
laureioxanyne
HOMe OH
laurediolMe OH
O H
Br
OH
O H
Br
Me
Br
"Br " "Br "
[loss of Br ]
[intramolecularcyclization]
Value and Challenges of a Bis-Oxonium Biosynthetic Intermediate
with D. S. Treitler, A. P. Brucks, W. Sattler, J. Am. Chem. Soc. 2011, 133, 15898.
OBr
Me
HOO
H
laurefucin
OBr
MeH
deacyllaurencinOH
OBr
Me
O
H
Br
laureioxanyne
HOMe OH
laurediolMe OH
O H
Br
OH
O H
Br
Me
Br
"Br " "Br "
[loss of Br ]
[intramolecularcyclization]
[external nucleophileand SN2]
H2O
