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The Hetero Diels-AlderCycloaddition of Dienes withAldehydes: Developments inReactivity and Selectivity
Luke Zuccarello
Presentation Outline
1. Discovery and early work2. Methods for improved reactivity, regioselectivity, and diastereoselectivity
• Activation of diene • High pressure • Lewis acid catalysis
3. Asymmetric methods• Chiral auxiliaries• Chiral catalysts
4. References for applications to total synthesis5. Conclusions
Early Work
O
R
R2H
+O
R2
R
O
R2
+
R
• Diels-Alder reaction discovered in 1928• First report of a hetero Diels-Alder (HDA) reaction in 1951 by Gresham and Steadman
Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98.Gresham, T. L.; Steadman, T. R. J. Am. Chem. Soc. 1949, 71, 737.
• Under thermal conditions, R2 = strong EWG (e.g. glyoxylates) or H (formaldehyde)• Regioselectivity poor when R γ EDG.
O
R2H
+O
R2
OR OR
• 1962: EDG on diene shown to increase reactivity and regioselectivity
Kubler, D. G. J. Org. Chem. 1962, 27, 1435.
Early Work
Electron Donating Groups on Diene:Examples
Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 28, 1059.Hosomi, A.; Sakata, Y. Sakurai, H. Tetrahedron Lett. 1985, 26, 5175.
Electron Donating Groups on Diene:Examples
Schmidt, R. R.; Wagner, A. Synthesis 1982, 958.Schmidt, R. R.; Wagner, A. Tetrahedron Lett. 1983, 24, 4661.
FMO Rationale for Increased Reactivity
O
H
E
EDG
LUMO
HOMO
• The HDA cycloaddition between carbonyl compounds and dienes occurs with normal electron demand
FMO Rationale for IncreasedRegioselectivity
O
H R
EDG
O
R
EDG
FMO Rationale for IncreasedRegioselectivity
O
H REDG
O
REDG
Volumes of Activation in ChemicalReactions
• Volume of activation is a quantity derived from the dependence of a rate constant on pressure
• ΔV ‡ = V ‡ – Σ (r Vr)
• ≠ln(k)/≠P = - ΔV ‡ / RT
• If ΔV ‡ is negative, then increased pressure can, in principle, increase reaction rate
IUPAC Compendium of Chemical Terminology, 2nd Ed. 1997.Asano, T.; Le Noble, W. J. Chem. Rev. 1978, 78, 407.Holzapfel, W. B.; Isaacs, N. S. Eds. High Pressure Techniques in Chemistry and Physics- A Practical Approach. Oxford University Press: New York, 1997.
Volumes of Activation in OrganicReactions
Holzapfel, W. B.; Isaacs, N. S. Eds. High Pressure Techniques in Chemistry and Physics- A Practical Approach. Oxford University Press: New York, 1997.
Use of Pressure in HDA Reactions
O
RH
+
O
R
OMe OMe
70 : 30626520.0Me
78 : 22162023.5n-pentyl
73 : 27735019.52-Furyl
75 : 25805019.5Ph
Cis : TransYield(%)
Temp.(°C)
Pressure(kbar)
R
Jurczak, J.; Chmielewski, M.; Filipek, S. Synthesis 1979, 41.
-ΔV ‡ cis > -ΔV ‡
trans ?
Lewis Acid Catalysis of HDA Reaction:FMO Energy and Orbital Coefficient
Perturbation
Y
X
E
Y
LA
Lewis Acid Catalysis of HDA Reaction:Eu(fod)3
O
RH
+O
R
OMe
TMSO
1) Eu(fod)3
2) Et3N, MeOHO
O
RO
+
OMe OMe
2.8 : 1Me
1.2 : 1
6 : 112 : 1
Cis : Trans
C5H11
2-furylPh
R
Bernardski, M. D.; Danishefsky, S. J. J. Am. Chem. Soc. 1983, 103, 3716.
O
RH
+
O
R
OMe
TMSO
Eu(fod)3
O
O
RTMSO
OMe
O
RO
OMe
TFA Et3N, MeOH
R Yield (%)
Ph 66
Me 66
n-C6H13 49
R Yield (%)
Ph 60
Me 84
n-C6H13 90
R Yield (%)
Ph 71
Me 55
n-C6H13 66
Bernardski, M. D.; Danishefsky, S. J. J. Am. Chem. Soc. 1983, 103, 3716.
Lewis Acid Catalysis of HDA Reaction:Eu(fod)3
Lewis Acid Catalysis of HDA Reaction:ZnCl2
Danishefsky, S. J.; Kerwin, J. F. Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 104, 358.
43Pri
48Et65Ph80CHNHCBz70CH2SPh87CH2OBn
Yield (%)R
O
RH
+O
R
OMe
TMSO
1) ZnCl2
2) H+
O
Lewis Acid Catalysis of HDA Reaction:ZnCl2
O
RH
+O
R
OMe
TMSO
1) ZnCl22) TFA
O
O
RO
+
83
7891
Yield (%),Endo (cis)
2PH(CH2)3
2Ph2C5H11
Yield (%),Exo (trans)
R
Danishefsky, S. J.; Kerwin, J. F. Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 104, 358.
Lewis Acid Catalysis of HDA Reaction:Felkin or Anti-Felkin?
• MgBr2, ZnCl2, EuL3 : If X > R and X cannot chelate with LA, then endo (cis), Felkin cycloaddition products are favored
Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256.
Lewis Acid Catalysis of HDA Reaction:Felkin or Anti-Felkin?
If LA = MgBr2 and X has lone pair available for chelation, then major cycloaddition product is exo (trans), anti-Felkin
Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256.
Cylcoaddition or Aldol?
O
RH
+
OMe
TMSO
Y
OH
RO
Y
X
OMe
X
H+
O
RO
Y
X
OH
RO
Y
X
OMe
O
RO
Y
X
TiCl4
• TiCl4 catalyzes Mukaiyama aldol mechanism • R is chelating group: cis, anti- Felkin products• R is non-chelating: trans products
Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. J. Am. Chem. Soc. 1984, 106, 2456.
Summary
• ZnCl2 , EuL3 : pericyclic; gives endo, Felkin products w/ non-chelating aldehydes• MgBr2 : pericyclic; gives endo, Felkin products w/ non-chelating aldehydes, but exo, anti-Felkin w/ chelating aldehyde• TiCl4 : aldol; gives exo products w/ non-chelating aldehydes, but endo, anti-Felkin w/ chelating aldehyde• Exo, Felkin can be obtained by altering diene configuration (Z instead of E)
Asymmetric HDA: Chiral Auxiliaries• Protected sugars have been used as chiral auxiliaries on diene
• Result: high diene facial selectivity, but little endo/exo selectivity
David, S.; Eustache, J. J. Chem. Soc. Perkin Trans. 1979, 1, 2521. (and ref. therein)
Asymmetric HDA: Chiral Auxiliaries• Bornanesulfones have been shown to be useful chiral auxiliaries in HDA reaction
Bauer, T.; Chapuis, C.; Kozak, J.; Jurczak, J. Helv. Chim. Acta 1989, 72, 482.
Catalytic Asymmetric HDA Reactions• Jacobsen: chiral tridentate Schiff base chromium(III) catalyst
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 2398.
O
ON
Cr
SbF6
• Reacts non-activated aldehydes with dienes having one or more oxygen substituents
Catalytic Asymmetric HDA ReactionsOSiR3
R'CHO+
1) 3 mol% cat. 4 Å mol. sieves, acetone R.T.
2) TBAF, AcOH, THFO
O
R'
100
100
100
80
Conversion (%)
9885n-pentyl
9489CH2OBn
9997CH2OTBS
9072Ph
% eeYield (%)R’
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 2398.
Catalytic Asymmetric HDA Reactions
963128CH2CH2NHBOC
86
84
100
Conversion (%)
95772-furyl
9878CH2CH2Ph
9878(CH2)4CH=CH2
% eeYield (%)R’
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 2398.
OSiR3
R'CHO+
1) 3 mol% cat. 4 Å mol. sieves, acetone R.T.
2) TBAF, AcOH, THFO
O
R'
• The Schiff base catalyst acts as a point-binding LA: kinetics are 1st order, cat. and diene; saturation kinetics, aldehyde
• Mechanism: pericyclic. (Pericyclic hetero ene reactions also catalyzed by Schiff base complex)
Catalytic Asymmetric HDA Reactions
Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2883.
ArCHO +Me
OTMS
Ar
OTMSOH
*
Schiff base Cr cat.
Ene versus Cycloaddition Pathways
• Some substitutions on diene can lead to competition between ene and cycloaddition reactions
EtO
O
O
+
LA
O
OEt
OH
O
EtO
O
+
Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558.
Salen-Cr(III) Catalyst for HDA
Cr
N N
X X
HH
R R
BF4
R = t-Bu
X = OMe or t-Bu
Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403.
• Chiral salen-chromium(III) complexes also catalyze HDA reaction asymmetrically• Can offer improvements over indanol-based catalyst if aldehyde has bulk at α-carbon• Dienes must be more highly activated (e.g. Danishefsky’s diene)
Catalytic Asymmetric HDA Reactions:Other Examples
BINOL catalysts (X = O):
H
Ar
Ar
R
Danishefskyaliphatic,aromatic
Ti(OiPr)2
Unactivated(selective for
HDA over ene)
RO(C=O)CHOAlMe
DanishefskyArCHOAlMe
DieneAldehydeMLn
Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558.
Catalytic Asymmetric HDA Reactions:Other Examples
BINAP catalysts (X = PAr2):
H
RUnactivated
(selective for HDAover ene)
ArCOCHOPd
DieneAldehydeMLn
Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, Y. J. Org. Chem. 1999, 64, 8660.
Catalytic Asymmetric HDA Reactions:CAB Catalysts
O
O
O B
O
o-MeOC6H4
CO2HOiPr
OiPr
O
O
PhH
+
OMe
TMSO
1) CAB cat. (20%)
2) TFA
O
PhO
95% , 97% ee
Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H. J. Org. Chem. 1992, 57, 1951.
Catalytic Asymmetric HDA Reactions:CAB Catalysts
Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907.
N
O
N B
O
TsBu
H
O
ArH
+
OMe
TMSO
1) CAB cat. (20%)
2) TFA
O
ArO
96% , >99% ee
•Mukaiyama aldol mechanism observed
Catalytic Asymmetric HDA Reactions:Other Examples
• Chiral C2- symmetric bisoxazoline (BOX)-metal complexes have been used to catalyze HDA reactions between activated aldehydes and activated/unactivated dienes
Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558.
Applications in Total Synthesis
• Avermectin: Dansihefsky, S. J.; Armistead, D. M.; Selnick, H. G.; Wincott, F. E.; Hungate, R. J. Am. Chem. Soc. 1987, 109, 119. • Laulimalide: Ghosh, A. K.; Mathicanan, P.; Cappiello, J.; Krishnan, K. Tetrahedron Lett. 1997, 38, 2427.• Phorboxazole A: Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749–3754.• Ambruticin: Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
• Additional examples: Trost, B.; Fleming, I. Comprehensive Organic Synthesis 1991, Vol. 2, 661.
Conclusions for the HDAAldehyde-Diene Cycloaddition
• A useful method for dihydropyran and dihydropyrone synthesis• Factors governing and methods for controlling regio-, diastereo-, and enantioselectivity are now known• These methods have been used in the context of total synthesis
Conclusions for the HDAAldehyde-Diene Cycloaddition
• Additional improvements in the area of chiral auxiliary-controlled asymmetric induction desirable• HDA chemistry with unactivated dienes needs additional exploration
Diastereoselectivity in L.A. CatalyzedHDA Reaction
O
H
R
O
R
H
LA
LA
Exo approach: favored if solvated LA issmaller than R, and if 2° orbital overlap is not possible
Endo approach: favored if solvated LA islarger than R, and if 2° orbital overlap is possible
Trost, B.; Fleming, I. Comprehensive Organic Synthesis 1991, Vol. 2, 669.
