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Massachusetts Institute of TechnologyOrganic Chemistry 5.511
December 7, 2007Prof. Rick L. Danheiser
Unit 6
Stereocontrolled Aldol Reactions
Overview of the Stereochemistry of the Aldol Reaction and Substrate Control
Reagent Control: Chiral Auxiliary Strategies
Reagent Control: Chiral Controller Strategies
Reagent Control: Chiral Lewis Acid Catalyzed Aldol Reactions
R1OH
R2
O
Z234
The Aldol Retron
Lecture 20
Chiral Controller Strategies
Catalytic Chiral Auxiliary Strategies
Chiral Lewis Acid Catalyzed Aldol Reactions
Catalytic Asymmetric Aldol Reactions
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Reviews(1) "Proline-Catalyzed Asymmetric Reactions" List, B. Tetrahedron 2002, 58, 5573(2) "Enamine Catalysis Is a Powerful Strategy for the Catalytic Generation and Use of Carbanion Equivalents" List, B. Acc. Chem. Res. 2004, 37, 548(3) "Enamine-Based Organocatalysis with Proline and Diamines" Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580
Enamine Aldol Reactions
O
O
OO
O MVKaq AcOH
70 °C 1-2 h
1) 7.5 mol% (S)-proline DMF 16 °C 2-3 d2) H2SO4, DMF 95 °C 4 h
O
O
70-76%92-94% enantiomeric purity
Hajos-Parrish-Eder-Sauer-Wiechert Reaction
Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, 26
O H
NR
H
RO
O
H
I. Chiral Controller Strategies
Catalytic Asymmetric Aldol Reactions
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II. Catalytic Chiral Auxilary Strategies
Catalytic Asymmetric Aldol Reactions
Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352
Scott Nelson
III. Chiral Lewis Acid Strategies
Nelson, S. G.; Peelen, T. J.; Wan, Z.J. Am. Chem. Soc. 1999, 121, 9742Nelson, S. G.; Zhu, C.; Shen, X.J. Am. Chem. Soc. 2004, 126, 14Nelson, S. G.; Mills, P. M.Organic Syntheses 2005, 82, 170
(1) Nelson Ketene-Aldehyde Condensations
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III. Chiral Lewis Acid Strategies
(2) Carreira Chiral Ti Catalyst
Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837
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(3) Evans Copper BOX and PYBOX CatalystsD. A. Evans et al. J. Am. Chem. Soc. 1999, 121, 669 and 686. Reviewed in: J. S. Johnson and D. A. Nicewicz In Modern Aldol Reactions, Vol 2; Mahrwald, R., Ed.; Wiley-VCH, 2004; pp 69-103.
NCu
N
O O
Me Me
t-Bu t-Bu
2+2 OTf
Addition to Pyruvates
N N
O O
Ph Ph
2+2 SbF6
NCu
Addition to (Benzyloxy)acetaldehyde
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Case Study
Synthesis of (-)-Laulimalide
Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A.J. Am. Chem. Soc. 2002, 124, 13654
O
O
H
CH3 OSiR3
Laulimalidesubtarget