Chiral Phase Transfer Catalysis

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Chiral Phase Transfer Catalysis

• for the synthesis of ?-amino acids

John Jewett Rawal Group Meeting April 8th, 2005
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What is phase transfer catalysis?
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Making ?-Amino Acids
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Problems with dialkylation?

• Not really Phenyl groups sterically disrupt ion
  solvation

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Early PTC for ?-Amino Acids
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Early Chiral PTC

• Hiyama used PTC for chiral epoxides
• Fiaud first used chiral PTC for alkylations

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First use of Cinchorins for PTC

• Wynberg used chiral PTC for epoxidation
• Dolling later used chiral PTC for
• alkylation

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Dollings Proposed Model
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Early work with Chiral PTC on ?-Amino Acids
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ODonnells Racemization Study
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ODonnells Rationalization
ees the same for various catalysts
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Coreys and Lygos Next Step(done independently)
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Comparison of Conditions
Note that BnBr is the optimal substrate for Lygo
and ODonnell but the worst for Corey
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Newer generations Dimers
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New Generation More dimers
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Newer generations Electronics
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Making models more complex
When RMe, ees drop from 91 to 58
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Further confusion of models
Absolute configuration dependents (sometimes) on
counter-ion of hydroxide base
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Lygos Screening for New Catalysts

• After realizing in situ catalyst generation works
  nearly as well, Lygo screened for a new catalyst
  frame

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Biaryl Backbone already used
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Other Scaffolds for Chiral PTC
80-93 ee 71-82 yield R1t-Bu, R2Me,
Ar4-anisole
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Other Scaffolds for Chiral PTC
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Other Scaffolds for Chiral PTC
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Other Scaffolds for Chiral PTC
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Other Scaffolds for Chiral PTC
(This one is for Michael Reactions)
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Pros and Cons of PTC

• Very high yields and ees possible
• Mild reaction conditions
• Scalable (ideal for industry)
• Can be done on solid phase - substrate attached
  or catalyst attached

• For cinchorins the catalysts are unstable
• Limited reaction scope per catalyst
• LOTS of optimization (solvents, temps, etc.)
  required
• No general model for knowing what will work

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Good Places for Information(in order of how Id
look)

• Maruoka, K. Ooi, T., Chem. Rev., 2003, 103,
  3013.
• ODonnell, M. J. Acc. Chem. Res., 2004, 37, 506.
• Lygo, B. Andrews, B., Acc. Chem. Res., 2004, 37,
  518.
• ODonnell, M. J., Aldrichimica Acta, 2001, 34, 3.
• Comprehensive Asymmetric Catalysis I-III,
  Springer-Verlag Berlin, Germany, 2000,
• Hughes, D. L. Chapter 34.1 Alkylation of
  Enolates Phase Transfer Catalysis
• Yamaguchi, M. Chapter 31.2 Conjugate Addition
  of Stabilized Carbanions Phase Transfer Catalysts

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(No Transcript)
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Other Scaffolds for Chiral PTC
(This one is for Michael Reactions)