Catalytic asymmetric desymmetrization of prochiral and meso compounds

Abstract

The present invention relates to methods for the synthesis of chiral non-racemic products, e.g., enantiomerically-enriched hemiesters, from prochiral and meso starting materials, e.g., prochiral and meso cyclic anhydrides. The present invention also relates to catalysts for the aforementioned methods, and methods for synthesizing these catalysts.

1 . A method of preparing a chiral, non-racemic compound from a prochiral substituted cyclic anhydride or a meso substituted cyclic anhydride, comprising the step of: 
 reacting a prochiral substituted cyclic anhydride or a meso substituted cyclic anhydride with a nucleophile in the presence of a chiral, non-racemic tertiary amine catalyst; wherein said prochiral substituted cyclic anhydride or said meso substituted cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; wherein said meso substituted cyclic anhydride comprises at least two chiral centers; and wherein said nucleophile is an alcohol, thiol or amine; thereby producing a chiral, non-racemic compound.    
   
   
       2 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or a substituted glutaric anhydride.  
   
   
       3 . The method of  claim 1 , wherein said nucleophile is an alcohol.  
   
   
       4 . The method of  claim 1 , wherein said nucleophile is a primary alcohol.  
   
   
       5 . The method of  claim 1 , wherein said nucleophile is methanol or CF 3 CH 2 OH.  
   
   
       6 . The method of  claim 1 , wherein said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.  
   
   
       7 . The method of  claim 1 , wherein said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.  
   
   
       8 . The method of  claim 1 , wherein said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.  
   
   
       9 . The method of  claim 1 , wherein said chiral, non-racemic tertiary amine catalyst is QD-PP.  
   
   
       10 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.  
   
   
       11 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.  
   
   
       12 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP, QD-TB, (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQ) 2 PYR, (DHQD) 2 PYR, (DHQ) 2 AQN, (DHQD) 2 AQN, DHQ-CLB, DHQD-CLB, DHQ-MEQ, DHQD-MEQ, DHQ-AQN, DHQD-AQN, DHQ-PHN, or DHQD-PHN.  
   
   
       13 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.  
   
   
       14 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.  
   
   
       15 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is DHQD-PHN or (DHQD) 2 AQN.  
   
   
       16 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.  
   
   
       17 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.  
   
   
       18 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is methanol or CF 3 CH 2 OH; and said chiral, non-racemic tertiary amine catalyst is Q-PP, Q-TB, QD-PP or QD-TB.  
   
   
       19 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is an alcohol; and said chiral, non-racemic tertiary amine catalyst is QD-PP.  
   
   
       20 . The method of  claim 1 , wherein said prochiral substituted cyclic anhydride or meso substituted cyclic anhydride is a substituted succinic anhydride or substituted glutaric anhydride; said nucleophile is a primary alcohol; and said chiral, non-racemic tertiary amine catalyst is QD-PP.  
   
   
       21 - 28 . (canceled)