Enantioselective reactions of silyl ketene acetals and silyl ketene imines catalyzed by planar-chiral heterocycles

• Main Author: Mermerian, Ara Haig, 1976-
• Other Authors: Gregory C. Fu.
• Format: Others
• Language: en_US
• Published: Massachusetts Institute of Technology 2005
• Subjects: Chemistry.
• Online Access: http://hdl.handle.net/1721.1/28700

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2004. === Vita. === Includes bibliographical references. === (cont.) imine. === The enantioselective C-acylation of cyclic silyl ketene acetals was achieved catalytically by employing planar-chiral heterocycles derived from 4-(pyrrolidino)pyridine. Key mechanistic features of this process involve activation of both the electrophile (acylating agent --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate). This process accomodates a wide variety of aryl- and heteroaryl-substituted silyl ketene acetals, furnishing quaternary stereocenters with enantioselectivities up to 99%. Further investigation of this process revealed that acyclic disubstituted silyl ketene acetals can also participate in this nucleophile-catalyzed process, furnishing enantioselectivities up to 97%. Isomeric mixtures of silyl ketene acetals are efficiently converted into the same enantiomer of the product β-ketoester, rendering this a stereoconvergent catalytic C-acylation process. Silyl ketene imines were also shown to be suitable reaction partners in this catalytic enantioselective C-acylation reaction, affording nitriles bearing an adjacent quaternary stereocenter with enantioselectivies up to 83%. This process is also believed to proceed via activation of the electrophile (acylating agent --> acylpyridinium) and the nucleophile (silyl ketene imine --> nitrile anion), which is in direct analogy to the process developed for silyl ketene acetals. Application of this transformation to the enantioselective total synthesis of (S)-Verapamil was successfully achieved in 8 steps and 25% overall yield from commercially available 3,4-dimethoxyphenylacetonitrile. The key bond construction in this total synthesis involved enantioselective construction of the quaternary stereocenter via a catalytic C-acylation of a silyl ketene === by Ara Haig Mermerian. === Ph.D.