Synthesis Of A Novel Polyfunctionalized Chiral Pyrrolidines

Pyrrolidine motifs are biologically privileged structures which are present in a large number of alkaloids and nature products. They frequently show potent and diverse biological activities and have broad prospect in pharmaceutical research and development. The development of new and efficient methodology for the construction of polyfunctionalized chiral pyrrolidines is of great significance and potential applications.This study focused on Michael addition/Hemiaminal cascade reaction of Ts-amino-acetone and α,β-unsaturated aldehydes catalyzed by chiral secondary amines to construct pyrrolidine motifs with three stereocenters in one pot. The pyrrolidine motifs contain two functional groups(carbonyl and aminal) with rich possibilities for further modification, therefore play an important roles in nature product synthesis and combinatorial chemistry.Firstly, different proline-derived catalysts, solvents and additives were carefully screened and the optimized reaction conditions of the Michael addition/Hemiaminal casacade reaction are a,p-unsaturated aldehydes, Ts-aminoacetone,(S)-diphenylprolinol trimethyl silyl ether catalyst, benzoic acid additive in dichloromethane at room temperature.Secondly, the absolute configuration of the products were determined by single crystal X-ray analysis as (2S,3S,5R)-2-Acetyl-3-Phenyl-5-Hydroxy-N-Ts-Pyrrolidine and (2S,3R,5S)-2-Acetyl-3-Phenyl-5-Hydroxy-N-Ts-Pyrrolidine. The enatiomeric ratio(e.r) of (2S,3R,5S)-2-Acetyl-3-Phenyl-5-Hydroxy-N-Ts-Pyrrolidine was determined by chiral HPLC as99:1.Lastly, the Michael addition/Hemi-aminal cascade reaction of Ts-aminoacetone and4-Chloro-3-N-Cinnamaldehyde afforded target molecules in high yield and lay the foundation for total synthesis of natural product.