A Facile Asymmetric Synthesis of Either Enantiomer of 2-Substituted Pyrrolidines

A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines from a single starting material is described. Reductive cyclization of (S-S)-gamma-chloro-N-tert-butanesulfinyl ketimines with LiBHEt3 in THF at -78 to 23 degrees C afforded (S-S,R)-N-tert-butanesulfinyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99: 1). The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the corresponding epimers of (S-S,S)-2-substituted pyrrolidines were synthesized in good yields (87-98%) and With high diastereoslectivity (1:99) by simply switching the reducing agent from LiBHEt3 to DIBAL-H/LiHMDS. Deprotection of N-tert-butanesulfinyl-2-substituted pyrrolidines using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted pyrrolidines in qualitative yield. This method was IS found to be effective for a Variety Of substrates, including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the formation of 2-substituted piperidines is also illustrated. Reductive cyclization of (S-S)-delta-chloro-N-tert-butanesulfinyl ketimine with LiBHEt3 in THF at -78 to 23 degrees C or DIBAL-H/LiHMDS in toluene at -78 to 0 degrees C afforded the (S-S,R)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (S-S,S)-N-tert-butanesulfinyl-2-substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.