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 (SS)-γ-chloro-N-tert-butanesulfinyl ketimines with LiBHEt3 in THF at −78 to 23 °C afforded (SS,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 (SS,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 quantative yield. This method was 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 (SS)-δ-chloro-N-tert-butanesulfinyl ketimine with LiBHEt3 in THF at −78 to 23 °C or DIBAL-H/LiHMDS in toluene at −78 to 0 °C afforded the (SS,R)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (SS,S)-N-tert-butanesulfinyl-2-substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.