Asymmetric synthesis and molecular docking study of enantiomerically pure pyrrolidine derivatives with potential antithrombin activity

The (2R,4R,5S)- and (2S,4S,5R)-enantiomers of 4-(tert-butyl) 2-methyl 5-(4-bromophenyl)-pyrrolidine-2,4-dicarboxylate 3 were synthesized efficiently with an ee of >90% on a gram scale using a FAM-catalytic methodology. Subsequent modification afforded enantiopure N-((4-chlorophenyl)thio)acetyl pyrrolidine derivatives 4, which are potential thrombin inhibitors according to comprehensive molecular docking studies.

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(+)-4-(tert-Butyl) 2-methyl (2S,4S,5R)-5-(4-bromophenyl)-1-(2-((4-chlorophenyl)thio)acetyl)pyrrolidine-2,4-dicarboxylateC25H27BrClNO5See >99.0%[α]D20=+100.0 (c 0.15, C6H6)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,4S,5R)