Synthesis of highly substituted enantiopure piperazines and ketopiperazines from vicinal N-sulfinyl diamines.

Enantiopure 1-benzyl-2,3-disubstituted piperazines (4) have been synthesized by treatment of N-sulfinyl-N-benzyldiamino alcohols (1) with diethyl oxalate and sodium methoxide followed by reduction with borane. Alternatively, the sulfinamido group was preserved by an N-acylation/cyclization protocol using alpha-chloroacetyl chloride that led to the synthesis of N-sulfinyl ketopiperazines (11). Ensuing elimination of the sulfinyl group with NaH produced imino ketopiperazines (9) that are suitably functionalized for nucleophilic addition to the imino moiety. Stereoselective and high yielding allylation of imino ketopiperazines (9c) was achieved under Barbier conditions using CeCl3.7H2O as the additive.