Synthesis of a conformationally restricted analog of pregabalin by stereoselective alkylation of a chiral pyrrolidin-2-one

Abstract

The 4-benzyloxymethyl pyrrolidin-2-one, 5, was alkylated leading to 3,4- trans-disubstituted pyrrolidin-2-one 6 in good yield and total diastereoselection, as shown by 1H NMR data and NOE experiments. After reduction of the carbonyl group to give the trans-3,4-disubstituted pyrrolidine 7, and removal of the chiral auxiliary, followed by protection of the nitrogen with t-Boc group, the corresponding N-protected pyrrolidine, 8 was obtained. The cleavage of the benzyl ether moiety, followed by oxidation of the hydroxy function, gave in good yield the corresponding pyrrolidine carboxylic acid 2, a restricted analog of pregabalin.