Studies related to thietan-2-ones. Part 1. Conversion of D-penicillamine into DL-2-methylpenicillamine using thietan-2-one-based chemistry

Abstract

A series of N-substituted derivatives of (3R)-3-amino-4,4-dimethylthietan-2-one has been prepared from D-penicillamine (3). Attempts to effect the methylation at position 3 of the N-acetyl (7a), N,N-diacetyl (12), N-benzyloxycarbonyl (7b), or N-(p-nitrobenzylidene) derivative (15a) were unrewarding. Although the N-benzylidene and N-furfurylidene derivatives (15b) and (15c) were successfully methylated at position 3 by using iodomethane and potassium t-butoxide in tetrahydrofuran (THF), best results were achieved by treating the N-(2-hydroxy-1-naphthylmethylene) derivative (15d) with iodomethane and sodium hydride in N,N-dimethylformamide.

Cleavage of the imine linkage of the methylated derivatives of the thietanones (15c) and (15d), i.e. compounds (19b) and (19c), was effected by using, respectively, toluene-p-sulphonic acid in THF and dilute hydrochloric acid in acetone. The derived salts of (3RS)-3-amino-3,4,4-trimethylthietan-2-one, i.e.(21a) and (21b), underwent hydrolysis in boiling water to give the corresponding salts of DL-2-methylpenicillamine, i.e.(22a) and (22b).