SN2 Reaction of Sulfur Nucleophiles with Hindered Sulfamidates: Enantioselective Synthesis of α-Methylisocysteine

The work described here demonstrates that the five-membered cyclic alpha-methylisoserine-derived sulfamidate, (R)-1, behaves as an excellent chiral building block for the ring-opening reaction by S(N)2 attack with sulfur nucleophiles at the quaternary carbon. As a synthetic application of this methodology, and to show that this sulfamidate is a valuable starting material, the synthesis of two new alpha-methylisocysteine derivatives has been carried out to cover the lack of alpha- and beta-methylated amino acids that incorporate the cysteine or isocysteine skeleton. These compounds are two new alpha,alpha-disubstituted beta-amino acids (beta(2,2)-amino acids), and the synthetic routes involve nucleophilic ring opening followed by acid hydrolysis.