Synthesis of Orthogonally Protected (R)- and (S)-2-Methylcysteine via an Enzymatic Desymmeterization and Curtius Rearrangement

A synthesis of differentially protected (R)- and (S)-2-methylcysteines is described. Monomethylation of dimethylmalonate followed by alkylation with tert-butylchloromethyl sulfide gave an achiral diester. Desymmeterization by selective hydrolysis of one ester with pig-liver esterase gave the acid in 97% chemical yield and 91% enantiomeric excess. Heating this acid with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol gave protected (R)-2-methylcysteine. Alternately, the acid and ester groups were interchanged and heated with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol, giving protected (S)-2-methylcysteine.