An efficient, safe, and scalable method for the preparation of <scp>d</scp>- and <scp>l</scp>-penicillamines

The present work describes a simple, efficient and scalable route for the synthesis of D- and L-penicillamines from commercially available ethyl isocyanoacetate. The four-step synthesis mainly includes condensation of acetone with ethyl isocyanoacetate to form α-formylaminoacrylate 18. The key intermediate, β-sulfido carbonyl compound 22, was synthesized <i>via</i> a Rongalite and base-promoted cleavage of disulfides followed by a thia-Michael addition. Subsequent removal of the formyl and <i>p</i>-methoxybenzyl ether groups afforded the racemic penicillamine D,L-1. Finally, chiral resolution of the racemic penicillamine furnished enantiomerically pure D- and L-penicillamines in good yields. The salient features of the developed protocol are as follows: it is odorless, shows high efficiency, requires inexpensive starting materials and affords excellent yields, without the need for chromatographic purification processes. The current synthesis also avoids hazardous reaction conditions and the use of heavy metals and toxic cyanide.