George Barany

Mechanistic Insights Into the Zumach-Weiss-Kühle Synthesis of Dithiasuccinoyl (Dts)-Protected Amines

The 1,2,4-dithiazolidine-3,5-dione heterocycle was first prepared by Zumach, Weiss, and Kuhle [1] by reactions of primary O-ethyl thiocarbamates with (chlorocarbonyl)sulfenyl chloride [Scheme 1]. Subsequently, we adopted this heterocycle as the basis for the thiolysable dithiasuccinoyl (Dts) amino protecting group, which was used for orthogonal solid-phase peptide synthesis and related applications [2-7]. We report here that when substrates are changed from primary amines to carbamates, cyclization to the title heterocycle does not occur, but two acyclic (chlorocarbonyl)disulfanyl species corresponding to proposed intermediates in the ZWK reaction mechanism can be isolated and structurally characterized. The present work might also provide insight into why reactions of primary amines with bis(chlorocarbonyl)disulfane fail to provide the corresponding Dts-amines, while analogous reactions with bis(trimethylsilyl)amines give Dts-amines in high yields [8].