New Reactions of the Thiocarbonyl Function. The Synthesis of Hindered Peptides

Abstract

The well-known radical chemistry of the thiocarbonyl function has been expanded to include the concerted reaction between an O-acyl derivative of Nhydroxypyridine-2(l//)-thione (a Barton PTOC ester) and a sulfenamide. The atomeconomical process spawned a carboxamide and an unsymmetrical disulfide of synthetic and biological value. The reaction was successfully applied to the synthesis of sterically encumbered, urethane-protected dipeptides. The oxidation-reduction technology pertaining to the disulfide-phosphine combination facilitated the generation of transient Barton PTOC esters. In conjunction with the appropriate benzenesulfenamide, the Barton PTOC ester of benzoyl-L-leucine was shown to preserve optical integrity according to the sensitive Young test, albeit at low temperature. However, the thermodynamic forces at play are powerful and, as a result, the yields were not compromised. In all but the sterically demanding instances, the parent free amine almost matched the reaction time, yield, and enantiomeric excess of the corresponding benzenesulfenamide in its reaction with a Barton PTOC ester.

The thiohydroxamate system

“…The closely investigated reaction of these esters 31a with sulfeneimides 49 (Scheme 37) is of special importance. It is a convenient method of synthesis of crowded tertiary carboxyamides, and ␣-alkyl and ␣, ␣-dialkyldipeptides 50 easily isolated from the reaction mixture [89].…”

“…O-Acyl thiohydroxamates have found wide application in recent years in processes of rational generation of carbon [84], oxygen [71,85], nitrogen [86], and phosphorus radicals [87] and also as substrates for obtaining carboxyamides [88], including peptides [89].…”