Synthesis of endothiopeptides by using the 'azirine/oxazolone method'

Abstract

The reaction of tert-butyl- or THP-protected mandelic thioacid (7a and 7b) with N,N,2,2-tetramethyl-2H-azirin-3-amine (2a) gave the dipeptide analogues tBu- and THP-Mns-Aiby[CS]NMe2 (8a and 8b, resp.) with a C-terminal thioamide group. Treatment of 8a with HCl gas in toluene led to 2-(1-tert-butoxybenzyl)-4,4-dimethyl-1,3-thiazole-5(4H)-one (9), which reacted with dimethylamine via ring opening to give tBu-Mnsy[CSNH]Aib-NMe2 (11a), an isomer of 8a with the thioamide group within the chain, i.e., the product of a sulfur migration. In the case of 8b, selective deprotection of the THP-hydroxy group was achieved by treatment with pyridinium p-toluenesulfonate (PPTS) in ethanol. Cyclization of the resulting Mns-Aiby[CS]NMe2 (13) yielded the 2-thioxomorpholin-5-one 10. In a similar manner, Boc-Val-SH (14) reacted with azirine 2b to give Boc-Val-Aiby[CS]N(Me)Ph (15a), which was transformed to Fmoc-Val-Aiby[CS]N(Me)Ph (15b) and further to Fmoc-Valy[CSNH]Aib-N(Me)Ph (16) by treatment with ZnCl2 in acetic acid. Coupling of two of these molecules via the 1,3-thiazol-5(4H)-one 17 yielded the endodithiopeptide Fmoc-Valy[CSNH]Aib-Valy[CSNH]Aib-N(Me)Ph (19).