Synthetic Studies on Amipurimycin: Total Synthesis of a Thymine Nucleoside Analogue

Abstract

Amipurimycin, a member of the complex peptidyl nucleoside family of antibiotics, is a Streptomyces-derived potent antifungal agent. The mechanism of action of amipurimycin, however, remains undetermined. Additionally, there are no reports on the total synthesis or structure-activity relationships (SAR) of this potentially useful bioactive compound. In a study aimed at the total synthesis and SAR studies of this natural product, the present research reports the development of a synthetic route to the central pyranosyl amino acid core of amipurimycin and its further elaboration, culminating in the synthesis of a unique thymine analogue. Utilizing a d-serine-derived dihydroaminopyrone as a strategic building block, the synthesis involves de novo construction of the fully functionalized C-3-branched carbohydrate amino acid core, followed by glycosidic attachment of thymine at C-1, and peptidic linking of the C-6 amine with the 1,2-aminocyclopentane carboxylic acid side chain.