Total Synthesis of Antrimycins A and D

Abstract

Abstract Antrimycins A and D were isolated from Streptomyces bacteria through a screening program for natural products with anti-Mycobacterium tuberculosis activity. These compounds belong to a class of heptapeptide natural products containing four non-proteinogenic amino acids, α-(hydroxymethyl)serine, (2S,3S)-α,β-diaminobutyric acid, dehydropiperazic acid, and E-dehydroisoleucine (E-Δ-Ile). These natural products have received significant attention as drug leads to develop structurally unique antibacterial agents against M. tuberculosis. However, no total synthesis has been reported since their isolation in 1981 owing to their characteristic structural features. Herein, we report the first total synthesis of antrimycins A and D. The total synthesis features the use of an (α-phosphono)-N-Cbz-glycine ester as a synthetic equivalent of E-Δ-Ile, enabling its stereoselective construction and incorporation into the peptide chain.