Total Synthesis of Everninomicin 13,384-1—Part 1: Retrosynthetic Analysis and Synthesis of the A1B(A)C Fragment

Abstract

In this first of a series of four articles we introduce everninomicin 13,384‐1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A₁B(A)C fragment; 4: DE fragment; 5: FGHA₂ fragment), we describe herein two approaches to the A₁B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2‐phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A₁). The final stages of the synthesis of the required 2‐phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C‐1 of ring C followed by a novel, DAST‐promoted 1,2‐migration to produce the desired 2‐β‐phenylseleno glycosyl fluoride moiety.