Enantioselective, protecting-group-free total synthesis of sarpagine alkaloids--a generalized approach

Abstract

A generalized synthetic access to sarpagine alkaloids through a joint synthetic sequence has been accomplished. Its applicability is showcased by the enantioselective total syntheses of vellosimine (1), N-methylvellosimine (3), and 10-methoxyvellosimine (8). The synthetic sequence is concise (eight steps) from known compound 13, and requires no protecting groups. The indole heterocycle was introduced in the last step. This strategy allows access to sarpagine alkaloids through a shared synthetic route leading to precursor 10, which we term "privileged intermediate". Starting from this intermediate, all sarpagine alkaloids can be synthesized using phenylhydrazines with different substitution patterns (15-17). Our approach brings about the advantage, that synthesis optimization only needs to be performed once for many natural products. The key features of the synthesis are a [5+2]-cycloaddition and a ring enlargement.

Keywords: cycloaddition; oxidopyridinium ion; ring enlargement; sarpagine alkaloid; total synthesis.