Natural Product Synthesis Special Feature: Total synthesis of (±)-halichlorine (±)-pinnaic acid and (±)-tauropinnaic acid

摘要

The related marine natural products halichlorine, pinnaic acid, and tauropinnaic acid have been synthesized. The described route provided access to all three compounds from a common, late-stage intermediate. The synthesis began with 1-pyrrolidino-1-cyclopentene from which an intermediate possessing the three contiguous stereocenters of the natural products was synthesized in just four steps. Olefin cross metathesis followed by a hydrogenation/hydrogenolysis reaction stereoselectively formed the piperidine ring. Use of a β-lactam group provided internal protection for the highly congested nitrogen atom during side-chain elaboration. The β-lactam was subsequently reduced directly to an amino aldehyde, which after the Horner–Wadsworth–Emmons reaction was elaborated to pinnaic acid. The same amino aldehyde was also transformed into halichlorine after a thiol-mediated cyclization sequence to form the dehydroquinolizidine ring system.