PNAS 2004-08-17

Total synthesis of (+/-)-halichlorine, (+/-)-pinnaic acid, and (+/-)-tauropinnaic acid.

Hamish S Christie, Clayton H Heathcock

Index: Proc. Natl. Acad. Sci. U. S. A. 101(33) , 12079-84, (2004)

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Abstract

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 beta-lactam group provided internal protection for the highly congested nitrogen atom during side-chain elaboration. The beta-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.