Total synthesis of halichlorine, pinnaic acid and tauropinnaic acid

Several routes were examined for the total synthesis of the related marine natural products halichlorine, pinnaic acid and tauropinnaic acid. The ultimate 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. Novel 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 following Homer-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.