Total synthesis of (+/-)-halichlorine, (+/-)-pinnaic acid, and (+/-)-tauropinnaic acid.
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.
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Hamish S
HS
Christie
Clayton H
CH
Heathcock
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods; D015394:Molecular Structure; D008974:Mollusca / Q000737:chemistry; D011161:Porifera / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D000470:Alkaloids; D001688:Biological Products; D013141:Spiro Compounds; C412666:halichlorine; C412665:pinnaic acid