Sparling BA, Moebius DC, Shair MD * Harvard University, Cambridge, USA
Enantioselective Total Synthesis of Hyperforin.
J. Am. Chem. Soc. 2013;
135: 644-647
Key words
hyperforin - PPAP - polyprenylated natural products - epoxide opening
Significance
Hyperforin, a constituent of St. John’s wort, is a member of the polycyclic polyprenylated
acylphloroglucinol natural product family. Its well-studied antidepressant activity,
along with the structural complexity, renders it an attractive target for total synthesis.
To date, only one total synthesis has been reported with an overall length of 51 steps
(Angew. Chem. Int. Ed.
2010, 49, 1103; Synfacts
2010, 510). This synthesis by Shair and co-workers is significantly shorter, utilizing
an epoxide-opening cyclization to set four stereocenters in one step, thus affording
(+)-hyperforin in only 18 steps.
Comment
Intramolecular Lewis acid mediated opening of epoxide C by only one of the diastereotopic enol ethers furnished the key bicyclo-[3.3.1]nonane
core as the methyl ketal E. In this impressive display of stereocontrol, four stereocenters, including two quaternary
ones, were set in good yield from an enantiopure epoxide. The subsequent allylic oxidation
proceeded in a highly chemoselective fashion to furnish ketone F which was then transformed into (+)-hyperforin in ten further steps.
