Stereoselective Total Synthesis of (+/-)-Gymnomitrol via Reduction-Alkylation of α-Cyano Ketones

Article abstract of DOI:10.1021/ja00372a016

A 16-step total synthesis of the tricyclic sesquiterpene alcohol, gymnomitrol (1), from cis-tetrahydro-3a,6a-dimethyl-2,5(1H,3H)-pentalenedione (8) is described.Catalytic hydrogenation of the monoenol phosphate of 8 afforded the monoketone, cis-hexahydro-3a,6a-dimethyl-2(1H)pentalenone (7).Reduction-allylation of the α-(n-butylthio)methylene derivative of 7 gave allyl trimethyl ketone 14a having the allyl substituent in the exo orientation.The stereoisomer (19) of 14a was obtained by reduction-methylation af α-allyl α-cyano ketone 18.Ring closure was accomplished by conversion of the allyl trimethyl ketones, 14a and 19, to keto aldehydes 23 and 6, aldol cyclizations, and oxidation to give the isomeric bridged diketones 25 and 29, respectively.A more efficient synthesis of keto aldehyde 6 was based upon a Michael-like condensation of α-cyano ketone 16 with acrolein diethyl acetal which gave rise to α-ethoxyallyl α-cyano ketone 34.The enol ether in the side chain was converted to an ethylene acetal, the resulting α-cyano ketone (36) was subjected to reduction-methylation, and the acetal was hydrolyzed, affording keto aldehyde 6.Enol lactone 39, prepared from the corresponding keto acid (38), underwent efficient aldol cyclization upon reduction with diisobutylaluminium hydride, and the ketol so obtained was oxidized to bridged diketone 29.The synthesis of (+/-)-gymnomitrol was completed by regioselective addition of methyllithium to diketone 29, dehydration, and hydride reduction.