TOTAL SYNTHESIS OF THE CEMBRANOID DITERPENE LACTONE (-CLEOMEOLIDE - SOME REMARKABLE CONFORMATIONAL FEATURES OF 9-MEMBERED BELTS LINKED IN 2,6-FASHION TO A METHYLENECYCLOHEXANE CORE())

The total synthesis of (+)-cleomeolide (1) has been accomplished. The key construction elements of this cembranoid lactone were (i) improved conversion of optically pure Wieland-Miescher ketone into dienol ethe r 12 and oxidative cleavage of the latter to aldehydo ester 13; (ii) a voidance of complications arising from steric blockade of C-15 for int roduction of the methylene group at that site; (iii) exploitation of a n intramolecular Wadsworth-Emmons cyclization for macrocyclic ring con struction; (iv) modulation of the conformation adopted by the medium r ing by diastereofacial control of epoxidation of the C-3/C-4 double bo nd; and (v) intramolecular cyclization of the epoxy acid derived from 27 by nucleophilic capture at the more substituted oxiranyl carbon to deliver the target molecule. The deep-seated topographical change that accompanies the formation of 29 projects the macrocyclic ring quasi-a xially from the methylenecyclohexane subunit in the manner known by X- ray crystallography to be adopted by the target compound. The intramol ecular cyclization to set the bridgehead double bond was thereby facil itated.