ON THE DIASTEREOSELECTIVITY OF INTRAMOLECULAR PD-CATALYZED TMM CYCLOADDITIONS - AN ASYMMETRIC-SYNTHESIS OF THE PERHYDROAZULENE (-)-ISOCLAVUKERIN-A

The factors that influence the stereocontrol of trimethylenemethane (T MM) cycloadditions are examined in the context of a synthesis of a per hydroazulene. The diastereofacial selectivity with respect to the acce ptor is established in an intramolecular [3 + 2] reaction with a five- carbon tether. When a doubly activated acceptor is utilized, complete selectivity is observed wherein the Z-situated activating group is pro posed as a diastereoselectivity control element. Further, the use of t rimethylstannyl acetate as a cocatalyst for cycloadditions to electron deficient alkenes is illustrated for the first time, A one-pot, three -component coupling protocol provides a facile new entry into acyl-sub stituted TMM precursors specifically and a-hydroxy ketones more genera lly. The methodology led to a total synthesis of (-)-isoclavukerin A. The shortest version of the synthesis involves eleven steps from metha llyl alcohol.