ANNULATION VIA FREE RADICAL-CHEMISTRY: AN APPROACH TOWARDS THE SYNTHESIS OF BRIDGED POLYCYCLIC NATURAL COMPOUNDS

A novel approach to bridged polycyclic products has been devel- oped. The strategy revolves around the stereospecific exo-digonal addition of a carbon centered radical to a stereoproximal alkyne. This methodology has been successfully applied to the syntheses of the carbon skeletons of functionalized bicyclo 3.2.1 octane and bicyclo 3.3.1 nonane. The syntheses of bicyclo 2.2.2 octane and bicyclo 3.1.1 heptane were also attempted.;A model system of this synthetic scheme was first carried out. Thus, cyclization of 3-methyl-3-(4-trimethylsilyl-3-butynyl)cyclopent- enyl radical was tested, to give, in 65% 1-methyl-4-(1-trimethylsilyl- methylene)bicyclo 3.2.1 octane. However, when the same reaction conditions were applied to the gymnomitrene skeleton precursor 3-methyl-4-(trimethylsilyl-3-butynyl)-cis-bicyclo 3.3.0 octanyl radical (182) mainly reduction product was obtained. The synthesis of 182 was based on the dianion chemistry of 3-isobytoxycyclopen-2-en-1-one followed by sequential introduction of the necessary substitu- ents stereoselectively from the convex face of the bicyclic system. Finally, the synthesis of 1,5-dimethyl-4-(trimethylsilyl-3-butyl-cis-bicyclo 3.3.0 octan-2-one is described in an approach towards the total synthesis of gymnomitrene. The scope and limitations of this radical cyclization were studied and the reaction was tested with 3-methyl-4-(trimethylsilyl-3-butynyl)cyclohexenyl radical (108), 4- (3-trimethylsilyl-2-propenyl)cyclohexenyl radical (121), 3-cyano-3-methylcyclohexenyl radical (130) and 1-(1-methyl-3-methylenyl- cyclohexen-1-yl)-2,2-dimethoxy-1-ethylenyl radical (142). Whereas 108 cyclized in 47% yield, 121, 130, and 142 failed to cyclize.;The results of this investigation of radical cyclization were dis- cussed in terms of the strain energy associated with the structure of the transition state of the reaction.;A test of the intramolecular radical cyclization approach towards the synthesis of gymnomitrene required the intramolecular cycliza- tion of a radical precursor containing the bicyclo 3.3.0 octane skele- ton. The strategy involved the elaboration of this bicyclic system at early stages of the synthesis, and the completion of the bridged tri- cyclic system through the key intramolecular radical reaction.