Acyl radicals: Functionalized free radicals for the construction of carbocyclic compounds
Abstract
Primary alkyl-, vinyl- and aryl-substituted acyl radicals generated by Bu$\sb3$SnH treatment of the corresponding phenyl selenoesters participate cleanly in intermolecular addition reactions with alkenes bearing electron-withdrawing or radical-stabilizing substituents, at rates that exceed those of the potentially competitive decarbonylation or intermolecular hydrogen abstraction from Bu$\sb3$SnH (reduction). The intermolecular addition reactions of secondary alkyl-substituted acyl radicals with alkenes provided substantially lower adduct yields, presumably as a result of competitive decarbonylation of the intermediate acyl radicals. Similarly, the intramolecular additions of acyl radicals to electron-deficient or unactivated alkenes proceed without significant competitive reduction. Consistent with their behavior in intermolecular addition reactions, the 5-exo-trig cyclizations of secondary and tertiary alkyl-substituted acyl radicals to an unactivated olefin acceptor may be accompanied by varying degrees of decarbonylation. Studies demonstrated the effective participation of acyl radicals in each of the fundamental types of tandem free radical-alkene addition reaction, permitting stereoselective formation of 6-5 and 6-6 fused bicyclic carbocycles possessing varying degrees of functionality. Tandem cyclization of several 5-alkyl substituted 6-hexenoyl radicals bearing $\omega$-alkynyl substituents at C-6 proved to be a conceptually novel tandem radical cyclization sequence initiated by six-membered ring formation. Subsequent investigations into the mechanistic course of these polycyclization reactions not only led to the development of a relatively direct route to 7-5 and 8-5 fused carbocyclic systems based on a tandem free radical rearrangement-5-exo-dig 5-hexynyl cyclization process, but also established that the intramolecular additions of acyl radicals to alkenes under the conditions detailed herein are irreversible, kinetically-controlled processes. A range of phenyl selenoesters possessing a $\beta$-unsubstituted acrylate acceptor were observed to undergo effective endo cyclizations to form macrocyclic lactones. Examination of the cyclizations of substrates containing additional sites of unsaturation in the tethering chain revealed that the 16-endo acyl radical-acrylate addition reaction proceeds at a rate which exceeds that of 6-exo-trig acyl radical addition to an unactivated alkene and which is roughly comparable to 5-exo acyl radical addition to an unsubstituted alkene. Such acyl radical macrocyclization reactions permit the high-yield preparation of functionalized macrocyclic lactones under mild conditions. (Abstract shortened with permission of author.)
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry
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