Oxidation free-radical cyclization, in which the initial radical is generated oxidatively and/or the cyclic radical is oxidized to terminate the reaction, has considerable synthetic potential since more highly functionalized products can be prepared from simpler precursors than with the standard tin hydride reductive radical cyclizations. This research consists of several interrelated studies developing new synthetic methods based on, and examining the mechanism of, oxidative free-radical cyclization using Mn(III), Cu(II) or Ce(IV) as the oxidant, and several natural product syntheses designed to exploit and develop oxidative free-radical cyclization. In the area of methods development it is planned to examine: (1) addition to alkynes, solvent effects, (2) use of haloalkenes to control the regiochemistry of the cyclization, (3) new substitution patterns, (4) trapping by addition to nitriles, (5) trapping by addition to aldehydes, (6) oxidation, cyclization, oxidation, cyclization, (7) oxidative cyclization followed by intermolecular trapping, (8) oxidation, cyclization, allylation, oxidation and cyclization, (9) use of conjugated beta-keto esters, (10) use of sulfoxides for asymmetric free-radical cyclization, (11) probes for the reversibility of radical cyclization, (12) oxidative cyclization of unsaturated silyl enol ethers, (13) oxidative cyclization of unsaturated silyloxycyclopropanes, and (14) conversion of other radicals to alkenes with copper carboxylates. In the area of total synthesis, syntheses are planned of: (1) velloziolone, (2) a key tricyclic intermediate for gibberellic acid synthesis, (3) steviol, (4) iresin, (5) avenaciolide, and (6) models for aklavinone synthesis. The Organic Synthesis Program is continuing the support of Dr Snider's studies of Mn(III)-based oxidative free-radical cyclizations. This work has the potential to develop simplified new routes to complex polycyclic systems. These should help provide efficient paths to molecules needed by modern biology and agriculture.
