Abstract
Radical cyclizations are now widely used in organic synthesis for the construction of carbo- and heterocyclic compounds, including natural products. In this review, results of our recent studies on the control of regiochemistry of radical cyclizations are summarized. One factor determining the course (regiochemistry) of radical cyclizations is the reaction temperature used. For example, at a low temperature, i.e., under kinetically controlled conditions, 4-exo-trig cyclization predominated over another possible cyclization, 5-endo-trig cyclization, whereas at a high temperature, i.e., under thermodynamically controlled conditions, 5-endo cyclization products were obtained. Another factor determining the course of radical cyclizations involves the nature of the prefered conformation of the radical precursors. In general, a 5-exo-trig cyclization is prefered over a 6-endo-trig ring closure in systems having an alkenic bond at the 5-position relative to the aryl radical center. We found, however, that N- (ο-bromobenzyl) enamides underwent cyclization in a 6-endo-trig manner to give exclusively a tetrahydroisoquinoline derivative. The mode of the cyclization can be changed to 5-exo by introducing a (Z) -phenylthio group into the terminus of the N-vinylic bond, indicating that the stabilizing effect of the sulfur atom on an adjacent radical center is highly effective for controlling regiochemistry. The introduction of a phenylthio group into the terminus of the N-vinylic bond is also effective for achieving 6-exo-trig cyclization of aryl radicals. Applications of these radical cyclizations to the synthesis of some therapeutically important materials are also presented.
