Chapter Four Applications of radical cyclization reactions in total syntheses of naturally occurring indole alkaloids

Abstract

This chapter presents the recent accomplishments in the total syntheses of naturally occurring indole alkaloids where radical cyclization reactions have played a central role in the synthetic approach. It classifies these syntheses according to the size of the rings formed by radical cyclization—namely (a) Five-membered ring formation, (b) Six-membered ring formation, (c) Seven- and eight-membered ring formation, and (d) tandem cyclization. Most of the five-membered ring formations employing intramolecular radical cyclization proceed via the 5-exo-trig path. The few exceptions to Baldwin's rule occur when substrates possess structural moieties (such as an amide bond) that conformationally bias the substrates in favor of the 5-endo-trig mode. In contrast to the large body of data available on S-exo-trig cyclizations in indole alkaloid syntheses, there are relatively few examples of those using the 6-endo-trig cyclization. When a radical cyclization reaction involves the 5-hexenyl radical intermediate, the reaction proceeds preferentially in the 5 -exo-trig mode. However, when the 5-exo-trig mode of cyclization is stereoelectronically disfavored, the 6-endo-trig cyclization mode predominates. Generally, most radical cyclizations proceed kinetically in an exo fashion to provide the smaller of the two possible rings. Nonetheless, as an important exception, 7 -endo and 8 -endo cyclizations occur when the (conformationally restrained) intermediate radicals possess geometrical restrictions.