Radical Cyclizations in Alkaloid Synthesis

Abstract

Over twenty years ago, my research group became interested in free-radical cyclization chemistry because we were impressed with the efficiency of a 5-hexenyl radical cyclization which we used to prove the stereochemistry of a product derived from an N-acyliminium ion cyclization [ 1, 21. A survey of the literature suggested that, at that time, free-radical cyclizations had been well developed for the preparation of carbocyclic materials, but the use of such reactions in heterocycle synthesis was not well developed. As one can see from the wealth of information that appears in Radicals in Organic Synthesis, we were clearly mistaken in our judgement of the state of the field relative to carbocycles. Nonetheless, it was this point of view that prompted us to pursue a research program designed to develop free radical cyclization reactions for use in alkaloid synthesis. Since the onset of our program [3, 41, this field has expanded enormously. This chapter will review progress in the area with certain limitations. The major focus will be on intramolecular carbon-carbon bond-forming reactions, and the chapter will be organized largely according to the type of free radical cyclization featured in the synthesis. Intermolecular free-radical reactions and cyclizations involving carbon-heteroatom bond-forming reactions will be mentioned only in passing. Although emphasis will be placed on free radical cyclization chemistry, additional details will be described in an attempt to provide the reader with an overview of each synthesis. Whereas we recognize that the inherent value of a synthesis may lie in the methodology, there is no question that chemists judge syntheses in part by their length, and this information will therefore be provided in most instances. Finally, the focus will be on completed syntheses, and only a few model studies will be presented. a-Acylamino and a-Amino Radical CyclizationsOur own efforts began with failure. Inspired by the radical addition-atom transfercyclization-fragmentation sequence reported by Heiba (Eq. 1) [ 51, we attempted the Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

Thirty Years of (TMS)3SiH: A Milestone in Radical-Based Synthetic Chemistry

“…Formation of nitrogen-containing heterocycles, including natural alkaloids, through radical processes and cascades, has been thoroughly studied over the years. 214 TTMSS is often used in these reactions to initiate reactions and as hydrogen atom donor. Recent progress in this field may be summarized as depicted in Figure 2, with the radical formation of heterocycles, following two main routes, one involving the addition of C-centered alkyl radicals onto an unsaturated bond (olefin double bond or arene, route A) and a second one where an aryl radical is added onto the same type of unsaturated systems (route B).…”

“…Formation of nitrogen-containing heterocycles, including natural alkaloids, through radical processes and cascades, has been thoroughly studied over the years . TTMSS is often used in these reactions to initiate reactions and as hydrogen atom donor.…”

Silyl Radical-Mediated Carbocyclization of Acrylamide-/Vinyl Sulfonamide-Attached Alkylidenecyclopropanes via Photoredox Catalysis with a Catalytic Amount of Silane Reagent

“…Through radical cascade reactions, nitrogen-containing heterocycles including lactam and sultam moieties have been constructed, which has been fully investigated in recent years . These kinds of skeletons are highly important in medicinal chemistry, and they possess diverse pharmacological properties, such as anti-bacterial, anti-cancer, anti-HIV, and so on .…”

Acyl Radical Addition onto Aza‐Baylis–Hillman Adducts: A Stereocontrolled Access to 2,3,5‐Trisubstituted Pyrrolidines

“…Among the most effective synthetic strategies, however, mention may be made of stereocontrolled cycloadditions from nitrones,– intramolecular haloamidation reactions of olefins, or transition metal‐catalyzed olefin amidation ,. In this context, free‐radical approaches have also been reported and hold a special place, allowing the efficient construction of complex nitrogen heterocycles of various ring sizes using, for instance, cascade processes under conditions which are compatible with resident functional groups –…”