Indium-Mediated Atom-Transfer and Reductive Radical Cyclizations of Iodoalkynes:  Synthesis and Biological Evaluation of HIV-Protease Inhibitors

Abstract

Novel indium-mediated radical cyclization reactions of aliphatic iodoalkynes have been studied. Treatment of iodoalkynes with a catalytic amount of In (0.1 equiv) and I(2) (0.05 equiv) promotes atom-transfer 5-exo cyclization to give five-membered alkenyl iodides. In contrast, reaction with In (2 equiv) and I(2) (1 equiv) yields reductive 5-exo cyclization products via the same 5-exo cyclization. Both processes are most likely initiated by low-valent indium species. To demonstrate versatility of these reactions, optically active HIV protease inhibitors were synthesized by this reductive cyclization method. Among them, several products, which contain a hydroxyethylamine dipeptide isostere as a transition state-mimicking substructure, proved to possess potent activity (IC(50) = 5-39 nM) against a wide spectrum of HIV strains, including multidrug-resistant variants.

Visible light photoredox atom transfer Ueno–Stork reaction

“…The material was purified by silica gel column chromatography to give a mixture of isomers in a combined yield of 82%. See NMR spectra section for the actual 1 3-(iodomethylene)octahydrobenzofuran, 6a [4] , (…”

Radicals in organic synthesis. Part 1

“…15a,b A low-valent indium species, prepared in situ from indium powder, can be employed in either ATRCs or reductive radical cyclisations of iodoalkynes (Scheme 20). 96,97 Treatment of iodide 61 with 1 equiv of indium and 0.5 equiv of iodine gives the alkenyl iodide 62 in good yield. The reaction permits the synthesis of a range of mono-and bi-cyclic heterocycles.…”

“…The evidence for the intermediacy of a radical comes from the success of a cyclisation-conjugate addition sequence; cyclisation of 61 in the presence of acrylonitrile 64 gives nitrile 65 in 65% yield (Scheme 21). 96 Alternatively, under reductive cyclisation conditions, an alkenylindium species is a good substrate for palladium-catalysed arylations. These results can be explained if a low-valent indium species (In, In þ or In 2þ ) is formed in situ and this species abstracts the iodine from 61 to give the initial radical; in the absence of excess reducing agent, cyclisation gives an alkenyl radical that has sufficient time to undergo conjugate addition to activated alkenes.…”

Indium Reagents in Heterocyclic Chemistry

“…heterocyclic alkenes (277) and (278) [83,84] -the synthons for various HIV-protease inhibitors have been obtained (Scheme 90). The indium-mediated intramolecular cascade free radical additions have been used for synthesis of heterocycles.…”