Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition–Elimination–Oxa-Michael Reactions

Abstract

A photocatalytic decarboxylative radical conjugate addition–elimination–oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones is developed to construct diverse cyclopentanonyl-fused functionalized 5–7 membered cyclic ethers. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC50 values.

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction

“…The successful application of darunavir in combination therapies has inspired the pursuit of improved syntheses of darunavir − and syntheses of derivatives with the potential for even greater potency (Figure ). − In this context, the seminal efforts of Ghosh and coworkers laid the foundation for structural aspects of darunavir and the domains where the structure could be modified. In 2023, Raines and coworkers modified the structure of darunavir by modifying the P2’ region with the use of a benzoborolone group (see 2a and 2b ) and demonstrated the utility of installing such groups as pharmacophores .…”

“…Reiser and coworkers changed the P2 domain of darunavir by the use of an ethereal bicyclic cyclopentyl system resulting in low nanomolar IC 50 values . Ghosh and coworkers have been leaders in this field with the development of a number of darunavir derivatives wherein the P2 domain has been changed to enhance drug efficacy. − In this context, darunavir derivative 5 was designed with modifications to the P1, P2, and P2’domains to enhance interactions with the active site of the HIV-1 protease.…”

Recent advances in visible-light-mediated functionalization of olefins and alkynes using copper catalysts

“…The photoinduced electron transfer chemistry has indeed brought forth an astoundingly diverse range of organic free radical and radical ion reactions with broad impact in organic synthesis, materials science and pharmaceutical chemistry. 3 Moreover, visible-light-mediated photoredox catalysis offers exciting opportunities to achieve challenging carbon–carbon and carbon–heteroatom bond formations under mild and ecologically benign conditions. 4 Over the past few years, photoredox-initiated reactions, catalyzed by transition metal complexes or organic dyes (organic photoredox catalysts), have brought an important revolution in organic synthesis.…”