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. 2015 Jun 3;56(23):3314-3317.
doi: 10.1016/j.tetlet.2015.01.019.

Enantioselective Synthesis of Dioxatriquinane Structural Motifs for HIV-1 Protease Inhibitors Using a Cascade Radical Cyclization

Arun K Ghosh  1 , Chun-Xiao Xu  1 , Heather L Osswald  1
Affiliations

Enantioselective Synthesis of Dioxatriquinane Structural Motifs for HIV-1 Protease Inhibitors Using a Cascade Radical Cyclization

Arun K Ghosh et al. Tetrahedron Lett. .

Abstract

Synthesis of novel HIV-1 protease inhibitors incorporating dioxatriquinane-derived P2-ligands is described. The tricyclic ligand alcohol contains five contiguous chiral centers. The ligand alcohols were prepared in optically active form by an enzymatic asymmetrization of mesodiacetate, cascade radical cyclization, and Lewis acid catalyzed reduction as the key steps. Inhibitors with dioxatriquinane-derived P2-ligands exhibited low nanomolar HIV-1 protease activity.

Keywords: Cascade; Dioxatriquinane; HIV-1 protease; Inhibitor; Radical.

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Figures

Figure 1
Figure 1
Structure of darunavir (1) and PIs 2-4.
Figure 2
Figure 2. 1H NOESY analysis of alcohols 12 and 17
Scheme 1
Scheme 1. Synthesis of syn-anti-syn-fused dioxatriquinane ring system
Scheme 2
Scheme 2. Synthesis of syn-syn-syn-fused ring system
Scheme 3
Scheme 3. Synthesis of inhibitors 4 and 21
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