Lewis Acid-Catalyzed Vinyl Acetal Rearrangement of 4,5-Dihydro-1,3-Dioxepines: Stereoselective Synthesis of Cis- and Trans-2,3-Disubstituted Tetrahydrofurans and Structure-Based Design and Synthesis of Novel Inhibitors of HIV-1 Protease and SARS-3CLPRO Protease

Miranda Raye Belcher, Purdue University

Abstract

Lewis acid-catalyzed rearrangement reactions of 4,5-dihydro-1,3-dioxepines were carried out in a highly stereoselective manner. Rearrangement of these vinyl acetals under an assortment of conditions afforded cis- or trans-2,3-disubstituted tetrahydrofuran products depending on the reaction conditions. Rearrangement reactions at lower temperatures produced the cis-2,3-disubstituted tetrahydrofuran carbaldehydes as major products whereas at elevated temperatures, the analogous trans-2,3-disubstituted tetrahydrofuran carbaldehydes prevailed as the major products. The precursors of the vinyl acetals, the 4,7-dihydro-1,3-dioxepines, were synthesized via a previously unprecedented ring-closing olefin metathesis of diallyl acetals mediated by Grubbs second-generation catalyst. Olefin isomerization of these 4,7-dihydro-1,3-dioxepines with catalytic RuCl2(PPh3)3provided us with our vinyl acetal substrates. We investigated the substrate scope, which included an array of substituted aromatic and aliphatic derivatives. Furthermore, the rearrangement was employed in the synthesis of the bis-tetrahydrofuranyl (bis-THF) alcohol, which is the vital P2 ligand of darunavir, a first-line FDA-approved drug for HIV/AIDS therapy. In 2019, the World Health Organization (WHO) reported that approximately 38 million people were enduring the effects of the Human Immunodeficiency Virus (HIV). Combination antiretroviral therapy (cART) has been utilized to quell replication of the virus down to undetectable levels. This has significantly decreased the mortality and morbidity rates of individuals who are HIV-positive. Unfortunately, with all the advancements toward eradicating HIV/AIDS, no successful treatment exists to expunge the virus from an infected individual. Therefore, more potent and effective HIV inhibitors are being sought out for long-term successful cART. The HIV-1 protease (PR) enzyme plays a significant role in the life cycle and replication of HIV and is therefore a useful drug target. Considerable progress has been obtained through structure-based design, along with X-ray crystallographic analysis of protease-bound to HIV-1, which resulted in the creation of several FDAapproved protease inhibitors (PI). This work focuses on the design, synthesis, and evaluation of new protease inhibitors containing (2-aryl or alkytetrahydrofuran-3-yl)methanol derivatives as the P2 ligand. While these inhibitors displayed potent activity toward HIV-1 protease, they were significantly less active in MT-4 cells. December of 2019 brought about a global health crisis, that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak originated in Wuhan, in central China’s Hubei Province and is continuing to spread at an alarming rate. As the world grapples with the unpredictability of this novel virus, efforts toward the development of new broad-spectrum antiviral agents are necessary. The coronavirus main protease (3CLpro) is a major viral protease that serves as the target for this work. Herein, the design, synthesis, and biological evaluation of chloropyridinyl ester and dipeptide molecules as SARS-CoV 3CLpro protease inhibitors is described. These inhibitors displayed weak to moderate inhibitory activity against SARS-CoV 3CLpro.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Public health

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