Enantioselective Syntheses of (-)-Alloyohimbane and (-)-Yohimbane by an Efficient Enzymatic Desymmetrization, and Design and Synthesis of High-Affinity P2 Ligands and (Hydroxyethyl)Urea Isosteres for HIV-1 Protease Inhibitors

Anindya Sarkar, Purdue University

Abstract

Enantioselective syntheses of (–)-alloyohimbane and (–)-yohimbane were achieved in a convergent fashion. The key step involved a modified mild procedure for the enantioselective enzymatic desymmetrization of a meso-diacetate, providing expedient access to an optically pure monoacetate in multi-gram amounts. This monoacetate was converted to (–)-alloyohimbane. Reductive amination of the resulting aldehyde caused isomerization to the trans-product, which was utilized for the synthesis of (–)-yohimbane. An efficient, enantioselective synthesis of hexahydro-4H-furopyranol (Tp-THF), a high-affinity P2 ligand for HIV-1 Protease inhibitors has been achieved from commercially available, inexpensive starting materials. The key steps were a highly enantioselective enzymatic desymmetrization of meso-diacetate, an intramolecular transacetalization, and a highly diastereoselective reduction of a ketone. The synthetic route is amenable to large-scale synthesis of the P2 ligand. Design and synthesis of another high-affinity P2 ligand, 2-((3 R,3aS,6aR)-hexahydrofuro[2,3- b]furan-3-yl)acetic acid, has been accomplished. HIV-1 Protease inhibitors containing the (hydroxyethyl)urea isostere have also been designed and synthesized. Inhibitory potency of all the above three classes of inhibitors were studied.

Degree

Ph.D.

Advisors

Ghosh, Purdue University.

Subject Area

Chemistry|Organic chemistry

COinS