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


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.




Ghosh, Purdue University.

Subject Area

Chemistry|Organic chemistry

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