Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds.

A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the ß-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.

Chemoselective Umpolung of Enals for Asymmetric Homoenolate Cross-Annulation of Enals and Aldehydes Catalyzed by N-Heterocyclic Carbene.

An asymmetric homoenolate cross-annulation of enals and aldehydes with high enantioselectivity is realized by NHC-catalyzed chemoselective umpolung of enals. The reaction proceeds in a highly chemoselective manner, selectively generating the conjugated Breslow intermediates from enals rather than aldehydes, enabling the homoenolate addition of enals to aldehydes in preference to competing acyl anion-mediated reactions. Enantioenriched substituted γ-butyrolactones are formed in good yields with high enantioselectivities.