Convergent synthesis of (+)-carambolaflavone A, an antidiabetic agent using a bismuth triflate-catalyzed C-aryl glycosylation.

We describe a convergent total synthesis of carambolaflavone A, a natural flavonoid C-aryl glycoside with significant antihyperglycemic properties. The synthesis features a bismuth triflate-catalyzed stereoselective C-aryl glycosylation of a flavan derivative and an appropriately protected D-fucose derivative as the key step. Inexpensive and non-toxic bismuth triflate provided the best results among various other Lewis acids screened for this C-aryl glycosylation. The method can be utilized for the synthesis of other bioactive C-glycosyl flavonoids. The glycosylation partners were synthesized from commercially available (±)-naringenin and D-(+)-galactose, respectively. An oxidative bromination and elimination reaction sequence was utilized to construct the flavone. The natural product is obtained in 13 steps (longest linear sequence) from D-(+)-galactose.

Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation.

We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (R)-hydroxyethylamine sulfonamide isostere. Inhibitor 3h with an N-methyl-3-(R)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory Ki value of 0.51 nM. An energy minimized model of 3h revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent activity.

Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.

We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.

Enantioselective total synthesis of decytospolide A and decytospolide B using an Achmatowicz reaction.

Enantioselective syntheses of decytospolide A and decytospolide B are described here. The current synthesis highlights an Achmatowicz rearrangement of an optically active furanyl alcohol followed by reduction of the resulting dihydropyranone hemiacetal with BF3·OEt2 and Et3SiH to provide the saturated tetrahydropyranyl alcohol directly. This reduction was investigated with a variety of other Lewis acids. The synthesis also features Noyori asymmetric transfer hydrogenation and Friedel-Crafts acylation. Overall, the synthesis provides ready access to the natural products and may be useful in the preparation of bioactive derivatives.