Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.

A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized in silico. The designed compound 9 demonstrated weak but evident inhibitory activity (IC50 = 54 µM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound 14 (IC50 = 0.0071 µM, EC50 = 0.86 µM), an almost 10,000-fold improvement in activity from 9. The structure of the designed molecules proved to be novel with high synthetic feasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore.

Rhodium-catalyzed borylation of aryl 2-pyridyl ethers through cleavage of the carbon-oxygen bond: borylative removal of the directing group.

The rhodium-catalyzed reaction of aryl 2-pyridyl ethers with a diboron reagent results in the formation of arylboronic acid derivatives via activation of the C(aryl)-O bonds. The straightforward synthesis of 1,2-disubstituted arenes was enabled through catalytic ortho C-H bond functionalization directed by the 2-pyridyloxy group followed by substitution of this group with a boryl group. Several control experiments revealed that the presence of a sp(2) nitrogen atom at the 2-position of the substrate and the use of a boron-based reagent were crucial for the activation of the relatively inert C(aryl)-O bond of aryl 2-pyridyl ethers.

1,3-Dicyclohexylimidazol-2-ylidene as a superior ligand for the nickel-catalyzed cross-couplings of aryl and benzyl methyl ethers with organoboron reagents.

A new catalytic system has been developed involving the use of Ni(cod)2 in conjunction with 1,3-dicyclohexylimidazol-2-ylidene for the cross-coupling of aryl and benzyl methyl ethers with organoboron reagents. This method not only allows for the use of readily available methyl ethers as halide surrogates but also provides a functional group tolerant method for the late-stage derivatization of complex molecules.

1,5-Migration of rhodium via C-H bond activation in catalytic decyanative silylation of nitriles.

Unprecedented aryl-to-aryl 1,5-rhodium migration is involved in decyanative silylation of aryl cyanides bearing a tethered arene. The 1,5-migration proceeds through remote C-H bond activation. 1,5-Migration also occurs in other rhodium-catalyzed reactions, including borylation and oxidative Mizoroki-Heck reactions.

Rhodium(I)-catalyzed borylation of nitriles through the cleavage of carbon-cyano bonds.

The reaction of aryl cyanides with diboron in the presence of a rhodium/Xantphos catalyst and DABCO affords arylboronic esters via carbon-cyano bond cleavage. This unprecedented mode of reactivity for a borylrhodium species allows the regioselective introduction of a boryl group in a late stage of synthesis.