Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops.

The HIV-1 envelope (Env) spike (gp120(3)/gp41(3)) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full-length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a "ground state" for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from "snapping" into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e.g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry.

Efficient aqueous-phase Heck and Suzuki couplings of aryl bromides using tri(4,6-dimethyl-3- sulfonatophenyl)phosphine trisodium salt (TXPTS).

[reaction: see text] Sterically demanding, sulfonated arylphosphines TXPTS and TMAPTS have been applied to the aqueous-phase Heck and Suzuki coupling of aryl bromides. TXPTS provides good yields of Heck coupling products from aryl bromides at 80 degrees C, while both TMAPTS and TPPTS gave significantly less active catalysts. TXPTS is the first ligand to promote the aqueous-phase Heck coupling under such mild conditions. Both TXPTS and TMAPTS provide active catalysts for Suzuki couplings of aryl bromides at 50 degrees C.

A heterogeneous-catalyst-based, microwave-assisted protocol for the synthesis of 2,2'-bipyridines.

A new method of preparing 2,2'-bipyridines with short reaction times by using microwave assistance and heterogeneous catalysts has been developed. With a Negishi-like protocol, it was found that Ni/Al(2)O(3)-SiO(2) afforded 2,2'-bipyridine products in up to 86% yield in 1 h. Palladium supported on alumina also provided yields of 2,2'-bipyridines comparable to those seen for homogeneous PEPPSI (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II)dichloride) and tetrakis(triphenylphosphanyl)palladium complexes.

Bulky alkylphosphines with neopentyl substituents as ligands in the amination of aryl bromides and chlorides.

Di(tert-butyl)neopentylphosphine (DTBNpP) in combination with palladium sources provided catalysts with comparable or better activity for the Hartwig-Buchwald amination of aryl bromides than tri(tert-butyl)phosphine (TTBP) under mild conditions. DTBNpP also provided effective catalysts for amination reactions of aryl chlorides at elevated temperatures. Further replacement of tert-butyl groups with neopentyl substituents resulted in less effective ligands for amination reactions. Computationally derived cone angles showed that replacement of a tert-butyl group with a neopentyl group significantly increased the cone angle of the phosphine. The larger cone angle of DTBNpP than TTBP appears to correlate with the higher activity of catalysts derived from DTBNpP in the amination of aryl bromides. TTBP is a stronger electron donor than DTBNpP, which may explain the higher activity for TTBP-derived catalysts toward aryl chlorides.

Aqueous-phase, palladium-catalyzed cross-coupling of aryl bromides under mild conditions, using water-soluble, sterically demanding alkylphosphines.

Sterically demanding, water-soluble alkylphosphines have been used in combination with various palladium salts in Suzuki, Sonogashira, and Heck couplings of aryl bromides under mild conditions in aqueous solvents. The tert-butyl-substituted ligands 2-(di-tert-butylphosphino)ethyltrimethylammonium chloride (t-Bu-Amphos) and 4-(di-tert-butylphosphino)-N,N-dimethylpiperidinium chloride (t-Bu-Pip-phos) in combination with palladium(II) salts were found to give catalysts that were significantly more active than catalysts derived from tri(3-sulfonatophenyl)phosphine trisodium (TPPTS). Suzuki couplings of unactivated aryl bromides occurred efficiently at room temperature in water/acetonitrile and water/toluene biphasic mixtures or in neat water. Notably, Suzuki couplings of hydrophilic aryl bromides gave high yields without using organic solvents for the reaction or purification. This methodology has been applied to a highly efficient synthesis of diflunisal. The catalyst derived from t-Bu-Amphos was recycled three times in Suzuki couplings in water/toluene before catalyst activity began to significantly drop. The average yield of four cycles was >80% per cycle. Heck and Sonogashira couplings were carried out under mild conditions (50 and 80 degrees C, respectively) with unactivated aryl bromides to give coupled products in high yield.