Computational ligand design for the reductive elimination of ArCF3 from a small bite angle Pd(II) complex: remarkable effect of a perfluoroalkyl phosphine.

To date only three ligands are known to trigger the challenging reductive elimination of ArCF3 from Pd(II). We report the computational design of a bidentate trifluoromethylphosphine ligand that although exhibiting a generally ineffective small bite angle is predicted to give facile reductive elimination. Our experimental verification gave quantitative formation of ArCF3 at 80 °C within 2 h. This highlights the distinct effect of P-CF3 in organometallic reactivity and constitutes a proof-of-principle study of computational reactivity design.

Trifluoromethylation of ketones and aldehydes with Bu3SnCF3.

The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH4Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.

Chemoselectivity in the reductive elimination from high oxidation state palladium complexes--scrambling mechanism uncovered.

With the objective to increase understanding of the factors that control selectivities in high oxidation state palladium chemistry, we examined the chemoselectivity in the reductive elimination of a dinuclear Pd(III) complex bearing different apical ligands. Experimental, computational, and spectroscopic studies were applied to understand the product selectivity derived from the mixed Cl/OAc dinuclear Pd(III) complex. Analogous species were previously implicated in oxidative C-H functionalizations. The observed experimental chemoselectivity for ArCl was found to be inconsistent with the direct reductive elimination of the mixed Cl/OAc containing Pd(III) dimer. The latter complex is therefore not the key intermediate that ultimately determines the product selectivity. Our spectroscopic and computational studies of the stoichiometric reactivity suggest that the mixed dinuclear Pd(III) complex scrambles readily to give the two Pd(III) homodimers [AcO-Pd(III)-Pd(III)-OAc and Cl-Pd(III)-Pd(III)-Cl], of which the dichlorinated Pd(III) dimer ultimately gives ArCl upon reductive elimination.

Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors.

Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 µM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn(II) identified compounds with increased potencies, with 7 reaching highest potency at CCR1 (EC(50) of 0.85 µM), 20 at CCR8 (0.39 µM), and 8 at CCR5 (1.0 µM). Altered selectivity for CCR1 and CCR8 over CCR5 (11, 12) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (20). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention.

Synthesis and in vitro evaluation of a selective antagonist and the corresponding radioligand for the prostaglandin D2 receptor CRTH2.

Synthesis and preliminary in vitro biological evaluation of a selective high-affinity CRTH2 antagonist is described. The stability of an N-benzyl group facilitated synthesis of the corresponding radioligand by tritiation of a brominated precursor. The compound [(3)H]TRQ11238 represents the first selective CRTH2 antagonist radioligand and exhibited a specific radioactivity of 52 Ci/mmol and a pK(d) of 9.0.