Richard G. Ball

Activation of dihydrogen by ruthenium(II)-chelating phosphine complexes, and activation of dioxygen by ruthenium(II) porphyrin complexes: an update

Abstract This presentation reviews some recent studies from these laboratories that concern activation of dihydrogen and of dioxygen by various ruthenium complexes in solution. Part 1 describes developments in the catalytic chemistry of Ru(II)/chelating ditertiary phosphine complexes, in particular their applications in asymmetric hydrogenation, while Part 2 outlines work on O 2 -oxidation of thioethers catalyzed by Ru(II) porphyrin complexes. An experimental section, giving full details on the syntheses and characterization of the complexes, including X-ray crystallographic analyses, and on the catalysis experiments, is not given in this paper; such details will appear in future publications, but are meanwhile available on request.

Carbonyl-η-hexamethylbenzene complexes of osmium. Carbon-hydrogen activation by (η-C6Me6)Os(CO)(H)2

Abstract Reduction of (η-C6Me6)Os(CO)Cl2 (1) with zinc/acetic acid/methanol gives (η-C6Me6)Os(CO)(Cl)H (2), which can be further reduced with Na[H2Al(OCH2- CH2OCH3)2] to (η-C6Me6)Os(CO)H2 (3). Photolysis of 3 in hydrocarbons (benzene, cyclohexane, neopentane) results in formation of the carbon-hydrogen bond activation products (η-C6Me6Os(CO)(R)(H) (6a–6c, R = C6H5, C6H11 and CH2C(CH3)3, respectively) and free hexamethylbenzene. Independent syntheses of the hydrides 6a–6c are described as well as syntheses of the complexes (η-C6Me6)Os(CO)(R)2 (4a–4c) and (η-C6Me6)Os(CO)(R)Cl (5a–5c). The structure of (η-C6Me6)Os(CO)(cyclohexyl)2 (4b) determined by single crystal X-ray diffraction is reported.

Conformational Analysis and Receptor Docking of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (Taranabant, MK-0364), a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist

X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.

Actinide poly(pyrazol-1-yl)borate complexes: synthesis and structure of hydrotris(3,5-dimethylpyrazol-1-yl)boratotrichlorotetrahydrofuran actinide(IV), M[HB(3,5-Me2Pz)3]Cl3(THF) (M=Th and U)

Abstract The reaction of MCl4 with K[HB(3,5-Me2Pz)3] in THF gives the monosubstituted derivatives M[HB(3,5-Me2Pz)3]Cl3(THF) (M=Th (1) and U (2)) in excellent yields. The NMR spectra of the molecules indicate symmetrical structures with equivalent pyrazolyl groups. This has been corroborated by single-crystal X-ray analysis. The uranium center in 2 is seven-coordinate and displays capped octahedral geometry. The tridentate pyrazolylborate moiety and the three Cl atoms define the two staggered triangular faces respectively, the latter is capped by the THF oxygen. The coordination geometry is close to C3v symmetry. The steric congestion imposed by the bulky pyrazolylborate ligand is evidenced by the relative low coordination number and the long U—O bond length, 2.546(4) A. Crystal data 2: monoclinic, P21/n, a=10.195(2), b=14.905(2), c=17.414(4) A, β=100.08(2)°, V= 2605.32 A3 and Z=4. Complex 1 is isomorphous with 2.

A Cavaet on the Swern Oxidation

Abstract The Swern oxidation of structurally diverse alcohols (3,4,7, and11) employing the oxalyl chloride-DMSO protocol unexpectedly gave rise to products resulting from concomitant electrophilic chlorination. This potential problem can be avoided either by using the reagents in stoichiometric amount or by employing trifluoroacetic anhydride-DMSO or acetic anhydride-DMSO.

Complexes of substituted benzothiazoles. 2. Copper(II) complexes of the 'tripod' ligand tris(2-benzothiazolylmethyl)amine

A series of copper(II) complexes of the title ligand are reported which exhibit both five-coordinate trigonal bipyramidal and pseudo-octahedral stereochemistries. Mixed stereochemistry complexes [C...

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

Synthesis, X-ray crystal structure and photochemistry of (η5-pentamethylcyclopentadienyl)(dicarbonyl)(dihydrido) rhenium in cyclohexane and liquid xenon solutions and in low temperature media at about 12 K

An improved synthesis of ( η 5 -C 5 Me 5 )Re(CO) 2 (H) 2 has been devised (yield 88%) via ( η 5 -C 5 Me 5 )Re CO) 3 and ( η 5 -C 5 Me 5 )-Re(CO) 2 (Br) 2 . An X-ray crystallographic determination has shown that the hydrido ligands occupy trans positions, in confirmation of IR and NMR measurements. The properties and reactions of trans -( η 5 -C 5 Me 5 )Re(CO) 2 (H) 2 and related compounds ( η 5 -C 5 Me 5 )Re-(CO) 2 (X)(Y) (X  H, Me; Y  H, Me, Cl) are described. The solution photoctemistry of trans -( η 5 -C 5 Me 5 )Re CO 2 (H) 2 ) in cyclohexane at 298 K and in liquid xenon at 200 K, including studies under D 2 , indicate that the primary photoproduct is the cis isomer and that trans to cis interconversion, which can be reversed thermally, is an intramolecular process. Photochemical studies of ( η 5 -C 5 Me 5 )Re-(CO) 2 N 2 ) in liquid Xe under H 2 and D 2 pressures at 200 K gave cis -( η 5 -C 5 Me 5 )Re(CO) 2 and cis -( η 5 -C 5 Me 5 )Re(CO) 2 (D) 2 , respectively. Matrix isolation studies at about 12 K, including 13 CO labelling, confirmed that the photoisomerisation process is an intramolecular process since no ejected CO is observed and no 13 CO uptake occurred. subsequent photolysis affords H2 and CO ejection yielding ( η 5 -C 5 Me 5 )Re(CO) 2 and ( η 5 -C 5 Me 5 )Re(CO)(H) 2 , respectively . In N 2 and CO matrices the subsequent photolysis also yielded ( η 5 -C 5 Me 5 )Re(CO) 2 ( N 2 ) and ( η 5 -C 5 Me 5 )Re(CO) 3 but in CH 4 matrices there was no evidence of CH photoactivation to yield ( η 5 -C 5 Me 5 )Re(CO) 2 (CH 3 )(H). Reversals from cis to trans could not be observed for gas matrices but was observed at near ambient temperatures for the cis isomer produced at about 12 K in Nujol mull media.

Discovery of N-[(4R)-6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist for the Treatment of Obesity

This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.

Synthesis and structure of five-coordinate bis(hydrocarbyl)iridium(III) complexes of the formula Ir(R)R′[N(SiMe2CH2PPh2)2]

Abstract Reaction of the hydrocarbyliridium(III)-halide complexes Ir(R)X[N(SiMe 2 CH 2 -PPh 2 ) 2 ] (R = CH 3 , X = I; R = CH 2 Ph, X = Br; R = C 6 H 5 , X = I) with organolithium reagents generates the coordinatively unsaturated, five-coordinate complexes Ir(R)R′[N(SiMe 2 CH 2 PPh 2 ) 2 ], where R′ can be CH 3 , CH 2 CMe 3 , CH 2 SiMe 3 , or C 6 H 5 . These highly colored, crystalline materials are trigonal bipyramidal in the solid state and in solution. The crystal structure of the dibenzyl derivative, Ir(CH 2 Ph) 2 [N(SiMe 2 CH 2 PPh 2 ) 2 ], shows a distorted trigonal bipyramidal structure with the tridentate ligand occupying the two axial positions (PPh 2 donors) and one equatorial site (NSi 2 ); the two benzyl groups are at the remaining equatorial positions with the angle between these two ligands being 77.6 (1)°.