An Unexpected Degradation Pathway of N-Hydroxy-5-Methylfuran-2-Sulfonamide (BMS-986231), a pH Sensitive Prodrug of HNO, in a Prototype Formulation Solution.

N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231, Cimlanod) was being developed as a pH-sensitive prodrug of HNO (nitroxyl) for the treatment of acute decompensated heart failure. During a stressed study of Cimlanod in a prototype formulation solution (pH 4.5) at 40°C, a predominant unknown degradant along with three previously identified degradants were observed. The unknown degradant was isolated from the stressed solution via preparative HPLC but totally decomposed during freeze-drying. LC-HRMS analysis of the isolated unknown degradant, prior to freeze-drying, revealed an empirical formula equivalent to the adduct of Cimlanod with SO2 even though SO2 was not added in the prototype formulation solution. The unknown degradant was synthesized from Cimlanod and DABSO ((1,4-diazabiscyclo[2,2,2]octane bis(sulfur dioxide) adduct) and isolated as a crystalline DABCO (1,4-diazabiscyclo[2,2,2]octane) salt for single crystal X-ray structure elucidation. The degradation of Cimlanod increased when the solution was exposed to air, as compared to N2 atmosphere. A plausible mechanism was postulated for the unexpected degradation pathway of Cimlanod. This study provided in-depth stability knowledge of Cimlanod, which will be beneficial to the subsequent stability indicating method development and validation as well as the registrational applications on the content and qualification of impurities in new drug products.

α-Alkylation and Asymmetric Transfer Hydrogenation of Tetralone via Hydrogen Borrowing and Dynamic Kinetic Resolution Strategy Using a Single Iridium(III) Complex.

Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.

Controlled synthesis of polycarbonate diols and their polylactide block copolymers using amino-bis(phenolate) chromium hydroxide complexes.

A diamine-bis(phenolate) chromium(III) complex, CrOH[L] ([L] = dimethylaminoethylamino-N,N-bis(2-methylene-4,6-tert-butylphenolate)), 2, in the presence of tetrabutylammonium hydroxide effectively copolymerizes CO2 and cyclohexene oxide (CHO) into a polycarbonate diol. The resultant low molar mass (6.3 kg mol-1) diol is used to initiate ring-opening polymerization of rac-lactide with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) giving ABA-type block copolymers with good molar mass control through varying rac-LA-to-diol loadings and with narrow dispersities. As the degree of rac-LA incorporation increases, the glass transition temperatures (Tg) are found to decrease, whereas decomposition temperatures (Td) increase. (Diphenylphosphonimido)triphenylphosphorane (Ph2P(O)NPPh3) was used as a neutral nucleophilic cocatalyst with 2, giving phosphorus-containing polycarbonates with an Mn value of 28.5 kg mol-1, a dispersity of 1.13, a Tg value of 110 °C and a Td value of over 300 °C. A related Cr(III) complex (4) having a methoxyethyl pendent group rather than a dimethylaminoethyl group was structurally characterized as a hydroxide-bridged dimer.

Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Synthesis of Bicyclo[1.1.0]butanes from Iodo-Bicyclo[1.1.1]pentanes.

We describe a two-step process for the synthesis of substituted bicyclo[1.1.0]butanes. A photo-Hunsdiecker reaction generates iodo-bicyclo[1.1.1]pentanes under metal-free conditions at room temperature. These intermediates react with nitrogen and sulfur nucleophiles to afford substituted bicyclo[1.1.0]butane products.

Amination of Nitro-Substituted Heteroarenes by Nucleophilic Substitution of Hydrogen.

An open-air method for the transition metal-free direct amination of nitro(hetero)arenes by anilines is disclosed. In this methodology, an aromatic C-H bond is substituted via oxidative nucleophilic aromatic substitution of hydrogen (ONSH). Density functional theory calculations and mechanistic studies support a dianion pathway with oxidation by molecular oxygen as the rate-limiting step.

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

Structural and Thermal Characterization of Halogenated Azidopyridines: Under-Reported Synthons for Medicinal Chemistry.

Owing to their participation in Click reactions, bifunctional azides are valuable intermediates in the preparation of medicines and biochemical tool compounds. Despite the privileged nature of pyridines among pharmaceutical scaffolds, reports of the synthesis and characterization of azidopyridines bearing a halogen substituent for further elaboration are almost completely unknown in the literature. As azidopyridines carry nearly equal numbers of nitrogen and carbon atoms, we hypothesized that safety concerns limited the application of these useful bifunctional building blocks in medicinal and biological chemistry. To address this concern, we prepared and characterized nine azidopyridines bearing a single fluorine, chlorine, or bromine atom. All were examined by differential scanning calorimetry (DSC), in which they demonstrated exotherms of 228-326 kJ/mol and onset temperatures between 119 and 135 °C. Selected azidopyridines were advanced to mechanical stress testing, in which impact sensitivity was noted for one regioisomer of C5H3FN4. The utility of these versatile intermediates was demonstrated through their use in a variety of Click reactions and the diversification of the halogen handles.

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

A Stereocontrolled Synthesis of a Phosphorothioate Cyclic Dinucleotide-Based STING Agonist.

We describe a stereodefined synthesis of the newly identified non-natural phosphorothioate cyclic dinucleotide (CDN) STING agonist, BMT-390025. The new route avoids the low-yielding racemic approach using P(III)-based reagents, and the stereospecific assembly of the phosphorothioate linkages are forged via the recently invented P(V)-based platform of the so-called PSI (Ψ) reagent system. This P(V) approach allows for the complete control of chirality of the P-based linkages and enabled conclusive evidence of the absolute configuration. The new approach offers robust procedures for preparing the stereodefined CDN in eight steps starting from advanced nucelosides, with late-stage direct drop isolations and telescoped steps enabling an efficient scale-up that proceeded in an overall 15% yield to produce multigram amounts of the CDN.

Discovery of Annulating Reagents Enabling the One-Step and Highly Stereoselective Synthesis of Cyclopentyl and Cyclohexyl Cores.

The use of the unprecedented annulating reagents methyl N-(tert-butylsulfinyl)-4-chlorobutanimidate and methyl N-(tert-butylsulfinyl)-5-bromopentanimidate enables the diastereoselective preparation of 5- and 6-membered carbocycles bearing three contiguous stereocenters. These synthons undergo cycloaddition with a variety of Michael acceptors to form cyclopentane/cyclohexane rings with excellent stereochemical control, generating only one of the eight possible diastereomers. This novel methodology has enabled the highly enantioselective and high yielding synthesis of novel chemotypes of pharmacological relevance.

Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of Heterocycles for Building Molecular Complexity.

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

Synthesis of 1-(tert-Butyl) 4-Methyl (1R,2S,4R)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann's tert-Butyl Ester for an Improved Synthesis of BMS-986251.

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.

Mixed-Valence Superstructure Assembled from a Mixed-Valence Host-Guest Complex.

Herein, we report an unprecedented mixed-valence crystal superstructure that consists of a 2:1 host-guest complex [MV⊂(CBPQT)2]2/3+ [MV = methyl viologen, CBPQT = cyclobis(paraquat- p-phenylene)]. One electron is distributed statistically between three [MV⊂(CBPQT)2]•+ composed of a total of 15 viologen units. The mixed-valence state is validated by single-crystal X-ray crystallography, which supports an empirical formula of [MV⊂(CBPQT)2]3·(PF6)2 for the body-centered cubic superstructure. Electron paramagnetic resonance provides further evidence of electron delocalization. Quantum chemistry calculations confirm the mixed-valence state in the crystal superstructure. Our findings demonstrate that precise tuning of the redox states in host-guest systems can lead to a promising supramolecular strategy for achieving long-range electron delocalization in solid-state devices.

Aqua-chlorido-(2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine)-copper(II) chloride hydrate.

A copper(II) complex of the non-symmetric bidentate ligand 2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine (L1) is reported. The single-crystal X-ray structure of aqua-[aqua/chlorido-(0.49/0.51)](2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine)-copper(II) 0.49-chloride 1.51-hydrate, [CuCl1.51(C10H13N7S)(H2O)1.49]Cl0.49·1.51H2O or [(L1)Cl1.51(H2O)1.49Cu]0.49Cl·1.51H2O, exhibits distorted square-pyramidal geometry around the metal centre, with disorder in the axial position, occupied by chloride or water. The six-membered metal-chelate ring is in a boat conformation, and short inter-molecular S⋯S inter-actions are observed. In addition to its capacity for bidentate metal coordination, the ligand has the ability to engage in further supra-molecular inter-actions as both a hydrogen-bond donor and acceptor, and multiple inter-actions with lattice solvent water mol-ecules are present in the reported structure.

Tricaesium citrate monohydrate, Cs3C6H5O7·H2O: crystal structure and DFT comparison.

The crystal structure of tricaesium citrate monohydrate, 3Cs+·C6H5O73-·H2O, has been solved and refined using laboratory X-ray single-crystal diffraction data, and optimized using density functional techniques. This compound is isostructural to the K+ and Rb+ compounds with the same formula. The three independent Cs cations are eight-, eight-, and seven-coordinate, with bond-valence sums of 0.91, 1.22, and 1.12 valence units. The coordination polyhedra link into a three-dimensional framework. The hy-droxy group forms the usual S(5) hydrogen bond with the central carboxyl-ate group, and the water mol-ecule acts as a donor in two strong hydrogen bonds.

Crystal structure of dicesium hydrogen citrate from laboratory single-crystal and powder X-ray diffraction data and DFT comparison.

The crystal structure of dicesium hydrogen citrate, 2Cs+·C6H6O72-, has been solved using laboratory X-ray single-crystal diffraction data, refined using laboratory powder X-ray data, and optimized using density functional techniques. The Cs+ cation is nine-coordinate, with a bond-valence sum of 0.92 valence units. The CsO9 coordination polyhedra share edges and corners to form a three-dimensional framework. The citrate anion is located on a mirror plane. Its central hy-droxy/carboxyl-ate O-H⋯O hydrogen bond is short, and (unusually) inter-molecular. The centrosymmetric end-end carboxyl-ate hydrogen bond is exceptionally short (O⋯O = 2.416 Å) and strong. These hydrogen bonds contribute 16.5 and 21.7 kcal mol-1, respectively, to the crystal energy. The hydro-phobic methyl-ene groups occupy pockets in the framework.

Flexible ferroelectric organic crystals.

Flexible organic materials possessing useful electrical properties, such as ferroelectricity, are of crucial importance in the engineering of electronic devices. Up until now, however, only ferroelectric polymers have intrinsically met this flexibility requirement, leaving small-molecule organic ferroelectrics with room for improvement. Since both flexibility and ferroelectricity are rare properties on their own, combining them in one crystalline organic material is challenging. Herein, we report that trisubstituted haloimidazoles not only display ferroelectricity and piezoelectricity-the properties that originate from their non-centrosymmetric crystal lattice-but also lend their crystalline mechanical properties to fine-tuning in a controllable manner by disrupting the weak halogen bonds between the molecules. This element of control makes it possible to deliver another unique and highly desirable property, namely crystal flexibility. Moreover, the electrical properties are maintained in the flexible crystals.