Efficient and general asymmetric syntheses of (R)-chroman-4-amine salts

Starting from a variety of substituted chroman-4-ones, a highly enantioselective CBS reduction using in situ-generated B-H catalyst gave (S)-chroman-4-ols. Azide inversion and reduction gave crude (R)-chroman-4-amines, which could be purified without chromatography by isolation as the (R)-mandelic or d-tartaric acid salts with good yields and excellent ee.     

A solid-phase approach to the phallotoxins: total synthesis of [Ala7]-phalloidin

Herein we report a solid-phase synthetic approach to [Ala7]-phalloidin (1). Prior syntheses of phallotoxins were carried out using solution-phase routes that required large scale and preclude library production. The route presented here consists of solution-phase preparation of key orthogonally protected amino acid building blocks, followed by a solid-phase peptide synthesis sequence, featuring two resin-bound macro-cyclization reactions. The final product mixture was composed of two atropisomeric compounds, one designated "natural" (1) and the other designated "non-natural" (1'). The structures of these species were modeled using restrained energy minimization with NMR-derived restraints.     

Global phenotypic screening for antimalarials

Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a "malaria box" of publicly accessible active compounds.     

Cheminformatics aspects of high throughput screening: from robots to models: symposium summary

The “Cheminformatics aspects of high throughput screening (HTS): from robots to models” symposium was part of the computers in chemistry technical program at the American Chemical Society National Meeting in Denver, Colorado during the fall of 2011. This symposium brought together researchers from high throughput screening centers and molecular modelers from academia and industry to discuss the integration of currently available high throughput screening data and assays with computational analysis. The topics discussed at this symposium covered the data-infrastructure at various academic, hospital, and National Institutes of Health-funded high throughput screening centers, the cheminformatics and molecular modeling methods used in real world examples to guide screening and hit-finding, and how academic and non-profit organizations can benefit from current high throughput screening cheminformatics resources. Specifically, this article also covers the remarks and discussions in the open panel discussion of the symposium and summarizes the following talks on “Accurate Kinase virtual screening: biochemical, cellular and selectivity”, “Selective, privileged and promiscuous chemical patterns in high-throughput screening” and “Visualizing and exploring relationships among HTS hits using network graphs”.     

Interfacial interaction and morphology of EVOH and ionomer blends by scanning thermal microscopy and its correlation with barrier characteristics

In a blend, the interfacial interaction between the component phases can be effectively utilized to bring about homogeneous mixing and unique performances. While in conventional blends, preserving the morphology of the melt mixed state is unfeasible because of the strong thermodynamic tendency of the components to phase separate, herein, we report the intermolecular interaction of two hydrogen bonded polymers such as a barrier polymer poly(ethylene-co-vinyl alcohol) (EVOH) with an ionic polymer in their blends, which work symbiotically to achieve the desirable characteristics. We demonstrate the creation of a unique ellipsoid microfibrilliar morphology and melt exfoliation of one polymer in the blends through intermolecular interaction and achieve high oxygen barrier characteristics. Scanning thermal microscopy and scanning electron microscopy investigations confirm the presence of such unique morphology. The interfacial interaction and formation of interphase was evident from the local thermal analysis results combined with photoacoustic Fourier transform infrared spectroscopy (PA-FTIR). PA-FTIR confirms the chemical nature of the interaction, while the differential scanning calorimetry results indicate modification of the EVOH phase by the ionomer. The shift of Tg and broadening of the tan delta curve is evident from dynamic mechanical analysis confirming the interaction of the blend components. The blend B(60) with microfibrillar morphology shows fourfold drop in oxygen permeability indicating the role of interfacial interaction and desired morphology.     

Electron scattering with LiH molecule including a realistic dipole potential

Various electron scattering processes are examined theoretically for the strongly polar lithium hydride molecule. We have introduced a realistic dipole potential to calculate rotational cross sections of LiH upon electron impact. From the ionization threshold onwards total cross sections for elastic and inelastic scattering are evaluated in the complex molecular potential, and total ionization cross sections are extracted by CSP-ic method developed in recent years. While most of the results are new some indirect comparisons are made to draw conclusions.     

Determination of minor impurities in temafloxacin hydrochloride by high-performance liquid chromatography

Minor impurities in the antibacterial agent temafloxacin hydrochloride were determined using high-performance liquid chromatography. Manufacturing impurities and degradation products were separated using a reversed-phase system with gradient elution. Detector response was linear for the individual impurities to approximately 50 micrograms/ml which represents 2.5% of the drug concentration. The procedure provides quantitation of impurities to approximately the 0.05% level with precision (relative standard deviations) of 4.7% to 29% in typical bulk drug lots. A variety of reversed-phase columns were evaluated for the assay method with optimum resolution achieved using a 5-microns Nucleosil C18 packing.     

Desymmetrization of pibrentasvir for efficient prodrug synthesis

A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C₂-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Horeau principle statistical amplification and solubility-driven selectivities allow C₂-desymmetrization of pibrentasvir without typically required internal functionalization or steric proximity effects.