Flow-Injection MS/MS for Gas-Phase Chiral Recognition and Enantiomeric Quantitation of a Novel Boron-Containing Antibiotic (GSK2251052A) by the Mass Spectrometric Kinetic Method

The present work demonstrates, for the first time, the application of the mass spectrometric kinetic method for quantitative chiral purity determination by automatic flow-injection MS/MS. The particular compound analyzed is GSK2251052A, a novel boron-containing systemic antibiotic for the treatment of multidrug-resistant Gram-negative bacterial infections. Chiral recognition and quantitation of GSK2251052A was achieved based on the competitive dissociation kinetics of the Cu^II-bound trimeric complex [Cu^II(A)­(ref*)₂–H]⁺ (A = GSK2251052A or its R-enantiomer, ref* = l-tryptophan) that gives rise to Cu^II-bound dimeric complexes. The sensitive nature of the methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the optical purity, characteristic of the kinetic method, allow chiral purity determination of pharmaceutical compounds during enantioselective synthesis. By using flow-injection MS/MS, enantiomeric quantitation of GSK2251052A by the kinetic method proved to be fast (2 min for analysis of each sample) and to have accuracy comparable to chiral LC–MS/MS and LC–UV methods as well as the method using chiral derivatization followed by LC–MS/MS analysis. This flow-injection MS/MS method represents an alternative approach to commonly used chromatographic techniques as a means of chiral purity determination and is particularly useful for rapid screening of chiral drugs during pharmaceutical development

¹⁷O Solid-State NMR as a Sensitive Probe of Hydrogen Bonding in Crystalline and Amorphous Solid Forms of Diflunisal

¹⁷O solid-state NMR (SSNMR) can provide insight into hydrogen bonding interactions in pharmaceutical polymorphs, cocrystals, and amorphous dispersions. When combined with straightforward ¹⁷O synthetic labeling, the use of ¹⁷O SSNMR allows for direct study of key interactions such as hydrogen bonding in these systems. In this work, novel applications of ¹⁷O SSNMR are demonstrated in the analysis of a polymorph of diflunisal, a cocrystal of diflunisal with pyrazinamide, and amorphous dispersions of diflunisal in two polymers. The observation of the ¹⁷O nucleus is shown to be a highly specific and useful alternative to more conventional studies of the ¹H, ¹³C, and ¹⁹F nuclei in these systems and offers unique insight into hydrogen bonding interactions. Quantum chemical calculations are used to assess the ¹⁷O SSNMR measurements for the polymorph of diflunisal for which a crystal structure has been previously determined. Empirical hydrogen bonding trends are then examined in the cocrystal and amorphous solid forms using ¹⁷O NMR parameters. A novel application of ¹H–¹⁷O cross-polarization heteronuclear correlation (CP-HETCOR) experiments is also demonstrated for the cocrystal and two dispersions. This experiment offers specific information about proton environments in proximity to the labeled oxygen sites. The use of ¹⁷O SSNMR techniques extends the utility of SSNMR in applications to cocrystals and amorphous dispersions

An Efficient and Highly Diastereoselective Synthesis of GSK1265744, a Potent HIV Integrase Inhibitor

A novel synthesis of GSK1265744, a potent HIV integrase inhibitor, is described. The synthesis is highlighted by an efficient construction of the densely functionalized pyridinone core as well as a highly diastereoselective formation of the acyl oxazolidine moiety. The latter exploits the target molecule’s ability to chelate to Mg²⁺, a key feature in the integrase inhibitor’s mechanism of action

An Efficient and Highly Diastereoselective Synthesis of GSK1265744, a Potent HIV Integrase Inhibitor

A novel synthesis of GSK1265744, a potent HIV integrase inhibitor, is described. The synthesis is highlighted by an efficient construction of the densely functionalized pyridinone core as well as a highly diastereoselective formation of the acyl oxazolidine moiety. The latter exploits the target molecule’s ability to chelate to Mg²⁺, a key feature in the integrase inhibitor’s mechanism of action

Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A

HCV NS5B polymerase inhibitor GSK852A (<b>1</b>) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (<b>3</b>) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core <b>15</b> from the β-keto ester in one pot and the efficient conversion of ester <b>6</b> to amide <b>19</b> via enamine lactone <b>22</b>. Serendipitous events led to identification of the isolable enamine lactone intermediate <b>22</b>. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone <b>22</b>. The hydrogen bond was considered an enabler in the proposed pathway from ester <b>6</b> to enamine lactone <b>22</b> and its rearrangement to amide <b>19</b>. GSK852A (<b>1</b>) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of <b>1</b>. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps