Grit and uncertainty: Grit predicts performance and West Point graduation during pandemic conditions.

Grit, or the passionate pursuit of long-term goals, is an important predictor of performance and success across various domains, including within some military contexts. Whether grit predicts such outcomes at a military service academy during a multi-year period of prolonged uncertainty, however, is unknown. Using institutional data collected prior to the COVID-19 pandemic onset, we assessed how well grit, physical fitness test scores, and entrance examination scores predicted performance in academic, military, and physical domains, as well as on-time graduation for 817 cadets from the West Point Class of 2022. This cohort spent more than 2 years of their time at West Point functioning under the uncertainty of pandemic-related conditions. Multiple regression results showed that grit, fitness test, and entrance examination scores were all significant predictors of performance outcomes in the academic, military, and physical domains. Results from binary logistic regression showed that, in addition to physical fitness, grit scores significantly predicted graduation from West Point and accounted for unique variance. Consistent with results from pre-pandemic studies, grit was an important predictor of performance and success for West Point cadets even under pandemic conditions.

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

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the ß-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone 22. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) 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 1. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same ß-keto ester in 5% yield over 13 steps.

Elucidating the pathways of degradation of denagliptin.

Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway.

Novel synthesis of desymmetrized resorcinol derivatives: aryl fluoride displacement on deactivated substrates.

A short, high-yielding synthesis of differentially substituted resorcinol derivatives has been developed that utilizes 1,3-difluorobenzene as the starting material and employs sequential nucleophilic aromatic substitution (S(N)Ar) reactions to generate desymmetrized products. The scope and limitations of the second S(N)Ar reaction on the deactivated 1-alkoxy-3-fluorobenzene intermediates have been investigated. This methodology has also been employed in the synthesis of desymmetrized catechol derivatives from 1,2-difluorobenzene.