Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

A Catalytic Method for the Enantioselective Synthesis of α-Quaternary Ketones, α-Ketoesters and Aldehydes.

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.

Improving practice patterns in patients with newly diagnosed bladder masses treated with transurethral resection.

CONTEXT: Transurethral resection (TUR) is the mainstay for diagnosis, staging, and treatment of both high-grade and low-grade nonmuscle invasive bladder cancer (NMIBC). It is reported that 51% of initial transurethral resection of bladder tumors (iTURBT) does not contain muscle, which results in higher rates of clinical upstaging on repeat transurethral resection (reTUR) and worse oncologic outcomes. Presence of muscle on iTURBT specimen and performing reTUR within 6 weeks in high-risk NMIBC aids in accurate staging and, therefore, guides proper treatment. OBJECTIVES: This study aimed to assess and improve TURBT quality by making surgeons aware of their practice patterns and setting improvement goals. METHODS: Patients who received TURBT for a newly diagnosed bladder mass were analyzed by retrospective chart review for 9 months prior to quality improvement (QI) intervention. Data were collected pertaining to muscle presence/absence on biopsy, pathology of the tumor, risk stratification, whether reTUR was indicated, and time to reTUR. The primary endpoints were the presence of muscle on initial TURBT, whether a reTUR was performed when clinically indicated, and time to reTUR. Tumors requiring reTUR were defined as being HGT1 or HGTa >3 cm. The QI intervention, physician education, was then implemented by presenting initial performance results to the physicians, and a second dataset was then collected by prospective analysis for another 9 months to assess for changes in practice patterns. A total of 101 patients receiving TURBT were reviewed, including 52 patients prior to and 49 patients following QI intervention. Patients with a history of, or treatment for, bladder cancer were excluded, along with those without assessment of muscle on pathological analysis. Fisher's exact test was utilized to determine differences in categorical data by comparing each of the following groups prior to and following QI intervention: percent of muscle presence on iTURBT, percent reTUR performed when indicated, and mean time to reTUR in days. A p<0.05 was considered statistically significant. RESULTS: After comparing the TURBT results before and after our QI intervention, we found a significant improvement in the number of patients receiving a reTUR when indicated, with 5/13 (38.5%) before compared to 15/19 (78.9%) after, p=0.03. The number of specimens on iTURBT with muscle present were not significantly different, with 38/52 (73.1%) before and 33/49 (67.3%) after, p=0.66. The average time to reTUR before (32.4 days; n=5; range, 21-50 days) and after (42.4 days; n=15; range, 11-77 days) QI intervention was also not significantly different, p=0.28. CONCLUSIONS: Our data suggest that critical analysis of physician practice patterns followed by education and setting improvement goals can significantly impact clinical practices and improve quality of care. Future studies will be performed to determine the impact that these changes have on oncologic outcomes.

Diastereo-, Enantio-, and anti-Selective Formation of Secondary Alcohol and Quaternary Carbon Stereocenters by Cu-Catalyzed Additions of B-Substituted Allyl Nucleophiles to Carbonyls.

A general method for the synthesis of secondary homoallylic alcohols containing α-quaternary carbon stereogenic centers in high diastereo- and enantioselectivity (up to >20:1 dr and >99:1 er) is disclosed. Transformations employ readily accessible aldehydes, allylic diboronates, and a chiral copper catalyst and proceed by γ-addition of in situ generated enantioenriched boron-stabilized allylic copper nucleophiles. The catalytic protocol is general for a wide variety of aldehydes as well as a variety of 1,1-allylic diboronic esters. Hammett studies disclose that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.

Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-Disubstituted Allyldiboron Compounds with Ketones.

A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.

Diastereo- and Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers.

A Cu-catalyzed method for the efficient enantio- and diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)-Cu complex and involve bench-stable γ,γ-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.

Tensile force exerted by suture during renorrhaphy using current techniques.

Partial nephrectomy has become the preferred treatment option for small renal masses. In particular, minimally invasive partial nephrectomy (MIPN) using laparoscopic or robotic approaches has shown decreased blood loss, shorter hospital stay, and faster return to normal activity compared to open surgery. However, MIPN still carries risk of postoperative complications including hemorrhage and urine leakage. Closure of the renal remnant, often called renorrhaphy, is a critical step to avoid these complications. The purpose of the study was to provide quantitative data on suture properties during partial nephrectomy. Multiple suture techniques have been proposed for renal closure during robotic-assisted partial nephrectomy. There is no consensus for preferred closure technique and this decision is at the discretion of the surgeon. Simulated partial nephrectomies were performed on porcine kidneys. Renorrhaphy was completed with barbed suture using a simple running, interrupted sliding-clip, or horizontal mattress technique. Suture tension was obtained prior to tissue failure with force sensors measuring in newtons (N). The interrupted sliding-clip and horizontal mattress techniques performed similarly with median force values of 11.06 N and 12.20 N, respectively. The simple running technique performed with a median force of 3.62 N. ANOVA proved statistical significance. Interrupted sliding-clip and horizontal mattress sutures exert similar forces prior to tissue failure during renorrhaphy. Both techniques were able to achieve forces great enough to overcome the hydrostatic pressure of perfused renal tissue. Simple running sutures failed at significantly lower forces. When closing renal defects after partial nephrectomy, sliding-clip and horizontal mattress should be utilized over simple running sutures.

Enantio- and Diastereoselective Synthesis of Functionalized Carbocycles by Cu-Catalyzed Borylative Cyclization of Alkynes with Ketones.

A single-pot Cu-catalyzed enantio- and diastereoselective tandem hydroboration/borylative cyclization of alkynes with ketones for the synthesis of carbocycles is reported. The reaction proceeds via desymmetrization and generates four contiguous stereocenters, including an all-carbon quaternary center. The method provides rapid access to [6,5]- and [5,5]-bicycles and cyclopentane products. Catalyst-controlled diastereoselectivity by selection of bisphosphine ligand is noted. Utility of the products is demonstrated by site- and chemoselective transformations that afford valuable alkenyl and allyl organoborons.

Enantio- and Diastereoselective Synthesis of Hydroxy Bis(boronates) via Cu-Catalyzed Tandem Borylation/1,2-Addition.

Catalytic enantioselective synthesis of 1-hydroxy-2,3-bisboronate esters through multicomponent borylation/1,2-addition is reported. Catalyst and substrates are readily available, form both a C-B and C-C bond, and generate up to three contiguous stereocenters. The reaction is tolerant of aryl, vinyl, and alkyl aldehydes and ketones in up to 95% yield, >20:1 dr, and 99:1 er. Intramolecular additions to aldehydes and ketones result in stereodivergent processes. The hydroxy bis(boronate) ester products are amenable to site-selective chemical elaboration.