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To make investigational drug candidates available to patients sooner, timelines for drug development are becoming shorter. Synthesis route scouting for active pharmaceutical ingredients (API) and drug product development often must occur simultaneously, requiring formulators to make decisions regarding drug product process selection before commercial API route finalization. Alternatively, the formulation strategy may be locked, thereby constraining drug substance processes with strict API attribute requirements. Critical quality attributes of the drug product can depend heavily on the API, yet final physical attributes may not be known early on in development. Furthermore, the desire to reduce pill burden means higher drug loading in formulations, leaving little room for excipients to compensate for suboptimal API performance. The opposing challenges of API synthetic route and drug product formulation development typically lead to elongated development timelines requiring an iterative approach. In this work, a coordinated strategy was designed and implemented to deliberately range API attributes via crystallization and milling techniques to enable robust assessment of downstream manufacturing and significantly reduce the time for final process selection. The study presented was conducted on a protease inhibitor targeted for treatment of Covid-19. Given the emergent need for treatment options, this dramatically accelerated approach was crucial for potential emergency use authorization (EUA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

A nickel-catalyzed reductive cross-coupling of redox active N -hydroxyphthalimide (NHP) esters and iodoarenes for the synthesis of α-aryl nitriles is described. The NHP ester substrate is derived from cyanoacetic acid, which allows for a modular synthesis of substituted α-aryl nitriles, an important scaffold in the pharmaceutical sciences. The reaction exhibits a broad scope, and many functional groups are compatible under the reaction conditions, including complex highly functionalized medicinal agents. Mechanistic studies reveal that reduction and decarboxylation of the NHP ester to the reactive radical intermediate are accomplished by a combination of a chlorosilane additive and Zn dust. We demonstrate that stoichiometric chlorosilane is essential for product formation and that chlorosilane plays a role beyond activation of the metal reductant.

Acinetobacter baumannii , a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C 2 -substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C 3 )-boronic pinacol esters (Bpin), leaving the C 2 -Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C 3 ) and bridge (C 2 ) positions enable access to C 1 ,C 2 -disubstituted and C 1 ,C 2 ,C 3 -trisubstituted BCPs that encompass previously unexplored chemical space., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp 3 )-C(sp 2 ) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Heterocycles are the backbone of modern medical chemistry and drug development. The derivatization of "an olefin" inside aromatic rings represents an ideal approach to access functionalized saturated heterocycles from abundant aromatic building blocks. Here, we report an operationally simple, efficient, and practical method to selectively access hydrosilylated and reduced N-heterocycles from bicyclic aromatics via a key diradical intermediate. This approach is expected to facilitate complex heterocycle functionalizations that enable access to novel medicinally relevant scaffolds.

The cyclopropanation of alkenyl boronates and subsequent derivatization of the boronate handle are a convenient strategy to quickly build molecular complexity and access diverse compounds with a high sp 3 fraction. Herein, we describe the asymmetric cyclopropanation of enantioenriched hydrobenzoin-derived alkenyl boronic esters toward the synthesis of tertiary and secondary cyclopropyl boronates.

The transition-metal-catalyzed α-arylation of secondary amides remains a synthetic challenge due to the presence of a free N-H bond. We report a strategy to synthesize secondary α-aryl amides via a Ni-catalyzed reductive arylation of redox-active N -hydroxyphthalimide (NHP) esters of malonic acid half amides. This transformation proceeds under mild conditions and displays excellent chemoselectivity for amide α-arylation in the presence of other enolizable carbonyls. The NHP ester substrates are readily prepared from Meldrum's acid.

The stereoselective synthesis of bicyclo[1.1.1]pentane (BCP) benzylamine derivatives from [1.1.1]propellane and mesityl sulfinimines via metal hydride hydrogen atom transfer (MH HAT) is reported. Medicinally relevant heterocyclic BCP methanamines are prepared with high diastereoselectivity. The strategic impact of the method is demonstrated via the streamlined synthesis of the BCP analogue of a key levocetirizine intermediate. Mechanistic evidence for a competitive H 2 evolution pathway and the importance of controlled silane addition during reaction initiation are disclosed.