Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)­aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo­(hetero)­arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro­(hetero)­arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.

We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)­aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki–Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C­(sp2)–C­(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki–Miyaura cross-coupling.

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography F-isotopologue validated our liver-targeting approach.

We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.

A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tertbutyl isocyanide as a CO source. The intermediate 1,2diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis-vs monoinsertion product.

The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.

The ability to discriminate between like functional groups, so as to transform organic molecules in a site-selective or chemoselective manner, [1] precludes the requirement of protecting groups and, hence, carries the potential to dramatically enhance synthetic efficiency. [2] Though an exceptionally daunting challenge, systematic efforts toward catalytic methods for the site-selective transformation of polyfunctional molecules have begun to emerge. For example, the groups of Miller [3] and Taylor [4] report catalytic methods for the site-selective manipulation of diols and higher polyols. Site-selective metal-catalyzed cross-couplings have been catalogued. [5] Further, in what is perhaps the most formidable theatre for site selectivity, impressive advances in catalytic methods for CÀH functionalization have been achieved, as illustrated in the seminal work of Barton, [6b] Murai and Kakiuchi, [6a] and in more recent studies by the groups of Davies, [6c] Sanford, [6d] Yu, [6e] Daugulis, [6f] Baran, [6g] and others.

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell‐free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F‐isotopologue validated our liver‐targeting approach.