Dipannita Kalyani

The Suzuki–Miyaura cross-coupling reaction is a cornerstone of C–C bond formation. However, heteroaryl boronic acids such as pyridyl and quinolyl derivatives remain challenging nucleophiles due to facile protodeboronation. Strategies enabling these substrates are limited to C(sp2)–C(sp2) formation. Efficient and modular C(sp2)–C(sp3) cross-coupling methods that directly employ these substrates remain underdeveloped. Here, we report a cross-organoboron platform that enables direct C(sp2)–C(sp3) bond formation from heteroaryl and alkyl organoboron reagents under visible-light irradiation using Ag2O/TiO2 nanoparticles (NPs). The two organoboron reagents undergo distinct Ag2O NP activations: alkyl boronates undergo single-electron photo-oxidation to generate alkyl radicals while arylboronates undergo transmetalation. Importantly, this method tolerates protodeboronation-prone pyridyl, quinolyl, α-heteroaryl boronic acids, and (hetero)aryl halide-containing substrates, including aryl iodides. High-throughput evaluation across 161 pharmaceutically relevant organoboron substrates identified 113 detectable couplings, and representative examples were validated at preparative scale. This work establishes photochemical cross-organoboron coupling as a complementary approach to classical transition-metal-catalyzed coupling and expands the accessible chemical space of heteroaryl organoboron reagents.

Within macrocyclic peptides of both natural products and pharmaceutical targets, aryl rings play a crucial role in linker structure, and C(sp3)-rich cyclophane linkers can imbue beneficial physicochemical properties. Yet, methods to deliver C(sp3)-rich cyclophane linkers remain limited, restricting the types of carbon-rich linkers that can be efficiently investigated in medicinal chemistry campaigns. Herein, we describe the development of a nickel-mediated deaminative macrocyclic arylation that uses amino acid monomers compatible with solid-phase peptide synthesis workflows, accommodates a wide range of peptide functionalities, and can access broad macrocycle architectures including those of a natural alkaloid derivative and polycyclic peptides.

Academia–industry partnerships are an important driver of innovation in drug discovery, and their success depends on intentional problem selection, effective resource sharing, and robust communication during project execution. This outlook highlights select Merck Sharp & Dohme Discovery Chemistry (MSD DC) collaborations reported over the past five years to illustrate principles that underpin productive academia–industry partnerships. Through representative case studies in synthesis collaborations, we illustrate two complementary collaboration strategies: targeted development of synthetic methods that address key medicinal chemistry bottlenecks, and capability-building efforts that enable technology transfer to accelerate drug discovery. We also highlight a few nonsynthetic collaborations by MSD DC in computational chemistry, structure elucidation, and chemical biology subfields, underscoring the cross-functional impact of these efforts on drug discovery. Beyond scientific advances, these collaborations also provide meaningful training and professional development opportunities for the next generation of chemists.

Nickel-catalyzed reductive cross-electrophile couplings offer powerful access to C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds from readily available electrophiles, yet their use in drug discovery has been hampered by difficult optimization, narrow scope, and limited tolerance of complex functionality. Through collaborations between MSD Discovery Chemistry and the Watson, Hazari, and Sevov groups, we established deaminative couplings of diverse alkyl pyridinium electrophiles with a wide range of aryl halides, dual Ni/Co and Ni/Ti catalysis that engages challenging primary and secondary alkyl and aryl halides using tunable homogeneous organic reductants, and isolable Ni(aryl)/Ni(alkyl) oxidative addition complexes as persistent organonickel platforms that accommodate both aryl and alkyl halide partners. Together, these complementary strategies improve control over key elementary steps, broaden substrate scope to challenging secondary and peptide-like partners, and enable late-stage functionalization of complex, drug-like scaffolds under high-throughput experimentation-compatible conditions.

Cross-electrophile coupling (XEC) reactions are widely employed to rapidly construct C(sp²)-C(sp³) bonds from available substrates. Key elementary steps of the reaction, such as oxidative addition and radical coupling, have been individually investigated with discrete complexes, but no studies exist that probe these and other key steps along the reaction pathway from a single, synthetically relevant platform. This work leverages the accessibility of persistent organonickel complexes to benchmark the effects of electronic and steric parameters of complexes and substrates on the rates of oxidative addition, the stabilities of organonickel intermediates, and the rates of radical coupling. Insights into the rates of oxidative addition help to rationalize synthetic limitations that are frequently encountered in Ni-catalyzed methodologies. Finally, the aggregate effects of the independently studied steps were evaluated by measuring the overall yields of the combinatorial coupling reactions. These insights established guidelines for selecting Ni complexes for XEC reactions of substrates that are challenging to couple.

Azetidines are four-membered saturated N-heterocycles that are of interest in discovery chemistry. However, the implementation of these structures is limited by their synthetic intractability, resulting from their inherent ring strain. An approach that circumvents this is the intermolecular [2 + 2] photocycloaddition between imines and alkenes. However, this is unworkable with simple acyclic imines and non-activated alkenes, due to the inability to generate suitably reactive imine-derived triplet intermediates. Here we show that simple acyclic imines bearing N-sulfamoyl fluoride substituents generate reactive triplet imines that react with a broad range of alkenes to produce azetidine products in high yields. Mechanistic and computational studies confirm the key role of the sulfamoyl fluoride unit in dictating the [2 + 2] pathway. In addition, the sulfamoyl fluoride substituents offer a convenient reaction site for product functionalization or for traceless removal. The advent of synthetically useful imine-derived triplets should initiate further research and applications of these elusive reactive intermediates.

This manuscript presents machine learning models for Pd-catalyzed C-N couplings constructed using a large, pharmaceutically relevant, structurally diverse dataset (4204 unique products) generated de novo using high-throughput experimentation. The dataset generation was enabled by the discovery of novel nanomole scale compatible automation friendly C-N coupling reaction conditions using LiOTMS as the base. The large dataset enabled the systematic evaluation of model performance using five different data-splitting strategies that were carefully designed to assess the models' ability to both interpolate and extrapolate. The models exhibit high predictive performance across all splits as gauged by standard metrics. In addition, the models predicted with high accuracy the outcome of validation libraries that were outside the scope of the training set. Employing these models in the context of medicinal chemistry campaigns should result in significant enrichment of successful C-N couplings.

This report describes a detailed study of the palladium-mediated directed C(2)-H functionalization of bicyclo[1.1.1]pentanes (BCPs). Previous attempts to achieve this transformation were reported as unsuccessful. To understand why, a combination of stoichiometric organometallic experiments (to isolate and study the coordination chemistry of these substrates), H/D exchange (to directly probe the C-H activation step), and DFT calculations (to predict optimal directing groups and supporting ligands) was conducted. Collectively, these revealed that cyclometalation at Pd(II) is kinetically facile but thermodynamically unfavorable with aminoquinoline as a directing group and acetonitrile as a supporting ligand. However, changing to a pyridine N-oxide directing group or dimethyl sulfoxide (DMSO) supporting ligand enabled the isolation of stable BCP palladacycles. The functionalization of these complexes was low-yielding with two-electron aryl iodide oxidants. However, moving to single-electron reactions (using in situ-generated aryl radicals) or to electrophilic functionalization (using I₂) resulted in synthetically useful yields of C(2)-functionalized products at room temperature. This C-H functionalization approach was leveraged to access derivatives of a key intermediate in the synthesis of bioisosteric analogues of the angiotensin II receptor blocker telmisartan. A four-step sequence from commercially available BCP carboxylic acids, involving directing group installation, cyclopalladation, C(2) arylation, and directing group cleavage, afforded a comparable or improved overall yield, step-count, and functional group compatibility relative to state-of-the-art synthetic approaches. Overall, these studies uncovered a mild Pd-mediated route for the C(2)-diversification of the BCP scaffold. In addition, the lessons learned herein provide a blueprint for achieving directed C-H functionalization of a broader array of strained ring benzene bioisosteres.

The structural diversification of pharmaceutically relevant compounds presents unique challenges to catalytic methodologies that have been developed and optimized on simpler substrates that lack drug-like complexity. Here we report a general strategy for carbon–heteroatom (C–X) bond formation through reactions between a wide range of nucleophiles and nickel-based oxidative addition complexes of drug-like aryl and heteroaryl electrophiles. These organonickel complexes are easily synthesized by oxidative addition of the corresponding electrophiles under electroreductive conditions using an inexpensive nickel precursor. Redox-induced oxidative coupling from these persistent complexes proved challenging, but mechanistic studies guided the development of a simple aerobic oxidation procedure to rapidly form C–X coupled products. Exposure of the organonickel complexes to ambient air forms a high-valent (peroxo)Ni^IIIAr complex intermediate that can undergo substitution with a variety of nitrogen-, oxygen-, sulfur-, carbon-, phosphorus- or halide-based nucleophiles, which are incorporated into the product. The breadth of this methodology was demonstrated by reactions with unreactive electrophiles, such as aryl chlorides, drug-like (hetero)aryl electrophiles and small peptides. Finally, the aerobic chemistry was miniaturized to allow for high-throughput exploration of substrate diversity with an equally complex set of nucleophilic partners.