Martins Sunday Oderinde

While migratory functionalization reactions provide a powerful means to navigate broader chemical space, their application to aliphatic amines remains particularly elusive. Herein, we describe the nickel-catalyzed migratory arylation of aliphatic amines using Katritzky salts enabled by a “store-and-release” strategy. This strategy leverages dihydropyridines, which are traditionally viewed as chemical dead-ends under reductive cross-coupling conditions, as latent reservoirs to store and release translocated alkyl radicals, thereby decoupling the chain-walking event from the cross-coupling cycle. The developed protocol enables migratory functionalization of Katritzky salts derived from a wide range of primary amines, and a variety of aryl and heteroaryl bromides. The reaction exhibits broad functional group tolerance, accommodating alkenes, polar functionalities, and substrates derived from pharmaceutically relevant compounds. This methodology enables expanded small-molecule library synthesis through regiodivergent deaminative arylations. Preliminary mechanistic studies support the “store-and-release” design principle, rendering it as a platform that can be applied for other migratory functionalization reactions.

Within the tumor microenvironment (TME), regulatory T (Treg) cells promote an immunosuppressive state with limited tumor antigen presentation and antitumor effector T (Teff) cell responses, which can drive resistance to cancer immunotherapies. IKZF2 (Helios) is a transcription factor essential for stabilizing the immunosuppressive Treg cell phenotype in tumors. Herein, we present the discovery of BMS-986449, a selective Cereblon E3 Ligase Modulatory Drug (CELMoD) degrader of IKZF2 and IKZF4 (Eos) that spares the closely related transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos). BMS-986449 is an orally available degrader that demonstrates single-agent growth inhibition of syngeneic MC38 tumors implanted in humanized Cereblon (CRBN) knock-in mice. Tumor growth inhibition was more robust when BMS-986449 was administered in combination with anti-PD-1. Nonhuman primates administered daily with BMS-986449 show sustained IKZF2 degradation in Treg cells providing confidence in human clinical doses. Collectively, these findings establish BMS-986449 as a promising clinical candidate for cancer immunotherapy.

The hit-to-lead phase of drug discovery is frequently bottlenecked by the time-consuming, iterative synthesis of analogs, especially when incorporating small C(sp3)-rich fragments such as methyl, cyclopropyl, or oxetanyl groups—moieties known to improve drug solubility, bioactivity, and metabolic stability. Conventional approaches like Suzuki or Negishi couplings suffer from unstable reagents, high costs, and harsh reaction conditions, while many modern radical-based methods rely on exogenous redox agents or costly metal catalysts. To overcome these limitations, a toolbox of 15 sulfonyl hydrazide reagents is disclosed to facilitate redox-neutral, nickel- catalyzed radical cross-coupling of 14 distinct small fragments onto (hetero)arenes under mild conditions. These crystalline, bench-stable reagents are straightforward to synthesize from accessible precursors and require no additional oxidants, reductants, or precious metals, offering a modular and operationally simple platform. Demonstrated across a diverse set of over 60 (hetero)aryl halides, the method exhibits exceptional substrate scope and functional group tolerance, accommodating complex, medicinally relevant scaffolds. Comparative studies with existing techniques underscore its advantages, including a 51% yield for trideuteromethylation of a MET kinase inhibitor precursor (versus a precedented 14% via Kumada coupling) and a streamlined one-step cyclobutylation of an NLRP3 inhibitor intermediate at 41% yield (versus a known <5% over a four-step sequence). By accelerating analog synthesis for hit-to-lead optimization and enabling late-stage functionalization of drug-like molecules, this sulfonyl hydrazide toolbox is a useful resource for synthetic and medicinal chemistry, with significant potential to advance drug discovery and beyond.

Sulfonyl hydrazides are stable and usually crystalline substances that can be accessed in a variety of ways, including transiently from hydrazones, to achieve a net reductive arylation of carbonyl compounds. We show their utility as versatile radical precursors, as exemplified with seven C–C bond–forming, redox-neutral cross-couplings with activated olefins, alkyl halides, redox-active esters, aryl halides, alkenyl halides, alkynyl halides, and a trifluoromethylating reagent, to forge C(sp ³ )-C(sp ³ ), C(sp ³ )-C(sp ² ), and C(sp ³ )-C(sp) bonds. Exogenous redox (chemical, photo/electrochemical) additives are not necessary because these functional groups serve the dual role of radical precursor and electron donor. The homogeneous, water-compatible reaction conditions are operationally simple and contribute to streamlining synthesis and mild late-stage functionalization.

A simple protocol for the Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse cereblon binding motifs is disclosed. The development of this C-N cross-coupling method was enabled by high-throughput combinatory screening of solvents, bases, temperatures, and ligands. Scope studies revealed generality across various heteroaryl and aryl halides with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant decrease in step count from known syntheses in the patent literature.

Increasingly complex, three-dimensional leads for drug discovery are testing the limits of modern organic synthesis. In this context, the need for new methods to access gem-diarylated cyclobutanes, azetidines, and oxetanes is apparent. The present study outlines a modular, scalable, chemoselective approach to solve this problem using simple a-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of Ni-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have never been accessible before, without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry.

Functionalized cyclobutanes are three‐dimensional scaffolds widely found in natural products and bioactive molecules. Herein, we report a visible‐light‐induced intermolecular [2+2] cycloaddition reaction of a diverse array of alkenes with N ‐substituted maleimides to access functionalized azabicyclo[3.2.0]heptanes. The reaction showed broad substrate scope with good chemo‐, regio‐ and diastereoselectivity under mild conditions. The robustness of this photo‐mediated [2+2] cycloaddition was demonstrated by carrying out a reaction on a 100 g scale (58 % yield). The prepared functionalized azabicyclo[3.2.0]heptanes are synthetic scaffolds for drug discovery.

A simple protocol for the direct Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse Cereblon Binding Motifs is disclosed. This C-N cross-coupling method development was enabled by high throughput combinatory screening of key reaction parameters namely solvents, temperatures and ligands. Scope studies revealed generality across various heteroaryl and aryl halides, with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant step count reduction from known syntheses in the patent literature.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.