Accelerating Medicinal Chemistry: A C(sp <sup>3</sup> )‐Rich Fragment Toolbox for Redox‐Neutral Cross‐Coupling
Abstract
Abstract The hit‐to‐lead phase of drug discovery is frequently bottlenecked by the time‐consuming, iterative synthesis of analogs, especially when incorporating small C(sp 3 )‐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 make use of 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).
Article Details
Authors (20)
Jet Tsien
Áron Péter
Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
Xin Zeng
Frontiers Science Center for New Organic Matter, Tianjin Key Lab for Rare Earth Materials and Applications, Renewable Energy Conversion and Storage Center (RECAST), School of Materials Science and Engineering, National Institute for Advanced Materials
Shuanghu Wang
Baiyang Jiang
Department of Chemistry Scripps Research 10550 North Torrey Pines Road La Jolla CA 92037 USA
Megan A. Emmanuel
Chemical Process Development Bristol Myers Squibb New Brunswick New Jersey USA
Martins S. Oderinde
Small Molecule Drug Discovery, Bristol Myers Squibb Research & Early Development Route 206 & Province Line Road Princeton NJ 08543 USA
Philippe N. Bolduc
Biogen Inc. 225 Binney Street Cambridge MA 02142 USA
Michael C. Nicastri
Biogen Inc. 225 Binney Street Cambridge MA 02142 USA
Shalini Dey
Biogen Inc. 225 Binney Street Cambridge MA 02142 USA
Michael R. Collins
Department of Chemistry La Jolla Laboratories, Pfizer Inc. 10770 Science Center Drive San Diego CA 92121 USA
Johnny W. Lee
Chemical Research and Development, Pfizer Research and Development Eastern Point Road Groton Connecticut 06340 USA
Martin Bravo
Department of Chemistry La Jolla Laboratories, Pfizer Inc. 10770 Science Center Drive San Diego CA 92121 USA
Paul F. Richardson
Department of Chemistry La Jolla Laboratories, Pfizer Inc. 10770 Science Center Drive San Diego CA 92121 USA
Neal W. Sach
Louise Bernier
Maximilian D. Palkowitz
Small Molecule Drug Discovery, Bristol Myers Squibb, 250 Water Street, Cambridge, Massachusetts 02141, United States
Jennifer X. Qiao
Discovery & Development Sciences
Yu Kawamata
Phil S. Baran