Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery
Year: 2026
Type: preprint
Abstract: Three-dimensional molecular shape is a fundamental determinant of protein recognition, yet chemical discovery is often biased toward regio- and stereoisomers that are more readily accessible by synthesis. Here we overcome this constraint using radical cross-coupling (RCC), converting stereoprobe synthesis from selective sampling into exhaustive exploration of three-dimensional chemical space. By combining stereorandomizing and stereopreserving RCC manifolds, we constructed complete piperidine and pyrrolidine matrices (40 and 24 members, respectively) encompassing every theoretically possible regio- and stereoisomer of the corresponding disubstituted scaffolds and expanded these collections to 108 covalent stereoprobes from a small set of readily available precursors. Proteome-wide activity-based protein profiling (ABPP) revealed highly differentiated engagement across regio- and stereoisomers that could further be diversified by changing the covalent reactive group. Selected engagements were structurally characterized by X-ray crystallography, and extension to complementary protein-directed ABPP further expanded the observable ligandability landscape. These findings establish RCC as a practical strategy for removing synthetic bias from stereochemical exploration and identified stereoselective small molecule-protein engagements that could have been missed by conventional non-exhaustive screening.
Source: ChemRxiv
Authors: Yin Li, Jiayan He, Jeffery J. Yu, Jiawei Sun, Rajan R. Gollapudi, Christopher A. Toth, Steffen M. Bernard, Christie L. Eissler, Steven C Wang, Brian E. Nordin, Annabel Q. Ansel, Connor Scheuerman, Tracey Nguyen, Ann Shih, Cody L. Fullenwider, Benjamin D. Horning, Jonathan Pollock, Matthew P. Patricelli, David S. Weinstein, Gabriel M. Simon, Brian N. Cook, Quynh N. Wong, Jillian E. Smith, Benjamin F. Cravatt, Yu Kawamata, Cian Kingston, Phil S. Baran
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7221773215