Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery
6 affiliations
- 1Department of Chemistry
- 2Scripps Research
- 3School of Chemistry and Chemical Engineering
- 4South China University of Technology
- 5Vividion Therapeutics, Inc.
- 6Automated Synthesis Facility
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.
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BibTeX
@misc{li2026radical,
title = {{Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery}},
author = {Yin Li and Jiayan He and Jeffery J. Yu and Jiawei Sun and Rajan R. Gollapudi and Christopher A. Toth and Steffen M. Bernard and Christie L. Eissler and Steven C Wang and Brian E. Nordin and Annabel Q. Ansel and Connor Scheuerman and Tracey Nguyen and Ann Shih and Cody L. Fullenwider and Benjamin D. Horning and Jonathan Pollock and Matthew P. Patricelli and David S. Weinstein and Gabriel M. Simon and Brian N. Cook and Quynh N. Wong and Jillian E. Smith and Benjamin F. Cravatt and Yu Kawamata and Cian Kingston and Phil S. Baran},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010428/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010428/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Radical Cross-Coupling Delivers Complete Sets of Saturated-Heterocyclic Regio- and Stereoprobes for Chemoproteomic Discovery
AU - Yin Li
AU - Jiayan He
AU - Jeffery J. Yu
AU - Jiawei Sun
AU - Rajan R. Gollapudi
AU - Christopher A. Toth
AU - Steffen M. Bernard
AU - Christie L. Eissler
AU - Steven C Wang
AU - Brian E. Nordin
AU - Annabel Q. Ansel
AU - Connor Scheuerman
AU - Tracey Nguyen
AU - Ann Shih
AU - Cody L. Fullenwider
AU - Benjamin D. Horning
AU - Jonathan Pollock
AU - Matthew P. Patricelli
AU - David S. Weinstein
AU - Gabriel M. Simon
AU - Brian N. Cook
AU - Quynh N. Wong
AU - Jillian E. Smith
AU - Benjamin F. Cravatt
AU - Yu Kawamata
AU - Cian Kingston
AU - Phil S. Baran
PY - 2026
DA - 2026/10/13
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010428/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010428/v1
AB - 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.
ER -