Modeling Reaction Feasibility to Identify New Opportunities for Sigmatropic Rearrangements
4 affiliations
- 1Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, Massachusetts, 02139
- 2Ecole Nationale Supérieure de Chimie de Paris
- 3Université PSL, CNRS
- 4Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, Massachusetts, 02139
Abstract
Defining the scope and limitations of synthetic methods enables bolder, lower-risk synthetic design. Computation can facilitate this if able to anticipate reaction success or failure. Herein, we combine a machine-learned interatomic potential with the TS-tools package for high-throughput prediction of transition state geometries and barriers for hypothetical reactions. We focus on sigmatropic rearrangements, which are of synthetic interest, enable non-obvious retrosynthetic disconnections, and are explicable by electronic structure theory. Benchmarking against reference theory and experimental kinetics establishes quantitative accuracy, and retrospective case studies illustrate utility in synthesis planning. Prospectively, we identify and experimentally realize a methylenation/Claisen sequence toward the natural product (±)-norbrachycoumarin and a UR-144 degradant. A coarse-grained kinetic study across ten substrates, seven installing all-carbon quaternary centers β to a ketone, reveals good agreement between computed barriers and experimental outcomes. Collectively, this work demonstrates how computational reaction feasibility modeling uncovers opportunities to apply existing methodologies to valuable chemical spaces.
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BibTeX
@misc{liles2026modeling,
title = {{Modeling Reaction Feasibility to Identify New Opportunities for Sigmatropic Rearrangements}},
author = {Jordan P. Liles and Nicholas Casetti and Thijs Stuyver and Connor W. Coley},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008353/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008353/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Modeling Reaction Feasibility to Identify New Opportunities for Sigmatropic Rearrangements
AU - Jordan P. Liles
AU - Nicholas Casetti
AU - Thijs Stuyver
AU - Connor W. Coley
PY - 2026
DA - 2026/09/04
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008353/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008353/v1
AB - Defining the scope and limitations of synthetic methods enables bolder, lower-risk synthetic design. Computation can facilitate this if able to anticipate reaction success or failure. Herein, we combine a machine-learned interatomic potential with the TS-tools package for high-throughput prediction of transition state geometries and barriers for hypothetical reactions. We focus on sigmatropic rearrangements, which are of synthetic interest, enable non-obvious retrosynthetic disconnections, and are explicable by electronic structure theory. Benchmarking against reference theory and experimental kinetics establishes quantitative accuracy, and retrospective case studies illustrate utility in synthesis planning. Prospectively, we identify and experimentally realize a methylenation/Claisen sequence toward the natural product (±)-norbrachycoumarin and a UR-144 degradant. A coarse-grained kinetic study across ten substrates, seven installing all-carbon quaternary centers β to a ketone, reveals good agreement between computed barriers and experimental outcomes. Collectively, this work demonstrates how computational reaction feasibility modeling uncovers opportunities to apply existing methodologies to valuable chemical spaces.
ER -