A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels–Alder Reactions

Jamie A. Cadge; Cedric Lozano; Morgan Merriman; Matthew Sigman; Sarah Reisman

doi:10.1021/jacs.5c09948

A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels–Alder Reactions

Jamie A. Cadge
, Cedric Lozano
, Morgan Merriman
, Matthew Sigman
, Sarah Reisman

University of Utah
California Institute of Technology

Research output: Contribution to journal › Article › peer-review

2 Citations (SciVal)

102 Downloads (Pure)

Abstract

The Ni-catalyzed homo-Diels–Alder (hDA) reaction represents a convergent but under-investigated approach to preparing bridged bicyclic ring systems. Using the kraken monophosphine descriptor library, Ni-catalyzed hDA reactions of acyclic and cyclic electron deficient olefins were investigated, and key ligand effects required for reactivity were identified using classification models. This analysis guided the discovery of the monophosphine (S)-AntPhos as a chiral ligand for the enantioselective hDA of acyclic dienophiles. However, these conditions were not compatible with cyclic substrates. Further mechanistic and computational studies revealed a putative role of Ni(I) species and mechanistic divergence between cyclic and acyclic enone dienophiles. Using reaction space design and Bayesian optimization, conditions were developed that expanded the scope to cyclic dienophiles. The resultant cycloadducts were transformed into bicycloheptane structures via cyclopropane cleavage reactions, demonstrating the ability to rapidly access structurally complex scaffolds using this method.

Original language	English
Pages (from-to)	31175–31186
Number of pages	12
Journal	Journal of the American Chemical Society
Volume	147
Issue number	34
Early online date	15 Aug 2025
DOIs	https://doi.org/10.1021/jacs.5c09948
Publication status	Published - 27 Aug 2025

Funding

We acknowledge the financial support from the NSF under the CCI Center for Computer Assisted Synthesis (C-CAS) (CHE-2202693) for work completed in the Sigman and Reisman laboratories. The support and resources from the Center for High Performance Computing (CHPC) at the University of Utah are gratefully acknowledged. NMR results included in this report were recorded at the David M. Grant NMR Center, a University of Utah Core Facility. Funds for construction of the Center and the helium recovery system were obtained from the University of Utah and the National Institutes of Health awards 1C06RR017539-01A1 and 3R01GM063540-17W1, respectively. NMR instruments were purchased with support of the University of Utah and the National Institutes of Health award 1S10OD25241-01. We thank Dr. Eugene Kwon (Merck) for helpful discussions regarding the natural abundance C KIE experiments. We gratefully acknowledge Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory. We thank Dr. Michael K. Takase for assistance with X-ray crystallography. We thank Jeff Kerkovius (Caltech) for early discussions and ideas related to this project. We acknowledge the financial support from the NSF under the CCI Center for Computer Assisted Synthesis (C-CAS) (CHE-2202693) for work completed in the Sigman and Reisman laboratories. The support and resources from the Center for High Performance Computing (CHPC) at the University of Utah are gratefully acknowledged. NMR results included in this report were recorded at the David M. Grant NMR Center, a University of Utah Core Facility. Funds for construction of the Center and the helium recovery system were obtained from the University of Utah and the National Institutes of Health awards 1C06RR017539-01A1 and 3R01GM063540-17W1, respectively. NMR instruments were purchased with support of the University of Utah and the National Institutes of Health award 1S10OD25241-01. We thank Dr. Eugene Kwon (Merck) for helpful discussions regarding the natural abundance13C KIE experiments. We gratefully acknowledge Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory. We thank Dr. Michael K. Takase for assistance with X-ray crystallography. We thank Jeff Kerkovius (Caltech) for early discussions and ideas related to this project.

Funders	Funder number
National Science Foundation
University of Utah Core Facility
University of Utah
Beckman Institute X-ray Crystallography Facility at Caltech
Sigman and Reisman laboratories
Casualty Actuarial Society	CHE-2202693
National Institutes of Health	1C06RR017539-01A1, 3R01GM063540-17W1, 1S10OD25241-01

ASJC Scopus subject areas

Catalysis
Biochemistry
General Chemistry
Colloid and Surface Chemistry

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10.1021/jacs.5c09948

2025-7-29_Ni-hDA (accepted author manuscript)Accepted author manuscript, 4.42 MBLicence: CC BY

Cite this

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title = "A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels–Alder Reactions",

abstract = "The Ni-catalyzed homo-Diels–Alder (hDA) reaction represents a convergent but under-investigated approach to preparing bridged bicyclic ring systems. Using the kraken monophosphine descriptor library, Ni-catalyzed hDA reactions of acyclic and cyclic electron deficient olefins were investigated, and key ligand effects required for reactivity were identified using classification models. This analysis guided the discovery of the monophosphine (S)-AntPhos as a chiral ligand for the enantioselective hDA of acyclic dienophiles. However, these conditions were not compatible with cyclic substrates. Further mechanistic and computational studies revealed a putative role of Ni(I) species and mechanistic divergence between cyclic and acyclic enone dienophiles. Using reaction space design and Bayesian optimization, conditions were developed that expanded the scope to cyclic dienophiles. The resultant cycloadducts were transformed into bicycloheptane structures via cyclopropane cleavage reactions, demonstrating the ability to rapidly access structurally complex scaffolds using this method.",

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AU - Sigman, Matthew

AU - Reisman, Sarah

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A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels–Alder Reactions

Abstract

Funding

ASJC Scopus subject areas

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