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Accessing three-dimensional molecular diversity through benzylic C–H cross-coupling

Nature Synthesis volume 2, pages 998–1008 (2023)Cite this article

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Abstract

Pharmaceutical discovery efforts rely on robust synthetic methods that rapidly access diverse molecules. Cross-coupling reactions are the most widely used reactions, but these methods typically form bonds with C(sp2)-hybridized atoms and lead to a prevalence of ‘flat’ molecules with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling offers an appealing strategy to address this limitation, as emerging methods exhibit synthetic versatility that rivals conventional cross-coupling to access drug-like products. Here we use a virtual library of benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized centres affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. These concepts are validated through an informatics-guided synthesis and high-throughput experimentation to prepare three-dimensional products that are broadly distributed across drug-like chemical space.

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Fig. 1: Benzylic C–H cross-coupling reactions provide access to 3D chemical space.
Fig. 2: Enumeration of benzylic ethers and ureas derived from P01–P20 scaffolds and topological comparison of P01–P20 coupling products and CIC.
Fig. 3: Analysis of functionalization products and structural derivatives of A11 highlighting the improved three-dimensionality accessed through C(sp3) coupling.
Fig. 4: PCA showing that benzylic cross-coupling products derived from P01–P20 scaffolds exhibit physicochemical features aligned with CIC.
Fig. 5: Benzylic C–H cross-coupling products exhibit drug-like physicochemical properties while showing improved three-dimensionality relative to CIC.
Fig. 6: Benzylic C–H cross-coupling is amenable to HTE methods to access diverse medicinally relevant molecules.

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Data availability

The authors declare that all of the data supporting the findings of this study are available within the paper and its supplementary information file. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2164953. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All raw data that support the findings of this study have been deposited at the figshare repository and may be obtained free of charge via https://doi.org/10.6084/m9.figshare.22213894.v2.

Code availability

Enumeration sequences and molecular property calculations described in this work are available for use as components in Pipeline Pilot. See Section 10 of Supplementary Information for the Python code used for PBF calculations and Section 11 for the R code used for PCA.

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Acknowledgements

We thank S.-E. Suh for helpful discussions about applications of the benzylic C–H isocyanation–urea synthesis, T. G. Greshock for suggestions on the PCA and HTE, I. A. Guzei and K. M. Sanders for assistance with X-ray crystallographic characterization of A16-1, B. A. Parvizian for LC–MS support and A. Bleskacek for assistance with melting point and optical rotation measurements. This work was supported by the National Institutes of Health (NIH) (R35 GM134929, to S.S.S.) and Merck & Co., Inc., Kenilworth, NJ, USA (travel funds to S.-J.C.). Spectroscopic instrumentation was supported by a gift from P. J. Bender, the NSF (CHE-1048642) and the NIH (S10 OD020022).

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Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin−Madison, Madison, WI, USA

    Si-Jie Chen & Shannon S. Stahl

  2. Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA

    Si-Jie Chen, May Kong & Jun Wang

  3. Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA

    Cyndi Qixin He, Shishi Lin & Shane W. Krska

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Contributions

This project was conceived by S.S.S., in collaboration with S.W.K. and S.-J.C. S.-J.C. performed the informatics studies and experiment work and led the data interpretation and analysis. M.K. and J.W. supported purification of selected products in high-throughput synthesis. C.Q.H. performed conformational analysis and provided guidance and insights into library enumeration, PCA and PMI analysis. S.-J.C. and S.L. selected the alcohol and amine building blocks for library enumeration. All work was done in consultation with S.W.K. and S.S.S. All authors contributed to preparation of the paper.

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Correspondence to Shannon S. Stahl.

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Peer review information

Nature Synthesis thanks György Keserű, Peng Zhan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

General experimental considerations, enumeration workflows, PCA plots information (Section 6), characterization of compounds (Section 12), Supplementary Figs. 1–6 and Tables 1–11.

Supplementary Data 1

Crystallographic data for A16-1, CCDC 2164953.

Supplementary Data 2

Sample structure input for PBF procedure demonstration.

Supplementary Data 3

Sample data output for PBF procedure demonstration.

Supplementary Data 4

Sample data input for PCA procedure demonstration.

Supplementary Data 5

Sample data output for PCA procedure demonstration.

Supplementary Data 6

Procedure operations instructions for PCA and PBF calculations.

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Chen, SJ., He, C.Q., Kong, M. et al. Accessing three-dimensional molecular diversity through benzylic C–H cross-coupling. Nat. Synth 2, 998–1008 (2023). https://doi.org/10.1038/s44160-023-00332-4

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