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Complex Molecule Synthesis & Retrosynthesis

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Complex molecules drive new reaction development and provide lead compounds for therapeutic translation. The identification of high-value retrosynthetic disconnections represent one of the most challenging tasks in accessing these complex scaffolds efficiently. In C-CAS, we aim to employ tools that inform chemists of optimal synthetic routes among the endless theoretical space of possible disconnects.

Publications

  • Bartholomew, G.L.; Kraus, S.L.; Karas, L.J.; Carpaneto, F.; Bennett, R.; Sigman, M.S.; Yeung, C.S.; Sarpong, R. “14N to 15N Isotopic Exchange of Nitrogen Heteroaromatics through Skeletal Editing” ChemRxiv 2023 .10.26434/chemrxiv-2023-30dtw

  • Jie Xu, Samantha Grosslight, Kyle A. Mack, Sierra C. Nguyen, Kyle Clagg, Ngiap-Kie Lim, Jacob C. Timmerman, Jeff Shen, Nicholas A. White, Lauren E. Sirois, Chong Han, Haiming Zhang*, Matthew S. Sigman*, and Francis Gosselin. Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036. J. Am. Chem. Soc. 2022, 144, 45, 20955-20963.  https://doi.org/10.1021/jacs.2c09917

  • Shen, Y., Borowski, J., Hardy, M., Sarpong, R. Doyle, A., Cernak, T. Automation and computer-assisted planning for chemical synthesis. Nat Rev Methods Primers, 2021, 23, 1.    https://www.nature.com/articles/s43586-021-00022-5

  • Jordan, J. Dotson, Lucy van Dijk, Jacob C. Timmerman, Samantha Grosslight, Richard C. Walroth, Francis Gosselin, Kurt Püntener, Kyle A. Mack*, and Matthew S. Sigman*.  Data-Driven Multi-Objective Optimization Tactics for Catalytic Asymmetric Reactions using Bisphosphine Ligands. J. Am. Chem. Soc. 2022, Dec 27, 2022.     https://doi.org/10.1021/jacs.2c08513

  • Schleinitz, J., Carreteri-Cerdan, A., Gurajapu, A., Harnik, Y., Lee, G., pandey, A., Milo, A., Reisman, S.E. Designing Target-specific Data Sets for Regioselectivity Predictions on Complex Substrates. J. Am. Chem. Soc. 2025. https://pubs.acs.org/action/showCitFormats?doi=10.1021/jacs.4c15902&ref=pdf

  • Wiest, O., Bauer, C., Helquist, P., Norrby, P.O. and Genheden, S., Finding relevant retrosynthetic disconnections for stereocontrolled reactions. J. Chem. Inf. Mod. 2024, 64, 5796–5805 https://doi.org/10.1021/acs.jcim.4c00370

  • Roh, J., Joung, J.F., Yu, K., Tu, Z., Bartholomew, G.L., Santiago-Reyes, O.A., Fong, M.H., Sarpong, R., Reisman, S.E.; Coley, C.W. Higher-level strategies for computer-aided retrosynthesis. ACS Cent. Sci.2026, 12, 345-357. https://doi.org/10.1021/acscentsci.5c02014

  • Raghavan, P., Rago, A.J., Verma, P., Hassan, M.M., Goshu, G.M., Dombrowski, A.W., Pandey, A., Coley, C.W. and Wang, Y., Incorporating Synthetic Accessibility in Drug Design: Predicting Reaction Yields of Suzuki Cross-Couplings by Leveraging AbbVie’s 15-Year Parallel Library Data Set. J., Am Chem. Soc. 2024, 146, 15070–15084. https://doi.org/10.1021/jacs.4c00098

  • Wiesler, S., Sennari, G., Popescu, M.V., Gardner, K.E., Aida, K., Paton, R.S., Sarpong, R. Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide. Nature Communications. 2024, 15:4125. doi: 10.1038/s41467-024-48586-6.

  • Wright, B.A., Sarpong, R. Molecular Complexity as a Driving Force for the Advancement of Organic Synthesis. Nat Rev Chem (2024). doi:10.1038/s41570-024-00645-8

  • Wright, Brandon A., Taku Okada, Alessio Regni, Guilian Luchini, Shree Sowndarya S. V, Nattawadee Chaisan, Sebastian Kölbl, Sojung F. Kim, Robert S. Paton, and Richmond Sarpong. "Molecular Complexity-Inspired Synthetic Strategies toward the Calyciphylline A-Type Daphniphyllum Alkaloids Himalensine A and Daphenylline." Journal of the American Chemical Society. (2024). ASAP https://doi.org/10.1021/jacs.4c11252

  • Guo, K.; Liu, Z.; Guo, Z.; Nan, B.; Isayev, O.; Chawla, N.V.; Wiest, O.; Zhang, X. Proto-Yield: An Uncertainty-Aware Prototype Network for Yield Prediction in Real-world Chemical Reactions. 34th ACM Intl. Conf. Inf. Knowl. Man. (CIKM’25) 2025 accepted.

  • Jones, K.E.; Park, B.; Doering, N.A.; Baik, M.H.; Sarpong, R.  Rearrangements of the Chrysanthenol Core: Application to a Formal Synthesis of Xishacorene B. J. Am. Chem. Soc. 2021, 143, 20482–20490 https://doi.org/10.1021/jacs.1c10804

  • Smith, A.L., Toste, F.D. Stereoselective Generalizations over Diverse Sets of Chiral Acids Enabled by Buried Volume. J. Am. Chem. Soc. 2026, 148, 2792-2800. https://doi.org/10.1021/jacs.5c20342

  • Hardy, M.A.; Nan, B.; Wiest, O.; Sarpong, R.  Strategic elements in computer-aided retrosynthesis: A case study of the pupukeanane natural products Tetrahedron 2022, 103, 132584   https://doi.org/10.1016/j.tet.2021.132584

  • Shen, Y. Tian, Y.; Ju, C.-W.; Wiest, O.; Zhang, X. Towards Few-shot Chemical Reaction Outcome Prediction. 34th ACM Intl. Conf. Inf. Knowl. Man. (CIKM’25) 2025 accepted

  • Gallarati, S., Bucci, E.M., Doyle, A.G. et al. Transferable enantioselectivity models from sparse data. Nature (2026). https://doi.org/10.1038/s41586-026-10239-7

  • Hardy, M.A.; Cooke, J.H.; Feng, Z.; Noda, K.; Kerschgens, I.; Massey, L.A.; Tantillo, D.J.; Sarpong, R. Unified Synthesis of 2-Isocyanoallopupukeanane and 9-Isocyanopupukeanane through a "Contra-biosynthetic" Rearrangement. Angew. Chem. Int. Ed. 2024, 63. https://doi.org/10.1002/anie.202317348

Experimental Chemistry

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