Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling

Benxiang Zhang, Jiayan He, Yang Gao, Laura Levy, Martins S. Oderinde, Maximilian D. Palkowitz, T. G. Murali Dhar, Michael D. Mandler, Michael R. Collins, Daniel C. Schmitt, Philippe N. Bolduc, TeYu Chen, Sebastian Clementson, Nadia Nasser Petersen, Gabriele Laudadio, Cheng Bi, Yu Kawamata () and Phil S. Baran ()
Additional contact information
Benxiang Zhang: Scripps Research
Jiayan He: Scripps Research
Yang Gao: Scripps Research
Laura Levy: Scripps Research
Martins S. Oderinde: Bristol Myers Squibb Research & Early Development
Maximilian D. Palkowitz: Bristol Myers Squibb Research & Early Development
T. G. Murali Dhar: Bristol Myers Squibb Research & Early Development
Michael D. Mandler: Bristol Myers Squibb Research & Early Development
Michael R. Collins: Pfizer Pharmaceuticals
Daniel C. Schmitt: Pfizer Worldwide Research and Development
Philippe N. Bolduc: Biogen Inc.
TeYu Chen: Biogen Inc.
Sebastian Clementson: LEO Pharma A/S
Nadia Nasser Petersen: LEO Pharma A/S
Gabriele Laudadio: Scripps Research
Cheng Bi: Scripps Research
Yu Kawamata: Scripps Research
Phil S. Baran: Scripps Research

Nature, 2023, vol. 623, issue 7988, 745-751

Abstract: Abstract Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2–4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.

Date: 2023
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DOI: 10.1038/s41586-023-06677-2

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