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 charges2,3,4. 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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The data that support the findings in this work are available within the paper and in the Supplementary Information.
References
Corey, E. J. & Cheng, X.-M. Logic of Chemical Synthesis (Wiley, 1995).
Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Ed. 18, 239–258 (1979).
Warren, S. G. & Wyatt, P. Organic Synthesis: The Disconnection Approach (Wiley, 2008).
Hoffmann, R. W. Elements of Synthesis Planning (Springer, 2009).
Clayden, J., Greeves, N. & Warren, S. G. Organic Chemistry (OUP, 2012).
Kürti, L. & Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis (Elsevier Science, 2005).
Smith, M. B. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (Wiley, 2013).
Palkowitz, M. D. et al. Overcoming limitations in decarboxylative arylation via Ag–Ni electrocatalysis. J. Am. Chem. Soc. 144, 17709–17720 (2022).
Harwood, S. J. et al. Modular terpene synthesis enabled by mild electrochemical couplings. Science 375, 745–752 (2022).
Nicolaou, K. C., Sorensen, E. J. & Winssinger, N. The art and science of organic and natural products synthesis. J. Chem. Educ. 75, 1225–1258 (1998).
Nicolaou, K. C., Vourloumis, D., Winssinger, N. & Baran, P. S. The art and science of total synthesis at the dawn of the twenty‐first century. Angew. Chem. Int. Ed. 39, 44–122 (2000).
Shen, Y. et al. Automation and computer-assisted planning for chemical synthesis. Nat. Rev. Methods Primers 1, 23 (2021).
Smith, J. M., Harwood, S. J. & Baran, P. S. Radical retrosynthesis. Acc. Chem. Res. 51, 1807–1817 (2018).
Zhang, B. et al. Ni-electrocatalytic Csp3–Csp3 doubly decarboxylative coupling. Nature 606, 313–318 (2022).
Yadav, J. S. & Rajendar, G. Stereoselective total synthesis of polyrhacitides A and B. Eur. J. Org. Chem. 2011, 6781–6788 (2011).
Gaich, T. & Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673 (2010).
Peters, D. S. et al. Ideality in context: motivations for total synthesis. Acc. Chem. Res. 54, 605–617 (2021).
Giese, B. & Dupuis, J. Anomeric effect of radicals. Tetrahedron Lett. 25, 1349–1352 (1984).
Zhang, Y., Ma, D. & Zhang, Z. Utilization of photocatalysts in decarboxylative coupling of carboxylic N-hydroxyphthalimide (NHPI) esters. Arab. J. Chem. 15, 103922 (2022).
Goldfogel, M. J., Huang, L. & Weix, D. J. in Nickel Catalysis in Organic Synthesis: Methods and Reactions (ed. Ogoshi, S.) Ch. 9, 183–222 (Wiley, 2019).
Halperin, S. D. & Britton, R. Chlorine, an atom economical auxiliary for asymmetric aldol reactions. Org. Biomol. Chem. 11, 1702–1705 (2013).
Borg, T., Danielsson, J. & Somfai, P. Mukaiyama aldol addition to α-chloro-substituted aldehydes. Origin of the unexpected syn selectivity. Chem. Commun. 46, 1281–1283 (2010).
Binder, J. T. & Kirsch, S. F. Iterative approach to polyketide-type structures: stereoselective synthesis of 1,3-polyols utilizing the catalytic asymmetric Overman esterification. Chem. Commun. (Camb) 40, 4164–4166 (2007).
Vanjivaka, S. et al. An alternative stereoselective total synthesis of verbalactone. Arkivoc 2018, 50–57 (2018).
Wu, J.-Z. et al. Facile access to some chiral building blocks. Synthesis of verbalactone and exophilin A. Tetrahedron 65, 289–299 (2009).
Allais, F., Louvel, M.-C. & Cossy, J. A short and highly diastereoselective synthesis of verbalactone. Synlett 2007, 0451–0452 (2007).
Cunha, V. L. S., Liu, X., Lowary, T. L. & O’Doherty, G. A. De novo asymmetric synthesis of avocadyne, avocadene, and avocadane stereoisomers. J. Org. Chem. 84, 15718–15725 (2019).
Wang, J. et al. Cu-catalyzed decarboxylative borylation. ACS Catal. 8, 9537–9542 (2018).
Markad, S. B., Bhosale, V. A., Bokale, S. R. & Waghmode, S. B. Stereoselective approach towards the synthesis of 3R, 5 S gingerdiol and 3 S, 5 S gingerdiol. ChemistrySelect 4, 502–505 (2019).
Sabitha, G., Srinivas, C., Reddy, T. R., Yadagiri, K. & Yadav, J. S. Synthesis of gingerol and diarylheptanoids. Tetrahedron Asymmetry 22, 2124–2133 (2011).
Wan, Z., Zhang, G., Chen, H., Wu, Y. & Li, Y. A chiral pool and cross metathesis based synthesis of gingerdiols. Eur. J. Org. Chem. 2014, 2128–2139 (2014).
Blechert, S. & Dollt, H. Synthesis of (−)-streptenol A, (±)-streptenol B, C and D. Liebigs Ann 1996, 2135–2140 (1996).
Mallampudi, N. A., Reddy, G. S., Maity, S. & Mohapatra, D. K. Gold(I)-catalyzed cyclization for the synthesis of 8-hydroxy-3- substituted isocoumarins: total synthesis of exserolide F. Org. Lett. 19, 2074–2077 (2017).
Dumpala, M., Kadari, L. & Krishna, P. R. Brønsted acid promoted intramolecular cyclization of O-alkynyl benzoic acids: concise total synthesis of exserolide F. Synthetic Commun. 48, 2403–2408 (2018).
Kumar, H., Reddy, A. S. & Reddy, B. V. S. The stereoselective total synthesis of PF1163A. Tetrahedron Lett. 55, 1519–1522 (2014).
Tatsuya, K., Takano, S., Ikeda, Y., Nakano, S. & Miyazaki, S. The total synthesis and absolute structure of antifungal antibiotics (−)-PF1163A and B. J. Antibiotics 52, 1146–1151 (1999).
Krishna, P. R. & Srinivas, P. Total synthesis of the antifungal antibiotic PF1163A. Tetrahedron Asymmetry 23, 769–774 (2012).
Li, N., Shi, Z., Tang, Y., Chen, J. & Li, X. Recent progress on the total synthesis of acetogenins from Annonaceae. Beilstein J. Org. Chem. 4, 48 (2008).
Gulavita, N., Hori, A., Shimizu, Y., Laszlo, P. & Clardy, J. Aphanorphine, a novel tricyclic alkaloid from the blue-green alga Aphanizomenon flos-aquae. Tetrahedron Lett. 29, 4381–4384 (1988).
Shigehisa, H., Ano, T., Honma, H., Ebisawa, K. & Hiroya, K. Co-catalyzed hydroarylation of unactivated olefins. Org. Lett. 18, 3622–3625 (2016).
Wang, C. & Guan, Y. Concise total synthesis of (+)-aphanorphine. Synlett 32, 913–916 (2021).
Ziarani, G. M., Mohajer, F. & Kheilkordi, Z. Recent progress towards synthesis of the indolizidine alkaloid 195B. Curr. Org. Synth. 17, 82–90 (2020).
Harding, C. I., Dixon, D. J. & Ley, S. V. The preparation and alkylation of a butanedione-derived chiral glycine equivalent and its use for the synthesis of α-amino acids and α,α-disubstituted amino acids. Tetrahedron 60, 7679–7692 (2004).
Xu, Y. & Tan, D. S. Total synthesis of the bacterial diisonitrile chalkophore SF2768. Org. Lett. 21, 8731–SF8735 (2019).
Kamanos, K. A. D. & Withey, J. M. Enantioselective total synthesis of (R)-(−)-complanine. Beilstein J. Org. Chem. 8, 1695–1699 (2012).
Acknowledgements
We are grateful to D.-H. Huang and L. Pasternack (Scripps Research) for nuclear magnetic resonance spectroscopic assistance and J. Chen and Q. Nguyen Wong (Scripps Automated Synthesis Facility) for assistance with high-resolution mass spectrometry. Financial support for this work was provided by the National Science Foundation Center for Synthetic Organic Electrochemistry (grant CHE-2002158 for optimization of reactivity and initial scope) and the National Institutes of Health (grant GM-118176 for the application of the method to natural product synthesis). We also thank the George E. Hewitt Foundation (to G.L.) for support.
Author information
Authors and Affiliations
Contributions
B.Z., Y.K. and P.S.B. conceptualized the study. B.Z., J.H., Y.G., L.L., M.S.O., M.D.P., C.B. and Y.K. performed the experimental investigation. B.Z., J.H., Y.G., L.L., M.S.O., M.D.P., T.G.M.D., M.D.M., M.R.C., D.C.S., P.N.B., T.C., S.C., N.N.P., G.L., Y.K. and P.S.B. performed data analysis. B.Z., J.H., Y.K. and P.S.B. wrote the manuscript. Y.K. and P.S.B. acquired funding. Y.K. and P.S.B. performed project administration.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature thanks Christian Malapit and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary text, compounds and references.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, B., He, J., Gao, Y. et al. Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling. Nature 623, 745–751 (2023). https://doi.org/10.1038/s41586-023-06677-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-023-06677-2
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
