Abstract
Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon–carbon (C–C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.
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
References
Fleming, I. Pericyclic Reactions (Oxford Univ. Press, Oxford, 2015).
Nicolaou, K. C., Snyder, S. A., Montagnon, T. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 1668–1698 (2002).
Corey, E. J. & Cheng, X. M. The Logic of Chemical Synthesis (Wiley, New York, 1989).
de Meijere, A., Bräse, S. & Oestreich, M. Metal Catalyzed Cross-Coupling Reactions and More (Wiley-VCH, New York, 2014).
Lovering, F., Bikker, J. & Humblet, C. Escape from Flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).
Schneider, N., Lowe, D. M., Sayle, R. A., Tarselli, M. A. & Landrum, G. A. Big data from pharmaceutical patents: a computational analysis of medicinal chemists’ bread and butter. J. Med. Chem. 59, 4385–4402 (2016).
Fleming, I. Frontier Orbitals and Organic Chemical Reactions (Wiley, New York, 1991).
Olivo, H. F. & Hemenway, M. S. Recent syntheses of epibatidine. A review. Org. Prep. Proced. Int. 34, 1–25 (2002).
Carini, D. J. et al. Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. J. Med. Chem. 34, 2525–2547 (1991).
Dolitzky, B.-Z., Nisnevich, G., Ruchman, I. & Kaftanov, J. Processes for preparing losartan and losartan potassium. Canadian patent CA2482857A1 (2003).
Larsen, R. D. et al. Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. J. Org. Chem. 59, 6391–6394 (1994).
Cornella, J. et al. Practical Ni-catalyzed aryl–alkyl cross-coupling of secondary redox-active esters. J. Am. Chem. Soc. 138, 2174–2177 (2016).
Wang, J. et al. Nickel-catalyzed cross-coupling of redox-active esters with boronic acids. Angew. Chem. Int. Ed. 55, 9676–9679 (2016).
Edwards, J. T. et al. Decarboxylative alkenylation. Nature 545, 213–218 (2017).
Smith, J. M. et al. Decarboxylative alkynylation. Angew. Chem. Int. Ed. 56, 11906–11910 (2017).
Qin, T. et al. A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352, 801–805 (2016).
Chen, Y., Tian, S.-K. & Deng, L. A highly enantioselective catalytic desymmetrization of cyclic anhydrides with modified cinchona alkaloids. J. Am. Chem. Soc. 122, 9542–9543 (2000).
Padwa, A. & Dent, W. Use of N-[(trimethylsilyl)methyl]amino ethers as capped azomethine ylide equivalents. J. Org. Chem. 52, 235–244 (1987).
Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
Trost, B. M. & Chan, D. M. T. Palladium-mediated cycloaddition approach to cyclopentanoids. Introduction and initial studies. J. Am. Chem. Soc. 105, 2315–2325 (1983).
Poplata, S., Tröster, A., Zou, Y.-Q. & Bach, T. Recent advances in the synthesis of cyclobutanes by olefin [2 + 2] photocycloaddition reactions. Chem. Rev. 116, 9748–9815 (2016).
Fan, Y.-Y., Gao, X.-H. & Yue, J.-M. Attractive natural products with strained cyclopropane and/or cyclobutane ring systems. Sci. China Chem. 59, 1126–1141 (2016).
Bartoli, G., Bencivenni, G. & Dalpozzo, R. Asymmetric cyclopropanation reactions. Synthesis 46, 979–1029 (2014).
Committee for Medicinal Products for Human Use (CHMP) assessment report EMA/CHMP/583011/2010 (2010).
Anugu, R. R., Mainkar, P. S., Sridhar, B. & Chandrasekhar, S. The Ireland-Claisen rearrangement strategy towards the synthesis of the schizophrenia drug, (+)-asenapine. Org. Biomol. Chem. 14, 1332–1337 (2016).
Trivedi, M., Budihardjo, I., Loureiro, K., Reid, T. R. & Ma, J. D. Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer. Future Oncol. 4, 483–500 (2008).
Nicolaou, K. C. et al. Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. J. Am. Chem. Soc. 123, 9313–9323 (2001).
Myers, M. R. et al. Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 1: SAR exploration and effective bioisosteric replacement of a phenyl substituent. Bioorg. Med. Chem. Lett. 13, 3091–3095 (2003).
Hatakeyama, T. et al. Iron-catalyzed Suzuki−Miyaura coupling of alkyl halides. J. Am. Chem. Soc. 132, 10674–10676 (2010).
Corey, E. J., Shibata, T. & Lee, T. W. Asymmetric Diels−Alder reactions catalyzed by a triflic acid activated chiral oxazaborolidine. J. Am. Chem. Soc. 124, 3808–3809 (2002).
He, Y. et al. The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol. 13, 389–395 (2017); erratum 13, 922 (2017).
Acknowledgements
Financial support for this work was provided by Leo Pharma and the US National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS; grant GM-118176). Shenzhen Haiwei M&E Co. Ltd supported a fellowship to T.–G.C.; the Uehara Memorial Foundation supported a research fellowship to S.A.; the Basque Government supported a fellowship to I.B.; Nankai University supported Y.L. and C.B.; the University of Science and Technology of China supported J.T.; and the Swiss National Science Foundation supported an Early Postdoc Mobility Fellowship to D.K. We thank L. Buzzetti for the synthesis of intermediates; D.-H. Huang and L. Pasternack for assistance with nuclear magnetic resonance spectroscopy; and A.L. Rheingold, M. Gembicky and C.E. Moore for X-ray crystallographic analysis.
Author information
Authors and Affiliations
Contributions
T.–G.C., T.Q. and P.S.B. conceived the work. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A., C.B., J.S.C., M.S., H.F., F.G.F., H.-W.C., L.H., T.Q. and P.S.B. designed the experiments and analysed the data. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A. and C.B. performed the experiments. M.S., H.F., F.G.F., H.-W.C. and L.H. performed the experiments described in Fig. 3f. P.S.B. wrote the manuscript. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A., C.B., J.S.C. and T.Q. assisted in writing and editing the manuscript.
Corresponding author
Ethics declarations
Competing interests
M.S., H.F., F.G.F., H.-W.C. and L.H. are employees of Eisai Inc. This work was part-funded by Leo Pharma.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 Complete substrate scope of [4+2] cycloadditions/cross-couplings.
See Supplementary Information for synthetic details. R1, R2 = (Het)Aryl, alkyl, alkenyl, alkynyl. X-ray structure data are available for compounds 11, 19, 23, 25, 28, 44, 45 and 49.
Extended Data Fig. 2 Complete substrate scope of [3+2], [2+2] and [2+1] sections.
See Supplementary Information for synthetic details. R1, R2 = (Het)Aryl, alkyl, alkenyl, alkynyl. X-ray structure data are available for compounds C2 and 65.
Supplementary information
Supplementary Information
This file contains Supplementary Text and Data – see contents pages for details.
Supplementary Data
This file contains NMR Spectra data.
Supplementary Data
This zipped file contains the crystallographic data files for the compounds used.
Supplementary Data
This zipped file contains the checkcif files for the compounds used.
Rights and permissions
About this article
Cite this article
Chen, T., Barton, L.M., Lin, Y. et al. Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions. Nature 560, 350–354 (2018). https://doi.org/10.1038/s41586-018-0391-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-018-0391-9
This article is cited by
-
Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin
Nature Communications (2024)
-
Reaction combination opens up 3D molecular diversity for drug discovery
Nature (2018)
-
Solar Photochemistry in Flow
Topics in Current Chemistry (2018)
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.