Abstract
Carbon–oxygen bonds are commonplace in organic molecules, including chiral bioactive compounds; therefore, the development of methods for their construction with simultaneous control of stereoselectivity is an important objective in synthesis. The Williamson ether synthesis, first reported in 18501, is the most widely used approach to the alkylation of an oxygen nucleophile, but it has significant limitations (scope and stereochemistry) owing to its reaction mechanism (SN2 pathway). Transition-metal catalysis of the coupling of an oxygen nucleophile with an alkyl electrophile has the potential to address these limitations, but progress so far has been limited2,3,4,5,6,7, especially with regard to controlling enantioselectivity. Here we establish that a readily available copper catalyst can achieve an array of enantioconvergent substitution reactions of α-haloamides, a useful family of electrophiles, by oxygen nucleophiles; the reaction proceeds under mild conditions in the presence of a wide variety of functional groups. The catalyst is uniquely effective in being able to achieve enantioconvergent alkylations of not only oxygen nucleophiles but also nitrogen nucleophiles, giving support for the potential of transition-metal catalysts to provide a solution to the pivotal challenge of achieving enantioselective alkylations of heteroatom nucleophiles.
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 of this study are available within the paper, its Supplementary Information (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/structures; crystallographic data are available free of charge under CCDC reference numbers CCDC 2192280–2192286).
References
Williamson, A. Theory of etherification. Philos. Mag. 37, 350–356 (1850).
Kazmaier, U. (ed.) Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis (Springer, 2012).
Nakajima, K., Shibata, M. & Nishibayashi, Y. Copper-catalyzed enantioselective propargylic etherification of propargylic esters with alcohols. J. Am. Chem. Soc. 137, 2472–2475 (2015).
Li, R.-Z. et al. Site-divergent delivery of terminal propargyls to carbohydrates by synergistic catalysis. Chem 3, 834–845 (2017).
Li, R.-Z. et al. Enantioselective propargylation of polyols and desymmetrization of meso 1,2-diols by copper/borinic acid dual catalysis. Angew. Chem. Int. Ed. 56, 7213–7217 (2017).
Li, R.-Z., Liu, D.-Q. & Niu, D. Asymmetric O-propargylation of secondary aliphatic alcohols. Nat. Catal. 3, 672–680 (2020).
Xu, X., Peng, L., Chang, X. & Guo, C. Ni/chiral sodium carboxylate dual catalyzed asymmetric O-propargylation. J. Am. Chem. Soc. 143, 21048–21055 (2021).
Kennemur, J. L., Maji, R., Scharf, M. J. & List, B. Catalytic asymmetric hydroalkoxylation of C−C multiple bonds. Chem. Rev. 121, 14649–14681 (2021).
Takemoto, Y. & Miyabe, H. in Catalytic Asymmetric Synthesis 3rd edn (ed. Ojima, I.) 227–267 (Wiley, 2010).
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).
Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).
Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).
Zhang, X. & Tan, C.-H. Stereospecific and stereoconvergent nucleophilic substitution reactions at tertiary carbon centers. Chem 7, 1451–1486 (2021).
Grange, R. L., Clizbe, E. A. & Evans, P. A. Recent developments in asymmetric allylic amination reactions. Synthesis 48, 2911–2968 (2016).
Lauder, K., Toscani, A., Scalacci, N. & Castagnolo, D. Synthesis and reactivity of propargylamines in organic chemistry. Chem. Rev. 117, 14091–14200 (2017).
Zhang, D.-Y. & Hu, X.-P. Recent advances in copper-catalyzed propargylic substitution. Tetrahedron Lett. 56, 283–295 (2015).
Zhang, H. et al. Construction of the N1−C3 linkage stereogenic centers by catalytic asymmetric amination reaction of 3-bromooxindoles with indolines. Org. Lett. 16, 2394–2397 (2014).
Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).
Zhang, X. et al. An enantioconvergent halogenophilic nucleophilic substitution (SN2X) reaction. Science 363, 400–404 (2019).
Bartoszewicz, A., Matier, C. D. & Fu, G. C. Enantioconvergent alkylations of amines by alkyl electrophiles: copper-catalyzed nucleophilic substitutions of racemic α-halolactams by indoles. J. Am. Chem. Soc. 141, 14864–14869 (2019).
Wang, Y., Wang, S., Shan, W. & Shao, Z. Direct asymmetric N-propargylation of indoles and carbazoles catalyzed by lithium SPINOL phosphate. Nat. Commun. 11, 226 (2020).
Chen, C., Peters, J. C. & Fu, G. C. Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity. Nature 596, 250–256 (2021).
Zhang, Y.-F. et al. Enantioconvergent Cu-catalyzed radical C−N coupling of racemic secondary alkyl halides to access α-chiral primary amines. J. Am. Chem. Soc. 143, 15413–15419 (2021).
Cho, H. et al. Photoinduced, copper-catalyzed enantioconvergent alkylations of anilines by racemic tertiary electrophiles: synthesis and mechanism. J. Am. Chem. Soc. 144, 4550–4558 (2022).
Ding, C.-H. & Hou, X.-L. Catalytic asymmetric propargylation. Chem. Rev. 111, 1914–1937 (2011).
Zhou, Z., Behnke, N. E. & Kürti, L. Copper-catalyzed synthesis of hindered ethers from α-bromo carbonyl compounds. Org. Lett. 20, 5452–5456 (2018).
Fantinati, A., Zanirato, V., Marchetti, P. & Trapella, C. The fascinating chemistry of α-haloamides. ChemistryOpen 9, 100–170 (2020).
Umejiego, N. N. et al. Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosis. Chem. Biol. 15, 70–77 (2008).
Tanaka, T., Oyamada, M., Igarashi, K. & Takasawa, Y. Plant growth-regulating activity, and photolytic and microbial decomposition of optical isomers of naproanilide. Weed Res. 36, 50–57 (1991).
Whitehurst, B. C. et al. Identification of 2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-N-phenylpropanamides as a novel class of potent DprE1 inhibitors. Bioorg. Med. Chem. Lett. 30, 127192 (2020).
Kalita, D. et al. Interactions of amino acids, carboxylic acids, and mineral acids with different quinoline derivatives. J. Mol. Struct. 990, 183–196 (2011).
Maurya, S. K. et al. Triazole inhibitors of Cryptosporidium parvum inosine 50-monophosphate dehydrogenase. J. Med. Chem. 52, 4623–4630 (2009).
Yu, J., Wang, Y., Zhang, P. & Wu, J. Direct amination of phenols under metal-free conditions. Synlett 24, 1448–1454 (2013).
Lengyel, I. & Sheehan, J. C. α-Lactams (aziridinones). Angew. Chem. Int. Ed. 7, 25–36 (1968).
Hoffman, R. V. & Cesare, V. α-Lactams. Sci. Synth. 21, 591–608 (2005).
Baumgarten, H. E., Chiang, N.-C. R., Elia, V. J. & Beum, P. V. Reactions of l-tert-butyl-3-phenyaziridinone and α-bromo-tert-butylphenylacetamide with benzyl-Grignard reagents. J. Org. Chem. 50, 5507–5512 (1985).
Boyer, C. et al. Copper-mediated living radical polymerization (atom transfer radical polymerization and copper(0) mediated polymerization): from fundamentals to bioapplications. Chem. Rev. 116, 1803–1949 (2016).
Montanari, F. & Quici, S. in e-EROS Encyclopedia of Reagents for Organic Synthesis 1–12 (Wiley, 2016).
Casitas, A. & Ribas, X. The role of organometallic copper(III) complexes in homogeneous catalysis. Chem. Sci. 4, 2301–2318 (2013).
Musa, O. M., Choi, S.-Y., Horner, J. H. & Newcomb, M. N. Absolute rate constants for α-amide radical reactions. J. Org. Chem. 63, 786–793 (1998).
Anslyn, E. V. & Dougherty, D. A. Modern Physical Organic Chemistry 155–157 (University Science Books, 2006).
Acknowledgements
Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, R01–GM109194 and R35–GM145315), the Beckman Institute (support for the Caltech Center for Catalysis and Chemical Synthesis, EPR Facility and X-ray Crystallography Facility), the Dow Next-Generation Educator Fund (grant to Caltech) and Boehringer–Ingelheim Pharmaceuticals. We thank R. Anderson, H. Cho, S. Munoz, P. H. Oyala, F. Schneck, M. K. Takase and X. Tong for assistance and discussions.
Author information
Authors and Affiliations
Contributions
C.C. performed all experiments. C.C. and G.C.F. wrote the paper. Both authors contributed to the analysis and the interpretation of the results.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature thanks the anonymous reviewers 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.
Extended data figures and tables
Extended Data Fig. 1 Copper-catalyzed enantioconvergent alkylations of oxygen nucleophiles.
a. Functional-group compatibility. b. Other families of electrophiles.
Extended Data Fig. 2 Mechanistic observations.
a. Exploration of a radical intermediate. b. Synthesis and catalytic activity of Cu(LX*)(MeCN). c. DFT studies of the spin density of Cu(LX*)(OPh): BP86-d3(BJ)/def2-TZVP/SMD(THF); contour values of 0.048 and 0.020 for N and K, respectively.
Supplementary information
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
Chen, C., Fu, G.C. Copper-catalysed enantioconvergent alkylation of oxygen nucleophiles. Nature 618, 301–307 (2023). https://doi.org/10.1038/s41586-023-06001-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-023-06001-y
This article is cited by
-
SO2-Insertion induced enantioselective oxysulfonylation to access β-chiral sulfones with quaternary carbon stereocenters
Science China Chemistry (2024)
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.
