Enantioselective Chan–Lam S-arylation of sulfenamides | Nature Catalysis

Nature Catalysis volume 7, pages 1010–1020 (2024)Cite this article

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Sulfur stereogenic molecules have a significant impact on drug development. Among them, sulfilimines are chiral molecules bearing S(IV) stereocentres, which exhibit great value in chemistry and biology but have so far been synthetically challenging to achieve. Similarly, it has also been a challenge to control the stereochemistry in Chan–Lam coupling, which has been widely used to construct C–N, C–O and C–S bonds by coupling nucleophiles with boronic acids using copper complexes. Here we report a highly chemoselective and enantioselective Chan–Lam S-arylation of sulfenamides with arylboronic acids to deliver an array of thermodynamically disfavoured aryl sulfilimines containing a sulfur stereocentre. A copper catalyst from a 2-pyridyl N-phenyl dihydroimidazole ligand has been designed that enables effective enantiocontrol by means of a well-defined chiral environment and high reactivity that outcompetes the background racemic transformation. A combined experimental and computational study establishes the reaction mechanism and unveils the origin of chemoselectivity and stereoselectivity.

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Detailed experimental procedures, characterization data, NMR spectra of compounds, detailed computational results and calculated structures are available within the Supplementary Information and related files. The X-ray crystallographic coordinates for the structure reported in this study have been deposited at the CCDC under deposition number CCDC 2215359 (for 3ba). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif. Any further relevant data are available from the authors upon request.

Lücking, U. Sulfoximines: a neglected opportunity in medicinal chemistry. Angew. Chem. Int. Ed. 52, 9399–9408 (2013).

Article Google Scholar

Lücking, U. New opportunities for the utilization of the sulfoximine group in medicinal chemistry from the drug designer’s perspective. Chem. Eur. J. 28, e202201993 (2022).

Article PubMed Google Scholar

Kaiser, D., Klose, I., Oost, R., Neuhaus, J. & Maulide, N. Bond-forming and -breaking reactions at sulfur(IV): sulfoxides, sulfonium salts, sulfur ylides, and sulfinate salts. Chem. Rev. 119, 8701–8780 (2019).

Article CAS PubMed PubMed Central Google Scholar

Wojaczynska, E. & Wojaczynski, J. Modern stereoselective synthesis of chiral sulfinyl compounds. Chem. Rev. 120, 4578–4611 (2020).

Article CAS PubMed PubMed Central Google Scholar

Gilchrist, T. L. & Moody, C. J. The chemistry of sulfilimines. Chem. Rev. 77, 409–435 (1977).

Article CAS Google Scholar

Taylor, P. C. Sulfimides (sulfilimines): applications in stereoselective synthesis. Sulfur Rep. 21, 241–280 (1999).

Article CAS Google Scholar

Bizet, V., Hendriks, C. M. & Bolm, C. Sulfur imidations: access to sulfimides and sulfoximines. Chem. Soc. Rev. 44, 3378–3390 (2015).

Article CAS PubMed Google Scholar

Vanacore, R. et al. A sulfilimine bond identified in collagen IV. Science 325, 1230–1234 (2009).

Article CAS PubMed PubMed Central Google Scholar

Lin, S. et al. Redox-based reagents for chemoselective methionine bioconjugation. Science 355, 597–602 (2017).

Article CAS PubMed PubMed Central Google Scholar

Christian, A. H. et al. A physical organic approach to tuning reagents for selective and stable methionine bioconjugation. J. Am. Chem. Soc. 141, 12657–12662 (2019).

Article CAS PubMed PubMed Central Google Scholar

Xu, K. et al. An ultrasensitive cyclization-based fluorescent probe for imaging native HOBr in live cells and zebrafish. Angew. Chem. Int. Ed. 55, 12751–12754 (2016).

Article CAS Google Scholar

Lücking, U. Neglected sulfur(VI) pharmacophores in drug discovery: exploration of novel chemical space by the interplay of drug design and method development. Org. Chem. Front. 6, 1319–1324 (2019).

Article Google Scholar

Zhang, X., Wang, F. & Tan, C.-H. Asymmetric synthesis of S(IV) and S(VI) stereogenic centers. JACS Au 3, 700–714 (2023).

Article CAS PubMed PubMed Central Google Scholar

Takada, H. et al. Catalytic asymmetric sulfimidation. J. Org. Chem. 62, 6512–6518 (1997).

Article CAS Google Scholar

Tomooka, C. S. & Carreira, E. M. Enantioselective nitrogen transfer to sulfides from nitridomanganese(V) complexes. Helv. Chim. Acta 85, 3773–3784 (2002).

3.0.CO;2-O" data-track-item_id="10.1002/1522-2675(200211)85:113.0.CO;2-O" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F1522-2675%28200211%2985%3A11%3C3773%3A%3AAID-HLCA3773%3E3.0.CO%3B2-O" aria-label="Article reference 15" data-doi="10.1002/1522-2675(200211)85:113.0.CO;2-O">Article CAS Google Scholar

Armstrong, A., Edmonds, I. D. & Swarbrick, M. E. Efficient nitrogen transfer from aldehyde-derived N-acyloxaziridines. Tetrahedron Lett. 44, 5335–5338 (2003).

Article CAS Google Scholar

Collet, F., Dodd, R. H. & Dauban, P. Stereoselective rhodium-catalyzed imination of sulfides. Org. Lett. 10, 5473–5476 (2008).

Article CAS PubMed Google Scholar

Wang, J., Frings, M. & Bolm, C. Enantioselective nitrene transfer to sulfides catalyzed by a chiral iron complex. Angew. Chem. Int. Ed. 52, 8661–8665 (2013).

Article CAS Google Scholar

Uchida, T. & Katsuki, T. Asymmetric nitrene transfer reactions: sulfimidation, aziridination and C–H amination using azide compounds as nitrene precursors. Chem. Rec. 14, 117–129 (2014).

Article CAS PubMed Google Scholar

Lebel, H., Piras, H. & Bartholoméüs, J. Rhodium-catalyzed stereoselective amination of thioethers with N-mesyloxycarbamates: DMAP and bis(DMAP)CH2Cl2 as key additives. Angew. Chem. Int. Ed. 53, 7300–7304 (2014).

Article CAS Google Scholar

Yoshitake, M., Hayashi, H. & Uchida, T. Ruthenium-catalyzed asymmetric N-acyl nitrene transfer reaction: imidation of sulfide. Org. Lett. 22, 4021–4025 (2020).

Article CAS PubMed Google Scholar

Annapureddy, R. R. et al. Silver-catalyzed enantioselective sulfimidation mediated by hydrogen bonding interactions. Angew. Chem. Int. Ed. 60, 7920–7926 (2021).

Article CAS Google Scholar

Greenwood, N. S., Champlin, A. T. & Ellman, J. A. Catalytic enantioselective sulfur alkylation of sulfenamides for the asymmetric synthesis of sulfoximines. J. Am. Chem. Soc. 144, 17808–17814 (2022).

Article CAS PubMed PubMed Central Google Scholar

Kikuchi, K., Furukawa, N., Moriyama, M. & Oae, S. Nucleophilic substitution of tricoordinate sulfur atom of sulfonium salt with retention of configuration. Different stereochemistry of substitution by amidate anions. Bull. Chem. Soc. Jpn 58, 1934–1941 (1985).

Article CAS Google Scholar

Takada, H., Oda, M., Oyamada, A., Ohe, K. & Uemura, S. Catalytic diastereoselective sulfimidation of diaryl sulfides and application of chiral sulfimides to asymmetric allylic alkylation. Chirality 12, 299–312 (2000).

3.0.CO;2-S" data-track-item_id="10.1002/(SICI)1520-636X(2000)12:5/63.0.CO;2-S" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291520-636X%282000%2912%3A5%2F6%3C299%3A%3AAID-CHIR2%3E3.0.CO%3B2-S" aria-label="Article reference 25" data-doi="10.1002/(SICI)1520-636X(2000)12:5/63.0.CO;2-S">Article CAS PubMed Google Scholar

Tsuzuki, S. & Kano, T. Asymmetric synthesis of chiral sulfimides through the O-alkylation of enantioenriched sulfinamides and addition of carbon nucleophiles. Angew. Chem. Int. Ed. 62, e202300637 (2023).

Article CAS Google Scholar

West, M. J., Fyfe, J. W. B., Vantourout, J. C. & Watson, A. J. B. Mechanistic development and recent applications of the Chan–Lam amination. Chem. Rev. 119, 12491–12523 (2019).

Article CAS PubMed Google Scholar

Chen, J. Q., Li, J. H. & Dong, Z. B. A review on the latest progress of Chan-Lam coupling reaction. Adv. Synth. Catal. 362, 3311–3331 (2020).

Article CAS Google Scholar

King, A. E., Brunold, T. C. & Stahl, S. S. Mechanistic study of copper-catalyzed aerobic oxidative coupling of arylboronic esters and methanol: insights into an organometallic oxidase reaction. J. Am. Chem. Soc. 131, 5044–5045 (2009).

Article CAS PubMed Google Scholar

King, A. E., Ryland, B. L., Brunold, T. C. & Stahl, S. S. Kinetic and spectroscopic studies of aerobic copper(II)-catalyzed methoxylation of arylboronic esters and insights into aryl transmetalation to copper(II). Organometallics 31, 7948–7957 (2012).

Article CAS PubMed PubMed Central Google Scholar

Vantourout, J. C., Miras, H. N., Isidro-Llobet, A., Sproules, S. & Watson, A. J. Spectroscopic studies of the Chan–Lam amination: a mechanism-inspired solution to boronic ester reactivity. J. Am. Chem. Soc. 139, 4769–4779 (2017).

Article CAS PubMed Google Scholar

Bose, S., Dutta, S. & Koley, D. Entering chemical space with theoretical underpinning of the mechanistic pathways in the Chan–Lam amination. ACS Catal. 12, 1461–1474 (2022).

Article CAS Google Scholar

Pooventhiran, T., Khilari, N. & Koley, D. Mechanistic avenues in the Chan-Lam-based etherification reaction: a computational exploration. Chem. Eur. J. 29, e202302983 (2023).

Article CAS PubMed Google Scholar

Hardouin Duparc, V., Bano, G. L. & Schaper, F. Chan–Evans–Lam couplings with copper iminoarylsulfonate complexes: scope and mechanism. ACS Catal. 8, 7308–7325 (2018).

Article CAS Google Scholar

Liang, Q. et al. Synthesis of sulfilimines enabled by copper-catalyzed S-arylation of sulfenamides. J. Am. Chem. Soc. 145, 6310–6318 (2023).

Article CAS PubMed PubMed Central Google Scholar

Chen, Y. et al. Synthesis of sulfilimines via selective S–C bond formation in water. Org. Lett. 25, 2134–2138 (2023).

Article CAS PubMed Google Scholar

Jutand, A. & Grimaud, L. Role of fluoride ions in palladium-catalyzed cross-coupling reactions. Synthesis 49, 1182–1189 (2016).

Article Google Scholar

Akutagawa, K., Furukawa, N. & Oae, S. Preparation of N-(arylsulfonyl)sulfoximines by oxidation of N-(arylsulfonyl)sulfilimines with sodium hypochlorite in a two-phase system. J. Org. Chem. 49, 2282–2284 (2002).

Article Google Scholar

Siemeister, G. et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol. Cancer Ther. 11, 2265–2273 (2012).

Article CAS PubMed Google Scholar

Kim, E. et al. Novel compound and pharmaceutical composition comprising same as active ingredient. US patent 2020/0190024 A1 (2020).

Albrecht, B. K. et al. Modulators of methyl modifying enzymes, compositions and uses thereof. US patent 9206128 B2 (2015).

Lee, C., Yang, W. & Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785–789 (1988).

Article CAS Google Scholar

Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

Article CAS Google Scholar

Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 132, 154104 (2010).

Article PubMed Google Scholar

Petersson, G. A. & Al-Laham, M. A. A complete basis set model chemistry. II. Open-shell systems and the total energies of the first-row atoms. J. Chem. Phys. 94, 6081–6090 (1991).

Article CAS Google Scholar

Andrae, D., Häußermann, U., Dolg, M., Stoll, H. & Preuß, H. Energy-adjusted ab initio pseudopotentials for the second and third row transition elements. Theor. Chim. Acta 77, 123–141 (1990).

Article CAS Google Scholar

Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008).

Article CAS Google Scholar

McLean, A. D. & Chandler, G. S. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z=11–18. J. Chem. Phys. 72, 5639–5648 (1980).

Article CAS Google Scholar

Krishnan, R., Binkley, J. S., Seeger, R. & Pople, J. A. Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 72, 650–654 (1980).

Article CAS Google Scholar

Cossi, M., Rega, N., Scalmani, G. & Barone, V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J. Comput. Chem. 24, 669–681 (2003).

Article CAS PubMed Google Scholar

Kozuch, S. & Shaik, S. How to conceptualize catalytic cycles? The energetic span model. Acc. Chem. Res. 44, 101–110 (2011).

Article CAS PubMed Google Scholar

Kitaura, K. & Morokuma, K. A new energy decomposition scheme for molecular interactions within the Hartree‐Fock approximation. Int. J. Quantum Chem. 10, 325–340 (1976).

Article CAS Google Scholar

Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction-activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

Article CAS Google Scholar

Horn, P. R. & Head-Gordon, M. Alternative definitions of the frozen energy in energy decomposition analysis of density functional theory calculations. J. Chem. Phys. 144, 084118 (2016).

Article PubMed Google Scholar

Horn, P. R., Mao, Y. & Head-Gordon, M. Defining the contributions of permanent electrostatics, Pauli repulsion, and dispersion in density functional theory calculations of intermolecular interaction energies. J. Chem. Phys. 144, 114107 (2016).

Article PubMed Google Scholar

Horn, P. R., Mao, Y. & Head-Gordon, M. Probing non-covalent interactions with a second generation energy decomposition analysis using absolutely localized molecular orbitals. Phys. Chem. Chem. Phys. 18, 23067–23079 (2016).

Article CAS PubMed Google Scholar

Shao, Y. et al. Advances in molecular quantum chemistry contained in the Q-Chem 4 program package. Mol. Phys. 113, 184–215 (2015).

Article CAS Google Scholar

Thomas, A. A. et al. Mechanistically guided design of ligands that significantly improve the efficiency of CuH-catalyzed hydroamination reactions. J. Am. Chem. Soc. 140, 13976–13984 (2017).

Article Google Scholar

Chan, L., Morris, G. M. & Hutchison, G. R. Understanding conformational entropy in small molecules. J. Chem. Theory Comput. 17, 2099–2106 (2021).

Article CAS PubMed Google Scholar

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T.J. thanks the National Natural Science Foundation of China (U23A20528), Guangdong Basic and Applied Basic Research Foundation (2021B1515120046 and 2022B1515120075), the Science and Technology Innovation Commission of Shenzhen Municipality (JCYJ20220818101404010 and 20220815113214003) and the High Level of Special Funds (G03050K003) for financial support. M.C.K. thanks the National Institutes of Health (NIH; R35 GM131902) for financial support and Advanced Cyberinfrastructure Coordination Ecosystem: Services and Support (ACCESS; TG-CHE120052) for computational support. We are grateful to Y. Yu and X. Chang (both at SUSTech) for High Resolution Mass Spectrum and X-ray crystallography, respectively. We also acknowledge the assistance of SUSTech Core Research Facilities.

These authors contributed equally: Qingjin Liang, Xinping Zhang, Madeline E. Rotella.

Research Center for Chemical Biology and Omics Analysis, Department of Chemistry, Southern University of Science and Technology, Shenzhen, P. R. China

Qingjin Liang, Xinping Zhang, Zeyu Xu & Tiezheng Jia

Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA, USA

Madeline E. Rotella & Marisa C. Kozlowski

State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, P. R. China

Tiezheng Jia

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T.J. conceived and supervised the project. Q.L., X.Z. and Z.X. performed the experiments. M.C.K. directed the computational study. M.E.R. carried out the computational study. T.J., Q.L. and X.Z. analysed the data. All authors participated in writing the manuscript.

Correspondence to Marisa C. Kozlowski or Tiezheng Jia.

The authors declare no competing interests.

Nature Catalysis thanks Taichi Kano, Debasis Koley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–333, Tables 1–21, Methods, notes and references.

Crystallographic data for compound 3ba.

Cif check report for 3ba.

Computational data.

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Liang, Q., Zhang, X., Rotella, M.E. et al. Enantioselective Chan–Lam S-arylation of sulfenamides. Nat Catal 7, 1010–1020 (2024). https://doi.org/10.1038/s41929-024-01213-5

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Received: 14 February 2024

Accepted: 24 July 2024

Published: 09 September 2024

Issue Date: September 2024

DOI: https://doi.org/10.1038/s41929-024-01213-5

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