Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres

Nature Chemistry volume 15, pages 550–559 (2023)Cite this article

Subjects

Abstract

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)–C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Alkyl sulfinates as programmable and modular coupling reagents.
Fig. 2: Synthetic applications.
Fig. 3: Experimental studies on the mechanism of sulfinate coupling.
Fig. 4: Reaction coordinate diagram of direct C(sp2)–C(sp3) cross-coupling.

Similar content being viewed by others

Data availability

Experimental data, as well as characterization data for all compounds prepared in the course of these studies, are provided in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2086919 (40), 2086920 (41), 2172148 (74) and 2172149 (116) (see X-ray crystallographic data in the Supplementary Information). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Talele, T. T. Opportunities for tapping into three-dimensional chemical space through a quaternary carbon. J. Med. Chem. 63, 13291–13315 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Bauer, M. R. et al. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 12, 448–471 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mykhailiuk, P. K. Saturated bioisoteres of benzene: where to go next? Org. Biomol. Chem. 17, 2839–2849 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Li, J. J. Medicinal Chemistry for Practitioners Ch. 4 (Wiley, 2020)

  6. Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 61, 5822–5880 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Barnes-Seeman, D. et al. Metabolically stable tert-butyl replacement. ACS Med. Chem. Lett. 4, 514–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Westphal, M. V., Wolfstädter, B. T., Plancher, J. M., Gatfield, J. & Carreira, E. M. Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies and activities. ChemMedChem 10, 461–469 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Bezencon, O. et al. Discovery of a potent, selective T-type calcium channel blocker as a drug candidate for the treatment of generalized epilepsies. J. Med. Chem. 60, 9769–9789 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Phelan, J. P. et al. Redox-neutral photocatalytic cyclopropanation via radical/polar crossover. J. Am. Chem. Soc. 140, 8037–8047 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kautzky, J. A., Wang, T., Evans, R. W. & MacMillan, D. W. C. Decarboxylative trifluoromethylation of aliphatic carboxylic acids. J. Am. Chem. Soc. 140, 6522–6526 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cyr, P., Flynn-Robitaille, J., Boissarie, P. & Marinier, A. Mild and diazo-free synthesis of trifluoromethyl-cyclopropanes using sulfonium ylides. Org. Lett. 21, 2265–2268 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Mercadante, M. A. et al. 1,3-γ-Silyl-elimination in electron-deficient cationic systems. Chem. Sci. 5, 3983–3994 (2014).

    Article  CAS  Google Scholar 

  15. Zhao, Q.-H. et al. An efficient substrate-induced method for the synthesis of CF3-substituted cyclopropanes by metal-free reaction of trifluoromethyl styrylisoxazoles with nitromethane. Synthesis 53, 1597–1604 (2020).

    Google Scholar 

  16. Bugera, M. et al. Deoxofluorination of aliphatic carboxylic acids: a route to trifluoromethyl-substituted derivatives. J. Org. Chem. 84, 16105–16115 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, S., Huang, Y., Qing, F.-L. & Xu, X.-H. Transition-metal-free decarboxylation of 3,3,3-trifluoro-2,2-dimethylpropanoic acid for the preparation of C(CF3)Me2-containing heteroarenes. Org. Lett. 20, 5497–5501 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Tanbouza, N., Carreras, V. & Ollevier, T. Photochemical cyclopropenation of alkynes with diazirines as carbene precursors in continuous flow. Org. Lett. 23, 5420–5424 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Denton, J. R., Sukumaran, D. & Davies, H. M. L. Enantioselective synthesis of trifluoromethyl-substituted cyclopropanes. Org. Lett. 9, 2625–2628 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, X. et al. Fluoroalkyl N-triftosylhydrazones as easily decomposable diazo surrogates for asymmetric [2 + 1] cycloaddition: synthesis of chiral fluoroalkyl cyclopropenes and cyclopropanes. ACS Catal. 11, 8527–8537 (2021).

    Article  CAS  Google Scholar 

  21. Kelly, C. B. et al. Synthesis of perfluoroalkyl-substituted vinylcyclopropanes by way of enhanced neighboring group participation. Eur. J. Org. Chem. 2015, 4071–4076 (2015).

    Article  CAS  Google Scholar 

  22. Huang, W.-S. et al. General catalytic enantioselective access to monohalomethyl and trifluoromethyl cyclopropanes. Chem. Eur. J. 24, 10339–10343 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Fuchibe, K., Oki, R., Hatta, H. & Ichikawa, J. Single C−F bond activation of the CF3 group with a Lewis acid: CF3-cyclopropanes as versatile 4,4-difluorohomoallylating agents. Chem. Eur. J. 24, 17932–17935 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Smith, J. M., Dixon, J. A., deGruyter, J. N. & Baran, P. S. Alkyl sulfinates: radical precursors enabling drug discovery. J. Med. Chem. 62, 2256–2264 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Kuttruff, C. A., Haile, M., Kraml, J. & Tautermann, C. S. Late-stage functionalization of drug-like molecules using diversinates. ChemMedChem 13, 983–987 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Michaudel, Q., Ishihara, Y. & Baran, P. S. Academia-industry symbiosis in organic chemistry. Acc. Chem. Res. 48, 712–721 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fujiwara, Y. et al. Practical and innate carbon–hydrogen functionalization of heterocycles. Nature 492, 95–99 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smith, J. M., Harwood, S. J. & Baran, P. S. Radical retrosynthesis. Acc. Chem. Res. 51, 1807–1817 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Proctor, R. S. J. & Phipps, R. J. Recent advances in minisci-type reactions. Angew. Chem. Int. Ed. 58, 13666–13699 (2019).

    Article  CAS  Google Scholar 

  31. Gianatassio, R. et al. Simple sulfinate synthesis enables C-H trifluoromethyl-cyclopropanation. Angew. Chem. Int. Ed. 53, 9851–9855 (2014).

    Article  CAS  Google Scholar 

  32. Oae, S. & Furukawa, N. Heteroaromatic sulfoxides and sulfones: ligand exchange and coupling in sulfuranes and ipso-substitutions. Adv. Heterocycl. Chem. 48, 1–63 (1990).

    Article  CAS  Google Scholar 

  33. Oae, S. & Uchida, Y. Ligand-coupling reactions of hypervalent species. Acc. Chem. Res. 24, 202–208 (1991).

    Article  CAS  Google Scholar 

  34. Oae, S. Ligand coupling reactions of hypervalent species. Pure Appl. Chem. 68, 805–812 (1996).

    Article  CAS  Google Scholar 

  35. Zhou, M., Tsien, J. & Qin, T. Unsymmetrical heterocycle cross-couplings enabled by sulfur(IV) reagents. Synlett 31, 1962–1966 (2020).

    Article  CAS  Google Scholar 

  36. Oae, S., Kawai, T. & Furukawa, N. Ligand coupling through σ-sulfurane complete retention of configuration of 1-phenylethyl group in the reaction of 1-phenylethyl 2-pyridyl sulfoxide with Grignard reagent. Tetrahedron Lett. 25, 69–72 (1984).

    Article  CAS  Google Scholar 

  37. Oae, S., Kawai, T., Furukawa, N. & Iwasaki, F. Ligand coupling within σ-sulphurane intermediates formed in the reaction of benzyl 2-pyridyl and related sulphoxides with Grignard reagents. J. Chem. Soc. Perkin Trans. 2, 405–411 (1987).

    Article  Google Scholar 

  38. Wakabayashi, S., Ishida, M., Takeda, T. & Oae, S. Sensitive nature of ligand coupling and pseudorotation to electronic effect of substituent ligand coupling in the reactions of benzylic aryl sulfoxides with benzylic Grignard reagents. Tetrahedron Lett. 29, 4441–4444 (1988).

    Article  CAS  Google Scholar 

  39. Oae, S., Kawai, T. & Furukawa, N. Ligand exchange and ligand coupling via the σ-sulfurane intermediate in the reaction of alkyl 2-pyridyl sulfoxide with Grignard reagents: convenient preparation of 2,2′-bipyridines. Phosphorus Sulfur Relat. Elem. 34, 123–132 (1987).

    Article  CAS  Google Scholar 

  40. Furukawa, N., Shibutani, T. & Fujihara, H. Preparation of pyridyl grignard reagents and cross coupling reactions with sulfoxides bearing azaheterocycles. Tetrahedron Lett. 28, 5845–5848 (1987).

    Article  CAS  Google Scholar 

  41. Oae, S., Takeda, T. & Wakabayashi, S. Ligand coupling through σ-sulfurane—complete retention of geometric configuration of allylic and vinylic groups in the reactions of allylic and vinylic sulfoxides with Grignard reagents. Tetrahedron Lett. 29, 4445–4448 (1988).

    Article  CAS  Google Scholar 

  42. Oae, S., Kawai, T. & Furukawa, N. A convenient preparation of bipyridines through ligand coupling reaction with α-sulfurane formed by treatment of methyl 2-pyridyl sulfoxide with Grignard reagents. Tetrahedron Lett. 25, 2549–2552 (1984).

    Article  Google Scholar 

  43. LaRochelle, R. W. & Trost, B. M. Reactions of organolithiums with arylsulfonium salts. J. Am. Chem. Soc. 93, 6077–6086 (1971).

    Article  CAS  Google Scholar 

  44. Trost, B. M. & Arndt, H. C. σ-Sulfurane chemistry. Effect of substituents on the coupling reactions. J. Am. Chem. Soc. 95, 5288–5298 (1973).

    Article  CAS  Google Scholar 

  45. Oae, S., Takeda, T., Kawai, T. & Furukawa, N. Ligand coupling and pseudorotation in the reaction of alkyl 2-pyridyl sulfoxide with Grignard reagents. Phosphorus Sulfur Relat. Elem. 34, 133–137 (1987).

    Article  CAS  Google Scholar 

  46. Oae, S., Takeda, T., Uenishi, J. & Wakabayashi, S. Ligand coupling reactions of 2-pyridyl, 4-pyridyl and 2-pyrimidyl sulfoxides with Grignard reagents. Phosphorus Sulfur Relat. Elem. 115, 179–182 (1996).

    Article  CAS  Google Scholar 

  47. Oae, S., Inabushi, Y. & Yoshihara, M. Occurrence of ligand coupling in the reaction of the 2‐thienyl sulfoxides with organometallic compounds. Heteroatom. Chem. 4, 185–188 (1993).

    Article  CAS  Google Scholar 

  48. Dean, W. M., Šiaučiulis, M., Storr, T., Lewis, W. & Stockman, R. A. Versatile C(sp2)-C(sp3) ligand couplings of sulfoxides for the enantioselective synthesis of diarylalkanes. Angew. Chem. Int. Ed. 55, 10013–10016 (2016).

    Article  CAS  Google Scholar 

  49. Šiaučiulis, M., Ahlsten, N., Pulis, A. P. & Procter, D. J. Transition-metal-free cross-coupling of benzothiophenes and styrenes in a stereoselective synthesis of substituted (E, Z)-1,3-dienes. Angew. Chem. Int. Ed. 58, 8779–8783 (2019).

    Article  Google Scholar 

  50. Duong, V. K., Horan, A. M. & McGarrigle, E. M. Synthesis of pyridylsulfonium salts and their application in the formation of functionalized bipyridines. Org. Lett. 22, 8451–8457 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Morofuji, T., Yoshida, T., Tsutsumi, R., Yamanaka, M. & Kano, N. Arylation of aryllithiums with S-arylphenothiazinium ions for biaryl synthesis. Chem. Commun. 56, 13995–13998 (2020).

    Article  CAS  Google Scholar 

  52. Yoshida, T., Honda, Y., Morofuji, T. & Kano, N. N-methylphenothiazine S-oxide enabled oxidative C(sp2)-C(sp2) coupling of boronic acids with organolithiums via phenothiaziniums. Org. Lett. 23, 9664–9668 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Yoshida, T., Honda, Y., Morofuji, T. & Kano, N. Transition-metal-free O-arylation of alcohols and phenols with S-arylphenothiaziniums. J. Org. Chem. 87, 7565–7573 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Chen, D.-L. et al. Desulfurization of diaryl(heteroaryl) sulfoxides with benzyne. Org. Lett. 21, 3986–3989 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Ritts, C. B. & Hoye, T. R. Sulfurane [S(IV)]-mediated fusion of benzynes leads to helical dibenzofurans. J. Am. Chem. Soc. 143, 13501–13506 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Melzig, J., Rauhut, C. B., Naredi-Rainer, N. & Knochel, P. Difunctionalisation of arenes and heteroarenes by directed metallation and sulfoxide-magnesium exchange. Chem. Eur. J. 17, 5362–5372 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Zhou, M., Tsien, J. & Qin, T. Sulfur (IV)-mediated heterocycle cross-couplings. Angew. Chem. Int. Ed. 59, 7372–7376 (2020).

    Article  CAS  Google Scholar 

  58. Kawai, T. et al. Occurrence of ligand coupling in the reactions of various sulfoxide with Grignard regents. Phosphorus Sulfur Relat. Elem. 34, 139–148 (1987).

    Article  CAS  Google Scholar 

  59. Morgan, K. F., Doran, R., Croft, R. A., Hollingsworth, I. A. & Bull, J. A. 2-Sulfinyl oxetanes: synthesis, stability and reactivity. Synlett. 27, 106–110 (2016).

    CAS  Google Scholar 

  60. Shi, W.-Q. et al. Synthesis of CMe2CF3‑containing heteroarenes via tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles. J. Org. Chem. 83, 15236–15244 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Johnston, L. J., Scaiano, J. C. & Ingold, K. U. Kinetics of cyclopropyl radical reactions. 1. Absolute rate constants for some addition and abstraction reactions. J. Am. Chem. Soc. 106, 4877–4881 (1984).

    Article  CAS  Google Scholar 

  62. Sun, A. C., McClain, E. J., Beatty, J. W. & Stephenson, C. R. J. Visible light-mediated decarboxylative alkylation of pharmaceutically relevant heterocycles. Org. Lett. 20, 3487–3490 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kirihara, M., Kambayashi, T. & Momose, T. Allylic fluorides via the cleavage of tertiary cyclopropyl silyl ethers with diethylaminosulfur trifluoride. Chem. Commun. 1996, 1103–1104 (1996).

    Article  Google Scholar 

  64. Meyer, O. G. J., Fröhlich, R. & Haufe, G. Asymmetric cyclopropanation of vinyl fluorides: access to enantiopure monofluorinated cyclopropane carboxylates. Synthesis 10, 1479–1490 (2000).

    Article  Google Scholar 

  65. Arlt, A. et al. Novel heteroaryl-triazole compounds as pesticides. PCT patent WO2021013720A1 (2018).

  66. Fang, Z., Cordes, D. B., Slawin, A. M. Z. & O’Hagan, D. Fluorine containing cyclopropanes: synthesis of aryl substituted all-cis 1,2,3- trifluorocyclopropanes, a facially polar motif. Chem. Commun. 55, 10539–10542 (2019).

    Article  CAS  Google Scholar 

  67. Conte, A. et al. Anthranilamide/2-amino-heteroarene carboxamide derivatives. PCT patent WO2007090752A1 (2007).

  68. Lapointe, T. et al. Substituted indazole compounds as RORγT inhibitors and uses thereof. PCT patent WO2017/075182A1 (2017).

  69. Liang, S., Hofman, K., Friedrich, M. & Manolikakes, G. Recent advances in the synthesis and direct application of sulfinate salts. Eur. J. Org. Chem. 2020, 4664–4676 (2020).

    Article  CAS  Google Scholar 

  70. Reddy, R. J. & Kumari, A. H. Synthesis and applications of sodium sulfinates (RSO2Na): a powerful building block for the synthesis of organosulfur compounds. RSC Adv. 11, 9130–9221 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sarver, P. J., Bissonnette, N. B. & MacMillan, D. W. C. Decatungstate-catalyzed C(sp3)-H sulfinylation: rapid access to diverse organosulfur functionality. J. Am. Chem. Soc. 143, 9737–9743 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Johnson, M. G., Gribble, M. W. Jr., Houze, J. B. & Paras, N. A. Convenient route to secondary sulfinates: application to the stereospecific synthesis of α‑C‑chiral sulfonamides. Org. Lett. 16, 6248–6251 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. O’ Neill, M. J. & Cornella, J. Retaining alkyl nucleophile regiofidelity in transition-metal mediated cross-couplings to aryl electrophiles. Synthesis 50, 3974–3996 (2018).

    Article  Google Scholar 

  74. Li, L., Wang, C. Y., Huang, R. & Biscoe, M. R. Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides. Nat. Chem. 5, 607–612 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Khim, Y. H. & Oae, S. The mechanism of the alkaline decomposition of triarylsulfonium bromide with phenyllithium. Bull. Chem. Soc. Jpn. 42, 1968–1971 (1969).

    Article  CAS  Google Scholar 

  76. Moc, J., Dorigo, A. & Morokuma, K. Transition structures for H2 elimination from XH4 hypervalent species (X = S, Se and Te). Ab initio MO study. Chem. Phys. Lett. 204, 65–72 (1993).

    Article  CAS  Google Scholar 

  77. Krasovskiy, A. & Knochel, P. A LiCl-Mediated Br/Mg exchange reaction for the preparation of functionalized aryl- and heteroarylmagnesium compounds from organic bromides. Angew. Chem. Int. Ed. 43, 3333–3336 (2004).

    Article  CAS  Google Scholar 

  78. Krasovskiy, A., Krasovskaya, V. & Knochel, P. Mixed Mg/Li amides of the type R2NMgCl·LiCl as highly efficient bases for the regioselective generation of functionalized aryl and heteroaryl magnesium compounds. Angew. Chem. Int. Ed. 45, 2958–2961 (2006).

    Article  CAS  Google Scholar 

  79. Jaric, M., Haag, B. A., Unsinn, A., Karaghiosoff, K. & Knochel, P. Highly selective metalations of pyridines and related heterocycles using new frustrated Lewis pairs or tmp-zinc and tmp-magnesium bases with BF3·OEt2. Angew. Chem. Int. Ed. 49, 5451–5455 (2010).

    Article  CAS  Google Scholar 

  80. Huang, P. Q. et al. Spirocyclic compounds. PCT patent WO2016/161160A1 (2016).

  81. Schirok, H. et al. Substituted 2-aminopyrazolyl-[1,2,4]triazolo [1,5a]pyridine and use. PCT WO2020/215094A1 (2020).

  82. Caravatti, G., Fairhurst, R. A., Furet, P., Guagnano, V. & Imbach, P. Organic compounds. US patent 20090163469A1 (2009).

  83. Bell, I. M. et al. Heterocyclic CGRP receptor antagonists. PCT patent WO2016/022644A1 (2016).

  84. Aversa, R. J. et al. Compounds and compositions as RAF kinas inhibitors. PCT patent WO2016/038582A1 (2016).

  85. Xi, N., Wang, L. & Wang, T. Substituted pyridine compounds and methods of use. PCT patent WO2015/034729A1 (2015).

  86. Kang, C.-Q., Cheng, Y.-Q., Guo, H.-Q., Qiu, X.-P. & Gao, L.-X. The natural alkaloid isoanabasine: synthesis from 2,3′-bipyridine, efficient resolution with BINOL, and assignment of absolute configuration by Mosher’s method. Tetrahedron Asymmetry 16, 2141–2147 (2005).

    Article  CAS  Google Scholar 

  87. Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Asymmetric Suzuki–Miyaura coupling of heterocycles via rhodium-catalysed allylic arylation of racemates. Nat. Commun. 8, 15762 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. van Dijk, K. et al. Mechanistic investigation of Rh(I)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides. Nat. Catal. 4, 284–292 (2021).

    Article  Google Scholar 

  89. Peltzer, R. M., Eisenstein, O., Nova, A. & Cascella, M. How solvent dynamics controls the Schlenk equilibrium of Grignard reagents: a computational study of CH3MgCl in tetrahydrofuran. J. Phys. Chem. B 121, 4226–4237 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Peltzer, R. M., Gauss, J., Eisenstein, O. & Cascella, M. The Grignard reaction – unraveling a chemical puzzle. J. Am. Chem. Soc. 142, 2984–2994 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Ess, D. H. Quasiclassical direct dynamics trajectory simulations of organometallic reactions. Acc. Chem. Res. 54, 4410–4422 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support for this work was provided by the Welch Foundation (I-2010-20190330 to T.Q. and A-2102-20220331 to O.G.), the National Institutes of Health (R01GM141088 to T.Q. and R35GM137797 to O.G.), the Camille and Henry Dreyfus Foundation (to O.G.), the American Chemistry Society Petroleum Research Fund (62223-DNI1 to T.Q.) and a UT Southwestern Eugene McDermott Scholarship (to T.Q.). We thank F. Lin (UTSW) for assistance with NMR spectroscopy, H. Baniasadi (UTSW) for HRMS and V. Lynch (UT-Austin) for X-ray crystallographic analysis. We thank the Chen, Tambar, Ready, De Brabander, Smith and Falck groups at UTSW for generous access to equipment and helpful discussions. We are grateful to E. Wappes, K. McClymont and C. Hethcox (Merck and Co., Inc.) for feedback on this manuscript.

Author information

Author notes

  1. These authors contributed equally: Min Zhou, Jet Tsien.

Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, Harry Hines Blvd, Dallas, TX, USA

    Min Zhou, Jet Tsien & Tian Qin

  2. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA

    Ryan Dykstra & Osvaldo Gutierrez

  3. Department of Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Jonathan M. E. Hughes & Byron K. Peters

  4. Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA

    Rohan R. Merchant

  5. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Osvaldo Gutierrez

Authors
  1. Min Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jet Tsien
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan Dykstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan M. E. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Byron K. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rohan R. Merchant
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Osvaldo Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tian Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.Z., J.T. and T.Q. performed experiments. R.D. and O.G. performed DFT theoretical studies. J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; M.Z., J.T., R.D., J.M.E.H., B.K.P., R.R.M., O.G. and T.Q. wrote the paper.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Tian Qin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Georg Manolikakes, Raju Reddy 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

General experimental, optimization studies, general procedures, reaction guidelines and troubleshooting, experimental procedures and characterization data of starting materials, experimental procedures and characterization data of substrates, control experiments, capture of sulfur part by-product, control experiments on stereochemistry fidelity, VT 19F-NMR experiment, ReactIR experiment, computer investigation, X-ray crystallographic data, references and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 40; CCDC no. 2086919.

Supplementary Data 2

Crystallographic data for compound 41; CCDC no. 2086920.

Supplementary Data 3

Crystallographic data for compound 74; CCDC no. 2172148.

Supplementary Data 4

Crystallographic data for compound 116; CCDC no. 2172149.

Supplementary Data 5

Coordinates and energies of calculated structures.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, M., Tsien, J., Dykstra, R. et al. Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres. Nat. Chem. 15, 550–559 (2023). https://doi.org/10.1038/s41557-023-01150-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-023-01150-z

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing