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Harnessing thia-Rh-carbenes for the enantioselective synthesis of chiral α,α-diheteroatomic carboxylic acids

Nature Catalysis volume 9, pages 173–183 (2026)Cite this article

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Abstract

Enantioselective X–H bond insertion into Rh-carbenoids offers a robust approach for constructing chiral centres with heteroatoms. However, the synthesis of carboxylic acid derivatives that have two distinct heteroatoms on the α-carbon remains highly challenging because of the difficulties in accessing suitable heteroatom-substituted metallocarbene intermediates and achieving enantioselectivity in highly polar environments. Here we present a method for enantioselective insertion of O–H or N–H bonds into an α-thia-RhII-carbene species. This approach facilitates the synthesis of α,α-diheteroatomic carboxylic acids, a previously inaccessible chiral pool with unique electronic and structural properties. We identified two chiral proton-shuttling catalysts that enable highly enantioselective O–H or N–H insertion. This study introduces a versatile and programmable method for the enantioselective incorporation of two heteroatoms into a carbon centre. It broadens the scope of asymmetric insertion reactions and expands the chemical space of chiral carboxylic acids.

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Fig. 1: Synthesis of α-heteroatomic chiral carboxylates.
Fig. 2: Scope of optically enriched α,α-O,S-carboxylates.
Fig. 3: Scope of optically enriched α,α-N,S-carboxylates.
Fig. 4: Computational analysis of key transition states.
Fig. 5: Synthetic applications of DHCA.
Fig. 6: t-SNE and PCA visualization of α-Het UAAs in a known chemical space for amino acids.
Fig. 7: Late-stage modifications of peptides and drug molecules via α-Het UAA incorporation.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2329117 (1as), 2329118 (1a), 2329119 (3k) and 2329120 (4k). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Data relating to the materials and methods, optimization studies, experimental procedures, DFT calculations, visualization analysis, bioactivity studies, NMR spectra and HPLC spectra are available in Supplementary Information. Other data are available from the authors upon reasonable request.

References

  1. Jacobsen, E. N. et al. Product Subclass 8: 2-Heteroatom-Substituted Alkanoic Acids. Category 3, Compounds with Four and Three Carbon Heteroatom Bonds (ed. Panek, J. S.) (Thieme, 2006); https://doi.org/10.1055/sos-SD-020-00455

  2. Parker, E. J. & Pratt, A. J. in Amino Acids, Peptides and Proteins in Organic Chemistry (ed. Hughes, A. B.) 1–82 (John Wiley, 2010); https://doi.org/10.1002/9783527631803.ch1

  3. Lopez, M. J. & Mohiuddin, S. S. Biochemistry, Essential Amino Acids (StatPearls, 2023).

  4. Ling, Z.-N. et al. Amino acid metabolism in health and disease. Signal Transduct. Target. Ther. 8, 345 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bongioanni, A., Bueno, M. S., Mezzano, B. A., Longhi, M. R. & Garnero, C. Amino acids and its pharmaceutical applications: a mini review. Int. J. Pharm. 613, 121375 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Lamberth, C. & Dinges, J. in Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals (eds Lamberth, C. & Dinges, J.) 1–11 (Wiley-VCH, 2016); https://doi.org/10.1002/9783527693931.ch1

  7. Xu, Q., Deng, H., Li, X. & Quan, Z.-S. Application of amino acids in the structural modification of natural products: a review. Front. Chem. 9, 650569 (2021).

  8. Blaskovich, M. A. T. Unusual amino acids in medicinal chemistry. J. Med. Chem. 59, 10807–10836 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Ballatore, C., Huryn, D. M. & Smith, A. B. Carboxylic acid (bio)isosteres in drug design. ChemMedChem 8, 385–395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Perez, L. J. et al. Role of the CAI-1 fatty acid tail in the Vibrio cholerae quorum sensing response. J. Med. Chem. 55, 9669–9681 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nakajima, M. et al. Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of γ-glutamyl transpeptidase for probing cysteinyl-glycine binding site. Bioorg. Med. Chem. 22, 1176–1194 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. White, A. et al. Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases. J. Biol. Chem. 293, 13851–13862 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu, Y.-J. & Meanwell, N. A. Geminal diheteroatomic motifs: some applications of acetals, ketals, and their sulfur and nitrogen homologues in medicinal chemistry and drug design. J. Med. Chem. 64, 9786–9874 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Jacobsen, E. N. et al. Product Subclass 6: 2,2-Diheteroatom-Substituted Alkanoic Acids. Category 3, Compounds with Four and Three Carbon Heteroatom Bonds (ed. Panek, J. S.) (Thieme, 2006); https://doi.org/10.1055/sos-SD-020-00324

  15. Akhavan, B. J., Khanna, N. R. & Vijhani, P. Amoxicillin (StatPearls, 2024).

  16. Dando, T. M. & Perry, C. M. Aprepitant. Drugs 64, 777–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. O’Hanlon, R. & Shaw, M. L. Baloxavir marboxil: the new influenza drug on the market. Curr. Opin. Virol. 35, 14–18 (2019).

    Article  PubMed  Google Scholar 

  18. Ford, A. et al. Modern organic synthesis with α-diazocarbonyl compounds. Chem. Rev. 115, 9981–10080 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Zhu, S.-F. & Zhou, Q.-L. Transition-metal-catalyzed enantioselective heteroatom–hydrogen bond insertion reactions. Acc. Chem. Res. 45, 1365–1377 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Ren, Y.-Y., Zhu, S.-F. & Zhou, Q.-L. Chiral proton-transfer shuttle catalysts for carbene insertion reactions. Org. Biomol. Chem. 16, 3087–3094 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Huang, M.-Y. & Zhu, S.-F. Uncommon carbene insertion reactions. Chem. Sci. 12, 15790–15801 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, E. C. & Fu, G. C. Copper-catalyzed asymmetric N−H insertion reactions: couplings of diazo compounds with carbamates to generate α-amino acids. J. Am. Chem. Soc. 129, 12066–12067 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Li, M.-L., Yu, J.-H., Li, Y.-H., Zhu, S.-F. & Zhou, Q.-L. Highly enantioselective carbene insertion into N–H bonds of aliphatic amines. Science 366, 990–994 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Yang, W. et al. Enantioselective formal vinylogous N–H insertion of secondary aliphatic amines catalyzed by a high-spin cobalt(II) complex. J. Am. Chem. Soc. 143, 9648–9656 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Maier, T. C. & Fu, G. C. Catalytic enantioselective O−H insertion reactions. J. Am. Chem. Soc. 128, 4594–4595 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tan, F. et al. Asymmetric catalytic insertion of α-diazo carbonyl compounds into O–H bonds of carboxylic acids. ACS Catal. 6, 6930–6934 (2016).

    Article  CAS  Google Scholar 

  27. Li, Y. et al. Highly enantioselective O–H bond insertion reaction of α-alkyl- and α-alkenyl-α-diazoacetates with water. J. Am. Chem. Soc. 142, 10557–10566 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Xu, B. et al. Highly enantioselective S–H bond insertion cooperatively catalyzed by dirhodium complexes and chiral spiro phosphoric acids. Chem. Sci. 5, 1442–1448 (2014).

    Article  CAS  Google Scholar 

  29. Chen, K., Zhang, S.-Q., Brandenberg, O. F., Hong, X. & Arnold, F. H. Alternate heme ligation steers activity and selectivity in engineered cytochrome P450-catalyzed carbene-transfer reactions. J. Am. Chem. Soc. 140, 16402–16407 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, Y.-T., Rao, X., Xu, W. & Xu, M.-H. Rhodium(I)-catalyzed C–S bond formation via enantioselective carbenoid S–H insertion: catalytic asymmetric synthesis of α-thioesters. Org. Chem. Front. 9, 3467–3472 (2022).

    Article  CAS  Google Scholar 

  31. Keipour, H., Carreras, V. & Ollevier, T. Recent progress in the catalytic carbene insertion reactions into the silicon–hydrogen bond. Org. Biomol. Chem. 15, 5441–5456 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Chen, D., Zhu, D.-X. & Xu, M.-H. Rhodium(I)-catalyzed highly enantioselective insertion of carbenoid into Si–H: efficient access to functional chiral silanes. J. Am. Chem. Soc. 138, 1498–1501 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, D., Zhang, X., Qi, W.-Y., Xu, B. & Xu, M.-H. Rhodium(I)-catalyzed asymmetric carbene insertion into B–H bonds: highly enantioselective access to functionalized organoboranes. J. Am. Chem. Soc. 137, 5268–5271 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, G. et al. Construction of boron-stereogenic compounds via enantioselective Cu-catalyzed desymmetric B–H bond insertion reaction. Nat. Commun. 13, 2624 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gu, X. et al. Catalytic asymmetric P–H insertion reactions. J. Am. Chem. Soc. 145, 20031–20040 (2023).

    Article  CAS  PubMed  Google Scholar 

  36. He, X. et al. Asymmetric carbene insertion into Se−S bonds by synergistic Rh(II)/guanidine catalysis involving chalcogen-bond assistance. Angew. Chem. Int. Ed. 64, e202417636 (2025).

  37. Hu, L., Li, J., Zhang, Y., Feng, X. & Liu, X. Enantioselective [1,2]-Stevens rearrangement of thiosulfonates to construct dithio-substituted quaternary carbon centers. Chem. Sci. 13, 4103–4108 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kubiak, R. W. I., Tracy, W. F., Alford, J. S. & Davies, H. M. L. Asymmetric cyclopropanation with 4-aryloxy-1-sulfonyl-1,2,3-triazoles: expanding the range of rhodium-stabilized donor/acceptor carbenes to systems with an oxygen donor group. J. Org. Chem. 87, 13517–13528 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Palomo, E. et al. Generating Fischer-type Rh-carbenes with Rh-carbynoids. J. Am. Chem. Soc. 145, 4975–4981 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Huang, M.-Y. et al. Enantioselective α-boryl carbene transformations. J. Am. Chem. Soc. 146, 9871–9879 (2024).

    Article  CAS  PubMed  Google Scholar 

  41. Huang, M.-Y., Zhao, Y.-T., Zhang, C.-D. & Zhu, S.-F. Highly regio-, stereo-, and enantioselective copper-catalyzed B−H bond insertion of α-silylcarbenes: efficient access to chiral allylic gem-silylboranes. Angew. Chem. Int. Ed. 61, e202203343 (2022).

    Article  CAS  Google Scholar 

  42. Li, L. et al. A carbene relay strategy for cascade insertion reactions. Angew. Chem. Int. Ed. 62, e202312793 (2023).

    Article  CAS  Google Scholar 

  43. Moreau, B. & Charette, A. B. Expedient synthesis of cyclopropane α-amino acids by the catalytic asymmetric cyclopropanation of alkenes using iodonium ylides derived from methyl nitroacetate. J. Am. Chem. Soc. 127, 18014–18015 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Zhou, C.-Y. et al. Dirhodium carboxylates catalyzed enantioselective coupling reactions of α-diazophosphonates, anilines, and electron-deficient aldehydes. Angew. Chem. Int. Ed. 51, 11376–11380 (2012).

    Article  CAS  Google Scholar 

  45. Marinozzi, M., Pertusati, F. & Serpi, M. λ5-Phosphorus-containing α-diazo compounds: a valuable tool for accessing phosphorus-functionalized molecules. Chem. Rev. 116, 13991–14055 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Li, Z. & Davies, H. M. L. Enantioselective C−C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and allylic alcohols. J. Am. Chem. Soc. 132, 396–401 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Zhu, S.-F. Catalytic hydrogen transfer reactions. Chin. J. Chem. 39, 3211–3218 (2021).

    Article  CAS  Google Scholar 

  48. Li, L. et al. Synthesis of I(III)/S(VI) reagents and their reactivity in photochemical cycloaddition reactions with unsaturated bonds. Nat. Commun. 13, 6588 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Okino, T., Hoashi, Y. & Takemoto, Y. Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts. J. Am. Chem. Soc. 125, 12672–12673 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Liang, Y., Zhou, H. & Yu, Z.-X. Why is copper(I) complex more competent than dirhodium(II) complex in catalytic asymmetric O−H insertion reactions? A computational study of the metal carbenoid O−H insertion into water. J. Am. Chem. Soc. 131, 17783–17785 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Liu, Y., Luo, Z., Zhang, J. Z. & Xia, F. DFT calculations on the mechanism of transition-metal-catalyzed reaction of diazo compounds with phenols: O–H insertion versus C–H insertion. J. Phys. Chem. A 120, 6485–6492 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Kisan, H. K. & Sunoj, R. B. Deciphering the origin of cooperative catalysis by dirhodium acetate and chiral spiro phosphoric acid in an asymmetric amination reaction. Chem. Commun. 50, 14639–14642 (2014).

    Article  CAS  Google Scholar 

  53. 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 

  54. Bryantsev, V. S., Diallo, M. S. & Goddard III, W. A. Calculation of solvation free energies of charged solutes using mixed cluster/continuum models. J. Phys. Chem. B 112, 9709–9719 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Grimme, S. Supramolecular binding thermodynamics by dispersion-corrected density functional theory. Chem. Eur. J. 18, 9955–9964 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Lu, T. & Chen, Q. Interaction region indicator: a simple real space function clearly revealing both chemical bonds and weak interactions. Chem. Methods 1, 231–239 (2021).

    Article  CAS  Google Scholar 

  57. Bader, R. F. W. A quantum theory of molecular structure and its applications. Chem. Rev. 91, 893–928 (1991).

    Article  CAS  Google Scholar 

  58. Nödling, A. R., Spear, L. A., Williams, T. L., Luk, L. Y. P. & Tsai, Y.-H. Using genetically incorporated unnatural amino acids to control protein functions in mammalian cells. Essays Biochem. 63, 237–266 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wang, L. et al. Therapeutic peptides: current applications and future directions. Signal Transduct. Target. Ther. 7, 48 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ding, Y. et al. Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics. Amino Acids 52, 1207–1226 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ji, X., Nielsen, A. L. & Heinis, C. Cyclic peptides for drug development. Angew. Chem. Int. Ed. 63, e202308251 (2024).

    Article  CAS  Google Scholar 

  62. Ye, C.-X., Shen, X., Chen, S. & Meggers, E. Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids. Nat. Chem. 14, 566–573 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, Y.-F. et al. Copper-catalyzed enantioconvergent radical C(sp3)−N cross-coupling: access to α,α-disubstituted amino acids. Angew. Chem. Int. Ed. 62, e202302983 (2023).

    Article  CAS  Google Scholar 

  64. Chen, J.-J. et al. Copper-catalyzed enantioconvergent radical C(sp3)–N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. J. Am. Chem. Soc. 145, 14686–14696 (2023).

    Article  CAS  PubMed  Google Scholar 

  65. Cheng, L. et al. Stereoselective amino acid synthesis by synergistic photoredox-pyridoxal radical biocatalysis. Science 381, 444–451 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zheng, W.-F., Chen, J., Qi, X. & Huang, Z. Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids. Nat. Chem. 15, 1672–1682 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Chen, J.-J. et al. Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines. Nature 618, 294–300 (2023).

    Article  CAS  PubMed  Google Scholar 

  68. Hong, F., Aldhous, T. P., Kemmitt, P. D. & Bower, J. F. A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids. Nat. Chem. 16, 1125–1132 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).

    Google Scholar 

  70. Li, J. et al. CycPeptMPDB: a comprehensive database of membrane permeability of cyclic peptides. J. Chem. Inf. Model. 63, 2240–2250 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Medina-Franco, J. L., Martinez-Mayorga, K., Giulianotti, M. A., Houghten, R. A. & Pinilla, C. Visualization of the chemical space in drug discovery. Curr. Comput. Aided Drug Des. 4, 322–333 (2008).

    Article  CAS  Google Scholar 

  72. Wang, Z., Wang, X., Wang, P. & Zhao, J. Allenone-mediated racemization/epimerization-free peptide bond formation and its application in peptide synthesis. J. Am. Chem. Soc. 143, 10374–10381 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was financially supported by Hong Kong RGC (16302122 and 16309021). We thank H. Sung for his kind help with the X-ray crystallographic analysis.

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Authors and Affiliations

  1. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China

    Yajie Xing, Yuqi Fang, Yicheng Zhao & Yong Huang

  2. Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, China

    Yuqi Fang & Jiean Chen

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  1. Yajie Xing
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Contributions

Y.H. designed the study. Y.H. and J.C. directed the project. Y.X. and Y.Z. conducted experiments. Y.F. performed DFT calculations and analysed the data. All authors contributed to the analysis of the experimental results as well as to the writing of this paper.

Corresponding authors

Correspondence to Jiean Chen or Yong Huang.

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Supplementary information

Supplementary Information (download PDF )

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Supplementary Data 1

Crystallographic data of compound 1as.

Supplementary Data 2

Crystallographic data of compound 1a.

Supplementary Data 3

Crystallographic data of compound 3k.

Supplementary Data 4

Crystallographic data of compound 4k.

Supplementary Data 5 (download XLSX )

Computational data for Cartesian coordinates of optimized structures.

Supplementary Data 6 (download CSV )

Statistical source data for t-distributed stochastic neighbour embedding (t-SNE) visualization.

Supplementary Data 7 (download XLSX )

Statistical source data for principal component analysis (PCA) visualization.

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Xing, Y., Fang, Y., Zhao, Y. et al. Harnessing thia-Rh-carbenes for the enantioselective synthesis of chiral α,α-diheteroatomic carboxylic acids. Nat Catal 9, 173–183 (2026). https://doi.org/10.1038/s41929-026-01481-3

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