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. 2025 Jul 16;147(28):24206-24212.
doi: 10.1021/jacs.5c06139. Epub 2025 Jul 7.

Rh-Catalyzed Atroposelective Single-Carbon Insertion

Bowen Li  1 , Valero G Alfonso  1   2 , Alessio Puggioli  1   2 , Albert Solé-Daura  1 , Feliu Maseras  1 , Marcos G Suero  1   3
Affiliations

Rh-Catalyzed Atroposelective Single-Carbon Insertion

Bowen Li et al. J Am Chem Soc. .

Abstract

Single-carbon insertion processes have gained considerable momentum over the past few years. Although innovative methods have emerged for converting indole or indene into quinoline or naphthalene cores, the enantioselective version of such ring-expansions to create (hetero)biaryl atropisomers has not been developed. Herein, we report the first enantioselective single-carbon insertion that converts 3-aryl indoles to atropochiral quinolines. Key in the process was the generation of a chiral Rh-carbynoid that mediated in the creation of the stereogenic C(sp2)-C(sp2) axis.

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Figures

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Atroposelective single-carbon insertion.
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Mechanistic hypothesis.
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Replacing triflate for alternative groups and, synthesis/applications of chiral phosphine ligand 10. See the SI for the experimental details.
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Comparison of the transition states for the enantio-determining step leading to S (left) and R (right) enantiomers of compound 3c. Relative Gibbs free energies (kcal mol–1) are shown in parentheses and key distances are given in Å.
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References

    1. For selected reviews:

    2. Bringmann G., Price Mortimer A. J., Keller P. A., Gresser M. J., Garner J., Breuning M.. Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005;44:5384–5427. doi: 10.1002/anie.200462661. - DOI - PubMed
    3. Kozlowski M. C., Morgan B. J., Linton E. C.. Total Synthesis of Chiral Biaryl Natural Products by Asymmetric Biaryl Coupling. Chem. Soc. Rev. 2009;38:3193–3207. doi: 10.1039/b821092f. - DOI - PMC - PubMed
    4. Bringmann G., Gulder T., Gulder T. A. M., Breuning M.. Atroposelective Total Synthesis of Axially Chiral Biaryl Natural Products. Chem. Rev. 2011;111:563–639. doi: 10.1021/cr100155e. - DOI - PubMed
    5. LaPlante S. R., Fader L. D., Fandrick K. R., Fandrick D. R., Hucke O., Kemper R., Miller S. P. F., Edwards P. J.. Assessing Atropisomer Axial Chirality in Drug Discovery and Development. J. Med. Chem. 2011;54:7005–7022. doi: 10.1021/jm200584g. - DOI - PubMed
    6. Smyth J. E., Butler N. M., Keller P. A.. A Twist of Nature–the Significance of Atropisomers in Biological Systems. Nat. Prod. Rep. 2015;32:1562–1583. doi: 10.1039/C4NP00121D. - DOI - PubMed

    7. See also:

    8. O’Connell P. J., Harms C. T., Allen J. R. F.. Metolachlor, S-Metolachlor and Their Role within Sustainable Weed-Management. Crop Prot. 1998;17:207–212. doi: 10.1016/S0261-2194(98)80011-2. - DOI
    9. Degenhardt C. F., Lavin J. M., Smith M. D., Shimizu K. D.. Conformationally Imprinted Receptors: Atropisomers with “Write”, “Save”, and “Erase” Recognition Properties. Org. Lett. 2005;7:4079–4081. doi: 10.1021/ol051325t. - DOI - PubMed
    10. Zhang D.-W., Li M., Chen C.-F.. Recent Advances in Circularly Polarized Electroluminescence Based on Organic Light-Emitting Diodes. Chem. Soc. Rev. 2020;49:1331–1343. doi: 10.1039/C9CS00680J. - DOI - PubMed
    11. Hamada H., Itabashi Y., Shang R., Nakamura E.. Axially Chiral Spiro-Conjugated Carbon-Bridged p-Phenylenevinylene Congeners: Synthetic Design and Materials Properties. J. Am. Chem. Soc. 2020;142:2059–2067. doi: 10.1021/jacs.9b13019. - DOI - PubMed
    1. Cheng J. K., Xiang S.-H., Li S., Ye L., Tan B.. Recent Advances in Catalytic Asymmetric Construction of Atropisomers. Chem. Rev. 2021;121:4805–4902. doi: 10.1021/acs.chemrev.0c01306. - DOI - PubMed
    2. Liu C.-X., Zhang W.-W., Yin S.-Y., Gu Q., You S.-L.. Synthesis of Atropisomers by Transition-Metal-Catalyzed Asymmetric C–H Functionalization Reactions. J. Am. Chem. Soc. 2021;143:14025–14040. doi: 10.1021/jacs.1c07635. - DOI - PubMed
    3. Rodríguez-Salamanca P., Fernández R., Hornillos V., Lassaletta J. M.. Asymmetric Synthesis of Axially Chiral C–N Atropisomers. Chem.Eur. J. 2022;28:e202104442. doi: 10.1002/chem.202104442. - DOI - PMC - PubMed
    4. Roos C. B., Chiang C.-H., Murray L. A. M., Yang D., Schulert L., Narayan A. R. H.. Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage. Chem. Rev. 2023;123:10641–10727. doi: 10.1021/acs.chemrev.3c00327. - DOI - PubMed
    5. Schmidt T. A., Hutskalova V., Sparr C.. Atroposelective Catalysis. Nat. Rev. Chem. 2024;8:497–517. doi: 10.1038/s41570-024-00618-x. - DOI - PubMed
    6. Zhang H., Li T., Liu S., Shi F.. Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field. Angew. Chem., Int. Ed. 2024;63:e202311053. doi: 10.1002/anie.202311053. - DOI - PubMed
    7. Xiang S.-H., Ding W.-Y., Wang Y.-B., Tan B.. Catalytic Atroposelective Synthesis. Nat. Catal. 2024;7:483–498. doi: 10.1038/s41929-024-01138-z. - DOI
    1. Liu Y., Tse Y.-L. S., Kwong F. Y., Yeung Y.-Y.. Accessing Axially Chiral Biaryls via Organocatalytic Enantioselective Dynamic-Kinetic Resolution-Semipinacol Rearrangement. ACS Catal. 2017;7:4435–4440. doi: 10.1021/acscatal.7b01056. - DOI
    1. Tang X., Tang Y., Peng J., Du H., Huang L., Gao J., Liu S., Wang D., Wang W., Gao L., Lan Y., Song Z.. Ligand-Controlled Regiodivergent Ring Expansion of Benzosilacyclobutenes with Alkynes En Route to Axially Chiral Silacyclohexenyl Arenes. J. Am. Chem. Soc. 2024;146:26639–26648. doi: 10.1021/jacs.4c00252. - DOI - PubMed
    1. Ciamician G. L., Dennstedt M.. Ueber die Einwirkung des Chloroforms auf die Kaliumverbindung Pyrrols. Berichte Dtsch. Chem. Ges. 1881;14:1153–1163. doi: 10.1002/cber.188101401240. - DOI
    2. Magnanini G.. Ueber die Acetylverbindungen des Methylketols und des Skatols. Berichte Dtsch. Chem. Ges. 1888;21:1936–1939. doi: 10.1002/cber.188802101373. - DOI
    3. Rees C. W., Smithen C. E.. 181. The Mechanism of Heterocyclic Ring Expansions. Part I. The Reaction of 2,3-Dimethylindole with Dichlorocarbene. J. Chem. Soc. Resumed. 1964:928–937. doi: 10.1039/jr9640000928. - DOI
    4. Dobbs H. E.. Radiotracer Study of the Reaction of Dichloro-Carbene with Dimethylindole. Tetrahedron. 1968;24:491–496. doi: 10.1016/0040-4020(68)89048-9. - DOI
    5. Jones R. L., Rees C. W.. Mechanism of Heterocyclic Ring Expansions. Part III. Reaction of Pyrroles with Dichlorocarbene. J. Chem. Soc. C Org. 1969;18:2249–2251. doi: 10.1039/j39690002249. - DOI
    6. Ogawa H., Aoyama T., Shioiri T.. Lithium Trimethylsilyldiazomethane: A Convenient Reagent for the Preparation of Cyclohepta­[b]­Pyrrol-2-Ones from N-Methylanilides of α-Keto Acids. Synlett. 1994;1994:757–758. doi: 10.1055/s-1994-22999. - DOI
    7. Morita M., Hari Y., Iguchi T., Aoyama T.. Facile Synthesis of 2-Azaazulenes from Thiobenzoyl Isocyanates Using Trimethylsilyldiazomethane. Tetrahedron. 2008;64:1753–1758. doi: 10.1016/j.tet.2007.11.107. - DOI
    8. Morita M., Hari Y., Aoyama T.. Facile Synthesis of 1-Methyl-1H-Benzo­[b]­Azepines from 1-Methylquinolinium Iodides and Diazo­(Trimethylsilyl)­Methylmagnesium Bromide. Synthesis. 2010;2010:4221–4227. doi: 10.1055/s-0030-1258306. - DOI
    9. Mortén M., Hennum M., Bonge-Hansen T.. Synthesis of Quinoline-3-Carboxylates by a Rh­(II)-Catalyzed Cyclopropanation-Ring Expansion Reaction of Indoles with Halodiazoacetates. Beilstein J. Org. Chem. 2015;11:1944–1949. doi: 10.3762/bjoc.11.210. - DOI - PMC - PubMed
    10. Wang H., Zhou C., Che C.. Cobalt-Porphyrin-Catalyzed Intramolecular Buchner Reaction and Arene Cyclopropanation of In Situ Generated Alkyl Diazomethanes. Adv. Synth. Catal. 2017;359:2253–2258. doi: 10.1002/adsc.201700205. - DOI
    11. Peeters S., Berntsen L. N., Rongved P., Bonge-Hansen T.. Cyclopropanation–Ring Expansion of 3-Chloroindoles with α-Halodiazoacetates: Novel Synthesis of 4-Quinolone-3-Carboxylic Acid and Norfloxacin. Beilstein J. Org. Chem. 2019;15:2156–2160. doi: 10.3762/bjoc.15.212. - DOI - PMC - PubMed
    12. Wang Z., Jiang L., Sarró P., Suero M. G.. Catalytic Cleavage of C­(sp 2)–C­(sp 2) Bonds with Rh-Carbynoids. J. Am. Chem. Soc. 2019;141:15509–15514. doi: 10.1021/jacs.9b08632. - DOI - PubMed
    13. Dherange B. D., Kelly P. Q., Liles J. P., Sigman M. S., Levin M. D.. Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines. J. Am. Chem. Soc. 2021;143:11337–11344. doi: 10.1021/jacs.1c06287. - DOI - PMC - PubMed
    14. Kim J., Yoo E. J.. Catalytic Ring Expansion of Activated Heteroarenes Enabled by Regioselective Dearomatization. Org. Lett. 2021;23:4256–4260. doi: 10.1021/acs.orglett.1c01173. - DOI - PubMed
    15. Ma D., Martin B. S., Gallagher K. S., Saito T., Dai M.. One-Carbon Insertion and Polarity Inversion Enabled a Pyrrole Strategy to the Total Syntheses of Pyridine-Containing Lycopodium Alkaloids: Complanadine A and Lycodine. J. Am. Chem. Soc. 2021;143:16383–16387. doi: 10.1021/jacs.1c08626. - DOI - PMC - PubMed
    16. Jiang L., Sarró P., Teo W. J., Llop J., Suero M. G.. Catalytic Alkene Skeletal Modification for the Construction of Fluorinated Tertiary Stereocenters. Chem. Sci. 2022;13:4327–4333. doi: 10.1039/D2SC00968D. - DOI - PMC - PubMed
    17. Piacentini P., Bingham T. W., Sarlah D.. Dearomative Ring Expansion of Polycyclic Arenes. Angew. Chem., Int. Ed. 2022;61:e202208014. doi: 10.1002/anie.202208014. - DOI - PMC - PubMed
    18. Joynson B. W., Cumming G. R., Ball L. T.. Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment. Angew. Chem., Int. Ed. 2023;62:e202305081. doi: 10.1002/anie.202305081. - DOI - PMC - PubMed
    19. Park S., Kim C.-E., Jeong J., Ryu H., Maeng C., Kim D., Baik M.-H., Lee P. H.. Selective Ring Expansion and C–H Functionalization of Azulenes. Nat. Commun. 2023;14:7936. doi: 10.1038/s41467-023-43200-7. - DOI - PMC - PubMed
    20. Guo H., Qiu S., Xu P.. One-Carbon Ring Expansion of Indoles and Pyrroles: A Straightforward Access to 3-Fluorinated Quinolines and Pyridines. Angew. Chem., Int. Ed. 2024;63:e202317104. doi: 10.1002/anie.202317104. - DOI - PubMed
    21. Lamb J. S., Koyama F., Suzuki N., Suzuki Y.. Carbon Atom Insertion into N -Heterocyclic Carbenes to Yield 3,4-Dihydroquinoxalin-2­(1H)-Ones. Org. Chem. Front. 2024;11:277–283. doi: 10.1039/D3QO01579C. - DOI
    22. Li C., Chen L., Wang H., Yan Z., Lyu B., Lyu W., Jiang C., Lu D., Li J., Jiao N., Song S.. CF Bond Insertion into Indoles with CHBr2F: An Efficient Method to Synthesize Fluorinated Quinolines and Quinolones. Chin. J. Chem. 2024;42:1128–1132. doi: 10.1002/cjoc.202400033. - DOI
    23. Timmann S., Wu T.-H., Golz C., Alcarazo M.. Reactivity of α-Diazo Sulfonium Salts: Rhodium-Catalysed Ring Expansion of Indenes to Naphthalenes. Chem. Sci. 2024;15:5938–5943. doi: 10.1039/D4SC01138D. - DOI - PMC - PubMed
    24. Wu F.-P., Chintawar C. C., Lalisse R., Mukherjee P., Dutta S., Tyler J., Daniliuc C. G., Gutierrez O., Glorius F.. Ring Expansion of Indene by Photoredox-Enabled Functionalized Carbon-Atom Insertion. Nat. Catal. 2024;7:242–251. doi: 10.1038/s41929-023-01089-x. - DOI - PMC - PubMed
    25. Wu F.-P., Tyler J. L., Daniliuc C. G., Glorius F.. Atomic Carbon Equivalent: Design and Application to Diversity-Generating Skeletal Editing from Indoles to 3-Functionalized Quinolines. ACS Catal. 2024;14:13343–13351. doi: 10.1021/acscatal.4c03868. - DOI
    26. Li L., Chen H., Zhang X., Murali K., Zhu Q., Liu M., Zhang H., Nenajdenko V., Bi X.. Silver-Catalyzed Single-Carbon Insertion of Indoles with Acetophenone N-Triftosylhydrazones. Org. Lett. 2024;26:7207–7211. doi: 10.1021/acs.orglett.4c02633. - DOI - PubMed
    27. Liu S., Yang Y., Song Q., Liu Z., Sivaguru P., Zhang Y., De Ruiter G., Anderson E. A., Bi X.. Halogencarbene-Free Ciamician-Dennstedt Single-Atom Skeletal Editing. Nat. Commun. 2024;15:9998. doi: 10.1038/s41467-024-54379-8. - DOI - PMC - PubMed
    28. Liu S., Yang Y., Song Q., Liu Z., Lu Y., Wang Z., Sivaguru P., Bi X.. Tunable Molecular Editing of Indoles with Fluoroalkyl Carbenes. Nat. Chem. 2024;16:988–997. doi: 10.1038/s41557-024-01468-2. - DOI - PubMed
    29. Liu L., Tian M., Lang Z., Wang Y., He C., Chen Y., Han W.. Indole-Quinoline Transmutation Enabled by a Formal Rhodium Carbynoid. Angew. Chem. Int. Ed. 2025;64:e202501966. doi: 10.1002/anie.202501966. - DOI - PubMed

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