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. 2025 Jul 1;15(14):12063-12074.
doi: 10.1021/acscatal.5c02260. eCollection 2025 Jul 18.

Cu-Catalyzed Chemoselective Borylcupration of Borylated (Z)‑Skipped Dienoates: A Case Study for the Synthesis of gem-diborylcyclobutanes

Mireia Pujol  1 , Gerard Bru  1 , Taras Mazuryk  1 , Anika Tarasewicz  2 , Jorge J Carbó  1 , María Méndez  2 , Elena Fernández  1
Affiliations

Cu-Catalyzed Chemoselective Borylcupration of Borylated (Z)‑Skipped Dienoates: A Case Study for the Synthesis of gem-diborylcyclobutanes

Mireia Pujol et al. ACS Catal. .

Abstract

Chemoselective borylcupration of borylated (Z)-skipped dienoates is controlled by the ester group to access 3,3-di-(pinacol)-borylalkenoates. Electrophilic trapping with H+, D+, alkyl-, benzyl-, or allyl halides, as well as isocyanates has proved to be efficient for α-functionalized products. The Cu-catalyzed borylcupration of skipped dienoates containing C-Br bonds resulted in concomitant ring closing sequences toward alkylidene gem-diborylcyclobutane scaffolds. We performed DFT calculations to characterize the reaction mechanism of the formation of gem-diborylcyclobutanes. The key steps of the proposal comprise a selective borylcupration directed by alkene substituents, followed by an intramolecular C-C coupling toward strained four-membered rings assisted by the potassium cation. We also analyzed the effect of the nature of the halogen leaving group on the selectivity. The versatility of alkylidene cyclobutanes has been demonstrated through postfunctionalization reactions.

Keywords: Cu-catalysis; DFT studies; alkylidene gem-diborylcyclobutane; borylated (Z)-skipped dienoate; ring closing.

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Figures

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1. Synthesis of Functionalized Mono- and Diborylated Alkylidene Cyclobutanes
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2. Synthesis of gem-Diborylated Cyclobutanes
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3. Cu-Catalyzed Synthesis of Borylated (Z)-Skipped Dienoate 2 and Ehyl 3,3-Diborylhex-5-Enoate 3
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4. Cu-Catalyzed Borylcupration/Electrophilic Trapping of Borylated (Z)-Skipped Dienoates
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5. Cu-Catalyzed Borylcupration/Electrophilic Trapping with Isocyanates
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6. Cu-Catalyzed Synthesis of Ethyl (Z)-4-(bromomethyl)-3-(pinacolboryl)­hexa-2,5-dienoate 20 and Substituted Cyclopropane 21
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7. Synthesis of Skipped Dienoate 22 and Cu-Catalyzed Borylcupration with Concomitant Ring Closing Sequence
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1
Free-energy profile (kcal·mol–1) for the Cu-catalyzed borylcupration with concomitant ring closing.
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8. Transformation of Alkylidene gem-Diborylcyclobutane 24
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References

    1. Lovering F.. Escape from Flatland 2: complexity and promiscuity. MedChemComm. 2013;4:515–519. doi: 10.1039/c2md20347b. - DOI
    1. Bauer M. R., Di Fruscia P., Lucas S. C. C., Michaelides I. N., Nelson J. E., Storer R. I., Whitehurst B. C.. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 2021;12:448–471. doi: 10.1039/D0MD00370K. - DOI - PMC - PubMed
    1. Iwamoto H., Ozawa Y., Hayashi Y., Imamoto T., Ito H.. Conformationally fixed chiral bisphosphine ligands by steric modulators on the ligand backbone: selective synthesis of strained 1,2-disubstituted chiral cis-cyclopropanes. J. Am. Chem. Soc. 2022;144:10483–10494. doi: 10.1021/jacs.2c02745. - DOI - PubMed
    2. Augustin A. U., Di Silvio S., Marek I.. Borylated Cyclopropanes as Spring-Loaded Entities: Access to Vicinal Tertiary and Quaternary Carbon Stereocenters in Acyclic Systems. J. Am. Chem. Soc. 2022;144:16298–16302. doi: 10.1021/jacs.2c07394. - DOI - PMC - PubMed
    3. Shi Y., Yang Y., Xu S.. Iridium-catalyzed enantioselective C­(sp3)-H Borylation of amino-cyclopropanes. Angew. Chem., Int. Ed. 2022;61:e202201463. doi: 10.1002/anie.202201463. - DOI - PubMed
    4. Mali M., Sharma G. V. M., Ghosh S., Roisnel T., Carboni B., Berrée F.. Simmons-Smith cyclopropanation of alkenyl 1,2-bis­(boronates): stereoselective access to functionalized cyclopropyl derivatives. J. Org. Chem. 2022;87:7649–7657. doi: 10.1021/acs.joc.2c00152. - DOI - PubMed
    5. Neouchy Z., Hullaert J., Verhoeven J., Meerpoel L., Thuring J.-W., Verniest G., Winne J.. Synthesis of cyclopropylpinacolboronic esters from dibromo cyclopropanes. Synlett. 2022;33:759–766. doi: 10.1055/s-0037-1610794. - DOI
    6. Gutiérrez-Bonet A. ´., Popov S., Emmert M. H., Hughes J. M. E., Nolting A. F., Ruccolo S., Wang Y.. Asymmetric synthesis of tertiary and secondary cyclopropylboronates via cyclopropanation of enantio enriched alkenyl boronicesters. Org. Lett. 2022;24:3455–3460. doi: 10.1021/acs.orglett.2c01018. - DOI - PubMed
    7. Wu F.-P., Luo X., Radius U., Marder T. B., Wu X.-F.. Copper-catalyzed synthesis of stereo defined cyclopropyl bis­(boronates) from alkenes with CO as the C1 source. J. Am. Chem. Soc. 2020;142:14074–14079. doi: 10.1021/jacs.0c06800. - DOI - PubMed
    8. Gregson C. H. U., Ganesh V., Aggarwal V. K.. Strain release of donor-acceptor cyclopropyl boronate complexes. Org. Lett. 2019;21:3412–3416. doi: 10.1021/acs.orglett.9b01152. - DOI - PubMed
    9. Edwards A., Rubina M., Rubin M.. Directed RhI-Catalyzed Asymmetric Hydroboration of Prochiral 1-Arylcycloprop-2-Ene-1-Carboxylic Acid Derivatives. Chem. - Eur. J. 2018;24:1394–1403. doi: 10.1002/chem.201704443. - DOI - PubMed
    10. Benoit G., Charette A. B.. Diastereoselective borocyclopropanation of allylic ethers using a boromethylzinc carbenoid. J. Am. Chem. Soc. 2017;139:1364–1367. doi: 10.1021/jacs.6b09090. - DOI - PubMed
    11. Tian B., Liu Q., Tong X., Tian P., Lin G.-Q.. Copper­(I)-catalyzed enantioselective hydroboration of cyclopropenes: facile synthesis of optically active cyclopropylboronates. Org. Chem. Front. 2014;1:1116–1122. doi: 10.1039/C4QO00157E. - DOI
    12. Parra A., Ameno’s L., Guisán-Ceinos M., López A., García Ruano J. L., Tortosa M.. Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: synthesis of cycl propylboronates. J. Am. Chem. Soc. 2014;136:15833–15836. doi: 10.1021/ja510419z. - DOI - PubMed
    13. Zhong C., Kunii S., Kosaka Y., Sawamura M., Ito H.. Enantioselective synthesis of trans-aryl and -heteroaryl-substituted cyclopropylboronates by copper­(I)-catalyzed reactions of allylic phosphates with a diboron derivative. J. Am. Chem. Soc. 2010;132:11440–11442. doi: 10.1021/ja103783p. - DOI - PubMed
    14. Ito H., Kosaka Y., Nonoyama K., Sasaki Y., Sawamura M.. Synthesis of optically active boron-silicon bifunctional cyclopropane derivatives through enantioselective copper­(I)-catalyzed reaction of allylic carbonates with a diboron derivative. Angew. Chem., Int. Ed. 2008;47:7424–7427. doi: 10.1002/anie.200802342. - DOI - PubMed
    15. Rubina M., Rubin M., Gevorgyan V.. Catalytic enantioselective hydroboration of cyclopropenes. J. Am. Chem. Soc. 2003;125:7198–7199. doi: 10.1021/ja034210y. - DOI - PubMed
    1. Prysiazhniuk K., Polishchuk O., Shulha S., Gudzikevych K., Datsenko O. P., Kubyshkin V., Mykhailiuk P.-K.. Borylated cyclobutanes via thermal [2 + 2]-cycloaddition. Chem. Sci. 2024;15:3249. doi: 10.1039/D3SC06600B. - DOI - PMC - PubMed
    2. McDonald T. R., Rousseaux S. A. L.. Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives. Chem. Sci. 2023;14:963–969. doi: 10.1039/D2SC06088D. - DOI - PMC - PubMed
    3. Gao Q., Xu S.. Site- and Stereoselective C­(sp3)–H Borylation of Strained (Hetero)­Cycloalkanols Enabled by Iridium Catalysis. Angew. Chem., Int. Ed. 2023;62:e202218025. doi: 10.1002/anie.202218025. - DOI - PubMed
    4. Michalland J., Casaretto N., Zard S. Z.. A Modular Access to 1,2- and 1,3-Disubstituted Cyclobutylboronic Esters by Consecutive Radical Additions. Angew. Chem., Int. Ed. 2022;61:e202113333. doi: 10.1002/anie.202113333. - DOI - PubMed
    5. Cui M., Zhao Z.-Y., Oestreich M.. Boosting the Enantioselectivity of Conjugate Borylation of α,β-Disubstituted Cyclobutenones with Monooxides of Chiral C2-Symmetric Bis­(phosphine) Ligands. Chem. - Eur. J. 2022;28:e202202163. doi: 10.1002/chem.202202163. - DOI - PMC - PubMed
    6. Chen X., Chen L., Zhao H., Gao Q., Shen Z., Xu S.. Iridium-Catalyzed Enantioselective C­(sp3)–H Borylation of Cyclobutanes. Chin. J. Chem. 2020;38:1533–1537. doi: 10.1002/cjoc.202000240. - DOI
    7. Hari D. P., Abell J. C., Fasano V., Aggarwal V. K.. Ring-Expansion Induced 1,2-Metalate Rearrangements: Highly Diastereoselective Synthesis of Cyclobutyl Boronic Esters. J. Am. Chem. Soc. 2020;142:5515–5520. doi: 10.1021/jacs.0c00813. - DOI - PubMed
    8. Fawcett A., Biberger T., Aggarwal V. K.. Carbopalladation of C–C σ-Bonds Enabled by Strained Boronate Complexes. Nat. Chem. 2019;11:117–122. doi: 10.1038/s41557-018-0181-x. - DOI - PubMed
    9. Giustra Z. X., Yang X., Chen M., Bettinger H. F., Liu S.-Y.. Accessing 1,2-Substituted Cyclobutanes Through 1,2-Azaborine Photoisomerization. Angew. Chem., Int. Ed. 2019;58:18918–18922. doi: 10.1002/anie.201912132. - DOI - PMC - PubMed
    10. Silvi M., Aggarwal V. K.. Radical Addition to Strained σ-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters. J. Am. Chem. Soc. 2019;141:9511–9515. doi: 10.1021/jacs.9b03653. - DOI - PubMed
    11. Clement H. A., Boghi M., McDonald R. M., Bernier L., Coe J. W., Farrell W., Helal C. J., Reese M. R., Sach N. W., Lee J. C., Hall D. G.. High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates. Angew. Chem., Int. Ed. 2019;58:18405–18409. doi: 10.1002/anie.201909308. - DOI - PubMed
    12. He J., Shao Q., Wu Q., Yu J.-Q.. Pd­(II)-Catalyzed Enantioselective C­(sp3)-H Borylation. J. Am. Chem. Soc. 2017;139:3344–3347. doi: 10.1021/jacs.6b13389. - DOI - PubMed
    13. Guisan-Ceinos M., Parra A., Martin-Heras V., Tortosa M.. Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach. Angew. Chem., Int. Ed. 2016;55:6969–6972. doi: 10.1002/anie.201601976. - DOI - PubMed
    14. Miralles N., Alam R., Szabó K. J., Fernández E.. Transition metal-free borylation of allylic and propargylic alcohols. Angew. Chem., Int. Ed. 2016;55:4303–4306. doi: 10.1002/anie.201511255. - DOI - PMC - PubMed
    15. Murakami R., Tsunoda K., Iwai T., Sawamura M.. Stereoselective C-H Borylations of Cyclopropanes and Cyclobutanes with Silica-Supported Monophosphane-Ir Catalysts. Chem. - Eur. J. 2014;20:13127–13131. doi: 10.1002/chem.201404362. - DOI - PubMed
    1. Whyte A., Torelli A., Mirabi B., Zhang A., Lautens M.. Copper-Catalyzed Borylative Difunctionalization of π-Systems. ACS Catal. 2020;10:11578–11622. doi: 10.1021/acscatal.0c02758. - DOI