Nickel-Catalyzed, Bromine-Radical-Promoted Enantioselective C(sp³)–H Cross-Couplings

Abstract

Catalytic C(sp³)–H cross-coupling offers an attractive strategy for constructing C(sp³)-rich complex molecules from simple feedstock chemicals. However, simultaneously controlling chemo- and enantioselectivity in these transformations, particularly for C(sp³)–C(sp³) bond formation, remains a formidable challenge. To address this longstanding challenge, we have recently developed a general strategy leveraging nickel photoredox catalysis to achieve various enantioselective C(sp³)–H cross-coupling reactions, including acylation, alkenylation, arylation, (trideutero)methylation, and alkylation. Our approaches exploit photocatalytically generated bromine radicals for hydrogen atom transfer, converting common hydrocarbons into carbon-centered radicals. These radicals are then enantioselectively coupled with diverse electrophiles in the presence of a suitable chiral nickel catalyst. These methods open new avenues for enantioselective C(sp³)–H cross-coupling, offering broad substrate scope, high functional group tolerance, and potential for late-stage diversification of complex molecules. Our strategy holds great promise for unlocking previously elusive C(sp³)-rich chemical space, with significant implications for drug discovery and development.

1 Introduction

2 Enantioselective C(sp³)–C(sp²) Cross-Couplings

3 Enantioselective C(sp³)–C(sp³) Cross-Couplings

4 Conclusions and Outlook

Key words

bromine radicals - nickel catalysis - C(sp³)–H cross-coupling - enantioselectivity - hydrogen atom transfer - hydrocarbons

Publication History

Received: 27 August 2024

Accepted after revision: 28 October 2024

Article published online:
19 November 2024

• References

• 1a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 1b Lovering F. Med. Chem. Commun. 2013; 4: 515
• 2 Choi J, Fu GC. Science 2017; 356: eaaf7230
• 3 Guillemard L, Kaplaneris N, Ackermann L, Johansson MJ. Nat. Rev. Chem. 2021; 5: 522
• 4 Saint-Denis TG, Zhu R.-Y, Chen G, Wu Q.-F, Yu J.-Q. Science 2018; 359: eaao4798
• 5a Jain P, Verma P, Xia G, Yu J.-Q. Nat. Chem. 2017; 9: 140
• 5b Jiang H.-J, Zhong X.-M, Yu J, Zhang Y, Zhang X, Wu Y.-D, Gong L.-Z. Angew. Chem. Int. Ed. 2019; 58: 1803
• 5c Zhang T, Zhang Z.-Y, Kang G, Sheng T, Yan J.-L, Yang Y.-B, Ouyang Y, Yu J.-Q. Science 2024; 384: 793
• 5d Davies HM. L, Liao K. Nat. Rev. Chem. 2019; 3: 347
• 5e Liao K, Negretti S, Musaev DG, Bacsa J, Davies HM. L. Nature 2016; 533: 230
• 5f Zhang RK, Chen K, Huang X, Wohlschlager L, Renata H, Arnold FH. Nature 2019; 565: 67
• 5g Ren X, Couture BM, Liu N, Lall MS, Kohrt JT, Fasan R. J. Am. Chem. Soc. 2023; 145: 537
• 6a Chan AY, Perry IB, Bissonnette NB, Buksh BF, Edwards GA, Frye LI, Garry OL, Lavagnino MN, Li BX, Liang Y, Mao E, Millet A, Oakley JV, Reed NL, Sakai HA, Seath CP, MacMillan DW. C. Chem. Rev. 2022; 122: 1485
• 6b Tellis JC, Primer DN, Molander GA. Science 2014; 345: 433
• 6c Zuo Z, Ahneman DT, Chu L, Terrett JA, Doyle AG, MacMillan DW. C. Science 2014; 345: 437
• 7a Cao H, Tang X, Tang H, Yuan Y, Wu J. Chem Catal. 2021; 1: 523
• 7b Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
• 7c Golden DL, Suh SE, Stahl SS. Nat. Rev. Chem. 2022; 6: 405
• 7d Holmberg-Douglas N, Nicewicz DA. Chem. Rev. 2022; 122: 1925
• 7e Bellotti P, Huang H.-M, Faber T, Glorius F. Chem. Rev. 2023; 123: 4237
• 7f Li T, Li J, Huo H. Chin. J. Chem. 2023; 41: 544
• 8a Zhang C, Li Z.-L, Gu Q.-S, Liu X.-Y. Nat. Commun. 2021; 12: 475
• 8b Li Z, Li C, Ding Y, Huo H. Coord. Chem. Rev. 2022; 460: 214479
• 8c Chen X, Kramer S. Chem Catal. 2024; 4: 100854
• 8d Li HH, Chen XM, Kramer S. Chem. Sci. 2023; 14: 13278
• 8e Xu GQ, Wang WD, Xu PF. J. Am. Chem. Soc. 2024; 146: 1209
• 8f Liu C, Kui X, Lu Q, Liu H, Qian D. Chem Catal. 2024; 4: 100798
• 8g Cheng X, Lu H, Lu Z. Nat. Commun. 2019; 10: 3549
• 8h Cheng X, Li T, Liu Y, Lu Z. ACS Catal. 2021; 11: 11059
• 8i Xu S, Ping Y, Li W, Guo H, Su Y, Li Z, Wang M, Kong W. J. Am. Chem. Soc. 2023; 145: 5231
• 8j Cuesta-Galisteo S, Schörgenhumer J, Hervieu C, Nevado C. Angew. Chem. Int. Ed. 2024; 63: e202313717
• 9a Ahneman DT, Doyle AG. Chem. Sci. 2016; 7: 7002
• 9b Shen Y, Gu Y, Martin R. J. Am. Chem. Soc. 2018; 140: 12200
• 9c Rand AW, Yin H, Xu L, Giacoboni J, Martin-Montero R, Romano C, Montgomery J, Martin R. ACS Catal. 2020; 10: 4671
• 9d Kawasaki T, Yamazaki K, Tomono R, Ishida N, Murakami M. Chem. Lett. 2021; 50: 1684 . For notable studies in enantioselective radical α–C(sp³)-H functionalization catalyzed by other metals using only 1.0 equiv of C-H substrate, see
• 9e Zhang W, Wang F, McCann SD, Wang D, Chen P, Stahl SS, Liu G. Science 2016; 353: 1014
• 9f Li J, Zhang Z, Wu L, Zhang W, Chen P, Lin Z, Liu G. Nature 2019; 574: 516
• 9g Zhang W, Wu L, Chen P, Liu G. Angew. Chem. Int. Ed. 2019; 58: 6425
• 9h Fu L, Zhang Z, Chen P, Lin Z, Liu G. J. Am. Chem. Soc. 2020; 142: 12493
• 9i Xu P, Fan W, Chen P, Liu G. J. Am. Chem. Soc. 2022; 144: 13468
• 9j Chen X, Lian Z, Kramer S. Angew. Chem. Int. Ed. 2023; 62: e202217638
• 9k Xu P, Xie J, Wang D.-S, Zhang XP. Nat. Chem. 2023; 15: 498
• 9l Ye C.-X, Dansby DR, Chen S, Meggers E. Nat. Synth. 2023; 2: 645
• 10a Shu X, Huan L, Huang Q, Huo H. J. Am. Chem. Soc. 2020; 142: 19058
• 10b Huan L, Shu X, Zu W, Zhong D, Huo H. Nat. Commun. 2021; 12: 3536
• 10c Zhang W, Shu X, Huan L, Cheng B, Huo H. Org. Biomol. Chem. 2021; 19: 9407
• 10d Xu J, Li Z, Xu Y, Shu X, Huo H. ACS Catal. 2021; 11: 13567
• 10e Li J, Cheng B, Shu X, Xu Z, Li C, Huo H. Nat. Catal. 2024; 7: 889
• 11a Heitz DR, Tellis JC, Molander GA. J. Am. Chem. Soc. 2016; 138: 12715
• 11b Shields BJ, Doyle AG. J. Am. Chem. Soc. 2016; 138: 12719
• 11c Lin Y, Shu X, Huo H. Synthesis 2024; 56: 1702
• 12 Pezzetta C, Bonifazi D, Davidson RW. M. Org. Lett. 2019; 21: 8957
• 13a Farney EP, Chapman SJ, Swords WB, Torelli MD, Hamers RJ, Yoon TP. J. Am. Chem. Soc. 2019; 141: 6385
• 13b Li G, Swords WB, Meyer G. J. Am. Chem. Soc. 2017; 139: 14983
• 14a Shu X, Zhong D, Lin Y, Qin X, Huo H. J. Am. Chem. Soc. 2022; 144: 8797
• 14b Shu X, Zhong D, Huang Q, Huan L, Huo H. Nat. Commun. 2023; 14: 125