Iron-Catalyzed Cross-Electrophile Coupling for the Formation of All-Carbon Quaternary Centers

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Nov 21

PMID 39568194

Authors

Andria L Pace

Felix Xu

Wei Liu

Marissa N Lavagnino

David W C MacMillan

Affiliations

Soon will be listed here.

Abstract

Quaternary carbon centers are desirable targets for drug discovery and complex molecule synthesis, yet the synthesis of these motifs within traditional cross-coupling paradigms remains a significant challenge due to competing β-hydride elimination pathways. In contrast, the bimolecular homolytic substitution (S2) mechanism offers a unique and attractive alternative pathway. Metal porphyrin complexes have emerged as privileged catalysts owing to their ability to selectively form primary metal-alkyl complexes, thereby eliminating the challenges associated with tertiary alkyl complexation with a metal center. Herein, we report an iron-catalyzed cross-electrophile coupling of tertiary bromides and primary alkyl electrophiles for the formation of all-carbon quaternary centers through a biomimetic S2 mechanism.

References

Quasdorf K, Overman L . Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature. 2014; 516(7530):181-91. PMC: 4697831. DOI: 10.1038/nature14007. View

Dongbang S, Doyle A . Ni/Photoredox-Catalyzed C(sp)-C(sp) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors. J Am Chem Soc. 2022; 144(43):20067-20077. PMC: 10281197. DOI: 10.1021/jacs.2c09294. View

Zhang Q, van der Donk W, Liu W . Radical-mediated enzymatic methylation: a tale of two SAMS. Acc Chem Res. 2011; 45(4):555-64. PMC: 3328197. DOI: 10.1021/ar200202c. View

Knappke C, Grupe S, Gartner D, Corpet M, Gosmini C, von Wangelin A . Reductive cross-coupling reactions between two electrophiles. Chemistry. 2014; 20(23):6828-42. DOI: 10.1002/chem.201402302. View

Hamby T, LaLama M, Sevov C . Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3-Csp2 coupling. Science. 2022; 376(6591):410-416. PMC: 9260526. DOI: 10.1126/science.abo0039. View

Peterson E, Overman L . Contiguous stereogenic quaternary carbons: a daunting challenge in natural products synthesis. Proc Natl Acad Sci U S A. 2004; 101(33):11943-8. PMC: 514413. DOI: 10.1073/pnas.0402416101. View

Everson D, Weix D . Cross-electrophile coupling: principles of reactivity and selectivity. J Org Chem. 2014; 79(11):4793-8. PMC: 4049235. DOI: 10.1021/jo500507s. View

Talele T . Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon. J Med Chem. 2020; 63(22):13291-13315. DOI: 10.1021/acs.jmedchem.0c00829. View

Gan X, Kotesova S, Castanedo A, Green S, Borcher Moller S, Shenvi R . Iron-Catalyzed Hydrobenzylation: Stereoselective Synthesis of (-)-Eugenial C. J Am Chem Soc. 2023; 145(29):15714-15720. PMC: 11055631. DOI: 10.1021/jacs.3c05428. View

10.

Zhang P, Le C, MacMillan D . Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling. J Am Chem Soc. 2016; 138(26):8084-7. PMC: 5103281. DOI: 10.1021/jacs.6b04818. View

11.

Dong Z, MacMillan D . Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature. 2021; 598(7881):451-456. PMC: 8643278. DOI: 10.1038/s41586-021-03920-6. View

12.

Liu J, Ye Y, Sessler J, Gong H . Cross-Electrophile Couplings of Activated and Sterically Hindered Halides and Alcohol Derivatives. Acc Chem Res. 2020; 53(9):1833-1845. DOI: 10.1021/acs.accounts.0c00291. View

13.

Sakai H, MacMillan D . Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C()-C() Cross-Coupling via Radical Sorting. J Am Chem Soc. 2022; 144(14):6185-6192. PMC: 9676086. DOI: 10.1021/jacs.2c02062. View

14.

Ibrahim M, Cumming G, Gonzalez de Vega R, Garcia-Losada P, de Frutos O, Kappe C . Electrochemical Nickel-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Halides with Alkyl Tosylates. J Am Chem Soc. 2023; 145(31):17023-17028. PMC: 10416217. DOI: 10.1021/jacs.3c07313. View

15.

Chen R, Intermaggio N, Xie J, Rossi-Ashton J, Gould C, Martin R . Alcohol-alcohol cross-coupling enabled by S2 radical sorting. Science. 2024; 383(6689):1350-1357. PMC: 11551712. DOI: 10.1126/science.adl5890. View

16.

Kim D, Ahn D, Oh Y, Lee S, Kil H, Oh S . A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules. J Am Chem Soc. 2006; 128(50):16394-7. DOI: 10.1021/ja0646895. View

17.

Tsymbal A, Bizzini L, MacMillan D . Nickel Catalysis via S2 Homolytic Substitution: The Double Decarboxylative Cross-Coupling of Aliphatic Acids. J Am Chem Soc. 2022; 144(46):21278-21286. PMC: 10680145. DOI: 10.1021/jacs.2c08989. View

18.

Smith R, Zhang X, Rincon J, Agejas J, Mateos C, Barberis M . Metallaphotoredox-Catalyzed Cross-Electrophile C-C Coupling of Aliphatic Bromides. J Am Chem Soc. 2018; 140(50):17433-17438. PMC: 6697083. DOI: 10.1021/jacs.8b12025. View

19.

Degoey D, Randolph J, Liu D, Pratt J, Hutchins C, Donner P . Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem. 2014; 57(5):2047-57. DOI: 10.1021/jm401398x. View

20.

Gould C, Pace A, MacMillan D . Rapid and Modular Access to Quaternary Carbons from Tertiary Alcohols via Bimolecular Homolytic Substitution. J Am Chem Soc. 2023; 145(30):16330-16336. PMC: 10680126. DOI: 10.1021/jacs.3c05405. View