Accelerating Reaction Generality and Mechanistic Insight Through Additive Mapping

Overview

Journal Science

Specialty Science

Date 2022 Apr 28

PMID 35482871

Authors

Cesar N Prieto Kullmer

Jacob A Kautzky

Shane W Krska

Timothy Nowak

Spencer D Dreher

David W C MacMillan

Affiliations

Soon will be listed here.

Abstract

Reaction generality is crucial in determining the overall impact and usefulness of synthetic methods. Typical generalization protocols require a priori mechanistic understanding and suffer when applied to complex, less understood systems. We developed an additive mapping approach that rapidly expands the utility of synthetic methods while generating concurrent mechanistic insight. Validation of this approach on the metallaphotoredox decarboxylative arylation resulted in the discovery of a phthalimide ligand additive that overcomes many lingering limitations of this reaction and has important mechanistic implications for nickel-catalyzed cross-couplings.

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References

Sun R, Qin Y, Ruccolo S, Schnedermann C, Costentin C, Nocera D . Elucidation of a Redox-Mediated Reaction Cycle for Nickel-Catalyzed Cross Coupling. J Am Chem Soc. 2018; 141(1):89-93. DOI: 10.1021/jacs.8b11262. View

Han C, Buchwald S . Negishi coupling of secondary alkylzinc halides with aryl bromides and chlorides. J Am Chem Soc. 2009; 131(22):7532-3. PMC: 2746668. DOI: 10.1021/ja902046m. View

Trnka T, Grubbs R . The development of L2X2Ru=CHR olefin metathesis catalysts: an organometallic success story. Acc Chem Res. 2001; 34(1):18-29. DOI: 10.1021/ar000114f. View

Pasquer Q, Tsakoumagkos I, Hoogendoorn S . From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems. Molecules. 2020; 25(23). PMC: 7730769. DOI: 10.3390/molecules25235702. View

Hioe J, Zipse H . Radical stability and its role in synthesis and catalysis. Org Biomol Chem. 2010; 8(16):3609-17. DOI: 10.1039/c004166a. View

Lee J, Uhlik M, Moxham C, Tomandl D, Sall D . Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J Med Chem. 2012; 55(10):4527-38. DOI: 10.1021/jm201649s. View

Szabo M, Akusjarvi S, Saxena A, Liu J, Chandrasekar G, Kitambi S . Cell and small animal models for phenotypic drug discovery. Drug Des Devel Ther. 2017; 11:1957-1967. PMC: 5500539. DOI: 10.2147/DDDT.S129447. View

Zheng W, Thorne N, McKew J . Phenotypic screens as a renewed approach for drug discovery. Drug Discov Today. 2013; 18(21-22):1067-73. PMC: 4531371. DOI: 10.1016/j.drudis.2013.07.001. View

Liao K, Negretti S, Musaev D, Bacsa J, Davies H . Site-selective and stereoselective functionalization of unactivated C-H bonds. Nature. 2016; 533(7602):230-4. DOI: 10.1038/nature17651. View

10.

Dykstra K, Streckfuss E, Liu M, Liu J, Yu Y, Wang M . Synthesis of HDAC Inhibitor Libraries via Microscale Workflow. ACS Med Chem Lett. 2021; 12(3):337-342. PMC: 7957937. DOI: 10.1021/acsmedchemlett.0c00596. View

11.

Choi T, Grubbs R . Controlled living ring-opening-metathesis polymerization by a fast-initiating ruthenium catalyst. Angew Chem Int Ed Engl. 2003; 42(15):1743-6. DOI: 10.1002/anie.200250632. View

12.

Till N, Oh S, MacMillan D, Bird M . The Application of Pulse Radiolysis to the Study of Ni(I) Intermediates in Ni-Catalyzed Cross-Coupling Reactions. J Am Chem Soc. 2021; 143(25):9332-9337. DOI: 10.1021/jacs.1c04652. View

13.

Johansson Seechurn C, Kitching M, Colacot T, Snieckus V . Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize. Angew Chem Int Ed Engl. 2012; 51(21):5062-85. DOI: 10.1002/anie.201107017. View

14.

Ruiz-Castillo P, Buchwald S . Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem Rev. 2016; 116(19):12564-12649. PMC: 5070552. DOI: 10.1021/acs.chemrev.6b00512. View

15.

Zuo Z, Ahneman D, Chu L, Terrett J, Doyle A, MacMillan D . Dual catalysis. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp³-carbons with aryl halides. Science. 2014; 345(6195):437-40. PMC: 4296524. DOI: 10.1126/science.1255525. View

16.

Dejonghe W, Russinova E . Plant Chemical Genetics: From Phenotype-Based Screens to Synthetic Biology. Plant Physiol. 2017; 174(1):5-20. PMC: 5411137. DOI: 10.1104/pp.16.01805. View

17.

Dombrowski A, Gesmundo N, Aguirre A, Sarris K, Young J, Bogdan A . Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp)-C(sp) Cross-Coupling Methods by Library Synthesis. ACS Med Chem Lett. 2020; 11(4):597-604. PMC: 7153271. DOI: 10.1021/acsmedchemlett.0c00093. View

18.

Park Y, Kim Y, Chang S . Transition Metal-Catalyzed C-H Amination: Scope, Mechanism, and Applications. Chem Rev. 2017; 117(13):9247-9301. DOI: 10.1021/acs.chemrev.6b00644. View

19.

Dreher S, Krska S . Chemistry Informer Libraries: Conception, Early Experience, and Role in the Future of Cheminformatics. Acc Chem Res. 2021; 54(7):1586-1596. DOI: 10.1021/acs.accounts.0c00760. View

20.

Vantourout J, Miras H, Isidro-Llobet A, Sproules S, Watson A . Spectroscopic Studies of the Chan-Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity. J Am Chem Soc. 2017; 139(13):4769-4779. DOI: 10.1021/jacs.6b12800. View