Beyond Ferryl-mediated Hydroxylation: 40 years of the Rebound Mechanism and C-H Activation

Overview

Journal J Biol Inorg Chem

Publisher Springer

Specialty Biochemistry

Date 2016 Dec 3

PMID 27909920

Citations 88

Authors

Xiongyi Huang

John T Groves

Affiliations

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Abstract

Since our initial report in 1976, the oxygen rebound mechanism has become the consensus mechanistic feature for an expanding variety of enzymatic C-H functionalization reactions and small molecule biomimetic catalysts. For both the biotransformations and models, an initial hydrogen atom abstraction from the substrate (R-H) by high-valent iron-oxo species (Fe=O) generates a substrate radical and a reduced iron hydroxide, [Fe-OH ·R]. This caged radical pair then evolves on a complicated energy landscape through a number of reaction pathways, such as oxygen rebound to form R-OH, rebound to a non-oxygen atom affording R-X, electron transfer of the incipient radical to yield a carbocation, R, desaturation to form olefins, and radical cage escape. These various flavors of the rebound process, often in competition with each other, give rise to the wide range of C-H functionalization reactions performed by iron-containing oxygenases. In this review, we first recount the history of radical rebound mechanisms, their general features, and key intermediates involved. We will discuss in detail the factors that affect the behavior of the initial caged radical pair and the lifetimes of the incipient substrate radicals. Several representative examples of enzymatic C-H transformations are selected to illustrate how the behaviors of the radical pair [Fe-OH ·R] determine the eventual reaction outcome. Finally, we discuss the powerful potential of "radical rebound" processes as a general paradigm for developing novel C-H functionalization reactions with synthetic, biomimetic catalysts. We envision that new chemistry will continue to arise by bridging enzymatic "radical rebound" with synthetic organic chemistry.

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References

Jin Y, Lipscomb J . Probing the mechanism of C-H activation: oxidation of methylcubane by soluble methane monooxygenase from Methylosinus trichosporium OB3b. Biochemistry. 1999; 38(19):6178-86. DOI: 10.1021/bi990068v. View

Filatov , Harris , Shaik . On the "Rebound" Mechanism of Alkane Hydroxylation by Cytochrome P450: Electronic Structure of the Intermediate and the Electron Transfer Character in the Rebound Step. Angew Chem Int Ed Engl. 1999; 38(23):3510-3512. DOI: 10.1002/(sici)1521-3773(19991203)38:23<3510::aid-anie3510>3.0.co;2-#. View

Jin Y, Lipscomb J . Mechanistic insights into C-H activation from radical clock chemistry: oxidation of substituted methylcyclopropanes catalyzed by soluble methane monooxygenase from Methylosinus trichosporium OB3b. Biochim Biophys Acta. 2000; 1543(1):47-59. DOI: 10.1016/s0167-4838(00)00199-0. View

van Rantwijk F, Sheldon R . Selective oxygen transfer catalysed by heme peroxidases: synthetic and mechanistic aspects. Curr Opin Biotechnol. 2000; 11(6):554-64. DOI: 10.1016/s0958-1669(00)00143-9. View

Egawa T, Proshlyakov D, Miki H, Makino R, Ogura T, Kitagawa T . Effects of a thiolate axial ligand on the pi-->pi* electronic states of oxoferryl porphyrins: a study of the optical and resonance Raman spectra of compounds I and II of chloroperoxidase. J Biol Inorg Chem. 2001; 6(1):46-54. DOI: 10.1007/s007750000181. View

Davydov R, Makris T, Kofman V, Werst D, Sligar S, Hoffman B . Hydroxylation of camphor by reduced oxy-cytochrome P450cam: mechanistic implications of EPR and ENDOR studies of catalytic intermediates in native and mutant enzymes. J Am Chem Soc. 2001; 123(7):1403-15. DOI: 10.1021/ja003583l. View

Ogliaro F, de Visser S, Groves J, Shaik S . Chameleon States: High-Valent Metal-Oxo Species of Cytochrome P450 and Its Ruthenium Analogue The research in HU was sponsored by the Binational German Israeli Foundation (GIF) and by the Israeli Ministry of Science, Culture and Sport. Partial.... Angew Chem Int Ed Engl. 2001; 40(15):2874-2878. View

Brazeau B, Austin R, Tarr C, Groves J, Lipscomb J . Intermediate Q from soluble methane monooxygenase hydroxylates the mechanistic substrate probe norcarane: evidence for a stepwise reaction. J Am Chem Soc. 2001; 123(48):11831-7. DOI: 10.1021/ja016376+. View

Solomon E, Sundaram U, Machonkin T . Multicopper Oxidases and Oxygenases. Chem Rev. 1996; 96(7):2563-2606. DOI: 10.1021/cr950046o. View

10.

Wallar B, Lipscomb J . Dioxygen Activation by Enzymes Containing Binuclear Non-Heme Iron Clusters. Chem Rev. 1996; 96(7):2625-2658. DOI: 10.1021/cr9500489. View

11.

Stubbe J, van der Donk W . Protein Radicals in Enzyme Catalysis. Chem Rev. 2002; 98(2):705-762. DOI: 10.1021/cr9400875. View

12.

Elkins J, Ryle M, Clifton I, Dunning Hotopp J, Lloyd J, Burzlaff N . X-ray crystal structure of Escherichia coli taurine/alpha-ketoglutarate dioxygenase complexed to ferrous iron and substrates. Biochemistry. 2002; 41(16):5185-92. DOI: 10.1021/bi016014e. View

13.

Auclair K, Hu Z, Little D, de Montellano P, Groves J . Revisiting the mechanism of P450 enzymes with the radical clocks norcarane and spiro[2,5]octane. J Am Chem Soc. 2002; 124(21):6020-7. DOI: 10.1021/ja025608h. View

14.

Labinger J, Bercaw J . Understanding and exploiting C-H bond activation. Nature. 2002; 417(6888):507-14. DOI: 10.1038/417507a. View

15.

Glieder A, Farinas E, Arnold F . Laboratory evolution of a soluble, self-sufficient, highly active alkane hydroxylase. Nat Biotechnol. 2002; 20(11):1135-9. DOI: 10.1038/nbt744. View

16.

Shaik S, de Visser S, Ogliaro F, Schwarz H, Schroder D . Two-state reactivity mechanisms of hydroxylation and epoxidation by cytochrome P-450 revealed by theory. Curr Opin Chem Biol. 2002; 6(5):556-67. DOI: 10.1016/s1367-5931(02)00363-0. View

17.

Hoffman B . Electron-nuclear double resonance spectroscopy (and electron spin-echo envelope modulation spectroscopy) in bioinorganic chemistry. Proc Natl Acad Sci U S A. 2003; 100(7):3575-8. PMC: 152963. DOI: 10.1073/pnas.0636464100. View

18.

Groves J . The bioinorganic chemistry of iron in oxygenases and supramolecular assemblies. Proc Natl Acad Sci U S A. 2003; 100(7):3569-74. PMC: 152962. DOI: 10.1073/pnas.0830019100. View

19.

OBrien J, Schuller D, Yang V, Dillard B, Lanzilotta W . Substrate-induced conformational changes in Escherichia coli taurine/alpha-ketoglutarate dioxygenase and insight into the oligomeric structure. Biochemistry. 2003; 42(19):5547-54. DOI: 10.1021/bi0341096. View

20.

Newcomb M, Aebisher D, Shen R, Chandrasena R, Hollenberg P, Coon M . Kinetic isotope effects implicate two electrophilic oxidants in cytochrome p450-catalyzed hydroxylations. J Am Chem Soc. 2003; 125(20):6064-5. DOI: 10.1021/ja0343858. View