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Review
. 2019 Sep 23;58(39):13954-13960.
doi: 10.1002/anie.201907460. Epub 2019 Aug 21.

Site-Selective Functionalization of (sp3 )C-H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium-Porphyrin Cofactor

Yang Gu  1   2 , Sean N Natoli  1   2 , Zhennan Liu  1   2 , Douglas S Clark  3   4 , John F Hartwig  1   2
Affiliations
Review

Site-Selective Functionalization of (sp3 )C-H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium-Porphyrin Cofactor

Yang Gu et al. Angew Chem Int Ed Engl. .

Abstract

The selective functionalization of one C-H bond over others in nearly identical steric and electronic environments can facilitate the construction of complex molecules. We report site-selective functionalizations of C-H bonds, differentiated solely by remote substituents, catalyzed by artificial metalloenzymes (ArMs) that are generated from the combination of an evolvable P450 scaffold and an iridium-porphyrin cofactor. The generated systems catalyze the insertion of carbenes into the C-H bonds of a range of phthalan derivatives containing substituents that render the two methylene positions in each phthalan inequivalent. These reactions occur with site-selectivity ratios of up to 17.8:1 and, in most cases, with pairs of enzyme mutants that preferentially form each of the two constitutional isomers. This study demonstrates the potential of abiotic reactions catalyzed by metalloenzymes to functionalize C-H bonds with site selectivity that is difficult to achieve with small-molecule catalysts.

Keywords: C−H functionalization; P450 enzymes; artificial metalloenzymes; biocatalysis; porphyrins.

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Figures

Figure 1.
Figure 1.
Structure of WT Fe-CYP119 (image prepared in Chimera from PDB 1IO7).[16] Red label: mutant positions that were generated by site-directed mutagenesis (A152, T213, V254, C317); Orange label: additional positions generated by error-prone PCR for para selectivity (D177 and H340) and meta selectivity (A247).
Figure 2.
Figure 2.
Activity studies of different mutants with slow addition of EDA with 1a. TONs refers to the formation of both meta and para C–H bond insertion products with dodecane as the internal stander.
Scheme 1.
Scheme 1.
Intermolecular insertion of acceptor-only carbenes into (sp3)C–H bonds with small-molecule catalysts and biocatalysts.
Scheme 2.
Scheme 2.
Site-selective intermolecular C–H insertion catalyzed by Ir(Me)-MPIX. Yields refers to the formation of all the carbene insertion products and were determined by GC with dodecane as the internal stander.
Scheme 3.
Scheme 3.
Scope of substrates that CYP119 mutants reverse site-selectivity[a] [a] TONs refers to the formation of both meta and para benzylic C–H bond insertion products and was determined by GC with dodecane as the internal stander. [b] 0.02 mol% Ir(Me)-MPIX CYP119 was used. [c] 0.1 mol% Ir(Me)-MPIX CYP119 was used.
Scheme 4.
Scheme 4.
Scope of substrates for which mutant enzymes are selective for reaction at the para C–H Bond. TONs refers to the formation of both meta and para C–H bond insertion products and were determined by GC with dodecane as the internal stander.
Scheme 5.
Scheme 5.
Enantioselective Intermolecular C–H Insertion Catalyzed by Ir(Me)-CYP119. TONs refer to the formation of both meta and para C–H bond insertion products with dodecane as the internal stander. The er values were determined by HPLC with a chiral column.
Scheme 6.
Scheme 6.
Scale up the reactions Catalyzed by mutant PG2.
See this image and copyright information in PMC

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References

    1. Yamaguchi J, Yamaguchi AD, Itami K, Angew. Chem. Int. Ed 2012, 51, 8960–9009 - PubMed
    2. Brückl T, Baxter RD, Ishihara Y, Baran PS, Acc. Chem. Res 2012, 45, 826–839 - PMC - PubMed
    3. Hartwig JF, J. Am. Chem. Soc 2016, 138, 2–24 - PMC - PubMed
    4. Das S, Incarvito CD, Crabtree RH, Brudvig GW, Science 2006, 312, 1941. - PubMed
    1. Engle KM, Mei T-S, Wasa M, Yu J-Q, Acc. Chem. Res 2012, 45, 788–802 - PMC - PubMed
    2. Liao K, Pickel TC, Boyarskikh V, Bacsa J, Musaev DG, Davies HML, Nature 2017, 551, 609–613 - PubMed
    3. Anding BJ, Dairo TO, Woo LK, Organometallics 2017, 36, 1842–1847
    4. Che C-M, Lo VK-Y, Zhou C-Y, Huang J-S, Chem. Soc. Rev 2011, 40, 1950–1975 - PubMed
    5. Metrano AJ, Miller SJ, Acc. Chem. Res 2019, 52, 199–215 - PMC - PubMed
    6. Liao K, Negretti S, Musaev DG, Bacsa J, Davies HML, Nature 2016, 533, 230. - PubMed
    7. Liao K, Liu W, Niemeyer ZL, Ren Z, Bacsa J, Musaev DG, Sigman MS, Davies HML, ACS Catal 2018, 8, 678–682.
    1. Narayan ARH, Jiménez-Osés G, Liu P, Negretti S, Zhao W, Gilbert MM, Ramabhadran RO, Yang Y-F, Furan LR, Li Z, Podust LM, Montgomery J, Houk KN, Sherman DH, Nat. Chem 2015, 7, 653–660 - PMC - PubMed
    2. Negretti S, Narayan ARH, Chiou KC, Kells PM, Stachowski JL, Hansen DA, Podust LM, Montgomery J, Sherman DH, J. Am. Chem. Soc 2014, 136, 4901–4904. - PMC - PubMed
    1. Isin EM, Guengerich FP, Biochim. Biophys. Acta 2007, 1770, 314–329. - PubMed
    1. Arnold FH, Angew. Chem. Int. Ed 2018, 57, 4143–4148 - PMC - PubMed
    2. Packer MS, Liu DR, Nat. Rev. Genet 2015, 16, 379. - PubMed
    3. Sun Z, Wikmark Y, Bäckvall J-E, Reetz MT, Chem. Eur. J 2016, 22, 5046–5054. - PubMed

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