In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration

Mueller CA, Akkapurathu B, Winkler T, Staudt S, Hummel W, Gröger H, Schwaneberg U (2013)
Advanced Synthesis & Catalysis 355(9): 1787-1798.

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Abstract
A novel concept for the direct oxidation of cycloalkanes to the corresponding cyclic ketones in a one-pot synthesis in water with molecular oxygen as sole oxidizing agent was reported recently. Based on this concept we have developed a new strategy for the double oxidation of n-heptane to enable a biocatalytic resolution for the direct synthesis of heptanone and (R)-heptanols in a one-pot reaction. The bicatalytic cascade employs an NADH driven P450 BM3 monooxygenase variant (WTNADH, 19A12NADH or CM1NADH) and an (S)-enantioselective alcohol dehydrogenase (RE-ADH). In the initial step n-heptane is hydroxylated under consumption of NADH to produce (R/S)-heptanol. In the second oxidation step the (S)-heptanol enantiomers are transformed to the corresponding ketones, reducing and thereby regenerating the cofactor. Characterization of initial hydroxylation step revealed high turnover frequencies (TOF) of up to 600min-1, as well as high coupling efficiencies using NADH as cofactor (up to 44%). In the cascade reaction a nearly 2-fold improved product formation was achieved, compared to the single hydroxylation reaction. The total product concentration reached 1.1mM, corresponding to a total turnover number (TTN) of 2500. Implementation of an additional cofactor regeneration system (D-glucose/glucose dehydrogenase) enabled a further enhancement in product formation with a total product concentration of 1.8mM and a TTN of 3500.
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Mueller CA, Akkapurathu B, Winkler T, et al. In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration. Advanced Synthesis & Catalysis. 2013;355(9):1787-1798.
Mueller, C. A., Akkapurathu, B., Winkler, T., Staudt, S., Hummel, W., Gröger, H., & Schwaneberg, U. (2013). In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration. Advanced Synthesis & Catalysis, 355(9), 1787-1798.
Mueller, C. A., Akkapurathu, B., Winkler, T., Staudt, S., Hummel, W., Gröger, H., and Schwaneberg, U. (2013). In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration. Advanced Synthesis & Catalysis 355, 1787-1798.
Mueller, C.A., et al., 2013. In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration. Advanced Synthesis & Catalysis, 355(9), p 1787-1798.
C.A. Mueller, et al., “In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration”, Advanced Synthesis & Catalysis, vol. 355, 2013, pp. 1787-1798.
Mueller, C.A., Akkapurathu, B., Winkler, T., Staudt, S., Hummel, W., Gröger, H., Schwaneberg, U.: In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration. Advanced Synthesis & Catalysis. 355, 1787-1798 (2013).
Mueller, Christina A., Akkapurathu, Beneeta, Winkler, Till, Staudt, Svenja, Hummel, Werner, Gröger, Harald, and Schwaneberg, Ulrich. “In Vitro Double Oxidation of n-Heptane with Direct Cofactor Regeneration”. Advanced Synthesis & Catalysis 355.9 (2013): 1787-1798.
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