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bioRxiv · 10.1101/2022.06.08.495276

A Modular Chemoenzymatic Approach to C14-Functionalized Steroids

Song, F.·Zheng, M.·Wang, J.·Liu, H.·Lin, Z.·Liu, B.·Deng, Z.·Zhou, Q.·Qu, X.
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Abstract

C14-functionalized steroids belong to a unique class of steroids with important biological activities. However, the lack of efficient methods to access C14-functionalized steroids impede related steroidal drug discovery. Herein we report a modular chemoenzymatic approach to access diversified C14-functionalized steroids. We first identified a novel C14-hydroxylase (CYP14A) from Cochliobolus lunatus with high catalytic efficiency and substrate promiscuity. Protein engineering of CYP14A generated three variants I111A, M115K and V124A that greatly improved the C14-hydroxy regioselectivity. Based on this efficient biocatalytic method, a range of C14-OH steroids with C17 side chain were prepared in good yields, which was then transformed into {Delta}14 olefins through a facile elimination. The newly formed {Delta}14 olefin served as a versatile handle to install diversified functional groups (e.g. epoxide, {beta}-OH, F, Cl and N3) at C14 position through hydrofunctionalization. Furthermore, the synthetic utility of this powerful chemoenzymatic methodology was demonstrated by performing a 7-step semisynthesis of periplogenin and the diversity-oriented synthesis of cardenolide (+)-digitoxigenin and its three diastereomers in a concise manner.

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Song, F., Zheng, M., Wang, J., Liu, H., Lin, Z., Liu, B., Deng, Z., Zhou, Q., Qu, X.. 2022-06-08. A Modular Chemoenzymatic Approach to C14-Functionalized Steroids. https://doi.org/10.1101/2022.06.08.495276

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