Journal article
Enantioselective oxidation of unactivated C–H bonds in cyclic amines by iterative docking-guided mutagenesis of P450BM3 (CYP102A1)
- Abstract:
- Selective oxidation of ring C–H bonds is an attractive route to functionalized cyclic amines, which are versatile intermediates in drug synthesis and important fragment molecules in drug discovery. Here we report a combined substrate and enzyme engineering approach to achieve enantioselective functionalization of all unactivated C–H bonds of azepane, azocane, 7-azabicyclo[2.2.1]heptane and 8-azaspiro[4.5]decane by cytochrome P450BM3 (CYP102A1). Different N-modifying groups provide product diversity at high enantioselectivity (up to 99% e.e.) from a panel of just 48 variants of P450BM3. Substrate docking into molecular-dynamics-simulated structures of enzyme variants is shown to be useful for designing mutations to increase enantioselectivity by disfavouring binding poses leading to the unwanted enantiomer, and to increase enzymatic activity by disfavouring non-productive poses from ten or so variants per generation. The synthetic application of remote C–H activation within cyclic amines is exemplified by the synthesis of anisodamine via enantioselective hydroxylation of N-Boc-nortropinone.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, pdf, 10.8MB, Terms of use)
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- Publisher copy:
- 10.1038/s44160-022-00166-6
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Synthesis More from this journal
- Volume:
- 1
- Pages:
- 936–945
- Publication date:
- 2022-09-29
- Acceptance date:
- 2022-08-18
- DOI:
- EISSN:
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2731-0582
- Language:
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English
- Keywords:
- Pubs id:
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1280385
- Local pid:
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pubs:1280385
- Deposit date:
-
2022-11-29
Terms of use
- Copyright holder:
- Zhang et al.
- Copyright date:
- 2022
- Rights statement:
- ©2022 The Author(s), under exclusive licence to Springer Nature Limited
- Notes:
-
For the purpose of open access, the authors have applied a creative commons attribution (CC BY)
licence to any author accepted manuscript version arising. This is the accepted manuscript version of the article. The final version is available online from Springer Nature at: https://doi.org/10.1038/s44160-022-00166-6
- Licence:
- CC Attribution (CC BY)
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