期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 46, 页码 18551-18559出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b09385
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资金
- University of Michigan Life Sciences Institute
- University of Michigan Department of Chemistry
- National Institutes of Health [R35 GM124880, R01 DK042303]
- Margaret J. Hunter Professorship
- National Institutes of Health Chemistry Biology Interface Training Grant [T32 GM008597]
- Graduate Assistance of Areas in National Need Training Grant [GAANN P200A150164]
- Rackham Merit Fellowship
- National Institutes of Health Kirschstein-NRSA predoctoral fellowship F31 [GM134671]
Selective access to a targeted isomer is often critical in the synthesis of biologically active molecules. Whereas small-molecule reagents and catalysts often act with anticipated site- and stereoselectivity, this predictability does not extend to enzymes. Further, the lack of access to catalysts that provide complementary selectivity creates a challenge in the application of biocatalysis in synthesis. Here, we report an approach for accessing biocatalysts with complementary selectivity that is orthogonal to protein engineering. Through the use of a sequence similarity network (SSN), a number of sequences were selected, and the corresponding biocatalysts were evaluated for reactivity and selectivity. With a number of biocatalysts identified that operate with complementary site- and stereoselectivity, these catalysts were employed in the stereodivergent, chemoenzymatic synthesis of azaphilone natural products. Specifically, the first syntheses of trichoflectin, deflectin-1a, and lunatoic acid A were achieved. In addition, chemoenzymatic syntheses of these azaphilones supplied enantioenriched material for reassignment of the absolute configuration of trichoflectin and deflectin-1a based on optical rotation, CD spectra, and X-ray crystallography.
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