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Stereodivergent, Chemoenzymatic Synthesis of Azaphilone Natural Products.

Joshua B PyserSummer A Baker DockreyAttabey Rodríguez BenítezLeo A JoyceRen A WisconsJanet L SmithAlison R H Narayan
Published in: Journal of the American Chemical Society (2019)
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.
Keyphrases
  • small molecule
  • highly efficient
  • high resolution
  • protein protein
  • magnetic resonance
  • amino acid
  • drug delivery
  • structural basis
  • metal organic framework
  • high speed