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Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy
Published on: November 9, 2019
Creating molecular complexity in the chemoenzymatic synthesis of chlorothricin analogues using tandem Diels-Alderases
Andrew J Devine1, Monserrat Manzo-Ruiz2,3, Catherine R Back3
1School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK. chris.willis@bristol.ac.uk.
Abstract:
Chlorothricin is a polyketide-derived natural product isolated from Streptomyces antibioticus. It possesses an elaborate pentacyclic aglycone core which incorporates a spirotetronic acid moiety, linked to a trans-decalin system, embedded within a macrocycle. Using synthetic substrate analogues and purified recombinant proteins, here we demonstrate that assembly of this scaffold proceeds via sequential biocatalytic Diels-Alder reactions, promoted by the enzymes ChlE3 and ChlL. Both Diels-Alderases exhibit sufficiently relaxed substrate selectivity to facilitate access to non-natural chlorothricin analogues via biotransformations. The X-ray crystal structure of ChlE3 reveals the molecular basis of decalin formation by this enzyme. Harnessing this enzymatic cascade in biocatalysis could provide a valuable biomimetic route to both natural and non-natural spirotetronates, and the work described herein lays the foundation for application of these enzymes in chemoenzymatic syntheses of complex products.
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