Biocatalytic site- and enantioselective oxidative dearomatization of phenols

Abstract

The biocatalytic transformations used by chemists are often restricted to simple functional-group interconversions. In contrast, nature has developed complexity-generating biocatalytic reactions within natural product pathways. These sophisticated catalysts are rarely employed by chemists, because the substrate scope, selectivity and robustness of these catalysts are unknown. Our strategy to bridge the gap between the biosynthesis and synthetic chemistry communities leverages the diversity of catalysts available within natural product pathways. Here we show that, starting from a suite of biosynthetic enzymes, catalysts with complementary substrate scope as well as selectivity can be identified. This strategy has been applied to the oxidative dearomatization of phenols, a chemical transformation that rapidly builds molecular complexity from simple starting materials and cannot be accomplished with high selectivity using existing catalytic methods. Using enzymes from biosynthetic pathways, we have successfully developed a method to produce ortho-quinol products with controlled site- and stereoselectivity. Furthermore, we have capitalized on the scalability and robustness of this method in gram-scale reactions as well as multi-enzyme and chemoenzymatic cascades.

Figure 1 ∣. Strategies for oxidative dearomatization of phenolic compounds and application in complex molecule synthesis.

a, Oxidative dearomatization of phenolic substrates to afford ortho-quinol products and small molecule reagents employed for this transformation. b, Natural products accessible from ortho-quinol intermediates. c, Potential products afforded by conditions for resorcinol oxidative dearomatization including potential product isomers, dimers, and undesired products, d, biocatalytic oxidative dearomatization leveraging the diversity of a suite of flavin-dependent monooxygenases from natural product biosynthetic pathways, protein structure shown is a homology model of TropB based on the structure of PDB ID 2DKH using the Phyre2 server.

Figure 2 ∣. Nature’s tools for oxidative dearomatization of resorcinol compounds.

a, Secondary metabolite pathways containing FAD-dependent monooxygenases that mediate the oxidative dearomatization of resorcinol substrates with orthogonal selectivities including the biosynthetic pathways to stipitatonic acid (16), azanigerone C (19) and sorbicillactone A (22). b, Generation of C4a-hydroperoxyflavin (12) from FAD (23) through NADPH reduction of FAD (23) to FADH₂ (24) and subsequent oxidation to 12.

Figure 3 ∣. One-pot cascades featuring biocatalytic oxidative dearomatization to access natural products.

a, Stipitatic aldehyde (48) synthesis from aldehyde 14 through a two-enzyme cascade. b, Synthesis of natural azaphilone 51 from methyl ketone 49, c, and the first synthesis of the natural product, urea sorbicillinoid 53 through a chemoenzymatic sequence initiated by the SorbC-catalyzed oxidative dearomatization of 20.