We report the development of a modular, one-pot, sequential chemoenzymatic system for the formal enantioselective construction of the C-C bond in 2-aryl 1,4-dicarbonyl compounds. This sequence comprises a rhodium-catalyzed diazocoupling that provides &gt;9:1 selectivity for heterocoupling of two diazoesters and a reduction mediated by an ene-reductase (ER), which occurs in up to 99% enantiomeric excess (ee). The high yield and enantioselectivity of this system result from the preferential generation of an (E)-alkene from the diazo coupling reaction and selective reduction of the (E)-alkene in a mixture of (E) and (Z) isomers by the ER. Screening of a panel of ERs revealed that OPR1 from Lycopersicum esculentum catalyzes the reduction of bulky tert-butyl or benzyl esters to afford chiral diesters that are poised for orthogonal reactions at the two distinct ester units of the product. Overall, this work demonstrates the benefit of combining organometallic and enzymatic catalysis to create unusual overall transformations that do not require the isolation and purification of intermediates.

Combining Rh-catalyzed diazocoupling and enzymatic reduction to efficiently synthesize enantioenriched 2-substituted succinate derivatives

254th National Meeting (2017)

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