Combining Rh-Catalyzed Diazocoupling and Enzymatic Reduction To Efficiently Synthesize Enantioenriched 2-Substituted Succinate Derivatives

Abstract

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 >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.

Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions

“…Steric and electronic perturbation of the aryl diazoacetate coupling partner (R1 and R2) were well tolerated, and both ethyl diazoesters and amides could be used (R3). With the exception of the previously unreported amide substrate, these substrates are in line with the known scope for dirhodium catalyzed diazo coupling, 23,25 indicating that the ArM enables the desired dirhodium activity while significantly reducing undesired side reactions such as water O-H insertion.…”

“…Finally, THF and dioxane were found to be suitable co-solvents for the diazo coupling reaction. In all cases, the observed selectivity is substantially lower than that typically observed for the analogous reaction in organic solvent under cryogenic conditions (>10/1) 23 , so improving this was a key goal of directed evolution. A significant amount (39%) of the donor-acceptor diazo substrate reacted with water, forming OH insertion product 6, so minimizing this side reaction would also be required as in our previous evolution efforts 18,19 .…”

“…The reactivities and selectivities of several previously-evolved dirhodium ArMs were first evaluated using a model diazo coupling reaction (Entries 1-3, Table 1). Because the ene reductases investigated are specific for the E-alkenes, 23 it was important to establish whether ArMs could provide the desired isomer in good yield under conditions suitable for biocatalysis. ArM variant 0-ZA4 catalyzed diazo coupling with 46% yield and a 2.9:1 E/Z ratio (4/5), while variant 3-VRVH, the most evolved variant from our cyclopropanation lineage, 19 provided a 53% yield and 3.5:1 E/Z ratio.…”

“…For example, dirhodium-catalyzed diazo cross-coupling has been used to generate fumaric acid esters that are converted by alkene reductases to 2-substituted succinate derivatives (Scheme 1B). 23 In this study, however, dirhodium catalysis was conducted in organic solvent at cryogenic temperatures, and following this step, the solvent was evaporated and the residue dissolved in aqueous buffer to enable biocatalytic reduction. Herein, we evolve a dirhodium ArM that catalyzes diazo coupling with high chemo-and stereoselectivity and demonstrate that the resulting ArM can be interfaced with an alkene reductase in a one-pot cascade reaction to produce substituted succinate derivatives with high enantioselectivity (Scheme 1C).…”

Chemoenzymatic conversion of amides to enantioenriched alcohols in aqueous medium

“…A subsequent study from the same laboratories reported a related system for the cooperative synthesis of styrenyl epoxides 29 . More recently, these groups have disclosed a chemoenzymatic synthesis of 2-aryl-succinate derivatives using a Rh-catalyzed diazocoupling-enereductase sequential reaction manifold 30 .…”