Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes

Abstract

Enzymatic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chemistry and in biology. Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts. To address this, we show that incorporation of a d(6)-piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis. To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades. Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L-pipecolic acid from L-lysine and (iv) regeneration of NADH to promote a monooxygenase-catalysed oxyfunctionalization reaction.

Tandem Reactions Combining Biocatalysts and Chemical Catalysts for Asymmetric Synthesis

“…By embedding a biotinylated d 6 -Ir pianostood complex within SAV, Ward and co-workers enabled Ir-based transfer hydrogenation in the presence of E. coli cell free extracts and cell lysates [87]. In addition, they applied a similar strategy to create an artificial transfer hydrogenase (ATHase) that was successfully coupled with various NADH-, FAD-and heme-dependent enzymes for orthogonal redox cascade reactions that could not have been generated when free Ir-complex was used [88]. Significantly, by coupling ATHase with monoamine oxidase (MAO-N), NADPH regeneration was achieved and L-pipecolic acid was prepared with 99% ee (Scheme 13).…”

One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

“…Accordingly, a one-pot/two-step methodology allowed the direct conversion of diallyl malonates into cyclic monoacid esters in aqueous media (Scheme 13C). Recently, and following this idea (Ru-catalyzed RCM + enzymatic organic transformations), Turner, Castagnolo and co-workers have reported the combination of the Ru-catalyzed ring-closing metathesis of diallyl anilines (to produce the corresponding 3-pyrrolines) and the subsequent biocatalytic aromatization of the resulting heterocycles (mediated by whole cells containing monoamine oxidases MAO-N variants D5, D9 and D11 [82][83][84] or the nicotine oxidase biocatalyst 6-HDNO (HDNO = 6-hydroxy-D-nicotine oxidase) [85]) for the synthesis of pyrroles in aqueous media (Scheme 14) [77]. In this case, and in contrast to the aforementioned results reported by Gröger, the authors firstly parametrized the biocatalytic transformation, thus studying the aromatization of different 3-pyrrolines promoted by monoamine oxidases MAO-N or 6-HDNO (Scheme 14A).…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…A formate salt was added for regeneration. [116] Thus, cyclic deracemization of secondary amines such as 1-methyltetrahydroisoquinoline or 2-cyclohexylpyrrolidine into the corresponding (R)-amines was investigated, achieving excellent conversions (99%) and ee (99%).…”