Enantioconvergent Biocatalytic Redox Isomerization

Abstract

Alcohol dehydrogenases can act as powerful catalysts in the preparation of optically pure γ-hydroxy-δ-lactones by means of an enantioconvergent dynamic redox isomerization of readily available Achmatowicz-type pyranones. Imitating the traditionally metal-mediated "borrowing hydrogen" approach to shuffle hydrides across molecular architectures and interconvert functional groups, this chemoinspired and purely biocatalytic interpretation effectively expands the enzymatic toolbox and provides new opportunities in the assembly of multienzyme cascades and tailor-made cellular factories.

Enzymatic self-sufficient hydride transfer processes

“…Such minimized construction has only been reported for the redox isomerization of particular pyranone compounds, during which two functional groups are exchanged within the same molecule in a redox-neutral fashion, rendering an ideal case of intramolecular hydride transfer. 110 Comparing the various strategies reviewed herein (Table 2), it is however striking that the enzymatic sequence which contains three biocatalysts and a pair of cofactors displays relatively high efficiency in terms of cofactor turnovers (78 each). The reaction was not studied at substrate concentrations higher than 20 mM and as highlighted in the introduction, the higher the number of enzymes, the narrower the operational window that can accommodate all enzymes (e.g., optimum pH and temperature, substrate tolerance).…”

“…In a recent study, a closely related concept was applied to a redox isomerization protocol applied to Achmatowicz pyranones, which present two functional groups accepted by ADHs. 110 The reaction scheme relied on a single ADH to catalyze the overall stereoselective oxidation-reduction sequence to yield corresponding g-hydroxylated d-lactones † in high enantiopurity via formation of intermediate g-oxo-lactones (Scheme 26). The overall reaction is not reversible since ADHs are not known to catalyze the reduction of ester functionality and the enzyme catalyzes the same reaction in opposite redox directions on two distinct functional groups in different redox states.…”

“…Redox isomerization reaction catalyzed by alcohol dehydrogenase (ADH) to enantioenriched g-hydroxylated d-lactones. 110 or two substrates with several enzymes, to one substrate and one enzyme -along with different levels of efficiency. This efficiency can be best represented by the turnover number (TON) of the hydride shuttle -typically a nicotinamide cofactor -as TON accurately represents the number of cycles a hydride can go through before getting lost to the 'outside', which automatically translates into a dead end.…”

Coding Synthetic Chemistry Strategies into Bacterial Designer Cells

“…Originally described by Tang and Guo using an iridium catalyst and 2,4-dichlorobenzoic acid as co-activator (Table 1, entry 6), [ 14 ] in 2018, we reported on the utilization of commercial alcohol dehydrogenases as proteinogenic counterpart for the borrowing hydrogen transformation of 2a to yield 3a not just in superior yields, but with very high enantioselectivity of up to 96% ee (Table 1, entry 7), a feature that has so far not been achieved in this reaction by transition metal-based catalysts. [ 15 ] The same E. coli BL21(DE3) DnemA was exploited as host for the expression of five different nicotinamide-dependent dehydrogenases (Table 1, entries [8][9][10][11][12]. Whereas the dehydrogenation to the corresponding ketolactone 4a was observed as a more or less common feature, only the dehydrogenase from Lactobacillus kefir was able to perform the full redox isomerization (lactol dehydrogenation and ketoreduction).…”

A Fully Biocatalytic Approach to Angiopterlactone B Based on a Chemoinspired Artificial in Vitro Metabolism

“…For the effective translation of Lawrence's elegant and short synthesis route of angiopterlactone B into a fully enzyme-based scenario, generally all individual modules had already been developed over the past years. [14][15][16][17] Nevertheless, aiming for a true one-pot biocatalytic cascade, a number of restrictions and potential pitfalls have been identified (Figure 2). Therefore, the successful implementation of the artificial metabolism requires a very thorough understanding of catalytic parameters, interferences and dependencies which will be discussed indepth in the following paragraphs.…”