Promiscuous Substrate Binding Explains the Enzymatic Stereo‐ and Regiocontrolled Synthesis of Enantiopure Hydroxy Ketones and Diols

Abstract

Abstract. Regio-and stereoselective reductions of several diketones to afford enantiopure hydroxy ketones or diols were accomplished using isolated alcohol dehydrogenases (ADHs). Results could be rationalised taking into account different (promiscuous) substrate-binding modes in the active site of the enzyme. Furthermore, interesting natural cyclic diketones were also reduced with high regio-and stereoselectivity.Some of the 1,2-and 1,3-diketones used in this study were reduced employing a low excess of the hydrogen donor (2-propanol) due to the quasi-irreversibility of these ADHcatalysed processes. Thus, using less quantity of cosubstrate, scale-up could be easily achieved.

Access to Enantiopure α‐Alkyl‐β‐hydroxy Esters through Dynamic Kinetic Resolutions Employing Purified/Overexpressed Alcohol Dehydrogenases

“…Since 1,2-or 1,3-diketones could be reduced with ADHs under quasi-irreversible conditions, [29] this is, employing a low excess of the required co-substrate (2-propanol), we took advantage of this principle to show that it can also work performing DKRs over these α-substituted β-ketoesters.…”

“…[23,27,28] This effect has also been observed in the case of bioreductions of 1,2-and 1,3-diketones, probably due to the fact that an intramolecular H-bond is formed between the formed alcohol moiety and the remaining carbonyl group, hampering their oxidation reaction. [29] With this in mind, we envisaged that bioreductions of these β-ketoester derivatives could be highly favoured due to the formation of an intramolecular H-bond affording a stabilised 6-member ring (Figure 2), and therefore a small excess of 2-propanol could be used to achieve quantitative conversions of the corresponding β-hydroxyesters. Consequently, substrate 1b was reduced with several ADHs that accept 2-propanol as co-substrate (ADH-A, CPADH, and LBADH), using only 2 equivalents of the hydrogen donor (corresponds to 0.45% v v -1 ).…”

Coupling biocatalysis and click chemistry: one-pot two-step convergent synthesis of enantioenriched 1,2,3-triazole-derived diols

“…After performing the bioreduction in phosphate buffer at 30ºC 65 with 2-propanol for 24 h, the copper wire and CuSO 4 were added into the reaction mixture, and it was heated up at 60ºC for 24 h. While with alkynone 1b diols syn-3 were obtained, in case of substrate 1a, since the enzyme recognised the ethynyl group as the 'big' moiety, 26 anti-3 were synthesised.…”

Biocatalysed concurrent production of enantioenriched compounds through parallel interconnected kinetic asymmetric transformations

“…7 In despite of all the advantages provided by these enzymes, their implementation at industrial scale usually remains impeded due to the high costs related to the nicotinamide cofactor needed by these redox biocatalysts. Therefore, various chemical, 8,9 electrochemical, 10 and 40 enzymatic 11 methods have been explored in order to regenerate the coenzymes NAD(P)H or NAD(P) + . However, these methodologies have several drawbacks such as harmful effects on the biocatalyst, high costs and loss of material, which diminishes the atom efficiency 12 of the process.…”

“…This shows that the selectivity of this system can simply be tuned by changing the employed biocatalysts. Reactions were also carried out using PAMO as biocatalyst (entries [8][9][10][11][12][13][14][15][16]. As shown in entry 8, when this enzyme was 35 employed in combination with ADH-T, (R)-1a, (S)-2a and (R)-3a were achieved with conversions close to 50% in a process with excellent selectivity.…”