One-Pot Enzymatic–Chemical Cascade Route for Synthesizing Aromatic α-Hydroxy Ketones

Abstract

2-Hydroxyacetophenone (2-HAP) is an important building block for the production of a series of natural products and pharmaceuticals; however, there is no safe, efficient, and economical method for 2-HAP synthesis. Here, a one-pot enzymatic-chemical cascade route was designed for synthesizing 2-HAP based on retrosynthetic analysis. First, a spontaneous proton-transfer reaction was designed using a computational simulation that enabled 2-HAP synthesis from the isomer 2-hydroxy-2-phenylacetaldehyde. A route for 2-hydroxy-2-phenylacetaldehyde synthesis was then constructed by introducing the unnatural substrate glyoxylic acid into a C–C ligation reaction catalyzed by Candida tropicalis pyruvate decarboxylase. Assembly and optimization of this enzymatic–chemical cascade route resulted in a final yield of 92.7%. Furthermore, stereospecific carbonyl reductases were introduced to construct a synthetic application platform that enabled further transformation of 2-HAP into (S)- and (R)-1-phenyl-1,2-ethanediol. This method of cascading spontaneous chemical and enzymatic reactions to synthesize chemicals offers insight into avenues for synthesizing other valuable chemicals.

Biocatalysis making waves in organic chemistry

“…Elegant analysis of these binding pockets allowed the engineering thereof. [68][69][70][71][72] As a result excellent control of the donor and acceptor molecule as well as the stereoselectivity was gained (Scheme 6). This work was further extended by engineering a decarboxylase in such a way that it could admit formaldehyde as acceptor, making it one of the few enzymes that can convert this toxic compound and at the same time enabling C1 chemistry also for the ThDPdependent enzymes.…”

Asymmetric Synthesis of N‐Substituted 1,2‐Amino Alcohols from Simple Aldehydes and Amines by One‐Pot Sequential Enzymatic Hydroxymethylation and Asymmetric Reductive Amination

“…It is worth noting that the interconversion of the α‐hydroxymethyl ketone by keto‐enol tautomerization was not observed under the reaction conditions. It is understandable because the relative Gibbs energy of α‐hydroxymethyl ketone was lower than α‐hydroxymethyl aldehyde based on the previous report [30] …”

Molecular Mechanism of the Mononuclear Copper Complex‐Catalyzed Water Oxidation from Cluster‐Continuum Model Calculations

“…As shown in Figure 5, such process experiences a small barrier of 7.5 kcal mol −1 ( 2 IC11 → 2 TS3 ). However, the so‐formed 2 IC12 is slightly higher than 2 TS3 owing to the inclusion of entropy and zero‐point energy corrections [81,106–108] . Indeed, 2 IC12 is 0.7 kcal mol −1 lower than 2 TS3 in the absence of the entropy and zero‐point energy corrections.…”

“…However, the so-formed 2 IC12 is slightly higher than 2 TS3 owing to the inclusion of entropy and zero-point energy corrections. [81,[106][107][108] Indeed, 2 IC12 is 0.7 kcal mol À 1 lower than 2 TS3 in the absence of the entropy and zero-point energy corrections. Starting from 2 IC12, the release of a proton from the H 3 O + ion to the hydrated OH À results in the spontaneous OÀ O bond formation between OH * radical and the Cu II À O *À species, leading to Cu II À OOH À species in 2 IC13 (also see Figure 5).…”