From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

Abstract

Although the classical enzymatic kinetic resolutions (EKRs) are among the most important reactions in biocatalysis, the requirement of application of chromatographic purification technique, which is responsible for the generation of large amounts of waste organic solvents, is its major drawback. To minimize the environmental impact of such attempts and to address the current sustainability challenges, we decided to develop a novel EKR methodology, which relies on the usage of cheap, fully renewable, nontoxic, and irreversible acyl group donor reagent, namely, α-angelica lactone. The employed activated enol lactone-based acyl donor proved to be a versatile reagent enabling efficient and highly enantioselective (up to E ≫ 500) lipase-catalyzed resolution of a set of racemic sec-alcohols with up to >99% ee and near to quantitative isolation yields according to conversions achieved during the respective EKR procedure. Moreover, α-angelica lactone provided, in this case, an ability of fast and straightforward separation of the enzymatic reactions’ products via chromatography-free reactive liquid–liquid extraction (LLE) workup using either saturated aqueous sodium bisulfate in dimethylformamide (DMF) or Girard’s P reagent in a mixture of EtOH/AcOH (90:10, v/v), respectively. The NaHSO3/DMF LLE workup and the subsequent reisolation of the respective levulinate from the aqueous layer turned out to be less efficient than a separation with Girard’s P reagent. The selective LLE of optically active levulinate-Girard P-hydrazones from the respective alcohols and further hydrolysis of the respective hydrazides with diluted HClaq. could be performed with high levels of recovery of both EKR products isolated usually without loss of enantiomeric purity.

Asymmetric Proton Transfer Catalysis by Stereocomplementary Old Yellow Enzymes for C═C Bond Isomerization Reaction

“…With 2, the instability of the resulting product 1 at basic pH and subsequent hydrolysis appears to provide a sufficient thermodynamic drive for the isomerization to happen on the more stable α,β-unsaturated isomer, likely further driven by the tautomerism of the opened enol-isomer to the more stable keto-isomer (see Supporting Information, Scheme S1). 42 Given recent studies demonstrating the influence of light irradiation on the promiscuous activity of OYEs, 14−16 the isomerization reaction of 1 was also performed in the dark with both GsOYE and OYE2 for 5 h. Upon workup, both amounts and ee values of product 2 were comparable to that obtained from the reaction performed under daylight, indicating a lightindependent mechanism (see Supporting Information, Table S7). Finally, the effect of FMN alone (0.5 mM and 10 mM) was investigated on 10 mM 1 under standard reaction conditions in the absence of enzyme.…”

Recent Insights and Future Perspectives on Promiscuous Hydrolases/Acyltransferases

“…In contrast to other lactones, the transesterification product quickly tautomerizes into a more stable methyl ketone, making the acylation irreversible and preventing further acylation of the reaction product. Angelica lactones are attractive for kinetic resolutions, especially since the methyl ketones can be derivatized to allow chromatography-free separations of the acylated and unacylated enantiomers. , …”

“…Angelica lactones are attractive for kinetic resolutions, especially since the methyl ketones can be derivatized to allow chromatography-free separations of the acylated and unacylated enantiomers. 58,59 Perhaps the most exciting application of promiscuous hydrolases/acyltransferases is the acylation of hydrophilic substrates. Therefore, the inability of MsAcT and the CpLIP2-related enzymes to acylate hydrophilic compounds like sugars in water is a significant limitation.…”

Chemoenzymatic deracemization of lisofylline catalyzed by a (laccase/TEMPO)-alcohol dehydrogenase system

“…With the aim to expand the synthetic toolbox for the synthesis of the titled API, we have recently developed two independent variants of lipase-catalyzed kinetic resolution (KR) of racemic LSF by either using a classic transesterification approach with vinyl acetate as acyl donor 13 or utilizing α-angelica lactone as a nonconventional irreversible acylating agent for chromatography-free KR. 14 However, enzymatic KR of sec -alcohols suffers from low reaction yields, which renders the use of this approach unsustainable for industrial applications.…”