Stereoselectivity-Tailored, Metal-Free Hydrolytic Dynamic Kinetic Resolution of Morita–Baylis–Hillman Acetates Using an Engineered Lipase–Organic Base Cocatalyst

Abstract

Metal-free enantiocomplementary hydrolytic dynamic kinetic resolution of Morita−Baylis−Hillman (MBH) acetates was developed using triethylamine (TEA) as a racemization catalyst and wild-type or engineered lipase B from Candida antarctica (CALB) as stereoselectivity-determining catalyst, leading to chiral MBH alcohols with tailor-made R or S configurations on an optional basis. In the TEA-WT CALB catalysis system, WT CALB displays excellent S enantioselectivity for a series of MBH acetates tested (up to 96% ee and 98% conversion). Reversal of enantioselectivity in favor of (R)-MBH alcohols (95% ee; 95% conversion) was achieved by generating a focused site-specific mutagenesis library composed of less than 20 variants. Molecular modeling explains the origin of stereoselectivity.

Biocatalytic asymmetric ring-opening of dihydroisoxazoles: a cyanide-free route to complementary enantiomers of β-hydroxy nitriles from olefins

“…Nowadays, benefitting from the great development of biotechnology and green chemistry, a variety of synthetic strategies to β-hydroxy nitriles have been developed using purified enzymes or whole cell catalysts. Among them, lipases, 2,22,23 reductases, 1,[24][25][26] dehydrogenases, 27 and nitrilases 28,29 have been mostly employed toward the synthesis of chiral β-hydroxy nitrile via the kinetic resolution of racemic hydroxyl nitriles or the asymmetric reduction of β-oxo-nitriles. In addition, few publications have reported the use of monooxygenase for the asymmetric hydroxylation of 3-phenylpropanenitrile 30 or multi-enzymatic biosynthesis system of alcohol dehydrogenase/halohydrin dehalogenase treating on α-halo ketones and cyanide 31 to form this family of chiral compounds.…”

The Application of Biocatalysis in the Preparation and Resolution of Morita‐Baylis‐Hillman Adducts and Their Derivatives

“…Xia et al recently demonstrated that the natural (S)-preference of CALÀ B for these substrates could be altered to (R) through point mutations. [85] The key mutation leading to a modification in the enzyme enantiopreference was W104V (from tryptophan to valine), with A281L and A282K acting in concert to improve enantioselectivity. In addition, the introduction of triethylamine to the reaction mixture allowed them to transform the EKR into a dynamic kinetic resolution (Scheme 20).…”

“…Xia et al. recently demonstrated that the natural ( S )‐preference of CAL−B for these substrates could be altered to ( R ) through point mutations [85] . The key mutation leading to a modification in the enzyme enantiopreference was W104V (from tryptophan to valine), with A281L and A282K acting in concert to improve enantioselectivity.…”

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

“…The dynamic kinetic resolution of alcohols using metal‐based racemization catalysts in combination with lipases is well reported and there have been several reviews on the use of complexes of metals such as iron, ruthenium, and iridium. [77b], [77c], [77d], [77e], Acids and bases, zeolite, even light activated catalysts have also been used as racemization catalysts for the dynamic kinetic resolution of alcohols …”