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

Abstract

From alkenes and nitromethane, a cyanide-free pathway to synthesize chiral β-hydroxy nitriles via the enantioselective ring-opening of 5-sub-4,5-dihydroisoxazoles catalyzed by aldoxime dehydratases has been developed.

A Cyanide‐free Biocatalytic Process for Synthesis of Complementary Enantiomers of 4‐Chloro‐3‐hydroxybutanenitrile From Allyl Chloride

“…Moreover, the reductive additive is essential to recover enzyme activity from inactive state [14e,h] . In this work, the reductant Na 2 S 2 O 4 , which has been identified as the best reductive additive for OxdA, [13] was used in the experiments. As shown in Table 2, no any inhibitory effect on the enzyme activity was observed up to 50 mM Na 2 S 2 O 4 , and slight activity enhancement was detected with the increase of Na 2 S 2 O 4 concentration.…”

“…The first method enables the efficient synthesis of racemic β‐hydroxy nitriles via a 2‐isoxazoline motif from readily available alkenes in a cyanide‐free reaction; however, the lack of chirality controlling means limits its application in asymmetric synthesis of chiral β‐hydroxy nitriles. To solve this problem, we recently reported an aldoxime dehydratase catalyzed kinetic resolution method for the synthesis of chiral β‐hydroxy nitriles from racemic 2‐isoxazolines substrates [13] …”

“…It has been used in the asymmetric synthesis of chiral nitriles, [16] and Kemp elimination [17] . In a recent study, [13] we successfully developed a new application of the enzyme wherein synthesis of chiral β‐hydroxy nitriles was achieved by enantioselective N−O bond cleavage in 4, 5‐dihydroisoxazoles, and the remaining chiral substrates can also be transformed into complementary chiral β‐hydroxy nitriles in alkali condition. In the substrate scope investigation, we found that all three enzymes exhibited poor enantioselectivity on aliphatic substrates, restricting its application on aliphatic β‐hydroxy nitriles synthesis.…”

Nitrile Synthesis with Aldoxime Dehydratases: A Biocatalytic Platform with Applications in Asymmetric Synthesis, Bulk Chemicals, and Biorefineries

“…The obtained mixture of a chiral β-hydroxy-nitrile and the remnant optically active dihydroisoxazol could be straightforwardly separated (e.g., chromatography), and a further base-mediated opening of the untouched substrate afforded the two enantiomers of important building blocks for fine chemicals and pharmaceuticals. Reactions were performed in buffer at 30 ℃, and several enzyme variants were used ( Scheme 2 ) [ 21 , 22 ]. Substrate concentrations were in the range of 100 mM (ca.…”

“… Aldoxime dehydratase-catalyzed Kemp elimination (above) and use of it to synthetize chiral β-hydroxy-nitriles, reported by the Asano group [ 21 , 22 ]. …”