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

Abstract

A biocatalyst used for selective ring scission of (±)‐5‐(chloromethyl)‐4, 5‐dihydroisoxazole to synthesize chiral (R)‐4‐chloro‐3‐hydroxybutanenitrile (90 % ee, 39 % isolated yield) and (S)‐5‐(chloromethyl)‐4, 5‐dihydroisoxazole (99 % ee, 39 % isolated yield) was developed by site‐saturated mutagenesis on aldoxime dehydratase derived from Pseudomonas chlororaphis B23 (OxdA). The positive mutant (OxdA‐L318I, E=68) improved the enantiomeric ratio E by 6‐fold as compared to the wild type enzyme (OxdA‐wild, E=11). The racemic precursor of (±)‐5‐(chloromethyl)‐4, 5‐dihydroisoxazole, used in the reaction, can be synthesized from readily available allyl chloride without utilizing highly toxic cyanide. The enantiopure (S)‐5‐(chloromethyl)‐4, 5‐dihydroisoxazole remaining in the kinetic resolution can be transformed into corresponding chiral (S)‐4‐chloro‐3‐hydroxybutanenitrile without loss of enantiomeric excess by treating it with triethylamine in acetonitrile (99 % ee, 72 % isolated yield) or catalysis of OxdA‐wild enzyme (99 % ee, 88 % isolated yield).

Highly Enantioselective Hydroxylation of 3-Arylpropanenitriles to Access Chiral β-Hydroxy Nitriles by Engineering of P450pyr Monooxygenase

“…Among these, the enzyme-catalyzed synthesis of β-hydroxy nitriles greatly meets the demands of green chemistry and sustainable development. The developed enzymatic syntheses of chiral β-hydroxy nitriles can mainly be summarized into the following types: (a) asymmetric reduction of β-keto nitriles , or haloketones by oxidoreductase and necessary cyano group substitution by halohydrin dehalogenase in haloketone-involved reactions; , (b) kinetic resolution from racemic β-hydroxy nitriles through hydrolysis or esterification using nitrilase or lipase, respectively; , (c) stereoselective ring opening of racemic epoxides catalyzed by halohydrin dehalogenase; and (d) asymmetric ring opening of dihydroisoxazoles. − Despite these achievements, previous studies require oxygen-functionalized alkylnitriles as substrates, which partially complicates the target synthesis. Hence, the exploration of direct enzyme-catalyzed efficient asymmetric C­(sp 3 )–H hydroxylation of alkylnitriles with improved synthetic efficiency, generality, and practicality is highly desirable.…”

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…Zheng and Asano reported the synthesis of chiral 2-chloromethyl isoxazoline via intramolecular cyclization of in situ-generated allyl nitronate followed by enzymatic resolution of obtained racemic isoxazoline— Scheme 284 [ 315 ]. In the next step, the obtained isoxazoline was smoothly transformed into ( S )-3-chloro-2-hydrohybutanonitrile, essential for organic synthesis, with high ee .…”

“…To sum up this short fragment of our review: undoubtedly, isoxazolines are valuable organic semiproducts, scaffolds and syntons, and numerous examples of the use of isoxazolines in organic synthesis can be found in the reviews and books [ 22 , 54 , 133 , 163 , 175 , 301 , 315 , 321 , 322 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 ].…”

“… Synthesis of ( S )-chloromethylisoxazoline from allyl chloride engaging enzymatic resolution [ 315 ]. a = Me 3 SiCl, Et 3 N, CH 2 Cl 2 , 50 °C, 48 h; 22% yield; b = enzyme (OxdA-L318I or lyophilized whole cell of OxdA-L318I), 3h; 30% yield; ee = 99%.…”

Programing a cyanide-free transformation of aldehydes to nitriles and one-pot synthesis of amides through tandem chemo-enzymatic cascades

“…34,38,39 Moreover, some Oxds have been applied for the synthesis of aliphatic nitriles, [40][41][42] and chiral b-hydroxy nitriles. 43,44 Prof. Gröger group designed a chemo-enzymatic cascade to synthesize n-octanenitrile from 1-octene. 45 To avoid the inhibition effect of hydroxylamine on the activity of Oxds, an in situ thermal decompositions (16 h, 100 C) strategy has been applied to remove residual NH 2 OH$HCl in the reaction solutions from chemical aldoxime formation.…”