Nitrile and Amide Biotransformations for Efficient Synthesis of Enantiopure gem‐Dihalocyclopropane Derivatives

Abstract

Catalyzed by Rhodococcus sp. AJ270 microbial cells, trans-2,2-dihalo-3-phenylcyclopropanecarbonitriles and -amides underwent enantioselective hydrolysis under very mild conditions. Both the efficiency and enantioselectivity of the nitrile hydratase and amidase involved in the cells were strongly determined by the nature of the halogen substituent. The synthetic utility of the biocatalytic process was illustrated by an efficient and multigram scale biotransformation and synthesis of enantiopure 2,2-dichloro-3-phenylcyclopropanecarboxylic acid and amide in both enantiomeric forms.

Enantioselective Biotransformations of Nitriles in Organic Synthesis

“…On the basis of these results, we have proposed a prediction model in terms of reaction efficiency and enantioselectivity based on the steric effect of the substituents on the cyclopropane ring. , The prediction is followed very well by the biocatalytic reactions of other cyclopropanecarbonitriles and amides (Figure ). Being comparable to (±)- 32 in size, nitrile (±)- 38 undergoes efficient biotransformations to produce amide (1 S ,3 R )- 42 and acid (1 R ,3 S )- 43 in good yields with high ee values.…”

“…Variation of the two germinal hydrogen atoms in (±)- 31 (Ar = Ph) to fluorine and chlorine atoms leads to a gradual decrease in the bioconversion rate. Meanwhile, the selectivity is greatly improved, with the enantiomeric ratio E increasing from 8.9 to 74 and 125 …”

An Unusual β-Vinyl Effect Leading to High Efficiency and Enantioselectivity of the Amidase, Nitrile Biotransformations for the Preparation of Enantiopure 3-Arylpent-4-enoic Acids and Amides and Their Applications in Synthesis

“…Recent studies have demonstrated that biotransformations of nitriles complement the existing asymmetric chemical and enzymatic methods for the synthesis of chiral carboxylic acids and their derivatives. , The distinct features of enzymatic transformations of nitriles are the straightforward generation of enantiopure amides, valuable organonitrogen compounds in synthetic chemistry, in addition to the formation of enantiopure carboxylic acids. For example, we 3c have shown that Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing whole cell catalyst, is able to efficiently and enantioselectively transform nitriles including α-aminonitriles, α-alkyl- and α-allyl-substituted arylacetonitriles, cyclopropanecarbonitriles, and oxiranecarbonitriles into the corresponding useful polyfunctionalized chiral carboxylic acids and amides. In contrast to the successful enantioselective nitrile biotransformations for the preparation of chiral carboxylic acids and amide derivatives bearing an α-stereocenter, − biotransformations of substrates having a chiral center remote from the cyano or the amido functional group have been reported to proceed with, in most cases, disappointingly low enantioselectivity and chemical yield − except for some biocatalytic desymmtrization reactions of 3-substituted glutoranitrile derivatives .…”

“…For example, we 3c have shown that Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing whole cell catalyst, is able to efficiently and enantioselectively transform nitriles including α-aminonitriles, α-alkyl- and α-allyl-substituted arylacetonitriles, cyclopropanecarbonitriles, and oxiranecarbonitriles into the corresponding useful polyfunctionalized chiral carboxylic acids and amides. In contrast to the successful enantioselective nitrile biotransformations for the preparation of chiral carboxylic acids and amide derivatives bearing an α-stereocenter, − biotransformations of substrates having a chiral center remote from the cyano or the amido functional group have been reported to proceed with, in most cases, disappointingly low enantioselectivity and chemical yield − except for some biocatalytic desymmtrization reactions of 3-substituted glutoranitrile derivatives . For instance, biotransformations of the Baylis−Hillman nitriles 11 and its one-carbon homologated nitriles 12 gave moderate enantioselectivity whereas β-phenylbutyronitrile, β-, γ-, or δ-hydroxylated alkanenitriles 15 gave no or extremely low enantiocontrol.…”

“…The high sensitivity of the amidase toward the structure of the amide substrates is intriguing. To interpret the biocatalysis of various racemic amides bearing an α-stereocenter, amidase of a deeply buried and highly steric demanding active site has been proposed . Taking the similarity between 3-phenylpent-4-enoic acid amide 2a and 3-phenylpentanoic acid amide 5 into consideration, the rationalization for the different catalytic efficiencies and enantioselectivities of the amidase displayed for two substrates remains a challenge at this stage because of the lack of molecular structure of the amidase .…”