Nitrile Biotransformation for Highly Enantioselective Synthesis of 3-Substituted 2,2-Dimethylcyclopropanecarboxylic Acids and Amides

Abstract

Biotransformations of differently configured 2,2-dimethyl-3-substitued-cyclopropanecarbonitriles were studied using a nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 whole-cell catalyst under very mild conditions. Although all of the cis-3-aryl-2,2-dimethylcyclopropanecarbonitriles appeared inert toward the biocatalyst, a number of racemic trans-isomers efficiently underwent a highly enantioselective hydrolysis to produce (+)-(1R,3R)-3-aryl-2,2-dimethylcyclopropanecarboxylic acids and (-)-(1S,3S)-3-aryl-2,2-dimethylcyclopropanecarboxamides in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of 1R-enantioselective nitrile hydratase and amidase, with the later being a dominant factor. The influence of the substrates on both reaction efficiency and enantioselectivity was discussed in terms of steric and electronic effects. Coupled with chemical transformations, biotransformations of nitriles provided convenient syntheses of optically pure geminally dimethyl-substituted cyclopropanecarboxylic acids and amides, including chrysanthemic acids, in both enantiomeric forms.

Enantioselective Biotransformations of Nitriles

“…Chiral cyclopropane structures [34] [35][36][37][38]. A large number of trans-configured racemic aryl-substituted cyclopropanecarbonitriles (±)-27 [35,37] and (±)-28 [38] as well as their amides (±)-29 and (±)-30, cis-configured aryl-substituted cyclopropanecarbonitriles (±)-31 [36,37] and (±)-32 [38] as well as their amides (±)-33 and (±)-34 ( Fig.…”

“…In terms of reaction velocity, it is found that trans-configured nitriles (±)-27 and amides (±)-29 are much better substrates than their cis-configured analogs (±)-31 and (±)-33 [37]. Increase of steric bulkiness of the substrates by the introduction of a pair of geminal methyl groups leads to decreased reaction rate of (±)-28 and (±)-30 [38]. The cis-configured nitriles (±)-32, for example, are not accepted at all by the biocatalyst studied [38].…”

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

“…To examine the effect of halogen substituent X on the reaction, biotransformations of 2-phenylcyclopropanecarbonitrile 1d and of the geminally dimethylated nitrile analogue 1e were also included. [24,25] The outcomes demonstrated in Table 1 indicated clearly that the substituent X played an important role in determining both the reaction rate and reaction enantioselectivity. Geminally difluoro-substituted cyclopropanecarbonitrile 1a, for example, underwent rapid and efficient hydrolysis to afford good yield of 1R,3R-2a and 1S,3S-3a with enantiomeric excess (ee) of >99% and 53%, respectively (Entry 1), a result comparable to that of biotransformation of the parent nitrile 1d [24] (Entry 5).…”

“…It has been also proposed that a readily reachable reactive site be embedded within the spacious pocket of the enantioselective nitrile hydratase while the amidase comprises a relatively deep-buried and size-limited enantioselective active site. [24,25] Our continuous interest in understanding the reaction scope and applications of both nitrile hydratase and amidase involved in Rhodococcus sp. AJ270, and in synthesizing enantiopure cyclopropane derivatives led us to undertake the current study on the biotransformation of racemic 2,2-dihalo-3-phenylcyclopropanecarbonitriles and -amides.…”

“…While the amidase is generally enantioselective, the nitrile hydratase shows either excellent or almost no enantioselectivity against trans-2-arylcyclopropanecarbonitriles depending on whether a pair of geminal methyl substituents is present or not. [24,25] Our current study has further demonstrated that the introduction of geminal halogen substituents [a] Reaction conditions were not optimized. [b] Isolated yield.…”