Highly Efficient and Enantioselective Biotransformations of Racemic Azetidine-2-carbonitriles and Their Synthetic Applications

Abstract

Catalyzed by the Rhodococcus erythropolis AJ270 whole cell catalyst in neutral aqueous buffer at 30 degrees C, a number of racemic 1-benzylazetidine-2-carbonitriles, trans-1-benzyl-4-methylazetidine-2-carbonitrile, and 1-benzyl-2-methylazetidine-2-carbonitrile and their amide substrates underwent efficient and enantioselective biotransformations to afford the corresponding azetidine-2-carboxylic acids and their amide derivatives in excellent yields with ee up to >99.5%. The overall excellent enantioselectivity of the biocatalytic reactions stemmed from a combined effect of a very active but virtually nonenantioselective nitrile hydratase and a high R-enantioselective amidase involved in microbial whole cells. The synthetic applications have been demonstrated by the nucleophilic ring-opening reactions of azetidiniums of the resulting chiral azetidine-2-carbox amide derivatives for the preparation of alpha,gamma-diamino, alpha-phenoxy-gamma-amino, and alpha-cyano-gamma-amino carboxamides. The intramolecular CuI-catalyzed cross-coupling reaction for the synthesis of azetidine-fused 1,4-benzodiazepin-2-one derivative was also presented.

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

“…The organic layers were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford the corresponding carboxylic acid intermediates 13a, 13b, 13c, and 13d. General Procedure B1 for the Synthesis of Compounds 1,2,15,16,19,20,21,22,23,27, and 50. To a solution of the relevant carboxylic acid (13a, 13b, 13c, or 13d) (1 equiv) in DCM under nitrogen was added DMF (0.01 equiv) then oxalyl chloride (2 equiv).…”

Conversion of Sterically Demanding α,α-Disubstituted Phenylacetonitriles by the Arylacetonitrilase from Pseudomonas fluorescens EBC191

“…There are also only very few examples in the literature that nitrile hydratases are able to convert nitriles that harbor a quaternary carbon atom in the ␣-position to the nitrile group. Thus, it was demonstrated that nitrile hydratases convert 2,2=-azobis (2-methylpropionitrile) and 1-benzyl-2-methylazetidine-2-carbonitriles to the corresponding amides (11,25).…”

Rhodococcus as a Versatile Biocatalyst in Organic Synthesis

“…Malononitriles are α, α-substituted dinitriles that form malonic diamides and malonic acid monoamides upon incubation with whole-cells of R. rhodochrous IFO 15564 [150]. Next to that, cyanohydrins (α-hydroxy nitriles) were also successfully hydrolyzed, leading to enantiopure α-hydroxy carboxylic acids like the pharmaceutical intermediate ( R )-chloromandelic acid on gram-scale [151] as was a large variety of aminonitriles ranging from α-aryl-, α-alkyl-substituted glycine nitriles [152,153,154] to aziridine-2-carbonitriles [155], azetidine-2-carbonitriles, and 4-oxoazetidine-2-carbonitriles [156,157].…”