P-aminonitriles

With acrylonitrile, mono- and dialkanolamines undergo a Michael addition to give the P-aminonitrile. 

Preparation of optically active P-aminoesters, P-aminonitriles, and P-aminocarbox-amides are of special relevance for the synthesis of enantiomerically pure P-aminoacids compounds of special relevance in several areas of medicinal chemistry. The resolution of P-aminoesters can be carried out by acylation of the amino groups or by other biocatalytic reactions of the ester groups, such as hydrolysis, transesterification, or aminolysis. The resolution of ethyl ( )-3-aminobutyrate... 

Other important derivatives for the preparation of (i-aminoacids are the corresponding P-aminonitriles. Lipase-catalyzed N-acylations of racemic cis-2-aminocyclopentane and cyclohexane carbonitriles with 2,2,2-trifluoroethyl butanoate have been successfully carried out in organic solvents and ionic liquids [53], PSL yielding better results than CALB (Scheme 7.29). 

Various p-aminonitriles, which are best prepared by the addition of ammonia, primary amines, or secondary amines to acrylonitrile,101 were successfully hydrogenated with Raney Ni at temperatures of 90-130°C and 6.7-27 MPa H2.102 A typical hydrogenation is shown in eq. 7.50 for P-morpholinopropionitrile. Hydrogenation of the nitrile at 190°C decreased the yield of y-morpholinopropylamine to 45%. The decrease in the yield may be explained by a reversal of the morpholine-acrylonitrile-... 

The synthesis of primary fluoroalkyl enamino phosphonates (362) from fluoronitriles and alkyl phosphonates has been described. These primary en-amines are versatile intermediates for the preparation of fluorinated a,p-un-saturated imines (363) and ketones (364) as well as of fluorinated allylamines (365) and vinylogous p-aminonitriles (366) (Scheme 91) ... 

Conjugate additions. Formation of P-aminonitriles and 1,5-dicarbonyl compounds by the Michael addition processes are mediated by InC. ... 

In 2010 the Palomo group used the related quinidine-derived phase-transfer catalyst 109 to facilitate the addition of sulfonylacetonitrile 110 to either A-Boc-protected a-amidosulfones 107 or imines (not shown) in order to obtain - upon subsequent treatment with Mg in MeOH - the enantioenriched a-unsubstituted P-aminonitriles llla-f (Scheme 5.45) [62]. The latter compounds were obtained in moderate to good yields (65-85%) and moderate ee (55-76%). 

Shibata and Tom used this strategy for a highly enantioselective mono-fluoromethylation by an asymmetric Mannich reaction using 1-fluorobi-s(phenylsulfonyl)methane (FBSM) with quinidine-derived catalyst 49c and subsequent removal of the sulfonyl group by treatment with magnesium powder (99% enantiomeric excess). Palomo and coworkers used sulfonyl acetonitrile as a synthetic equivalent of acetonitrile and obtained the optically active p-aminonitriles 97 (76% enantiomeric excess). Bernard , Ricci, and coworkers also introduced the same strategy to synthesise N-protected p -amino acid esters 98 (R = Ph, 92% enantiomeric excess) and a-alkylidene-p-aminoesters 99 (R = Ph, 91% enantiomeric excess) by an asymmetric Mannich reaction of sulfonylacetate followed by the subsequent reductive removal of the sulfonyl moiety and olefination with formaldehyde, respectively (Scheme 16.32). ... 

Figure 11.6 Biotransformations of racemic p-aminonitriles by nitrile hydratase and amidase in whole cells of Rhodococcus erythropolis A4 [38]. The enantiomeric excess is only specified for the reactions which proceeded with significant enantioselectivities.

Another biocatalytic option is the hydrolysis of p-aminonitriles, compounds that are relatively easily synthesized. There are two hydrolytic routes for the enzymatic conversion of nitriles to the corresponding carboxylic acids. These transformations can be achieved either through a two-step cascade reaction involving a nitrile hydratase followed by an amidase that hydrolyzes the intermediate amide, or through use of a nitrilase, an enzyme able to perform the two sequential transformations (Scheme 14.4). The focus of this chapter is on nitrile hydrolysis enzymes. 

Scheme 14.4 Biocatalytic conversion of P-aminonitriles to p-amino acids by nitrile hydrolyzing enzymes.

Winkler and coworkers tested the substrate spedfidty of three different Rhodococcus sp. strains on five- and six-membered cis- or tranx-aUcydic p-aminonitriles. They found that the five-membered substrates were hydrolyzed significantly faster than their corresponding six-membered counterparts, and the reaction products from the tranx-aminonitriles were formed considerably faster than for the cis-substrates [62]. In addition, the Rhodococci exhibited far greater enantioselectivity for the... 

R=CgH5CO- Hydrolysis of cyclic P-aminonitriles 94% ee (amide) >99% ee (amide) >99% ee (amide) Rhodococcus equi A4 [62] Rhodococcus erythropolis NCIMB 11540(62] Rhodococcus sp. R312 [62]... 

R-benzyl -ethyl Hydrolysis of aliphatic P-aminonitriles >99.5% ee (amide) >99.5% ee (acid) Rhodococcus erythropolis A) 270 [1]... 

Ghhiba, V.P., Bode, M.L., Mathiba, K., Kwezi, W., and Brady, D. (2012) Enantioselective biocatalytic hydrolysis of P-aminonitriles to P-amino-amides using Rhodococcus rhodochrous ATCC BAA-870. J. Mol. Catal. B Enzym., 76, 68-74. 

The third procedure, reported by the Palomo group, consists of the nucleophiUc addition of 2-(phenylsulfonyl)acetonitrile to in situ generated N-Boc imines catalyzed by 53 [69]. Although moderate enantiomeric excesses (up to 76%) were obtained, the methodology allowed for the simple synthesis of enantioenriched a-unsubstituted P-aminonitriles 59 [Scheme 29.31 (3)]. 

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