Nitrile resolution

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

Similarly, other cycloadducts of nitrile oxides with C6o were synthesized. The cycloadducts were characterized by 13C NMR spectroscopy and high-resolution fast atom bombardment (FAB) mass spectrometry. It should be mentioned that X-ray structure determination of the 3-(9-anthryl)-4,5-dihydroisoxazole derivative of C6o, with CS2 included in the crystals, was achieved at 173 K (255). Cycloaddition of fullerene C60 with the stable 2-(phenylsulfonyl)benzonitrile oxide was also studied (256). Fullerene formed with 2-PhSC>2C6H4CNO 1 1 and 1 2 adducts. The IR, NMR, and mass spectra of the adducts were examined. Di(isopropoxy)phosphorylformonitrile oxide gives mono- and diadducts with C60 (257). Structures of the adducts were studied using a combination of high performance liquid chromatography (HPLC), semiempirical PM3 calculations, and the dipole moments. 

Biocatalytic hydrolysis or transesterification of esters is one of the most widely used enzyme-catalyzed reactions. In addition to the kinetic resolution of common esters or amides, attention is also directed toward the reactions of other functional groups such as nitriles, epoxides, and glycosides. It is easy to run these reactions without the need for cofactors, and the commercial availability of many enzymes makes this area quite popular in the laboratory. 

This screening system has also been applied successfully in the directed evolution of enantioselective EHs acting as catalysts in the kinetic resolution of chiral epoxides 95,96) (Section IV.A.4). Moreover, the firm Diversa has applied the MS-based method in the desymmetrization of a prochiral dinitrile (l,3-dicyano-2-hydroxypropane) catalyzed by mutant nitrilases 46). In this industrial application, one of the nitrile moieties was labeled selectively with as in N-17, which means that the two pseiido-eaaniiovaenc products (S)- N-18 and (J )-18 differ by one mass unit. This is sufficient for the MS system to distinguish between the two products quantitatively 46). 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids 7-11). Enantioselectivity is relevant in the kinetic resolution of racemic nitriles or desymmetrization of prochiral dinitriles. Both versions have been applied successfully to a number of different substrates using one of the known currently available nitrilases. Recently, scientists at Diversa expanded the collection of nitrilases by metagenome panning 150). Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity and limited activity. 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

Another approach that relies on asymmetric induction from the alkene part, uses chiral auxiliaries of various types, thereby leading to enantiomerically enriched or pure isoxazoline products. The complexity of some of these auxiliaries is high, and more economical solutions are desirable since the competition is the resolution of racemic cycloadducts with an overall efficiency up to 50% yield. With chiral nitrile oxides, the situation is much less satisfactory since asymmetric induction of the 1,4-type (with 1-alkenes) is minimal, and hardly better with a 1,3-relationship of inducing-forming stereocenters, when 1,2-disubstituted alkenes are employed (Scheme 6.22). Upon separation of the two diastereomers, however, another entry to pure optically active isoxazolines is available. 

The cysteinyl proteases include papain calpains I and II cathepsins , H, and L proline endopeptidase and interleukin-converting enzyme (ICE) and its homologs. The most well-studied cysteinyl protease is likely papain, and the first x-ray crystallographic structures of papain [193] and a peptide chloromethylketone inhibitor-papain complex [194] provided the first high resolution molecular maps of the active site. Pioneering studies in the discovery of papain substrate peptide-based inhibitors having P, electrophilic moieties such as aldehydes [195], ketones (e.g., fluoromethylketone, which has been determined [196] to exhibit selectivity for cysteinyl proteases versus serinyl proteases), semicarbazones, and nitriles are noteworthy since 13C-NMR spectro-... 

Step 2 nitrile reduction In this step the two processes are very similar both are Raney nickel-catalyzed nitrile reductions using hydrogen. The reason the enzymatic process has an approximately halved energy is that it is being carried out in the enantiopure form, whereas in the classical resolution process this reaction is performed with a racemic substrate. 

Racemic pipecolic acid (6) is obtained by ring closure of TV-alkylglycines by ionic 203 or radical 204 mechanisms. It also may be obtained by conversion of suitable substituents at the C2 of piperidine into the 2-carboxy group, e.g. hydrolysis of a nitrile group 205 or oxidation of a 1,2-dihydroxyethyl group. 206 Resolution of the racemic mixture can be carried out by fractional crystallization. 207-209 Enzymatic resolution of racemic pipecolic acid 210-213 or of synthetic intermediates 214 has been reported. 

To determine the effect of mobile-phase composition on the sorption behavior of TGs on reverse-phase columns, two mixtures were employed acetonitrile/ethanol (80 20) and aceto-nitrile/methanol (80 20). A very rapid analysis resulted, with excellent peak shape and adequate resolution, when ethanol was used as the secondary solvent. Substituting an equal amount of methanol for ethanol resulted in increased solute retention, poor detector response, and asymmetrical peaks. Methanol forms a monomolecular layer on octadecyl-derived silica, which may explain the increase in solute retention caused by methanol. Also, the use of methanol would... 

Matoishi, K. Sano, A. Imai, N. Yamazaki, T. Yokoyama, M. Sugai, T. Ohta, H. Rhodococcus rhodochrous IFO 15564-mediated hydrolysis of alicyclic nitriles and amides stereoselectivity and use for kinetic resolution and asymmetri-zation. Tetrahedron Asymmetry 1998, 9, 1097-1102. 

Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycin derivatives [18]. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axial-chiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. 

In this example the resolution of racemic phenylalanine nitrile, readily obtained by a Strecker reaction with phenylacetaldehyde, is performed with IV-p-chlorobenzoyl-L-glutamic acid. The yield of this resolution nearly reaches the theoretic 50% maximum yield of enantiopure D-amino nitrile. After acidic workup of the crystalline diastereoisomeric salt, the (7 )-amino nitrile is easily hydrolyzed to D-phenylalanine. 

The previous methods of preparing levomethadone were based on separation of the D-tartrate salts of racemic methadone and also separation of the diastereoisomeric tartrates of the intermediate at the penultimate stage, namely the nitrile 17.17-19 Diastereoisomeric rf-oc- bromocamphor-10-sulfonate salts have also been separated.19 However, we and others have noted that there were difficulties in the resolution of racemic methadone by preparation of diastereoisomeric salts.20... 

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