Amino-nitriles Hydrolysis

An a-amino acid 3 can be prepared by treating aldehyde 1 with ammonia and hydrogen cyanide and a subsequent hydrolysis of the intermediate a-amino nitrile 2. This so-called Strecker synthesis - is a special case of the Mannich reaction-, it has found application for the synthesis of a-amino acids on an industrial scale. The reaction also works with ketones to yield a, a -disubstituted a-amino acids. 

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. 

Auxiliary-controlled Streeker syntheses have so far only been carried out with amines serving as the chiral components. In the first asymmetric Streeker synthesis a solution of sodium cyanide, ( — )-(S)-a-methylbeuzylamine and its hydrochloride in water was mixed with a methanolie solution of acetaldehyde and stirred for five days. Hydrolysis of the resulting amino nitrile and subsequent hydrogenolysis furnished L-alanine with 90% optical purity 38-39-85. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

The removal of the carbohydrate auxiliary group and the hydrolysis of the amino nitriles is achieved by acidolytic cleavage of the hemiaminal /V-glycosidic bond and the concomitant acid-catalyzed solvolysis of the nitrile using either hydrogen chloride in formic acid or hydrogen bromide in acetic acid56 57. 

Mild acidic hydrolysis of amino nitrile 369 gave m-4,9a-/7-rra r-9-7/-9-benzyloxy-4-phenyl-3,4,9,9a-tetrahydro-17/,67/-pyrido[2,l-d[l,4]oxazin-l-one <1996TL4001>. (2A)-2-Cyano-l-[(lR)-2-hydroxy-l-phenylethyl]piperidin-6-one, on standing for 20 days in ethanol saturated with HC1 gas, afforded (4/ ,9aA)-4-phenylperhydropyrido[l,2-4[l,4]oxazine-l,6-dione, which was sometimes accompanied by the unstable (26 )-l-[(l/ )-2-hydroxy-l-phenylethyl]-... 

In the Strecker synthesis an aldehyde is converted to an a-amino acid with one more carbon atom by a two-stage procedure in which an a-amino nitrile is an intermediate. The a-amino nitrile is formed by reaction of the aldehyde with ammonia or an ammonium salt and a source of cyanide ion. Hydrolysis of the nitrile group to a carboxylic acid function completes the synthesis. 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

When applied to formaldehyde, however, the reaction is somewhat anomalous in that methyleneaminoacetonitrile (CH2=N CH2-CN), the condensation product derived from the aldehyde and the amino nitrile, is formed (Expt 5.181). The free amino nitrile is obtained by careful basification of its sulphate salt, which is formed when methyleneaminoacetonitrile is treated with concentrated sulphuric acid in ethanol. Details of the hydrolysis of the amino nitrile (as the sulphate) under basic conditions are given. Barium hydroxide is used, the excess of which is finally removed by precipitation as the sulphate to facilitate the isolation of the glycine formed. 

The Strecker reaction is a three-component reaction of an aldehyde (or ketone), ammonia (86, or another amine) and hydrogen cyanide (87, or equivalents) to give a-amino nitriles and, after hydrolysis, a-amino acids (Scheme 9.16). 

As actually carried out, the aldehyde was converted to the amino nitrile by treatment with an aqueous solution containing ammonium chloride and potassium cyanide. Hydrolysis was achieved in aqueous hydrochloric acid and gave valine as its hydrochloride salt in 65% overall yield. 

The catalyst 6 can be recovered for re-use in 80-90% yield by extraction with oxalic acid. The a-amino nitrile products were easily transformed into the corresponding a-amino acids by removing the benzhydryl group by hydrolysis in HC1. 

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate a-amino nitriles to provide a-amino acids (Scheme 1), was first reported in 1850 [1], This method has been applied on an industrial scale toward the synthesis of racemic a-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of a-amino acids [2]. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of a-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. 

One of the possibilities to convert the amino nitrile (R,S)-3 to (5)-terMeucine (7) is shown in the reaction sequence of Scheme 25.3. Hydrolysis of the aminonitrile (R,S)-3 to the diamide 5 was performed in concentrated sulfuric acid. Removal of the phenylacetamide group using H2 and Pd-C gave (S)-tert-leucine amide (6). Acidic hydrolysis of the amide 6 yielded (S)-tert-leucine (7) in 73% overall yield for the 3 steps and an enantiomeric excess of >98%. The overall yield for this nonoptimized protocol is 66% based on pivaldehyde. Obviously, other routes to convert the amino nitrile to the amino acid can be envisaged. As an example, by heating the diamide in sulfuric acid, after dilution with water, the diacid can be obtained that, after hydrogenolysis, affords the amino acid in 2 steps from the amino nitrile 3. 

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

Treatment of ethyl l- 2-[(tm-butyl, dimethylsilyl)oxy]-l-phenylethyl -6-alkylpiperidine-2-carboxylates with 10% HF in MeCN afforded diastereo-meric mixtures of 4-phenyl-6-substituted perhydropyrido[2,l-c][l,4]oxazin-1-ones (94JOC3769). Dieckmann cyclization of ethyl 4-(3-ethoxy-carbonylpropyl)morpholine-3-carboxylate with ferf-BuOK in Et20 and subsequent ester hydrolysis and decarboxylation furnished perhydropy-rido[2,l-c][l,4]-oxazin-9-one (82EUP57536 92BMC1293). Mild acidic hydrolysis of the nitrile moiety of amino nitrile 185 gave pyrido[2,l-c][l,4]ox-azin-l-one 60 (96TL4001). 

In a separate step, hydrolysis of the a-amino nitrile (Section 21-7D) gives an a-amino acid. 

Synthesis of a-amino acids by reaction of an aldehyde with ammonia and cyanide ion, followed by hydrolysis of the intermediate a-amino nitrile, (p. 1167)... 

Cyanide will attack iminium ions the Strecker synthesis of amino acids Cyanide will react with iminium ions to form oc amino nitriles. Although these compounds are relatively unimportant in their own right, a simple hydrolysis step produces a amino acids. This route to amino acids is known as the Strecker synthesis. Of course, it s not usually necessary to make the amino acids that Nature produces for us in living systems they can be extracted from hydrolysed proteins. 

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

During our longstanding interest in the biohydrolysis of nitriles, we found that whole cell preparations of certain Rhodococci, such as R. erythropolis A4 (formerly R. equi A4), R. sp. R312, and R. erythropolis NCIMB 11540, containing the nitrile hydratase/amidase enzyme system, are efficient catalysts for stereoselective microbial hydrolysis of N-protected carbocyclic P-amino nitriles ( )-la-( )-4a, to P-amino acids lc-4c and amides lb-4b, respectively (Scheme 15.1) [33, 34]. 

The structures of N-tosylated amino nitriles for enantioselective hydrolysis are depicted in Figure 15.2. The results listed in Tables 15.1-15.3 are isolated yields of the whole cell transformations after extraction and chromatographic purification. The enantiomeric excesses (e.e.s) are listed in parentheses. AH reactions were... 

During our work on enzymatic nitrile transformation, carbocyclic y-amino nitriles have emerged from a comprehensive screening among structurally diverse amino nitriles as being weU-suited substrates for nitrilase-mediated hydrolysis. In contrast, as stated in the previous section, the analogous carbocychc 5-amino nitriles are strictly non-substrates for nitrilases. 

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