Strecker reaction mechanisms

Amino acid formation in the Urey-Miller experiment and almost certainly in the prebiotic environment is via the Stecker synthesis shown in Figure 8.3. This reaction mechanism shows that the amino acids were not formed in the discharge itself but by reactions in the condensed water reservoir. Both HCN and HCO are formed from the bond-breaking reactions of N2 and H2O in a plasma, which then react with NH3 in solution. The C=0 group in formaldehyde or other aldehydes is replaced by to form NH and this undergoes a reaction with HCN to form the cyano amino compound that hydrates to the acid. The Strecker synthesis does not provide stereo-control over the carbon centre and must result in racemic mixtures of amino acids. There is no room for homochirality in this pathway. 

On the basis of the observed stereoinduction trend, the addition of HCN took place over the diaminocyclohexane portion of the catalyst away from the amino acid and amide unit. The last hypothesis led to the prediction that a more sterically demanding amino acid or amide unit (Figure 6.14) could additionally favor the cyanide attack compared to the less bulky diaminocyclohexane unit and thus making the Schiff base catalyst more enantioselective in Strecker reactions of aldimines and ketimines. To evaluate this perspechve, the authors performed a model-(mechanism-) driven systematic structure optimizations by stepwise modification of the amide, the amino acid, and the (thio)urea unit of catalyst 42 and examined these derivatives of 42 (lmol% loading ) in the model Strecker reaction (toluene ... 

Job A, Janeck CF, Bettray W, Peters R, Enders D (2002) Tetrahedron 58 2253 Josephsohn NS, Kuntz KW, Snapper ML, Hoveyda AH (2001) Mechanism of enantioselective Ti-catalyzed Strecker reaction peptide-based metal complexes as bifunctional catalysts. J Am Chem Soc 123 11594—11599 Juhl K, Gathergood N, Jprgensen KA (2001) Catalytic asymmetric direct Man-nich reactions of carbonyl compounds with alpha-imino esters. Angew Chem Int Ed Engl 40 2995-2997... 

Josephsohn, N. S., Kuntz, K. W., Snapper, M. L., Hoveyda, A. H. Mechanism of Enantioselective Ti-Catalyzed Strecker Reaction Peptide-Based Metal Complexes as Bifunctional Catalysts. J. Am. Chem. Soc. 2001,123,11594-11599. 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

Li, J., Jiang, W.-Y, Han, K.-L. et al. (2003) Density functional study on the mechanism of bicyclic guanidine-catalysed Strecker reaction. The Journal of Organic Chemistry, 68, 8786-8789. 

Scheme 9.6 Supposed mechanism of the (thio)urea catalysed Strecker reaction...

The enantioselective Strecker reaction also succeeds with ketoimines. Thus, a-hranched amino-nitriles [94] and also unnatural amino acids [95] can he obtained hy this method. The precise mechanism of the catalysis is unclear. Kinetic investigations have previously shown, that the turnover reflects a Michaelis-Menton relationship. The imine is bonded reversibly to the catalyst. The addition of hydrogen cyanide is rate-determining. [96]... 

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

The most important reactions which provide volatile carbonyl compounds were presented in sections 3.7.2.1.9 (lipid peroxidation), 4.2.4.3.3 (caramelization) and 4.2.4.4.T (amino acid decomposition by the Strecker degradation mechanism). 

Monoaminomonocarboxylic a-amino acids with a primary amino group produce sensory active aldehydes called Strecker aldehydes. Strecker degradation of P-amino acids yields alkan-2-ones known as methylketones (see Section 8.2.4.1.2). By analogy, alkane-3-ones (ethylketones) are formed from y-amino acids. The general reaction is schematically indicated in Figure 2.43. The reaction mechanism, however, varies considerably depending on the type of oxidant and amino acid. 2-Imino acids and 2-oxoacids can in some cases apparently form as intermediates, analogous to enzymatically catalysed transamination and oxidative deamination of amino acids (see Section 2.5.1.3.2). Some Strecker aldehydes readily decompose, such as methional, or yield cyclic products, such as 5-aminopentanal, which dehydrates to 2,3,4,5-tetrahydropyridine. 

In another study catalyst 25d was the subject of investigation. Although this compound promoted both Strecker and Mannich reactions of imines (Scheme 12.3) the great differences in substrates imphed distinctly different reaction mechanisms. For instance, modifications to the salicylimine moiety had a significant impact on the outcome of the Strecker reaction, while having practically no affect on the Mannich reaction. Furthermore, the Mannich reaction was indifferent to the relative configuration of the diamino cyclohexyl group. This observation led to... 

Intensive studies using NMR methods, kinetic experiments, and computational calculations were conducted to elucidate the catalytic mechanism and observed stereoinduction [22]. The data revealed that the hydrocyanation catalyzed by 33 presumably proceed over an initial amido-thiourea catalyzed proton transfer from hydrogen isocyanide to imine 32 to generate a catalyst-bound diastereomeric iminium/cyanide ion pair. Thereby, hydrogen isocyanide, as the tautomeric form of HCN, is stabilized by the thiourea moiety of 33. The stabilization degree of the formed iminium ion by the catalyst is seen as the basis for enantioselectivity. Subsequent collapse of the ion pair and bond formation between the electrophile and the cyanide ion forms the a-amino nitrile. It should be emphasized that the productive catalytic cycle with 33 does not involve a direct imine-urea binding, although this interaction was observed both kinetically and spectroscopically in the Strecker reaction catalyzed by 25 (see above) [19],... 

There are expressions of uncertainty concerning the mechanism of the first step of the Strecker amino acid synthesis13-17. The reaction can proceed via the formation of an imine and subsequent nucleophilic attack of cyanide (path ). Alternatively, it has been speculated that the reaction of the aldehyde with hydrogen cyanide furnishes a cyanohydrin (path ), which then is subjected to a nucleophilic displacement of the hydroxy group by the amino function. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

Opatz and Ferenc [19] produced a small library of 3-amino -(arylamino)-l//-isochromen-l-ones from 2-formylbenzoic acid, potassium cyanide and a series of anilines. The reaction is based on a Strecker mechanism (Scheme 6). 

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