Amines keto-acids with

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

The enantiospecific synthesis of natural and unnatural a-amino acids has been reviewed. Some of the most successful approaches involve the stereoselective hydrogenation of chiral dehydroamino acid derivatives. Many of these transformations are equivalent to the stereoselective reductive amination of a-keto acids (eq 2). For example, catalytic reduction of the imines of a-keto acids with chiral a-methylbenzylamine gives a-substituted a-amino acids with 12-80% ee (eq 3). ... 

In the sequel, we will discuss a generalization of the chelation hypothesis as it applies to reactions other than hydrogenation of Schiff bases of a-keto acids with chiral amines. The catalytic hydrogenation of pyruvic acid amide resulted in the formation of lactcimide in high optical purity (75-99% diastereomeric excess)(] ). This might be explained by the chelate conformation of the substrate-catalyst complex shown in Scheme 8. 

Other combinations of two dehydrogenases, such as amino acid dehydrogenases and formate dehydrogenase, were described by several groups to achieve the reductive amination of a-keto acids into chiral amino acids in high yields and enantioselectivities. Formate dehydrogenase has also been combined by Bolte and co-workers with an amino acid aminotransferase to achieve enantioselective reductive amination of a-keto acids with small amino acids as the amination agent. ... 

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an a-keto acid with an A/-alkylhydroxyl-amine ... 

As expected, OATA was only able to convert a-keto acids with (Rsteric limitations of the small binding pocket (Table 2.3, Entries 1 and 3). On the other hand, ArRmutll developed for the amination of bulky-bulky ketones efficiently converted a-keto acids with linear groups although it failed for branched groups (Entries 2, 4-7). Preparative-scale experiments (15 mmol) were successfully performed for the synthesis of the pharmacologically relevant l- and D-homoalanine. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

From the very successful developments of the alcohol dehydrogenase technology for production of secondary alcohols and enzymatic reductive amination of keto-acids for production of amino acids, it is expected that we will also soon see applications for other enzymatic redox chemistries for example, reduction of unsaturated carbonyl compounds with... 

P-Keto esters.2 In the presence of a trace of tertiary amine, an acid reacts with 1 in THF at 0° to form a 2-acyl-3,5,dioxo-l,2,4-oxadiazolidine (2). This activated form of an acid reacts with the lithium enolate of an ester in THF at - 75°... 

The Klotz group has also found rate enhancements of decarboxylation reactions with PEI derivatives. Catalysis of decarboxylation of j -keto acids by small amines goes via a Schiff base intermediate. Mine s group has shown that unmodified PEI catalyzes dedeuteration effectively and that the reactions involve Schiff base intermediates 34, and references therein). Dodecyl-PEI containing free amino groups and quaternized nitrogens, dodecyl-PEI-Q-NHj, was found to be an effective catalyst for the decomposition of oxaloacetate (reaction 12) (92). At pH 4.5 the polymer is 10 times as effective as ethylamine. was found to be 3.5 x 10 " M at pH 4.5. 

The investigation of the aminotransferase activity of apple ACS carried out by Feng et al reveals that it is able to reductively aminate PLP to PMP by transamination of some L-amino acids to their corresponding a-keto acids. The enzyme has shown substrate specificity with the preference of Ala > Arg > Phe > Asp. The addition of excess pyruvate causes a conversion of the PMP form of the enzyme back to the PLP form. The quite unstable PMP form of ACS can generate apoenzyme, which captures PLP to restore its physiologically active form. 

The first designed catalyst where there was some understanding of the relationship between structure and function was oxaldie 1, a 14-residue peptide that folds in solution to form helical bundles [11] (Fig. 12). Oxaldie 1 was designed to catalyze the decarboxylation of oxaloacetate, the a-keto acid of aspartic acid, via a mechanism where a primary amine reacts with the ketone carbonyl group to form a carbinolamine that is decarboxylated to form pyruvate. The reaction is piCj dependent and proceeds faster the lower the piC of the primary amine if the reaction is carried out at a pH that is lower than the piCj, of the reactive amine. The sequence contains five lysine residues that in the folded state form... 

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