Amino acid by reductive amination

Ketoximes and oximes of 2-oxo-acids are hydrogenated to amines by [CoH(CN)5]3-. The latter reaction allows the preparation of a-amino-acids by reductive amination of 2-oxo-acids in aqueous ammonia. At 40-50 °C and 70 bar H2 the yields are ca. 90% [146]. 

Another example of solid phase DOS involves post-modification of the natural product macrolide antibiotic erythromycin (34) [77]. Erythromycin was first converted to analogue 32 which resembles a third generation macrolide antibiotic with high activity against resistant strains (ABT-773, 35), but is attached to solid phase-bound amino acids by reductive amination. Two further reductive amination steps and cleavage from solid support form a library of compounds of type 33 (Fig. 10). 

A laboratory synthesis that is patterned after a biological synthesis. For example, the synthesis of amino acids by reductive amination resembles the biosynthesis of glutamic acid. (p. 1164) Proteins that provide all the essential amino acids in about the right proportions for human nutrition. Examples include those in meat, fish, milk, and eggs. Incomplete proteins are severely deficient in one or more of the essential amino acids. Most plant proteins are incomplete, (p. 1160)... 

Hafenbradl D., Keller M., Wachtershauser G., and Stetter K. O. (1995) Primordial amino-acids by reductive amination of alpha-oxo acids in conjunction with the oxidative formation of pyrite. Tetrahedron Lett. 36(29), 5179-5182. 

Problem 36.12 (a) Synthesis of amino acids by reductive amination (Sec. 22.11) is illustrated by the following synthesis of leucine ... 

Because the resolution with acylase gave a theoretical maximum yield of only 50% and required separation of the desired product from the unreacted enantiomer at the end of the reaction, we next tried to prepare the amino acid by reductive amination of the corresponding ketoacid, a process with a theoretical maximum yield of 100%. A variety of ketoacids can be converted to L-amino acids by treatment with ammonia, reduced nicotinamide adenine dinucleotide (NADH), and a suitable amino acid dehydrogenase. 2-Keto-6-hydroxyhexanoic acid (in equilibrium with its cyclic hemiketal form) was prepared by chemical synthesis starting from 4-chloro-l-butanol, which was... 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

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. 

Reduction—Continued of a hydroxylamino acid to an amino acid by hydroxylamine, 33, 26 of a nitro compound to an amine, S3,9 of a nitro compound to an azo compound, 22, 28... 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

In contrast, amino acid dehydrogenases comprise a well-known class of enzymes with industrial apphcations. An illustrative example is the Evonik (formerly Degussa) process for the synthesis of (S)-tert-leucine by reductive amination of trimethyl pyruvic acid (Scheme 6.12) [27]. The NADH cofactor is regenerated by coupling the reductive amination with FDH-catalyzed reduction of formate, which is added as the ammonium salt. 

The two main resin linkers developed so far are shown in Scheme 18, i.e. tris(alk-oxy)benzylamide- 412 and 4-alkoxybenzylamide-type linkers)341 the former being TFA labile and thus fully compatible with Fmoc/tBu and the latter strongly acid labile and correspondingly compatible with Boc/Bzl chemistry. As shown in the case of the tris(alk-oxy)benzaldehyde handle such handles may be introduced into the C-terminal amino acid ester by reductive amination, and after suitable N -protection coupled to amino-functionalized resins (see Scheme 18). Alternatively, the tris(alkoxy)benzaldehyde-functionalized resin, BAL resin, (see Scheme 14) is used to link the C-terminal amino acid ester by reductive amination. To overcome the difficult acylation of the V -arylamino acid ester derivative on resin (best results with 10 equivalent symmetrical anhydrides), synthesis in solution of the C-terminal dipeptide building block containing the amide handle followed by its attachment to the resin has been proposed)341 ... 

Carboxy terminal amino acid or peptide thiols are prepared from various p-amino alcohols by conversion into a thioacetate (R2NHCHR1CH2SAc) via a tosylate followed by saponification.Several methods have been used to prepare N-terminal peptide thiols, the most common procedure is the coupling of (acetylsulfanyl)- or (benzoylsulfanyl)alkanoic acids or add chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 16 Other synthetic methods include deprotection of (trit-ylsulfanyl)alkanoyl peptides, 1718 alkaline treatment of the thiolactones from protected a-sulfanyl acids, 19 and preparation of P-sulfanylamides (HSCH2CHR1NHCOR2, retro-thior-phan derivatives) from N-protected amino acids by reaction of P-amine disulfides with carboxylic acid derivatives, followed by reduction. 20,21 In many cases, the amino acid or peptide thiols are synthesized as the disulfides and reduced to the corresponding thiols by the addition of dithiothreitol prior to use. 

L-6-Hydroxynorleucine, a different key chiral intermediate used for synthesis of the vasopeptidase inhibitor Omapatrilat (Vanlev ), was prepared in 89% yield and > 99% optical purity by reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate dehydrogenase from beefliver (Hanson, 1999) (Figure 13.22). In an alternative process, racemic 6-hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6-hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive amination procedure to convert the mixture entirely to L-6-hydroxynorleucine, with yields of 91-97% and optical purities of > 99%. 

The synthesis of enantiopure amino-functionalized compounds such as a- and (3-amino acids or nonfunctionalized amines can be envisaged by the use of aldehydes, ketones, a- or (3-keto acids, or derivatives thereof as substrates for imine formation followed by, for example, diastereoselective Strecker reactions, reductions, or organometallic addition reactions. In the literature, diastereoselective syntheses based on a large variety of chiral auxiliaries, such as a-arylethylamines,4... 

The amino acid alanine can be made in moderate yield in the laboratory by reductive amination of pyruvic acid. 

Fig. 8 Synthesis of amino acids by a multienzyme system consisting of leucine dehydrogenase (LeuDH) catalyzing the reductive amination of the corresponding keto acid, L-lactate dehydrogenase (l-LDH), and lactate for the regeneration of NADH and urease for the in situ generation of ammonia. The coenzyme NAD+ was covalently bond to dextran, enzymes and dextran-coupled NAD+ were...

Because of its bulky, inflexible, and hydrophobic side chain, terf-leucine (2-amino-3,3-dimethylbutanoic acid, Tie) is an important amino acid used as template or catalyst compound in asymmetric synthesis and in peptidic medicinal compounds. L-Tle has attracted much attention as a key component of newly emerged drugs or as building block of ligands, catalysts, and auxiliaries for asymmetric synthesis. It is synthesized in ton-scale by reductive amination of trimethylpyruvic acid by means of LeuDH from Bacillus stearothermophilus with very high yield and excellent optical purity [153]. NADH, which is consumed during the reaction, can be regenerated by FDH from C. boidinii (Fig. 35). 

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