N-Acetyl a-amino acids

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

N-Acetylated a-Amino Acids and N-Acetylated Non-a-Amino Acids. . . ... 

Initiated by work on proteinoid microspheres, which are formed from thermally condensed a-amino acid mixtures, various N-acetylated a-amino acids and N-acetylated non-a-amino acids were synthesized and evaluated regarding their permeation-enhancing properties. Among these compounds sodium A-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) turned out as the most likely promising permeation enhancer. SNAC was identified from a series of structurally related compounds on the basis of its permeation-enhancing properties on heparin in rats (Leon-Bay et al. 1998a). At doses of 300 mg/kg... 

The enantioselective hydrolysis of racemic N-acetylated a-amino acids d,l-1 at De-gussa represents a long established large-scale process for the production of L-ami-no acids, l-2 [4]. This enzymatic resolution requires an L-aminoacylase as the biocatalyst. The starting materials for this process are readily available, since racemic N-acetyl amino acids d,l-1 can be economically synthesized by acetylation of racemic a-amino acids with acetyl chloride or acetic anhydride under alkaline conditions via the so-called Schotten-Baumann reaction [5]. The enzymatic resolution reaction of N-acetyl d,L-amino acids, d,l-1, is achieved by a stereospecific L-aminoacylase which hydrolyzes only the L-enantiomer and produces a mixture of the corresponding L-amino acid, l-2, acetate, and N-acetyl D-amino acid, d-1 (Fig. 4) [6],... 

The 1,2-addition reartion of an anisidine imine 85 with phenyllithium was controlled by chiral diether 18 to give the corresponding secondary amine 86. N-Dearylation followed by oxidative conversion of the phenyl group of 87 to a carboxyl group without racemization afforded the N-acetyl-a-amino acid 88 (Scheme 26). 

A pyrrole derivatized with a guanidinium moiety (35a) has been reported by Schmuck as an effective host for N-acetyl-a-amino acid carboxylates. " The binding constants as determined by H-NMR titrations for a series of... 

A method has been described for the preparation of N-formyl-a-amino-acid t-butyl esters by formylation of the free base with a mixture of formic acid, DCC, and pyridine, thus overcoming the incompatibility of the t-butyl ester group with the usual acidic formylation conditions. The transfer hydrogenation technique has been recommended for the removal of N-benzyloxycarbonyl and benzyl ester groups from peptides. N-Acetyl-a-amino-acids are converted into the corresponding A-ethyl derivatives by reaction with Meerwein s reagent followed by reduction with sodium borohydride. ... 

After separation of the L-amino acid through ion exchange or by a crystallization step, the remaining N-acetyl-D-amino acid is recycled by thermal racemization under drastic conditions or by a racemase to achieve an overall yield of around 45% of L-amino acid (50% is the theoretical maximum) (Figure 7.11). D-Amino acids are also accessible by chemical hydrolysis of the N-acetyl-D-amino acid or directly by use of D-selective acylases. 

Low molecular mass permeation enhancers include numerous classes of compounds with diverse chemical properties including detergents, surfactants, N-acetylated x-amino acids, N-acetylated non-a-amino acids, fatty acids, medium-chain mono- and diglycerides, acyl carnitine, alkanoyl cholines, Ca2 + chelating agents, zonula occludens toxins and NO donors. 

The starting material for the acylase process is a racemic mixture of N-acetyl-amino acids 20 which are chemically synthesized by acetylation of D, L-amino acids with acetyl chloride or acetic anhydride in alkaU via the Schotten-Baumann reaction. The kinetic resolution of N-acetyl-D, L-amino acids is achieved by a specific L-acylase from Aspergillus oryzae, which only hydrolyzes the L-enantiomer and produces a mixture of the corresponding L-amino acid, acetate, and N-acetyl-D-amino acid. After separation of the L-amino acid by a crystallization step, the remaining N-acetyl-D-amino acid is recycled by thermal racemization under drastic conditions (Scheme 13.18) [47]. In a similar process racemic amino acid amides are resolved with an L-spedfic amidase and the remaining enantiomer is racemized separately. Although the final yields of the L-form are beyond 50% of the starting material in these multistep processes, the effidency of the whole transformation is much lower than a DKR process with in situ racemization. On the other hand, the structural requirements for the free carboxylate do not allow the identification of derivatives racemizable in situ therefore, the racemization requires... 

Subsequently, the L-amino acid, l-2, is separated and isolated by a crystallization step, and the remaining N-acetyl D-amino acid is recycled by, e.g., thermal racemization. As a preferred L-aminoacylase, the amino acylase I from Aspergillus oryzae [E.C.3.5.1.14] turned out to be particularly useful. 

The enzymatic hydrolysis of N-acylamino acids has been known for a century and was first detected in aqueous kidney preparations 3. Based on the finding that this enzymatic hydrolysis proceeds enantiospecifically 2, Greenstein and coworkers developed a general and very attractive procedure for the resolution of a vast number of racemic N-acylated amino acids to the corresponding L-amino acids catalyzed by aminoacylase (E.C. 3.5.1.14) whereas the N-acetyl-D-amino acid does not react13 (Fig. 12.3-1). 

Enzymes have been immobilized by covalent binding to polymeric supports, by entrapment in cross-linked polymer gels or by physical adsorption on to suitable materials such as ion-exchangers, with retention of activity. The first example of an industrially useful application of this technique was in the separation of L-amino acids from racemic mixtures. This procedure used the enzyme aminoacylase which is immobilized in suitable columns. The racemic amino acid mixture is acylated chemically to form a-N-acetyl-OL-amino acids. When this is passed through the column, only the N-acetyl-L-amino acids are deacylated by the enzyme and the resulting L-amino acids can then be purified. 

Acrylic acid, N-acetyl-a-amino Acrylic acid 0.49 1.41 661... 

The Dakin-West reaction, which dates from 1928, is the conversion of an a-amino acid (4) to an N-acetyl-a-amino ketone (5) with acetic anhydride/pyridine (Scheme 3). Although some alternatives have been proposed, the generally accepted mechanism involves an azlactone as an intermediate. This mechanism has now been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with density functional theory (DFT) calculations. The first two steps are the conversion of the a-amino acid (6) to the A-acetylated derivative (7) and then to the A-acetyl mixed anhydride (8), which cyclizes to the oxazolone (9) (the azlactone) (Scheme 4). Deprotonation of (9) by pyridine yields resonance-stabilized l,3-oxazol-5-olate (10),... 

Acetyl-a-amino-n-butyric acid [34271-24-4] M 145.2, pK 3.72. Crystd twice from water (charcoal) and air dried [King and King J Am Chem Soc 78 1089 7956]. 

Silica gel [11] or alumina [11a, 12] alone, or silica and alumina together modified by Lewis-acid treatment [13] and zeolites [14], have been widely used as catalysts in Diels-Alder reactions, and these solids have also been tested as catalysts in asymmetric Diels-Alder reactions [12,13b,14]. Activated silica gel and alumina at 140 °C were used [15] to catalyze the asymmetric cycloaddition of (-)-menthyl-N-acetyl-a, S-dehydroalaninate (3) (R = NHCOMe) with cyclopentadiene in the key step for synthesizing optically active cycloaliphatic a-amino acids. When the reactions were carried out in the absence of solvent, a higher conversion was obtained. Some results are reported in Table 4.5 and compared with those obtained by using silica and alumina modified by treatment with Lewis acids. Silica gel gives a reasonable percentage of conversion after 24 h with complete diastereofacial selectivity in exo addition. 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

N-Acetyl-4-chloro-2,5-dimethoxyamphetamine. A solution of 5g of N-acetyl-4-amino-2,5-dimethoxyamphetamine hydrochloride in 15 ml ofhydrochloric acid and 30 ml of water is cooled to 0°, To this stirred and cooled solution, 1.4 g of sodium nitrite in 10 ml of water is added. This cooled solution of diazoniutn salt is then added slowly to a solution of 2.5 g of cuprous chloride in 9 ml of hydrochloric acid. This reaction mixture is allowed to come to room temp, then is heated to 70° and cooled, and recrystallized from ethanol to give the title compound. Tield 2.8g,mp 150-152°... 

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