A-Amino acids, acylation

Ohba and co-workers developed a general synthesis of chiral iV-protected 5-(aminomethyl)oxazoles from a-lithiated isocyanides and Af-protected amino acid esters (Scheme 1.101). Metalation of an alkyl or benzyl isocyanide with n-BuLi or LDA and acylation with an A-Boc-ot-amino acid methyl ester afforded an iV-Boc-a-amino acid acyl isocyanide 369, which cyclized to a chiral A-Boc-5-(aminomethyl) oxazole 370. The products were obtained in > 98% ee based on chiral HPLC analysis. The yields of 370 were somewhat variable, ranging from 45 to 91%. A-Boc-protected glycine, alanine, phenylalanine, proline, serine, and (9-benzyl serine were all compatible with these reaction conditions. 

Stereoselective Acylations. Intramolecular Ftiedel-Crafts acylation reaction of A/-ataLkyl a-amino acid detivatives gives cycHc ketones with high enantioselectivity (100). This methodology has been used for the enantiospeciftc syntheses of tylophorine [482-20-2] and cryptopleutine [87302-53-2] the ptincipal representatives of phenanthroiadolizidine and phenanthroquiaolizidine alkaloids (qv) (101). 

Similarly, A[-carboxy-a-amino acid anhydrides react with aromatics such as toluene, xylenes, and mesitylene to give a-amino acylated products ia moderate yields with almost complete retention of configuration of the a-amino acid. 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

A further variant of Method B is the acylation of a 2-aminobenzophenone with a protected a-amino acid chloride, followed by conversion of the product 11 into the 2-(aminoacet-amido)benzophenone 12 by reaction with hydrobromic acid in acetic acid.196... 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

It can also be done by in situ generation of other types of electrophiles. For example, good yields of /V-acyl a-amino acids are formed in a process in which an amide and aldehyde combine to generate a carbinolamide and, presumably, an acyliminium ion. The organopalladium intermediate is then carbonylated prior to reaction with water.254... 

N-Acyl-a-amino acids are important compounds in both chemistry and biology. They are easily obtained in a transition metal-catalyzed, three-component domino reaction of an aldehyde, an amide, and CO. Whereas cobalt was mainly used for this process, Beller and coworkers [159] have recently shown that palladium has a... 

Brusilow, S., Tinker, J. and Batshaw, M. L. Amino acid acylation A mechanism of nitrogen excretion in inborn errors of urea synthesis. Science 207 659,1980. 

In addition to the asymmetric induction mentioned above, sultam 53 can also be used to prepare enantiomerically pure amino acids (Scheme 2-29 and Table 2-10).55 Me AI-mediated acylation of 53 with methyl A-[bis(methylthio)-methylene]glycinate 56 provided, after crystallization, glycinate 57, which can serve as a common precursor for various a-amino acids. In agreement with a kinetically controlled formation of chelated (Z)-enolates, alkylation happened from the SZ-face of the a-C, opposite to the lone pair electrons on the sultam nitrogen atom. High overall yield for both the free amino acid 58 and the... 

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]. 

Scheme 36 Anodic decarboxylation of N-acyl a-amino acids to a N-acycl iminium intermediates.

Oxidative decarboxylation of a-amino carboxylic acid The electrochemical oxidation of Al-acyl-a-amino acids (96) in MeOH affords N, O-acetals (98) through acyliminium intermediates (97) (Scheme 36) [121]. 

N-acylated and N-oxycarbonylated a-amino acids Quinine, quinidine, epiquinine and epiquinindine tcrt-butylcarbamate Methanol—O.IM 204 ammonium acetate, pH 6.0 (80 20)... 

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