V-acyl amino acids

In Scheme 8, five possible electrochemical pathways for the formation of V-acyli-minium ions are represented. Pathway a (see Sec. VIII.A) describes the direct anodic oxidation of amides and carbamates to the intermediated V-acylium ions via removal of one electron from the nitrogen lone pair followed by deprotonation in a-position of the nitrogen atom and further one-electron oxidation. In pathway b (see Sec. VIII.C), a decarboxylative methoxylation of an V-acylated amino acid (Hofer-Moset reaction) leads to the same intermediate. The radical that is formed after anodic decarboxylation is immediately further oxidized to the cation due to the electron donation of the nitrogen. Pathway c (see Sec. VIII.B) describes the anodic oxidation of an V-acylated amino... 

Table 3 Fonnation of a-Amino Ketones from Various o-V-Acylated Amino Acids and Organometallic Reagents...

Same properties as V-acyl amino acid salts Soluble in weak pH Compatible with cationic surfactants if n is high... 

The /V-acyl amino acids give the corresponding iV-alkyl amino alcohols under these conditions (eq 9) 44). 

Several hundred tons of L-methionine per year are produced by enzymatic conversion in an enzyme membrane reactor. An alternative approach is dynamic resolution, where the unconverted enantiomer is racemized in situ. Starting from racemic /V-acetyl-amino acid, the enantioselective L-acylase is used in combination with an TV-acyl-amino acid racemase to enable nearly total conversion of the substrate. 

Acylation of /V-Alkyl Amino Acids during Peptide Synthesis... 

Steric factors play a major role in the acylation of /V-alkyl amino acids during peptide synthesis. It is expected that the increased nucleophilicity of secondary amines, as compared to primary amines, will increase the rate of acylation. However, the opposite is observed acylation of /V-alkyl amino acids (except for Pro) is usually slower than the acylation of primary amines. This is explained by steric hindrance exerted by the /V-alkyl group, which shields the nucleophilic center. The steric effect increases with the size of the /V-alkyl group and is enhanced by bulky side chains and, to a lesser extent, by other remote groups. The relative rate of acylation of various types of /V-alkyl amino acids, as compared to amino acids, is shown in Scheme 35. 

Acylation of the secondary amino group of Pro usually occurs in excellent yields.[15016S1 Apparently, the steric effects exerted by the 8-methylene are minimized by the ring and are also compensated by the increase in nucleophilicity of the secondary amino group. In contrast, acylation of acyclic /V-alkyl amino acids is difficult and standard reagents are often inefficient. Acylation of /V-methyl amino acids and /V-alkylglycines (R2=H R4 other than... 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

The hydrolysis of an IV-acylated amino acid by an enzyme provides a resolution method to amino acids. Because the starting materials are readily available in the racemic series by the Schotten-Baumann reaction, the method can be cost effective (Scheme 2.21).68-71 The L-amino acid product can be separated by crystallization, whereas the D-amino acid, which is still /V-acylated, can be recycled by being resubjected to the Schotten-Baumann conditions used for the next batch. Tanabe has developed a process with an immobilized enzyme,72 73 whereas Degussa uses the method in a membrane reactor.69 74 The process is used to make L-methionine. 

A series of 3-V-acyl-betulinc acid derivatives were synthesized to explore the SAR. The structures of 3p-V-acyl-betulinc acid derivatives (276-278) and 3a-V-acyl-betuhnc acid analogs (279-281) are shown in Figure 9-13. None of them showed comparable activity with the corresponding 3p-0-acyl BA derivatives. Therefore, amino-acyl substitution at position 3 is not favorable for anti-HIV activity. ... 

An improved approach to enzyme-catalysed peptide synthesis stems from a thorough understanding of the kinetics and mechanism of action of proteinases. Many proteinases function by the Ping Pong Bi Bi mechanism (Roberts, 1977) and hydrolysis of an V-protected amino acid or peptide ester involves the acylation of a Ser or Cys side-chain by the ester with the liberation of the relevant alcohol or amino component and the formation of a covalent O- or S-acylated enzyme. The latter is hydrolysed in a second step ... 

The catalyst for cleavage of peptide deformylase was searched with a library of catalyst candidates synthesized by the Ugi reaction (Scheme 2) (134). In this multicomponent condensation reaction, the mixture of a carboxylic acid, an amine, an aldehyde, and an isocyanide produces an iV-acyl amino acid amide. The catalyst candidates, therefore, are iV-acylamino acid amides containing various polar and nonpolar pendants as well as the Co(III) complex of cyclen. The Co(III) complex of cyclen (135) was chosen as the proteolytic center in view of the results described in Section V.A. Cyclen with three secondary amines protected with ferf-butyloxycarbonyl (t-boc) groups was incorporated in either the carboxyl or the amine component of the Ugi reaction. Later, the t-boc groups were removed and Co(III) ion was inserted to the cyclen portion. 

Imide formation. N-Carboxy-a-dehydroamino acid anhydrides couple with. V-protected amino acids. Such anhydrides usually serve as acylating agents for amines. 

Tenuazonic acid (741), a phytotoxin produced by Alternaria spp., is structurally related to the tetramic acid family of compounds, and has been found to exhibit antibiotic activity (511). Since 1964, there have been several publications on the total synthesis of 741 (512-515), including the report by Poncet and his group in 1990 (516) (Scheme 11.10). A general method to synthesize the tetramic acids is an intramolecular Dieckmann cyclization of (V-acyl amino esters. Beginning with methyl L-isoleucinate 780, the A/-acyl compound 782 was obtained through a nucleophilic reaction (512), which then cyclized to tenuazonic acid 741 under basic conditions and neutralization by acidic work-up. The synthetic product showed a diastereomeric excess of 89%, with the major epimer presenting the same configuration as its precursor (517). 

Chuyen, N.V. Kurata, T. Fujimaki, M. Formation of V-[2(3-alkylpyrazin-2-on-l-yl)acyl] amino acids or peptides on heating tri- or tetra peptides with glyoxal. Agric. Biol. Chem. 1973b, 37, 1613-1618. 

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