Carboxy anhydrides, acylation with

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. 

Alkylation of ll-mercaptopyrido[l,2-h]cinnolin-6-ium hydroxide inner salts (e.g., 41) with ethyl bromoacetate gave ll-(ethoxycarbonylmethyl(thio derivatives 64 (R = H), which could be hydrolyzed to the ll-(carboxy-methyl)thio derivative or back to the starting compound 41 (74JHC125). Hydrolysis of the ll-bis(methoxycarbonyl)methylene 66 (R = H), and 2-cyano derivatives of 17 (R = H) in boiling HCl afforded 11-methyl and 2-carboxylic acid derivatives, respectively (74JHC125). The 2-nitro derivative of 17 (R = H) was reduced to the 2-amino derivative over Pd/C with NaBH4 in aqueous methanol, and the 2-amino group was acylated with acetic anhydride at 100°C. 

A route to /3-methyl-tetrahydroberberines has been developed from the hydra-stinine derivative (72), which can be acylated with the dimethoxyhomophthalic anhydride (73) to give acid (74). Reduction of this with lithium aluminium hydride followed by further reduction of the toluene-p-sulphonyl ester of the resulting hydroxymethyl compound yields the 13-methyl compound.91 An essentially similar synthesis of oxoberberines bearing a carboxy-group at C-13, of general type (74), has been reported by other workers.92... 

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

Polymerization via monomer anions without added activator behaves quite differently. In this case, theo>-amino acyl lactam activator is first formed in a slow reaction, and then, the polymer chain is started in a fast subsequent reaction. Further a>-amino acyl lactam molecules are formed continuously during the polymerization. Only when all base molecules react with monomer molecules before the other monomer molecules are consumed by formation of polymer chains is the degree of polymerization given by the ratio of monomer to base concentration. Since this is mostly not the case, there is no relationship between the ratio [monomer]/[base] and the degree of polymerization. Similar relationships occur for the polymerization of iV-carboxy anhydrides of a-amino acids with strong bases. 

The method was therefore improved by acylating N-hydroxyglycine and several derivatives (Scheme 65) with N-carboxy anhydrides (322) of amino acids, the reactions being carried out in acidic medium to... 

N-carboxy anhydrides of amino acids (326), obtained fromN-benzyloxy-amino acids as crystalline derivatives by reaction with phosgene. Acylation of glycine methyl ester by (326) gave the corresponding peptides... 

Quantitative N-acylation of the terminal Hmb residue, even with the aid of the acyl transfer mechanism, requires special attention. As illustrated in Figure 4, an initial base-catalysed esterification occurs which is favoured through tautomer 4c. Optimal acylation occurs via symmetric anhydride (7) Protocol 4), urethane-A -carboxy anhydride (58), or pre-formed acid fluoride (59) in the apolar aprotic solvent dichioromethane, conditions which preserve the crucial hydrogen-bonded structure 4c. Typical acylation times are detailed in Table 1. 

Enalapril [75847-73-3], antihypertensive (ACE inhibitor), 93. In one method, phosgene is used to activate L-alanine 89 as its N-carboxy anhydride (NCA) 90, which is then used to acylate the L-proline 91 affording the semisynthetic dipeptide Ala-Pro 92 [68], Processes based on the reaction of activated derivatives of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine with L-proline have also been reported [69-71]. 

Chlorothalidone Chlorothalidone, 2-chloro-5-(l-hydroxy-3-oxo-l-isoindolinyl)benzol-sulfamide (21.3.26), is synthesized by two proposed methods from 2 -carboxy-4-chloroben-zophenone (21.3.21), which is easily synthesized by acylating chlorobenzol with phthalic anhydride in the presence of aluminum chloride. The resulting benzophenone (21.3.21)... 

Limiting essential amino acids covalently attached to proteins by using activated amino acid derivatives can improve the nutritional quality and change the functional properties of proteins. The best chemical methods for incorporating amino acids into water-soluble proteins involve using car-bodiimides, N-hydroxysuccinimide esters of acylated amino acids, or N-carboxy-a-amino acid anhydrides. The last two methods can give up to 75% incorporation of the amount of amino acid derivative used. With the anhydride method, as many as 50 residues of methionine have been linked to the 12 lysine residues of casein. The newly formed peptide and isopeptide bonds are hydrolyzed readily by intestinal aminopeptidase, making the added amino acids and the lysine from the protein available nutritionally. 

Silyl esters are stable to nonaqueous reaction conditions, but are often too labile to mild acid or base or even neutral aqueous media to survive many simple manipulations. Thus, they have not found wide application in peptide synthesis. Due to easy formation and cleavage they may play an important role as intermediates in the synthesis of amino acid derivatives and for temporary carboxy protection in the preparation of small peptide fragments. The TMS group has been used for the solubilization of H-Arg-OH for the synthesis of Z-Arg(Z2)-OHP l and in the synthesis of Al -Nps- and Al -Tfa-protected amino acids.P Amino acid trimethylsilyl esters as well as the related A1 -TMS derivatives react rapidly with acylating agents and are used for the preparation of peptides with amino acid active esters, e.g. A-hydroxysuccinimide-, 4-nitrophenyl-, or 2,4,5-trichlorophenyl esters, or mixed anhydrides. 

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