N-Acylamino acids

As this review is devoted to derivatives of amino acids and peptides linked to fatty acids by amide bonds, lipids containing ester-bound amino acids such as ornithine esters of phosphatidylglycerol (i) or lysine esters of diglycerides (2) will not be considered. 

The search for lipids containing amino acids in a lipidic bacterial extract makes it necessary to exclude the presence of free amino acids or peptides that can frequently exist as contaminants in lipid extracts. Water-soluble contaminants can be removed by washing a chloroform phase with methanol-water ( Folch wash ) (5) or by passage of a chloroform solution of the crude extract through a column of Sephadex G-25 4,5). 

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CARBODIIMIDE-MEDIATED REACTIONS OF N-ACYLAMINO ACIDS AND PEPTIDES... 

Scheme 1 a Amidocarbonylation of aldehydes b Applications of N-acylamino acids... 

Nohira et al. treated N-acylamino acids 195 with thionyl chloride mixed anhydrides 196 were formed below 30°C. The latter compounds gave the first type of hexahydro-2//-3,l-benzoxazin-4-one 197 on triethylamine treatment [77H(7)301]. This reaction was also performed with diexo- and diendo-substituted j8-amino acids 198 yielded the 5,8-methano-2//-3,l-benzoxazin-4-ones 199 via the acyl derivatives 200 (84S345,84T2385). Further homologs were also prepared by the dehydration of N-acylamino acid derivatives (85MI1 88MI3). 

In the third transition state (TS3), the neutral catalyst is recovered by transferring the proton back from the catalyst to the substrate. In other words, the (former) azlactone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer, again a low-barrier hydrogen bond is formed (N—O distance 2.479A, <(0,H,N) = 166.2°). In the product complex, the catalyst is neutral and the N-acylamino acid ester is bound in its iminol form to the catalyst (Product [iminol]). Finally, an additional 66.6kJ/mol are gained by the subsequent iminol-amide tautomerization (Product [amide]). 

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

Munchnones were generated from the corresponding N-acylamino acids using acetic anhydride in toluene at 80°C. 

The miinchnones were generated in situ by the cyclodehydration of their N-acylamino acid precursors with DCC in toluene (25-60°C). 

From Other N-Acylamino Acid Derivatives and Glycine Equivalents... 

TABLE 7.34 SYNTHESIS OF UNSATURATED 5(4//)-OXAZOLONES FROM N-ACYLAMINO ACID DERIVATIVES AND VILSMEIER-HAACK REAGENT, 2/7... 

N-acylamino acids does not appear to have been studied previously. In solution, N-acyl-N-nitroso-a-amino acids are moderately stable to weak bases, such as triethylamine or sodium carbonate, but are decomposed rapidly at 0° to expel nitrogen on addition of sodium hydroxide (43). For example, treatment of N-nitroso-N-benzoyl-D,L-pheny1-alanine LXIIb with an aqueous sodium hydroxide solution at 0 gives benzoic acid and 1-hydroxy-3-phenylpropanoic acid LXVa in a 93% yield. The facile base-catalysed formations of a-hydroxy acids LXV are a general reaction and probably occur by intramolecular attack as shown in LXII->LXIII->LXIV. Oxadiazolone LXIV can decompose by various possible pathways to give LXV among which the carbonium ion pathway is least likely. 

Figure 10.16 Subtilisin-catalyzed hydrolysis of N-acylamino acid esters.

Subtilisin is an endoprotease that has been used in the enantioselective hydrolysis of N-acylamino acid esters (Figure 10.16) into the corresponding (S)-amino acid derivatives. An organic solvent, such as acetonitrile, is often added to improve the solubility of the amino acid derivative, and this function can also be performed by an ionic liquid mixture [133, 134, 135]. 

M.-R. Kula, Screening, overexpression and characterization of an N-acylamino acid racemase from Amycolatopsis orientalis subsp. lurida, Appl. Microbiol. Biotechnol. 2001, 55, 354-361. 

The 2,6-dichloropyridine /V-oxidc-Ru(IV)(TMP)Cl2 (TMP = tetramesitylporphy-rinato) system converts /V-acyl cyclic amines to N-acylamino acids via oxidative C-N bond cleavage. The kinetic isotope effect was measured using N-benzoyl [2,2-di Ipyrrolidine. The intramolecular kinetic isotope effect in the oxidation of was found to be 9.8 0.2, strongly suggesting that the rate-determining step is hydrogen abstraction and not one-electron oxidation.75... 

Most of the experiments on incorporating amino acid esters into proteins during the plastein reaction have been carried out with papain, indicating that it is one of the best enzymes for this purpose. Other enzymes such as chymotrypsin (40) or carboxypeptidase Y from Sac-charomyces cerevisiae (41) are potent catalysts for peptide synthesis in homogeneous systems using N-acylamino acid esters of peptides as substrates and amino acid derivatives or peptides as nucleophile components. Adding organic co-solvents favored peptide bond synthesis (42,43). 

All valence electron MO calculations have been extended to the prediction of amino acid residue conformations. The approach has generally been to consider a model compound, such as an N-acylamino acid amide to simulate the mid-chain residue. Beginning with three independent studies reported in 1969 ( 56—58) a number of amino acid residue conformations have been predicted to date from all valence MO methods. Specific examples of amino acid residues studied, with references in order of appearance in the literature are glycine (56-59), alanine (56, 57, 59), phenylalanine (57), proline (57, 60), hydroxyproline (60), serine (61, 62), isoleucine (61, 88), valine (61,88), threonine (62), leucine (61,88), arginine (N-terminal) (63), arginine (C-terminal) (63), arginine side... 

Phenolic esters are obtained similarly. The presence of a nitro group in the aromatic nucleus and the use of pyridine as solvent facilitates the reaction. This reaction is recommended for the characterization of phenols. 2,4,5-Trichlorophenyl-, pentachlorophenyl-, 4-nitrophenyl- and thiophenyl esters of N-acylamino acids are prepared in this manner. These aromatic esters are used in the stepwise lengthening of peptides, du Vigneaud and coworkers synthesized lysine vasopressin from a nonapeptide which they prepared stepwise using the nitrophenyl ester method. Room temperature esterification of dicarboxylic acids and diphenols are also carbodiimide mediated using the 1 1 complex derived from DMAP and p-toluenesulfonic acid as catalyst Methacrylic acid is also esterified with phenols using carbodiimides and DMPA to mediate the reaction. ... 

Cationic ruthenium bisphosphine complexes, particularly those of BINAP, have been extensively used for the hydrogenation of carbon-carbon double bonds in enamides ". For example, the Ru-BINAP catalyst [Ru(MeOH)2BINAP]BF4 (6.13) is used for the enantiose-lective synthesis of N-acylamino acid 6.15 from a-(acylamino)acrylic acid 6.14. 

Knorr, R., Huisgen, R. Mechanism of the Dakin-West reaction. I. Reaction of secondary N-acylamino acids with acetic anhydride. Chem. Ber. 1970,103, 2598-2610. 

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