A-Carboxyanhydride

Currently, a-amino acids are prepared by several routes such as by the fermentation of glucose, by enzyme action on several substances and by the hydrolysis of proteins. Many methods for synthesising the polymers are known, of which the polymerisation of A -carboxyanhydrides is of particular interest, as it yield-products of high molecular weight (Figure 18.24). 

FIGURE 4.20 Conversion of enantiomers to diastereomeric products by reaction with an amino acid A-carboxyanhydride.84... 

FIGURE 6.14 Peptide-bond formation by aminolysis of the A-carboxyanhydride of aspartic or glutamic acid, followed by release of carbon dioxide.48... 

FIGURE 7.21 Synthesis of a dipeptide by reaction of an amino-acid A-carboxyanhydride (A) with an amino-acid ester in tetrahydrofuran65 and (B) with an amino acid in aqueous solution.67... 

A-Carboxyanhydrides of amino acids (see Section 7.13) can undergo oligomerization if they are aminolyzed under conditions that are not strictly controlled. A variant of the anhydride that is employed because it does not undergo oligomerization during... 

Note 3 Propagation in chain polymerization often occurs without the formation of small molecules. However, cases exist where, at each propagation step, a low-molar-mass byproduct is formed, as in the polymerization of l,3-oxazolidine-2,5-diones derived from amino acids (commonly termed amino acid A-carboxyanhydrides). When a low-molar-mass by-product is formed, the adjective condensative is recommended to give the term condensative chain polymerization . 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

Figure 3.7 (a) Activation of amino acids by A-carboxyanhydride and (b) their condensation. (Adapted from Ferris, 2002.)... 

NCA-activated aminoacids (NCA = A-carboxyanhydride) to the lipophylic surface of palmitoyl-oleyl-phosphatidyl-choline (POPC) liposomes, has permitted the condensation of Trp-oligomers up to a polymerisation degree of eighteen, which is considerable, given that in water the synthesis by way of the same reaction is limited to oligomers of five to six due to their insolubility. The hydrophobic character of the liposome shell can also operate the chemical selection from a mixture of solutes, as illustrated qualitatively in the Figure 10.4 the most hydrophobic solute can in principle be selected out followed by selective polycondensafion. 

Blocher, M., Hitz, T., and Luisi, P. L. (2001). Stereoselectivity in the oligomerization of racemic Tryptophan A-Carboxyanhydride (NCA-Trp) as determined by isotopic labelling and mass spectrometry. Helv. Chim. Acta, 84, 842-8. 

Taillades, J., Cottet, H., Garrel, L et al. (1999). A-Carbamoyl amino acid solid-gas nitrosation by NO/NOx a new route to oligopeptides via a-amino acid A-carboxyanhydride. Prebiotic implications. /. Mol. Evol., 48, 638 5. 

Observations Until a method not requiring A-carboxyanhydride for the formation of... 

A flask charged with A-carboxyanhydrides of tyrosine (14.5 mmol), alanine (72.1 mmol), y-methoxyglutamate (22.2 mmol), and e-A-Boc-lysine (51.5 mmol) were treated with 583.3 ml of dioxane and then stirred for 30 minutes and treated with 116 jlL of diethyl amine. Within the first hour the mixture became viscous and very cloudy. After 24 hours the mixture was quenched by pouring into a second flask containing 1.58 liter of water and awhile colored solid collected. The precipitate was dried by vacuum filtration and washed six times with 250 ml of water and then dried overnight and the product isolated. 

The polymerisation of a-aminoacid A-carboxyanhydride, which is accompanied with the elimination of carbon dioxide, constitutes a convenient method for preparing high molecular weight polypeptide. This polymerisation, with the use of a-aminopropionic acid (alanine) A-carboxylic acid anhydride as a monomer, was also carried out in the presence of coordination catalysts such as group 2 and 3 metal alkyls [168-174] or their combinations with water, secondary amine or alcohol [168,173] and yielded polyalanine (Table 9.2). 

Poly(amino acids) are insoluble in common solvents, are difficult to fabricate due to high melting point, and absorb a significant amount of water when their acid content reaches over 50 mol%. To solve these problems, polyesters derived from amino acids and lactic acids [e.g., poly (lactic acid-co-lysine) PLAL] are developed. The PLAL system is further modified by reaction with lysine A-carboxyanhydride derivatives. Another modification of poly(amino acids) includes poly(iminocarbon-ates), which are derived from the polymerization of desaminotyrosyl tyrosine alkyl esters. These polymers are easily processable and can be used as support materials for cell growth due to a high tissue compatibility. Mechanical properties of tyrosine-derived poly(carbonates) are in between those of poly(orthoesters) and poly(lactic acid) or poly(gly-colic acid). The rate of degradation of poly(iminocarbonates) is similar to that of poly (lactic acid). 

Many processes have been proposed for the formation of prebiotic peptides. Peptide bond formation from free amino acids can become thermodynamically favorable using physical or chemical means for dehydration (6, 36). Alternatively, activated amino acid derivatives are capable of polymerizing into oligopeptides in aqueous solution. A pathway for the formation of a-amino acid thioesters starting from sugar precursors has been discussed (37). a-Amino acid A-carboxyanhydrides (NCAs) correspond to... 

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