N-carboxy-a-amino acid anhydrides

Swarc,M. The Kinetics and Mechanism of N-carboxy-a-amino-acid Anhydride (NCA) Polymerization to Poly-amino Acids. Vol. 4, pp. 1—65. 

Trichloromethyl chloroformate has proven effective in the preparation of N-carboxy-a-amino acid anhydrides from amino acids, and various compounds having isocyanate, acid chloride, and chloroformate groups.For example, trichloromethyl chloroformate may be used instead of phosgene in the preparation of 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile. The use of this reagent is illustrated here by the synthesis of 3-isocyanato-propanoyl chloride from 3-aminopropanoic acid hydrochloride. 

R Katakai, Y Iizuka. An improved rapid method for the synthesis of N-carboxy a-amino acid anhydrides using trichloromethyl chloroformate. (diphosgene). J Org Chem 50, 715, 1985. 

Avery interesting method of synthesis of polypeptides from N-carboxy-a-amino acid anhydrides was proposed by Ballard and Bamford. Opening the ring of N-carboxy-a-amino acid anhydrides by primary or secondary amines can be illustrated by the following reaction ... 

Ring-opening copolymerization was simultaneously investigated with homopolymerization of N-carboxy-a-amino acid anhydrides, NCAs, by Bamford at al Polymerization of a mixture of NCAs of y-ethyl-L-glutamate and sarcosine ... 

Anionic Polymerization. Anionic grafting polymerization initiated on the inorganic particles is also possible to give composite particles. The amino group incorporated into the surface of silica caused anionic polymerization of N-carboxy-a-amino acid anhydride to give poly(amino acid) grafting [Reaction (8)1 (21). 

Polypeptides obtained by the anionic polymerization of optically active N-carboxy-a-amino acid anhydrides are apt to have such an ordered structures as a-helices, which is useful for investigation on the relationship between the physical structure and the permeability of the membrane. Takizawa et al.44 46) studied the water permeation and solute separation through poly(n-alkyl L-glutamate) membranes 3. It was concluded that water molecules permeate through relatively large free spaces... 

N-carboxy-a-amino-acid anhydrides react in a variety of ways and, therefore, it is difficult to discuss their polymerisation in a conventional manner, i. e. by separately considering the initiation, propagation and termination steps. It is believed that the reader more easily may comprehend its nature if the material is presented in terms of the chemical behaviour of the monomer towards various reagents. This course, therefore, will be followed in the subsequent sections. 

The N-carboxy-a-amino-acid anhydrides, referred to as Leuchs anhydrides, or briefly as NCA s, are well-defined, colourless, crystalline substances having sharp melting points when pure. The synthesis of the simplest member of this class of compounds, viz. oxazolidine-2,5-dione,... 

Heinze et al. found that DMSO in combination with tetrabutylammonium fluoride trihydrate dissolved cellulose (degree of polymerization < 650) within 15 min at room temperature [38]. They also demonstrated that homogeneous esterification of cellulose is possible in this solvent system. The applicability of this new solvent system to cellulose grafting has recently been proved by adoption of cyclic compounds such as lactones and N-carboxy a-amino acid anhydrides (NCAs) [39]. e-Caprolactone was facilely graft-polymerized on cellulose at a graft rate of 65% (per trunk weight of 100), and NCAs at over 100%, in the respective homogeneous reaction systems at < 60 °C. 

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. 

Synthesis and Polymerization of Leuchs Anhydrides. The N-carboxy-a-amino acid anhydrides, referred to as Leuchs anhydrides or as NCAs, are synthesized either from N-alkoxycarbonyl derivatives of a-amino acids or from free amino acids. Cyclization of the amino acid derivative by SOCl2 or similar reagents was described first by Leuchs in 1906, but direct synthesis involves treating the a-amino acid or its hydrochloride with phosgene as shown in Figure 4. This method, commonly termed the Fuchs-Farthing method, is the one that is used most frequently since the N-carboxyanhydride may be freed easily from the carbamyl chloride, isocyanate derivative, and hydrogen chloride by crystallization. 

The stepwise addition of N-carboxy a-amino acid anhydrides to amino acids or peptides in organic solvents is well documented (for review see Refs. 69 and 70). More recently the method has been applied to peptide synthesis in aqueous solutions (71,72,73). Novel syntheses of N-substituted carboxyanhydrides of a-amino acids have been carried out (74,75) and the crystal molecular structures of several of them have been determined (76,77,78). 

Figure 4. Synthesis of N-carboxy-a-amino acid anhydrides (NCA). THF...

As shown in Figure 5, the coupling reaction between an amino acid and an N-carboxy-a-amino acid anhydride is performed at alkaline pH but the resulting carbamate intermediate is decomposed at acidic pH in order to give the dipeptide and allow further reaction leading to polyamino acids. Polymer formation is performed most frequently at neutral pH since the half-life of the intermediate carbamate is very short (see Figure 6). 

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