Carboxyanhydrides

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). 

Polymerization of amino acid iV-carboxyanhydrides to polypeptides exemplifies another interesting reaction which exhibits a number of unusual features. This reaction has been, and is still being, vigorously investigated by several independent groups of workers, and some recent results are particularly intriguing and deserve a detailed discussion. 

The polymerization of amino acid AT-carboxyanhydrides is described by the following overall equation,... 

Another limitation is related to the fact that synthetic poly(amino acids) have rather unfavorable material properties. For instance, most synthetic poly (amino acids) derived from a single amino acid are insoluble, high-melting materials that cannot be processed into shaped objects by conventional fabrication techniques. The often undesirable tendency to absorb a significant amount of water when exposed to an aqueous environment is another common property of many poly (amino acids) (7). Finally, high molecular weight poly-(amino acids) are best prepared via N-carboxyanhydrides which are expensive to make. Hence poly(amino acids) are comparatively costly polymers, even if they are derived from inexpensive amino acids (8). 

The easy processibility of hydroxyproline-derived polyesters is in marked contrast to the unfavorable material properties of most conventional poly (amino acids) that cannot usually be processed into shaped objects by conventional polymer-processing techniques (7). Furthermore, since the synthesis of poly(N-acylhydroxyproline esters) does not require the expensive N-carboxyanhydrides as monomeric starting materials, poly(N-acylhydroxyproline esters) should be significantly less expensive than derivatives of conventional poly(hy-droxyproline). 

Deming TJ (2000) Living polymerization of alpha-amino acid-N-carboxyanhydrides. J Polym Sci Polym Chem 38 3011-3018... 

Kricheldorf HR (1987) a-Amino acid-N-carboxyanhydrides and related materials. Springer, New York... 

Dimitrov I, Schlaad H (2003) Synthesis of nearly monodisperse polyst3Tene-polypeptide block copolymers via polymerisation of N-carboxyanhydrides. Chem Commun 2944—2945... 

Pickel DL, Politakos N, Avgeropoulos A, Messman JM (2009) A mechanistic study of alpha-(amino acid)-N-carboxyanhydride polymerization comparing initiation and termination events in high-vacuum and traditional polymerization techniques. Macromolecules 42 7781-7788... 

Vayaboury W, Giani O, Cottet FI, Bonaric S, Schue F (2008) Mechanistic study of alpha-amino acid N-carboxyanhydride (NCA) polymerization by capillary electrophoresis. Macromol Chem Phys 209 1628-1637... 

Knobler Y, Bittner S, Virov D, Frankel M (1969) Alpha-aminoacyl derivatives of aminoben-zoic acid and of amino-oxy-acids by reaction of their hydrochlorides with amino-acid N-carboxyanhydrides. J Chem Soc C 1821... 

Peggion E, Cosani A, Mattucci AM, Scoffone E (1964) Polymerization of gamma-ethyl-L-glutamate-N-carboxyanhydride initiated by Di-N-butyl and Di-isopropyl amine. Biopolymers 2 69-78... 

Xiao CS, Zhao CW, He P, Tang ZH, Chen XS, Jing XB (2010) Facile synthesis of glycopo-lypeptides by combination of ring-opening polymerization of an alkyne-substituted N-carboxyanhydride and click glycosylation . Macromol Rapid Commun 31 991-997... 

Kramer JR, Deming TJ (2010) Glycopolypeptides via living polymerization of glycosylated-1-lysine N-carboxyanhydrides. J Am Chem Soc 132 15068-15071... 

Wang J, Gibson MI, Barbey R, Xiao SJ, Klok HA (2009) Nonfouling polypeptide brushes via surface-initiated polymerization of N-epsilon-oligo(ethylene glycol)succinate-L-lysine N-carboxyanhydride. Macromol Rapid Commun 30 845-850... 

Kramer JR, Deming TJ (2010) General method for purification of alpha-amino acid-N-carboxyanhydrides using flash chromatography. Biomacromolecules 11 3668-3672... 

Mori H, Iwata M, Ito S, Endo T (2007) Ring-opening polymerization of gamma-benzyl-L-glutamate-N-carboxyanhydride in ionic liquids. Polymer 48 5867-5877... 

The most general and frequently used method to synthesize long chains of block copolypeptides for vesicle assembly is successive ring opening polymerizations of a-amino acid-Ai-carboxyanhydride (NCA) monomers [18, 20, 21, 39-51]. NCA monomers are readily prepared from commercially available amino acids, most commonly through direct phosgenation [52]. 

Leuchs and co-workers (1906-1908) prepared various polypeptides by decomposing the N-carboxyanhydrides of a-amino acids, but they did not suggest chain formulas for their products. Instead, they assumed that a three-membered ring structure was formed as indicated by the following equation ... 

In order to account for the nonvolatility, infusibility, and limited solubility, Leuchs postulated polymerization of the ground type cyclic compound, as indicated by the subscript x in his formula given above. It is now well established that linear polypeptides are produced on decarboxylation of the N-carboxyanhydrides of a-amino acids, and under favorable conditions the chain length may be fairly large. Leuchs favored the view that strained rings, i.e., those of other than five or six... 

The free amino group of the amino ester may then react analogously with another molecule of the monomer, etc. The kinetics of the polymerization are in harmony with a mechanism of this sort. The final polypeptide may contain up to 300 or more structural units. While the polymerization of N-carboxyanhydrides is closely analogous to the addition polymerizations of ethylene oxide and of other cyclic substances, definition unfortunately classifies it as a condensation polymerization inasmuch as carbon dioxide is eliminated in the process. 

The difficulties of devising a basis for conveniently classifying various polymerizations in an appropriate manner have been discussed earlier in this chapter and several borderline examples which offer particular difficulty have been mentioned. One of these, the polymerization of the N-carboxyanhydrides, falls within the definition of a condensation polymerization, proceeds by a mechanism resembling a vinyl addition polymerization, and yields a product which possesses the structure of a typical condensation polymer. Definitions have been... 

Other cyclic compounds such as the N-carboxyanhydrides of a-amino acids,and lactams may be polymerized similarly with regeneration of an amino group at each step. According to the mechanism postulated, the number of polymer molecules formed should equal the number of initiator molecules (e.g., ROH) introduced, and the average number of monomers per polymer molecule should equal the ratio of monomer consumed to initiator. 

Recently, the Okada group described a new class of polymerization systems [43] oligoglycopeptide-type sugar-balls were obtained by a radial growth polymerization (RGP) of a-amino acid AT-carboxyanhydrides with PAMAM dendrimers of different generations. 

Fig. 5.5 The oligopeptide synthesis at cationic micelles using the condensation agent CDI leads to the intermediate (I), which is in equilibrium with an IV-carboxyanhydride (II). A free primary or secondary amino acid reacts with (II) and forms an amide linkage as well as a carbamide terminus. ...

---