Amino acid A-Carboxyanhydride NCA

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... 

Fig. 32 Flow microreactor system consisting of a polydimethylsiloxane (PDMS) multilayered laminar micromixer and PTFE microtubes for polymerization of amino acid A-carboxyanhydride (NCA) initiated by triethylamine...

Over the past few decades, many functionalized monomers for chemical modification of PLA were designed and synthesized, including (1) morpholine-2,5-dione derivatives, (2) a-amino acid A-carboxyanhydrides (NCA), (3) cyclic carbonates, and (4) lactones. The monomer units are introduced into the PLA backbones via ROP with lactide and the obtained copolymers are usually random copolymers, block copolymers or block copolymers with a third hydrophilic block - poly(ethylene glycol) (PEG). 

Vayaboury W, Giani O, Cottet H, Deratani A, Schue F (2004) Living polymerization of alpha-amino acid N-carboxyanhydrides (NCA) upon decreasing the reaction temperature. Macromol Rapid Commun 25 1221-1224... 

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]. 

Acylation of anoino acids or peptides with Z-protected amino acids can be performed with aU known methods including the a-amino acid Al-carboxyanhydrides (NCAs), since protocols for the preparation of the highly reactive Z-protected NCAs are now available (see Section 3.4.2).t l Moreover, since formation of oxazol-5(4//)-ones is very slow with urethane-type protecting groups, racemization, at least by this mechanism, is largely suppressed (see Sections 1.2.1.2 and 7.4).[ 5.n,52]... 

There are several ways to prepare peptides, polypeptides, and artificial proteins carrying these aromatic amino acids as their constituents. Homopolypeptides can be prepared by the polymerization of amino acid N-carboxyanhydrides (NCAs) derived from the corresponding amino acids ( ). Sequential polypeptides of the form (ABC...W) are prepared by the polymerization of the corresponding oligopeptide active esters ABC...W-X. Small peptides of any sequence can be synthesized by a step-by-step procedure (5). Finally, cultivation of some bacteria in the presence of artificial amino acids will possibly incorporate them into the proteins produced by the bacteria. In the following, attention will be focused on homopolypeptides and sequential copolypeptides carrying one type of chromophore on a chain. 

Optimal reaction conditions were used for ball milling of stoichiometric amounts of variety of Boc-protected a-amino acid A-carboxyanhydrides (Boc-AA-NCA) 92 or Boc-protected a-amino acid A-hydroxysuccinimide esters (Boc-AA-OSu) 95 with a-amino acid alkyl ester salts (Schemes 3.26 and 3.27, Tables 3.9 and 3.10). In this way, di- to pentapeptides 97 and 100 were produced in high yield and environmentally benign manner. For some of the reactions, iBuOAc was used as a grinding auxiliary. Furthermore, it was established that no racemization could be observed as the diastereomeric excess of some products was checked and was found to be superior to 98%. After completion of Boc-AA-OSu reactions, mixture was milled for 5 min at 30 Hz with aqneous NaOH solution, diluted with EtOAc, and washed with sodium carbonate and dilnted acid. Pentapeptide Boc-Tyr(Bn)-Gly-Gly-Phe-Leu-OBn product obtained mechanochemically was successfully converted to Leu-enkephaUn by classical methods. 

The most popular approach for the synthesis of polyamides from amino acids [224] is the amino acid V-carboxyanhydride (NCA) method (Fig. 31) [225]. The initiation with a base such as a tertiary amine is followed by the reaction of another NCA molecule with the resulting activated NCA anirm to produce a dimer with an electrophilic N-acyl NCA end group and a nucleophihc carbamate group. Then, N-carbamic acid is detached as carbrai dioxide during the propagation reaction. It is known that deprotonation of NCA and attack of the NCA anion are relatively fast... 

Scheme 5.10 Anionic ring-opening polymerization of a-amino acid N-carboxyanhydride (NCA).

The benefit of microreaction systems is not limited to cationic or radical polymerization. Amino acid polymerization using a-amino acid V-carboxyanhydride (NCA) yielded better molecular weight distribution when performed in a microreactor [5]. Also, the average molecular weight could be controlled by changing the flow rates. 

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

Aoi K, Tsutsumiuchi K, Okada M (1994) Glycopeptide synthesis by an alpha-amino-acid n-carboxyanhydride (NCA) method - ring-opening polymerization of a sugar-substituted NCA. Macromolecules 27(3) 875-877... 

Synthetic peptide-based polymers are not new materials homopolymers of polypeptides have been available for many decades, yet have only seen limited use in materials applications. However, new methods in chemical synthesis have made possible the preparation of increasingly complex polypeptide sequences of controlled molecular weight that display properties far superior to ill-defined homopolypeptides. Examination of the different methods for polypeptide synthesis reveals the limitations of these techniques for preparation of well-defined copolymers. Conventional solid-phase peptide synthesis is neither useful nor practical for direct preparation of large polypeptides (> 100 residues) due to unavoidable deletions and truncations that result from incomplete deprotection and coupling steps. The most economical and expedient process for synthesis of long polypeptide chains is the polymerization of a-amino acid N-carboxyanhydrides (NCAs)... 

H) Combination of NMP and NCA poiymerization Another strategy to constmct polymer-peptide bioconjugates is to combine the polymerization of a-amino-acid-iV-carboxyanhydrides (NCA) with NMP. ° NCA... 

The oldest example of a CCP in a laboratory are polymerizations of a-amino acid N-carboxyanhydrides (NCAs, 2,5-dioxo-oxazolidines, see Formula 16.2). Synthesis and polymerization of these amino acid derivatives were first described by Leuchs and coworkers in the years 1906-1908 [3-5]. The existence of long covalent polymer chains was not accepted by the scientific community at that time, and poly(a-amino acid)s which are insoluble in almost all organic solvents were difficult to characterize. Therefore, Leuchs abandoned this working field after three... 

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