N-Carboxy anhydrides

By means of a ring-opening polymerization of the condensation type Vlasov et al. [50] synthesized polypeptide based MAIs with azo groups in the polymeric backbone. The method is based on the reaction of a hydracide derivative of AIBN and a N-carboxy anhydride. Containing one central azo group in the polymer main chain, the polymeric azo initiator was used for initiating block copolymerizations of styrene and various methacrylamides. 

Lutz JF, Schutt D, Kuhowicz S (2005) Preparation of well-defined diblock copolymers with short polypeptide segments by polymerization of N-carboxy anhydrides. Macromol Rapid Commun 26 23-28... 

WD Fuller, M Goodman, FR Naider, Y-F Zhu. Urethane-protected a-amino acid N-carboxy-anhydrides and peptide synthesis. Biopolymers (Pept Sci) 40, 183-205, 1996. 

D-Glutamic acid-g-(t-butyl)ester N-carboxy anhydride was previously polymerized by Fujimoto et al. (1) in a l,2-dichloroethane/l,4-dioxane mixture using sodium 4-methyl-2-pyrrolidone as initiator. Additional derivatives were... 

Rude and coworkers prepared the per-O-acetylated 3-O-glycosyl-serines from several mono- and di-saccharides, which were converted into the N-carboxy anhydrides (Leuchs anhydrides) of serine by treatment with phosgene in an inert solvent,68-70 as shown in Scheme 8. 

Lundenberg, R. D., and P. Doty Polypeptides. XVII. A study of the kinetics of the primary amine-initiated polymerization of N-carboxy-anhydrides with special reference to configurational and stereochemical effects. J. Amer. Chem. Soc. 79, 3961 (1957). 

Because the catalyst is usually prepared by the polymerization of amino acid N-carboxy anhydrides, induced by water or amines [66, 67], the Julia-Colonna epox-idation was soon recognized as a reaction of great practical value. In the course of exploration of the scope of the Julia-Colonna procedure many enone substrates were successfully epoxidized by use of the original three-phase conditions (Table 10.8). 

Kinetic resolution of chiral, racemic anhydrides In this process the racemic mixture of a chiral anhydride is exposed to the alcohol nucleophile in the presence of a chiral catalyst such as A (Scheme 13.2, middle). Under these conditions, one substrate enantiomer is converted to a mono-ester whereas the other remains unchanged. Application of catalyst B (usually the enantiomer or a pseudo-enantiomer of A) results in transformation/non-transformation of the enantiomeric starting anhydride ). As usual for kinetic resolution, substrate conversion/product yield(s) are intrinsically limited to a maximum of 50%. For normal anhydrides (X = CR2), both carbonyl groups can engage in ester formation, and the product formulas in Scheme 13.1 are drawn arbitrarily. This section also covers the catalytic asymmetric alcoholysis of a-hydroxy acid O-carboxy anhydrides (X = O) and of a-amino acid N-carboxy anhydrides (X = NR). In these reactions the electrophilicity of the carbonyl groups flanking X is reduced and regioselective attack of the alcohol nucleophile on the other carbonyl function results. 

Kinetic Resolution of N-Urethane-protected Amino Acid N-Carboxy Anhydrides... 

Deng et al. reported in 2001 that a wide variety of N-urethane-protected N-carboxy anhydrides such as, for example, rac-18 shown in Scheme 13.9 undergo kinetic resolution when treated at low temperature with alcohols in the presence of dimeric cinchona alkaloids such as (DHDQ)2AQN, 11 [20], The N-carboxy anhydrides rac-18 were prepared from the racemic amino acids rac-17 by a two-step procedure involving cyclization with diphosgene and subsequent N-protection with, e.g., Cbz or Fmoc. The kinetic resolution of rac-18 proceeded with excellent... 

Analogous treatment of the aryl N-carboxy anhydrides rac-18 at higher temperature induces simultaneous racemization of the starting material. As a conse-... 

Scheme 13.9 summarized kinetic resolution of N-urethane protected N-carboxy anhydrides rac-18 by methanolysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Deng et al. [20]. These kinetic resolutions were typically conducted at low temperature - from —78 to —60 °C. Deng et al. later observed that if the reaction temperature was increased racemization of the starting aryl N-carboxy anhydrides rac-18 becomes sufficiently rapid to enable a dynamic kinetic resolution [21]. Configurational stability of the product esters... 

R)-19 under the reaction conditions is a pre-requisite that is again fulfilled in this process. As shown in Scheme 13.13, enantiomeric excesses > 90% and almost quantitative yields were achieved for several aryl N-carboxy anhydrides. In these examples allyl alcohol was used as the nucleophile. The corresponding amino acids can be liberated quantitatively and with unchanged ee from the esters (R)-19 by Pd-catalyzed deallylation, using morpholine as the nucleophile (Scheme 13.13) [25]. 

Urethane-protected alkyl N-carboxy anhydrides do not racemize effectively under the conditions established for the dynamic kinetic resolution of aryl N-carboxy anhydrides. As for the l,3-dioxolane-2,4-diones rac-29 (aryl, Scheme 13.12) and rac-15 (alkyl, Scheme 13.8) this different reactivity can be attributed to the lower acidity of the a-CH in the alkyl-substituted anhydrides. To overcome this hurdle Deng and... 

Readily available by polymerization of e.g. amino acid N -carboxy anhydrides... 

They can be synthesized easily, up to a molecular weight of 106, by polymerization of N-carboxy anhydride derivatives of amino acids. When the configuration of the chiral carbon atoms is l for all the amino acid monomer units along the macromole-cular chains, they can be considered simple synthetic analogues of proteins. 

In pioneering articles published in 1966 and 1967, Goodman et al. described a series of polypeptides derived from p-phenylazo-L-phenylalanine and y-benzyl-L-glutamate by polymerization of the corresponding N-carboxy anhydrides (Scheme 2).118,191... 

UNCA urethane-protected a-amino acid N-carboxy anhydride... 

Kricheldorf HR (1987) a-Aminoacid-N-Carboxy-Anhydrides and Related Heterocycles. Springer, Berlin Heidelberg New York... 

The method of synthesis20-25 consists in the preparation by anionic polymerization of a monodisperse first block, followed by chemical modification of its living end in order to introduce a terminal primary amine function into the molecule this to aminated polymer is then used as a macromolecular initiator for the polymerization of the N-carboxy anhydride (NCA) of the desired amino add. 

Turning finally to redox-to-condensation energy coupling, the simplest case is shown in reaction (5). COS in turn will be the substrate for various forms of condensation-to-condensation energy couplings. For example, C-C-bond formation by car-boxylation with COS will generate thioacids (3). Similarly, carboxylations of a-amino acids by COS generate thiocarbox-amides en route to aminoacyl N-carboxy-anhydrides ... 

Kricheldorf, H., a-Aminoacid-N-Carboxy-anhydrides and Related Heterocycles - Synthesis Properties, Peptide Synthesis, Polymerization, Springer Berlin, (1987) p 3. Leuchs, H. Geiger, W., Ber. Dtsch. Chem. Ges, (1908) 41, 1721. 

Selection of Optical Antipode of the N-Carboxy Anhydride in the Polymerization to Helix-Forming Polypeptide.95... 

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