Leuchs anhydride

N-Carboxy-a -amino-carbonsaure-anhydride (Leuchs-Anhydride, 2,4-Dioxo-tetrahy-dro-l,3-oxazole) werden durch Lithiumalanat reduktivzu 2-Amino-alkoholen (neben wenig N-Formyl-aminosaure) aufgespalten z.B.2 ... 

However, in the presence of COCI2, the amino acids are converted to cyclic anhydrides, which are referred to in peptide chemistry as Leuchs anhydrides . These polymerize in aqueous media to give peptides, without the formation of larger amounts of diketopiperazines (Brack, 1982). 

The formation of peptides from Leuchs anhydrides proceeds without the use of protecting groups, and no racemisation occurs. However, the use of phosgene cannot be considered a prebiotic process ... 

Fig. 5.2 Peptide synthesis using Leuchs anhydrides amino acid 1 (with residue Ri) is reacted with phosgene to give the Leuchs anhydride. This reacts with amino acid 2 (residue R2) to give the peptide carbamate. The dipeptide is obtained after cleavage of C02...

While lactams are often polymerized by anionic ROPs, A-carboxyl-alpha-amino acid anhydrides, called Leuchs anhydrides, can be polymerized by either cationic or anionic techniques (structure 5.29). These polypeptide products, which are called nylon-2 products. 

Symmetrical piperazine-2,5-diones have been obtained in good yields by treating Leuchs anhydrides (l,3-oxazolidine-2,5-diones) with aziridine [70AG(E)162]. The reaction apparently proceeds through the formation of dipeptide aziridides (Scheme 5). 

Reaction of Leuchs Anhydrides (NCA) with primary and secondary amines 4... 

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,... 

The Leuchs anhydrides are extremely reactive compounds, and most of them may be stored in a dry state only below —20 or —30° C. At 10° C they dissolve in water with little decomposition1, but eventually... 

The reaction of Leuchs anhydrides with primary and secondary amines proceeds in two ways, viz. 

In an excess of Leuchs anhydride the amine formed from NCA by the action of another amine reacts again with a molecule of NCA and produces a dimer possessing a terminal amine group. Repetition of these reactions leads, therefore, to amine-terminated polypeptides. Hence, the "normal or "simple" amine-propagated polymerisation of Leuchs anhydrides is described by the overall reaction,... 

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. 

Mixed bis-lactim ethers of type (20) are best prepared by the following route, outlined for the bis-lactimether (20a) of Cyclo(L-Val-Ala). L-Val, the chiral auxiliary, is converted with phosgene into its N-carboxyanhydride (L-Val-NCA, Leuchs anhydride) (17)l5). This gives with D,L-Ala-OCH3 the dipeptide (18) which on heating in toluene cyclizes to the diketopiperazine (19). This is converted into the bis-lactim ether (20a) [(3RS, 6S)-2,5-dimethoxy-6-isopropyl-3-methyl-3,6-dihydropyra-zine] with methyl Meerwein s salt. 

The N-Carboxy-Amino Acid Anhydride Method. Since the isopeptide bond of e-methionyllysine was hydrolyzed readily by intestinal aminopeptidase and the released amino acid was biologically available, we decided to further increase the amount of covalently attached methionine through a polymerization reaction. The most suitable amino acid derivative for this approach is the N-carboxyanhydride or Leuchs anhydride. 

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. 

Anhydrides of A-carboxy-a-amino acids represent a separate class of monomers. They were discovered at the beginning of this century [57] (Leuchs anhydrides) and are of the general formula... 

The introduction of glycyl residues into proteins with the Leuchs anhydrides of glycine makes peptide bonds next to serine susceptible to cleavage by trypsin (Shalitin, 1961). 

Regarding the synthesis of AT -Fmoc-protected amino acid N-carboxyanhydrides (Leuchs anhydrides, amino acid-NCAs)t l as highly activated derivatives, see Section 3.4.4. 

A -Boc- and A -Z-protected amino acid fluorides are prepared from the corresponding acids employing cyanuric fluoride at low temperature. Interestingly, when either Boc-Phe-F or Z-Phe-F are refluxed in anhydrous tetrahydrofuran for 2h the crystalline protected amino acid fluorides are recovered after removal of solvent, demonstrating their increased stability relative to the corresponding acid chlorides which undergo conversion into the Leuchs anhydrides.P l Examples can be found in Table 4. 

Leuchs anhydride 599 lithium diphosphate 582 lithium metaphosphate 581—582... 

The polymerization of N-carboxy-a-amino acid anhydrides (Leuchs anhydrides) has also been achieved by water and by a variety of bases like amines, alkali metal hydroxides, alkali metal oxides, and organo-metallic compounds in bulk, inert solvents, or starting with the solid monomer (705). Despite a great interest in the polypeptides produced in these reactions, little attention has been paid to conditions which yield solid polymer. In case the solid was produced, no physical chemical analysis of the polymer was carried out. Pol5mierization of the crystalline monomer was already observed in 1940 705). 

For peptide chemistry, protected amino acid chlorides are too highly activated and therefore not used due to their racemization tendency, reactions with amino acid side chains e.g. asparagin), loss of selectivity against nucleophiles and the formation of internal Leuchs anhydrides. ... 

Thermal polylysine was more than 10 times as active as the equivalent amount of monomeric lysine, and 3 to 4 times as active as polylysine prepared from the Leuchs anhydride. The latter finding is comparable to the results of Hardebeck et al. with pyruvate 19) and of Krampita et al. in the amination of a-ketoglutaric acid [50 vide infra). 

In each example, the activity of the thermal polymer is greater than that of the equivalent amount of free amino acid(s). In many cases, no measurable activity was shown by the monomers. Several examples have shown that the activity of the thermal polymers can be greater than that of similar polymers prepared from Leuchs anhydrides. In some cases involving metal-proteinoid, the metal was active only with proteinoid. In one case, zinc-proteinoid acting on ATP, the metal appeared to be responsible for all of the activity. With amination reactions, the simultaneous presence of both cofactor Cu + and thermal polymer was required for activity. 

Synthesis of polyhydroxy-. -proline (6). In an improved procedure described by Katchalski et al., O-acetylhydroxy-L-proline (2) was converted into the carbonyl chloride (3), and this was cyclized to the Leuchs anhydride (4) by treatment with... 

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