Aspartyl residues benzyl esters

The cyclopentyl (cPe) ester group was introduced by Blake for the protection of carboxy groups. The ester bond is stable against TFA and readily cleaved with HF at 0 °C. This ester is 14 times more stable than the corresponding benzyl ester when exposed to 55% TFA in dichloromethane. However, there is little difference in the extent of HF-catalyzed succini-mide formation between peptidyl-resins containing benzyl- or cyclopentyl-protected aspartyl residues, although the latter protection reduces base-catalyzed succinimide formation. 

Proton abstraction from an amide nitrogen initiates a similar inramolecular nucleophilic attack in peptides which contain aspartyl residues with the side chain carboxyl group blocked in the form of benzyl ester ... 

While with y -benzyl aspartyl residue succinimide formation can be quite extensive, the corresponding tert.butyl ester are fairly inert toward intramolecular attack. 

We must add here that steric hindrance is not necessarily harmful. As mentioned before bulkiness in the activating portion of mixed anhydrides results in more unequivocal acylation reactions. Similarly, in jff-tert.butyl esters of aspartyl residues ring-closure to aminosuccinyl peptides, observed with the corresponding )8-benzyl esters, does not occur. Furthermore, formation of hydantoins and succinimide derivatives is considerably enhanced if glycine is involved in the process, because di-acylation of this unique amino acid without a side chain readily occurs. Accordingly, it is a mistake to use glycine in model experiments designed for the study of side reactions. 

An aspartyl-containing peptide aldehyde has also been synthesized using the same approach. Indeed, most of the previously described sjmtheses of peptide aldehydes are incompatible with the presence of protected Asp or Glu residues. We have shown in this work that benzyl ester derivatives of aspartic acid can be used to obtain aspartyl-containing peptide aldehydes by this methodology Protocol (10-12). 

To a solution of 180 parts of -benzyl N-benzyloxycarbonyl-L-aspartvI-L-phenylalanine methyl ester in 3,000 parts by volume of 75% acetic acid is added 18 parts of palladium black metal catalyst, and the resulting mixture is shaken with hydrogen at atmospheric pressure and room temperature for about 12 hours. The catalyst is removed by filtration, and the solvent is distilled under reduced pressure to afford a solid residue, which is purified by re-crystallization from aqueous ethanol to yield L-aspartyl-L-phenylalanine methyl ester. It displays a double melting point at about 190°C and 245°-247°C. 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

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