Amino acid derivatives, acyl migration

Stereoselective acyl migration of amino acid derivatives has been reported (Scheme 32).55... 

Although N -benzylated amino acids or peptides are known to be sterically hindered with respect to anninoacylation, acylation of A -(2-hydroxybenzyl) (Hbz) amino acid derivatives proceeds surprisingly well.P As shown in Scheme 1, the initial step in aminoacylation of A -Hbz-derivatized amino acid residues (Y = H) is esterification of the hydroxy group, which is followed by intramolecular, base-catalyzed O N acyl migration to produce the peptide bond.P l... 

A further development of this safety-catch principle led to A -[2-hydroxybenzyl-4-methoxy-5-(methylsulfinyl)] (SiMB) derivatives (Scheme 4) where the acylation potency of the intermediate 8-methoxy-4,5-dihydro-l,4-benzoxazepin-2(3//)-one derivatives (Scheme 2) is significantly enhanced and similarly the rate of intramolecular O N acyl migration. The related Fmoc-protected amino acid derivatives are readily prepared and cleavage is achieved by reductive acidolysis (SiCl4/TFA/anisole/ethandithiol 5 90 2.5 2.5, 2h at room temperature). 

Acylation. Reaction conditions employed to acylate an aminophenol (using acetic anhydride in alkaU or pyridine, acetyl chloride and pyridine in toluene, or ketene in ethanol) usually lead to involvement of the amino function. If an excess of reagent is used, however, especially with 2-aminophenol, 0,A/-diacylated products are formed. Aminophenol carboxylates (0-acylated aminophenols) normally are prepared by the reduction of the corresponding nitrophenyl carboxylates, which is of particular importance with the 4-aminophenol derivatives. A migration of the acyl group from the O to the N position is known to occur for some 2- and 4-aminophenol acylated products. Whereas ethyl 4-aminophenyl carbonate is relatively stable in dilute acid, the 2-derivative has been shown to rearrange slowly to give ethyl 2-hydroxyphenyl carbamate [35580-89-3] (26). 

The formation of tluorinated Q -hydroxy-jS-imino esters (180) by treatment of fluorinated imino ethers (179) with lithium 2,2,6,6-tetramethylpiperidide has been reported. A possible explanation for this interesting intramolecular rearrangement is proposed in Scheme 64. Acyclic imides derived from primary benzylic amines and amino acid esters have been found to undergo a novel nitrogen to carbon acyl migration via a base-generated carbanion to yield the corresponding a-amino... 

The second major metabolite from T. inflation is structurally closely related to cyclosporin A, as can be deduced by elemental analysis, mass spectrum (m/z 1217), IR and NMR spectra. Furthermore, the presence of the double bond and OH group of the unusual MeBmt was established. Sulphonic acids in methanol or dioxane effected the typical rearrangement reaction by N, O-acyl migration to the iso-compound (13). Hydrolysis furnished the same amino acids as cyclosporin A with the exception of L-a-aminobutyric acid, which is replaced in cyclosporin C (12) by L-threonine. The amino-acid sequence could be deduced by conversion of cyclosporin C into cyclosporin A via the corresponding tosylate (14) and iodo derivatives (15) [7]. Position 2 for L-threonine as well as the assumed twisted -pleated sheet conformation of the molecule were confirmed by 13C-NMR spectra. 

The chemical reactivity of aliphatic hydroxy groups is reduced by acylation, but the resulting esters are reactive toward amino groups. Thus, under basic conditions, as commonly used for Fmoc deprotection, an intramolecular O N migration of the acyl residue can occur.b l This O N shift, which produces N-acylated derivatives (Scheme 3), is nearly irreversible and further elongation of the peptide is prevented. The same reaction can occur during acidolytic deprotection of final peptides with TFA via intermediate formation of the tri-fluoroacetyl ester of N-terminal hydroxy amino acids,... 

As a further consequence of the high reactivity of the excessive 0-acyl isourea in the heterogeneous peptide synthesis mixture, a base-catalyzed intramolecular 0-N-acyl migration takes place, forming the inactive N-acyl dicyclohexylurea. At the same time, this by-product is formed by acylation of already formed still dissolved amounts of dicyclohexylurea, which can be attacked by the symmetric anhydride or the 0-acyl isourea of the carboxylic component as well. Both the N,0-acyl shift and the latter side reaction decrease the total concentration of the activated masked amino acid even N,N -diacyl derivatives of the urea also can be formed as further by-product. Fortunately, all of these acyl urea derivatives are not fixed to the polymer phase and are well soluble in dichloromethane, so that they can be washed out easily from the gel phase after the... 

These amino acid residues are usually esterified with methanolic HCl. There can be side reactions, such as methanolysis of amide derivatives or N,0-acyl migration in serine or threonine residues ... 

A potential problem in the coupling of S-acyl or S-alkoxy-carbonyl-L-cysteine derivatives to other -blocked amino acids is S - iV-acyl migration which results from the presence of the free amino group on the S-acyl cysteine residue. The mechanism for S - -N-dicy m ation has been disj ussed by Barnett and Jenks [145]. Patchornik et al. [8] noted that S- iV-acyl miration occurred when the free base of (60) was prepared and the low yields of S-benzoyl-L-cysteine peptides such as (61) were traced to the formation of (62), produced by S- -N-benzoyl migration during the coupling step [89, 146]. Similar difficulties have been noted in solid-phase synthesis [120]. Problems of this type may have also been encountered in the... 

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