O-N intramolecular acyl migration

Y Sohma, M Sasaki, Y Hayashi, T Kimura, Y Kiso. Novel and efficient synthesis of difficult sequence-containing peptides through O-N intramolecular acyl migration reaction of O-acyl isopeptides. Chem Commun 124, 2004. 

Figure 3 The production of Ap 1 -42 from the pH-triggered click peptide via a pH-dependent O N intramolecular acyl migration reaction.

Sohma Y, Sasaki M, Hayashi Y, Kimura T, Kiso Y. Design and synthesis of a novel water-soluble A(il-42 isopeptide an efficient strategy for the preparation of Alzheimer s disease-related peptide, Api-42, via O-N intramolecular acyl migration reaction. Tetrahedron Lett. 2004 45 5965-5968. 

Figure 4 A photo-triggered click peptide. The production of Ap 1-42 by photo-triggered click followed by O N Intramolecular acyl migration reaction.

Crossover experiments have been used to establish that the novel N to C acyl migration reaction of acyclic imides (69), to give o -amino ketones (70), proceeds by intramolecular reaction of the base-generated carbanion. ... 

In summary, it may be stated that the reaction of acyl esters of aldoses and aldobioses (see Section III, p. 92) with ammonia consists of a set of competitive pathways, including intramolecular O —> N migrations of acyl groups, deacylations, and transesterifications, with formation of aldose amides and variable proportions of the free sugar as the principal products. Significant proportions of basic or insoluble polymeric substances were not observed with aldose acetates or benzoates, although occurrence of extensive browning indicates the probable formation of soluble melanoidins. 

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). 

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,... 

The synthesis of reductomycin (59) [120] has been carried out starting from 3-(hydroxy-methyl)furan, which was oxidized with lead(IV) acetate to the corresponding 2,5-diacetoxy derivative. Subsequent hydrogenation of the double bond and oxidation afforded the appropriate aldehyde. A Wittig reaction of this compound and deprotection of the trichloroethyl ester followed by esterification with 3-hydroxy-2-nitrosocyclopent-2-en-1-one gave an ester, which was then reduced with zinc. Reductomycin (59) was obtained after intramolecular O—> N acyl migration (Scheme 33). 

The formation of an AT-acetylamide as the end product of the reaction of an isoxazolium salt with sodium acetate was described as early as 1910 (cf. Ref. 44). Also, an analogous intramolecular O—N acyl migration was noted in the reactive enol ester intermediate obtained with keteneimines, proposed as coupling reagents by CL. Stevens and E.M. Munk in 1958... 

O-acylation in peptide synthesis 18, 435 suppl. 26 O-acyl group migration 13,255 suppl. 26 allyl rearrangement 27, 578 coupling of halides 11, 731 suppl. 27 epimerization during oxidation 16, 319 suppl. 26 N-quaternization s. under N-Quaternization radical addition 27, 600 reduction of ketones in Grignard syntheses 19, 46 suppl. 26 ring closure, intramolecular 27, 799... 

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