Intramolecular -acyl migration

Y Hamada, J Ohtake, Y Sohma, T Kimura, Y Hayashi, Y Kiso. New water-soluble prodrugs of HIV protease inhibitors based on 0—>N intramolecular acyl migration. Bioorg Med Chem 10, 4155, 2002. 

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. 

It is of interest that the mechanism shown in Fig. 8.5 should be applicable to all catechol monoesters, but this is only seen when hydrolysis is comparatively slow. More studies are needed to examine the mechanistic hypothesis presented in Fig. 8.5 and the pharmacokinetic consequences of intramolecular acyl migration in monoesters of catechols. 

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.

Carboxylic acids react with phenyliminovinylidenetriphenylphosphorane (equation 106) via the intermediates (1) with formation of the alkylidenephosphoranes (2), which, on heating, rearrange in an intramolecular acyl migration to ylides (3). By heating (2) in the presence of an alcohol the acyl ylides (4) and N-phenylurethanes are formed. - The reaction sequence allows the replacement of the OH group in carboxylic acids by the ylide function. 

Four-component condensation with carboxylic acids is accompanied by intramolecular acyl migration and formation of a-(acylamino) carboxamides 32d... 

Intramolecular acyl migration 2-Hydroxymethyl-4-nitrophenyl trimethylacetate 6... 

Native chemical ligation is one of the most successful methods for the formation of linear peptide chains. Intramolecular acyl migration through a... 

To demonstrate the selectivity of intramolecular acyl migration over intermolecular migration a competitive experiment was devised in which chemical ligation of S-protected (a-aminoacyl)tripeptide(128) (via an 11-membered cyclic transition state) was carried out in the presence of five equivalents of a dipeptide (H-Gly-Leu-OH, 129). As shown by HPLC, the ligated product (130) contained no intermolecular acyl migration products (131 or 132) (Scheme 34). 

Benzotriazole methodology was also used to achieve the synthesis of cy-chc peptidominetics (146) via intramolecular acyl migration of the pyridine dithioesters (143) to form the diamides (144) followed by reaction with diamides (145) (Scheme 37) (2015OBC9492). 

S-Benzoyl-2-aminoethanethiol and its N-alkyl derivatives (50) rearrange immediately on liberation from the hydrobromide salts . However, besides the expected 2-benzamidoethanethiols (51) small amounts of N,S-dibenzoyl- -aminoethanethiols (52) were also obtained, which indicates that the intramolecular acyl migrations were followed by trans-thiolesterifications from the starting materials 50 to the rearranged products 51. The transesterifications must be accompanied by elimination of 2-aminoethanethiols (53) and although attempts to isolate 53a and 53b from the reactions of 50a and 50b failed, 50c afforded all three products... 

Backvall and coworkers also reported a DYKAT of unsymmetrical 1,3-diols with one small and one large group [83]. The method makes use of (0 selective enzymatic acylation of the least sterically hindered alcohol ii) epimerization of a secondary alcohol and in) intramolecular acyl migration in a syn-l,3-diol monoacetate in a one-pot procedure. Shvo s catalyst 1 (4 mol%) was used for the epimerization. CALB was used for the enzymatic resolution along with isopropenyl acetate as the acyl donor. The products were obtained in moderate to high yields (53-73%) and with ee values exceeding 99% in all cases. Also, the diastereomeric ratios for the sy -diacetates were consistently high, typically >90% syn (19). 

DYKAT is a dynamic system closely related to DKR. Although four types of DYKAT have been reported in the literature, all the examples reviewed here are included in DYKAT type 111. They focus on the asymmetric transformation of a diastereomeric mixture of enantiomeric pairs of acyclic and cyclic diols by means of lipase-catalyzed transesterification and epimerization of the chiral centers mediated by the Ru catalyst 3a. The major differences with respect to DKR reside in the formation of chiral intermediates (hydroxyketones) during the metal-catalyzed epimerization as well as the involvement of two successive enzymatic transformations with different selectivities. An additional complexity originates from possible intramolecular acyl-migrations. Nevertheless, if similar requirements to those described for an efficient DKR are fulfilled, the result of these DYKATs could be the formation of only one stereoisomer of the diacylated product. 

These results led to the proposal that tributyrin is initially hydrolyzed at the sn-3 position. Nonenzymatic, intramolecular acyl migration results in a mixture of 1,2- and 1,3-diacylglycerols, which then undergo further hydrolysis [17],... 

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