Acyl transfer intramolecular

Acyl-transfer reactions are some of the most important conversions in organic chemistry and biochemistry. Recent work has shown that adjacent cationic groups can also activate amides in acyl-transfer reactions. Friedel-Crafts acylations are known to proceed well with carboxylic acids, acid chlorides (and other halides), and acid anhydrides, but there are virtually no examples of acylations with simple amides.19 During studies related to unsaturated amides, we observed a cyclization reaction that is essentially an intramolecular acyl-transfer reaction involving an amide (eq 15). The indanone product is formed by a cyclization involving the dicationic species (40). To examine this further, the related amides 41 and 42 were studied in superacid promoted conversions (eqs 16-17). It was found that amide 42 leads to the indanone product while 41... 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

A simple example of non-covalent catalysis is the intramolecular acyl transfer [3] to [4] which is catalysed by a-CD but retarded by /3-CD (Griffiths and Bender, 1973). As seen by the constants in Table 1, the... 

Table 1 Non-covalent catalysis of intramolecular acyl transfer [3]—> [4].°...

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

DM Coltart. Peptide segment coupling by prior ligation and proximity-induced intramolecular acyl transfer. Tetrahedron 56, 3449-3491, 2000. 

Acetoxymethyl carbamates of primary amines behaved differently from the pathway depicted in Fig. 8.19, the predominant reaction being intramolecular acyl transfer to generate the A-acetylated amine as the major product [209]. This parasitic reaction was observed in buffer and proportionally less in plasma, disqualifying (acyloxy)methyl carbamates for use as prodrugs of primary amines. However, this type of derivative appears well suited for the preparation of prodrugs of secondary amines, as documented below. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

The base-induced transfer of the ester acyl group in an o-acylated phenol ester, which leads to a 1,3-diketone. This reaction is related to the Claisen Condensation, and proceeds through the formation of an enolate, followed by intramolecular acyl transfer. 

In a recently reported synthesis of pyridines, lithiated methoxyallenes react with nitriles in the presence of trifluoroacetic acid (Scheme 107) <2004CEJ4283>. The mechanism is postulated to proceed via initial protonation followed by nucleophilic addition of the trifluoroacetate ion with subsequent intramolecular acyl transfer and aldol condensation to give the pyridine. An additional pyridine formation starting from azaenyne allenes forms a-5-didehydro-3-picoline diradicals, which can be trapped by 1,4-cyclohexadiene, chloroform, and methanol to produce various pyridines <20040L2059>. 

Intermediate 23b can be obtained by a direct nucleophilic attack of the uncharged amino group (present at low equilibrium concentration at pH 7) but the mechanism of this step may be more complex as shown by the observation of a catalytic effect of CO2 in amidations using CDI [191]. Moreover, the reaction of the carboxylate group followed by an intramolecular acyl transfer is also a possibility. CDI-promoted peptide formation was shown to display... 

Syntheses of pyrimido[4,5-e]-1,2,4-triazines (6-azapteridines) by [6 + 0] component cyclization of pyrimidine precursors are uncommon. Two examples, however, are the preparation of compounds (410) and (414) (Equations (69) and (70)). Formation of the latter is interesting in that it involves an intramolecular acyl transfer of the ester group from one nitrogen atom to an adjacent one <65JA1976, 75JOC2329). 

It was noted that the intramolecular acyl transfer proceeded faster with Cyclo-(Tyr-His) than with Cyclo-(Gly-His-<3y-Tyr-Gly-Gly). This difference could be interpreted in either of the following ways (i) that in the cyclic hexapeptide the ade... 

With these cyclic peptides it was apparent that no difference of pKa vali s exists between cis and tram isomers and no specific interactions exist between the histidyl and the tyrosyl residues. It was again shown in the hydrolysis of PNPA by these cyclic peptides that the two functional groups do not cooperate for the formation of nitrophenolate ion. On the other hand, for the intramolecular acyl transfer from the acylated imidazole to the phenol group of tyrosine a histidyl side chain in proximity to a tyrosyl side chain facilitated the reaction. This is evident from the fact that the reaction rate was 1,2-cis > 1,2-tram, 1,4-cis > 1,4-trans, and 1,2-cis > 1,4-cis. Thus, a cooperative imidazole function is necessary for the acylation of the tyrosyl phenolic oxygen. Two possibilities illustrated in Fig. 35 a and b are considered... 

Fig. 35. The intermediates for the intramolecular acyl transfer catalyzed by cooperative histidyl and tyrosyl side chains...

Previous studies on amide bond formation via conversion of the bimolecular coupling reaction (see Scheme 1) into an intramolecular reaction by grafting the carboxy and amino component on a template has clearly demonstrated the strong entropic effect, i.e. the high effective local concentration on the subsequent base-catalyzed intramolecular acyl transfer reaction. 

Figure 5.3. Intramolecular acyl transfer between residues four positions apart in the sequence in a helical conformation, the key step in the site-selective functionalization reaction [13].

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