O -N Acyl migration

In the presence of weakly acidic additives, such as Ai-hydroxysuccinimide (HOSu),P l 1,2,3-benzotriazol-l-ol (HOBt),f l 3-hydroxy-l,2,3-benzotriazin-4(3//)-one (HODhbt),b l or 7-aza-l,2,3-benzotriazol-l-ol (HOAt),f l the O N acyl migration as well as racemization/ epimerization (vide infra) are largely prevented.f d Concurrently, conversion of the highly reactive O-acylisourea derivatives and symmetrical anhydrides into the related less reactive active esters 13 derived from these additives takes place which leads to still sufficiently activated species to allow rapid in situ amide formation. 

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... 

To facilitate aminoacylation of A -(2-hydroxybenzyl)annino acids or -peptide derivatives via O—> N acyl migration various related nitro derivatives were proposed,among which the A -(2-hydroxy-6-nitrobenzyl) and A -(2-hydroxy-5-nitrobenzyl) proved significantly more reactive in this context than the Hmb anoino acid residues. Incorporation of these protecting groups is performed by reductive alkylation as for the Hmb derivatives and removal of the N -protecting group is readily achieved by mild photolysis at 366 nm for 3 hours. 

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). 

Scheme 9 O—>N Acyl Migration in O-Acyltyrosines Catalyzed by Nucleophiles O...

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... 

The presence of a second nucleophile in the reaction mixture reduces the concentration of the O-acylisourea and thereby the extent of racemization. Also, HOBt, a weak acid, prevents proton abstraction from the chiral carbon atom and thus contributes to the conservation of chiral purity in a second manner as well. Last, but not least the availability of the auxiliary nucleophile (HOBt) efficiently shortens the lifetime of the overactivated O-acyl-isourea intermediate and thus diminishes the extent of O N acyl-migration leading to... 

Numerous reports describe the modification of natural amino-glycoside antibiotics or products derived from them by conventional methods. 1-/ -Alkylated kanamycins can be prepared very efficiently by utilizing an O N acyl migration to protect the sugar amino-groups selectively, leaving the deoxy-streptamine amino-groups free-, a formylation-deformylation sequence then... 

The structure of (24) was established by the chemical correlation shown in Scheme 3. Reduction of (24) with NaBH4 gave a mixture of (26), O-to-N acyl migration product, and (27) the latter was methylated to (29) which was identical with the product formed from the enamine (28) by oxidative hydroboration. 

Depsipeptide SPPS methodology, a method for SPPS applicable to difficult sequences arising from aggregation phenomena. It relies on the synthesis of Ser or Thr isopeptide intermediates with a final 0-N acyl migration step. The principle is identical to the O-acyl isopeptide method, also termed click peptide or switch peptide method that were developed independently by different groups. It was, for example, successfully employed to synthesize the extremely difficult WWDomain FBP28 [I. Coin et al.,/. Org. Chem. 2006, 71, 6171]. 

Nitramines from 1,1-nitroethylene derivatives G(N02) G with O N-acyl group migration and O-deacetylation... 

Aminoalcohols are an important class of compounds in medicinal chemistry because many drugs contain this structure. For their resolution, there are two possibilities acylation of amino function or an enzymatic transesterification with vinyl esters through the hydroxyl group. However, the amino or hydroxyl group must be protected, because if the starting material is the free aminoalcohol, the O- and N-acylation can take place, and in addition, there are migrations obtaining... 

Hydrolysis of 131 in wet tetrahydrofuran gave methyl isoanhydro-berberilate (135) through air oxidation and N-O acyl migration (Scheme 27)... 

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