N -0 Acyl migrations

Drefahl and Horhold discussed the mechanism of N 0 acyl migration in A -benzoyl-l,2-diphenyl-3-aminopropanols. The migration does not seem to be possible in the erythro isomer as it would give an intermediate tetrahydro-1,3-oxazine with a bulky phenyl group in axial position. Consequently the erythro isomer is cyclized with inversion to form 2,5,6-triphenyl-5,6-dihydro-l,3-4 -oxazine... 

N-Acetyl-L-phenylalanylsarcosine amide, 348 O-Acetylserine, 148 N-0 Acyl migrations, 157 Acyl-enzyme, 342-350 Z-0-Acylisoamide, 295 1,4-Addition, 221-242 1,6-Addition, 231 L-Ala-L-Ala-pNA,350 f-Ala-T-Pro-pNA, 350 AicohoT dehydrogenase, 340-341 Aldehydes, 209-211 Aldol condensation, 304-306 2-Alkoxytetrahydrofuran, 86 2-Alkoxytetrahydropyran, 18, 85-90 Alkylation of enamine, 282 Alkylation of enolate, 280 C and 0-Alkylation, 240 O-Alkylbenzohydroximoyl chloride, 155... 

Under acidic conditions (0.58 M HC1 in dioxan THF (1 1) at 50° for 2A h), the isomeric acetamidoalcohols 240 and 244 are converted into the ammonium salts of the isomeric aminoesters 243 and 247 respectively. These N — 0 acyl migrations take place via the intermediates 241, 242, and 245, 246 respectively. Interestingly, they found that when R=H, the conversion 240+ 243 takes place readily but when R=CH3, no reaction was observed. On the other hand, the conversions 224 + 247 (R=CH3 or H) are both sluggish. 

The above striking differences were found earlier in connection with the N—> O acyl migration of cis- and rra .y-2-hydroxymethyl-cyclopentylamine. These reactions were studied very thoroughly by Bernath et al., who found that the rate constant of the N—>0 acyl migration 117—>118 for the trans isomers was essentially lower than that for the cis counterparts [40, 148]. 

N 0-acyl migration via the oxazoline and subsequent hydrolysis of the ester bond ... 

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 ... 

Incorporation of extensive branching in the side chain similarly does not decrease pharmacologic activity. Reductive alkylation of aminoalcohol, 42, with isobutyraldehyde affords the amine, 43. Acylation of the amine with benzoyl chloride probably goes initially to the amide (44). The acid catalysis used in the reaction leads to an N to 0 acyl migration to afford iso-bucaine (45). ... 

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. 

The lithiation and carbonyl additions of piperidinecarboxatnides has been studied by both Beak and Seebach. An example of the addition of a lithiated derivative to propionaldehyde is shown in Scheme 50. Beak found that although the face-selectivity of the addition shown in Scheme SO is not high, acid hydrolysis affords a single diastereomer of the product of N- to 0-acyl migration. The stereospecificity must be obtained before the acyl migration the suggested mechanism is illustrated in Scheme... 

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... 

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). 

For acyl nitronates of the general formula RCH=N(0)OAc, two types of rearrangements were suggested (Scheme 3.102), which are associated, respectively, with 1,2-migrations of the N-oxide oxygen atom (223) or the OAc fragment (219). 

More recently, Aitken and coworkers described a short and convergent formal total synthesis of cyclotheonamide C using a process that involves a Passerini reaction, amine deprotection, and an acyl migration (PADAM sequence. Scheme 22) [90]. The key linear pentapeptide 22e is obtained by a Passerini reaction of isocyanide a, Fmoc-amino aldehyde b, and Boc-dipeptide acid e followed by Fmoc removal and consequently 0,N-acyl migration [91]. The macrocyclization was achieved with TBTU and HOBt after Boc and fBu removal in good yield (52%) to furnish intermediate f. 

The same isothiocyanate 5 was obtained when 6 was used as the starting material.32 For this 0- N acyl migration, a mechanism has been proposed that involves the oxazoline intermediate 8, which results after dehydration of the initially formed l,2-(orthoacetyl)amide (7). The oxazoline derivative subsequently reacts with the thiocyanate ion at C-l, with Walden inversion. 

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