Acylation of amino acids

In the following examples, acylations of amino acids were accomplished with the more reactive N-acylimidazolium compounds in aqueous systems [105]... 

FMF Chen and NL Benoiton. Diisopropylethylamine eliminates dipeptide formation during acylation of amino acids using benzoyl chloride and some alkyl chlorofor-mates. Can J Chem 65, 1224, 1987. 

N-Aryl isoindolo[2,l-f>][2,4]benzodiazepines 190 (Scheme 38, R = Ar) can be obtained by an intramolecular acylation of amino acids 189 in acetic anhydride (1998X1497). 

C) Intramolecular acylation of amino acids and their derivatives. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

Couplings with N-protected isoxazolidine-3-carboxylic acid can be performed without particular restrictions of the method, and the use of a mixed anhydride for acylation of amino acids or amide formation has been reported. 179 A similarly free choice of coupling methods is available for the acylation of isoxazolidine-3-carboxylic acid derivatives so far the use of carbodiimide and mixed anhydrides have been reported. 168179 Isoxazolidine-3-carboxylic acid derivatives are listed in Table 7. 

Fatty acylation of proteins is a common posttranslational modification that blocks sequencing of the N-terminal amino acids by Edman techniques. Mass spectrometry can play an essential role in such sequencing, but it is not always trivial to locate the blocked N-terminal peptide. Besides acetylation, acylation of amino acids with longer-chain fatty acids (e.g., myristic acid) has been reported. 

Several alternative procedures have been proposed to address this serious problem, a very simple one being changes in the reaction conditions. In fact, the amount of side product is substantially reduced when a slight excess of amino acid over acylating agent (1.25 equiv) and sodium carbonate (4 equiv) are used with a minimum amount of dioxane and with vigorous stirring at room temperature. This procedure, however, cannot be applied with hydrophobic amino acids such as leucine or vahne.t l Acylation of amino acids with 9-fluorenylmethyl azidoformate (Fmoc-N3, 18, prepared from Fmoc-Cl and pre-... 

Due to the easy removal of the byproducts, B0C2O (65) can also be used for the acylation of amino acids (Scheme 29) or peptide esters in organic solvents.Amino acid esters or their respective hydrochlorides react sluggishly when the reaction is performed in alcohols with sodium hydrogen carbonate as a solid, poorly soluble base. Sonication increases reaction rates leading to Boc-protected amino acid esters in good to quantitative yields within few hours instead of more than 24 hours. 

Scheme 29 Acylation of Amino Acids with B0C2O...

Boc-Cys-OMe Typical Procedure for Acylation of Amino Acid Esters with B0C2O (65) t l To a well-stirred slurry of H-Cys-OMe HCl (1.72 g, lO.Ommol) in CHjClj (20mL) was added TEA (1.01 g, lO.Ommol) followed after lOmin by BoCjO (65 2.18g, lO.Ommol). The mixture was stirred for 16 h, washed with H2O, the organic layer was dried, and concentrated to give the product as a colorless oil yield 2.29 g (97%) -1-28.5 (c 318 mM, CHCI3). 

The reagents for the synthesis of Al -l-adamantyloxycarbonyl amino acid derivatives are similar to those used for other urethane-type protecting groups (Scheme 36). Although the related 1-adamantyl chloroformate (Adoc-Cl, 68) is obtained as crystalline solid, the acylation of amino acids under Schotten-Baumann conditions leads to significant decomposition of the reagent and thus its use does not result in satisfactory yields in all cases. Better results are obtained with 1-adamantyl fluoroformate (Adoc-F, 69) (yields of A -Adoc amino acids 85-95%)P I which is conunerciaUy available or readily prepared from adamantan-l-ol and... 

Compounds such as 4-nitrophenyl and 2,4,5-trichlorophenyl esters of N-protected amino acids were originally prepared also by reaction of the N-protected acids with di- or trisub-stituted esters of carbonic,sulfinic,f l or phosphinic acids l in, or with addition of, pyridine. This was followed by the use of mixed carbonates 54 that served both for acylation of amino acid 53 to N-protected acid 55 and subsequent esterification to 56 using carbodiimide (Scheme 13).A variant of this was the preparation of the unusual l,l,4-trioxo-2,5-di-phenyl-4,5-dihydro-3-thienyl 57 esters of Boc amino acids 56c, which avoided the use of carbodiimide since esterification proceeds in the presence of tetramethylguanidine.P l... 

Preferred to cbloroacetyl chloride for N-acylation of amino acids in alkaline solution. ... 

The Schotten-Baumann technique has often been applied to acylation of amino acids, particularly for benzoylation and for introduction of the benzyl-oxycarbonyl group. 

The developed solid-phase approach started with the preparation of immobilised ureas 114 obtained via acylation of amino acids linked to acid-labile Sasrin resin 104 with ortho-methoxycarbonyl aryl isocyanates or activated para-nitrophenyl carbamates 113. Alternatively, ureas of type 114 could also be generated by reaction of anthranilic esters 115 with immobilised amino acid-derived isocyanates (easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of a base such as 2,6-lutidine) or activated carbamates 116 (Scheme 4.1.23). 

When low dielectric constant solvents are used, the carboxylic acid tends to dimerize, thus promoting symmetrical anhydride formation. This intermediate is stable enough to give good yields of the desired product. High dielectric solvents such as DME retard acylation of amino acids, and Al-acylurea can he a major byproduct. Unfortunately, many starting materials require polar solvents for dissolution. 

This reaction was first reported by Schotten in 1884 and subsequently extended by Baumann in 1886. It is the acylation of alcohols and amines from acyl halide or anhydride in an aqueous alkaline solution (e.g., 1 M NaOH), and is generally known as the Schotten-Baumann reaction or Schotten-Baumann acylation. Occasionally, it is also referred to as the Schotten-Baumann method,or Schotten-Baumann esterification. Likewise, the formation of benzoyl ester under these conditions is called the Schotten-Baumann benzoylation." It is assumed that the reaction would perform well if carried out in a biphasic system of water and an immiscible organic solvent (e.g., CH2CI2), which has an important application in the acylation of amino acids.For example, p-nitrohippuric acid and dibenzoylornithine (ornithuric acid) all can be prepared under these conditions. 

A few years after the first publication on acylamino acid thiophenyl esters [4] the peptide research team of the CIBA laboratories in Basel, led by Robert Schwyzer, described a systematic study of the aminolysis of methyl esters substituted with various electron-withdrawing groups [20]. From a series of esters examined with respect to their reaction rates in aminolysis cyanomethyl esters were selected as best suited for peptide synthesis. Cyanomethyl esters were readily prepared through the reaction of acylamino acid salts with chloroaceto-nitrile and they showed satisfactory rates in the acylation of amino acid esters... 

As described earlier, fatty acylation gives rise to the dramatic changes in the surface properties of proteins. If the attachment of fatty acyl groups to proteins is carried out not via chemical reaction but via enzyme-catalyzed reaction, the range of application of fatty acylated proteins should be expanded, especially in the food industry. However, most attempts concerning the fatty acylation of proteins via enzymatic methods have not been successful. On the contrary, enzyme-catalyzed synthesis of acyl-amino acids is still an important challenge worth facing. Several examples of enzymatic acylation of amino acids are discussed next. 

The —I effect of an a-NHR group in decarboxylative acylation of amino acids also allows the reaction to proceed by an analogous route However, with a-NR2 groups the corresponding tertiary amino ketones are not obtained, but undergo further reaction to give iV, -disubstituted amides (reaction 30) Tertiary amino acids. 

Acylation of amino acids with 5-dimethylami-nonaphthalene-l-sulfonyl chloride (dansyl chloride, DANS-Cl) is of great analytical importance ... 

One reaction type that merits special consideration is the acylation of amino acids. Other reactions of the amino acids are biologically important. For example, it will be seen later that it is Schiff base formation of the amino function with an aldehyde that provides the basis for all reactions with vitamin (see Chapter 7). However, it is acylation of the amino function of one amino acid with the carboxyl (activated) of another amino acid that leads to formation of the peptide bond and subsequent protein, or polymer formation. It then becomes of interest for the bioorganic chemist to consider and compare the synthesis of the most complex macromolecule in the test tube and the organism. 

The amide bond resulting from the acylation of amino acids is a planar hybrid structure, with an approximately equal distribution between two resonance forms. Because of the greater predominance of the (C=N <)... 

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