Amino acids acylating agents

Amino Acid Geiatinization Agent. See Acyl glutamic acid diamide Amino acids, corn gluten. See Com gluten amino acids... 

This procedure is restricted mainly to aminodicarboxyhc acids or diaminocarboxyhc acids. In the case of neutral amino acids, the amino group or carboxyl group must be protected, eg, by A/-acylation, esterification, or amidation. This protection of the racemic amino acid and deprotection of the separated enantiomers add stages to the overall process. Furthermore, this procedure requires a stoichiometric quantity of the resolving agent, which is then difficult to recover efficiendy. Practical examples of resolution by this method have been pubUshed (50,51). 

The most common O- and N-acylation procedures use acylating agents that are more reactive than caiboxylic acids or their esters. Carboxylic acid chlorides and anhydrides react rapidly with most unhindered hydroxy and amino groups to give esters and amides, respectively ... 

To fonn a peptide bond between two suitably protected amino acids, the free carboxyl group of one of them must be activated so that it is a reactive acylating agent. The most ffflniliar- acylating agents are acyl chlorides, and they were once extensively used to couple fflnino acids. Certain drawbacks to this approach, however, led chemists to seek alternative methods. 

In the first step, a resin-bound secondary amine is acylated with bromoacetic acid, in the presence of N,N-diisopropylcarbodiimide. Acylation of secondary amines is difficult, especially when coupHng an amino acid with a bulky side chain. The sub-monomer method, on the other hand, is facilitated by the use of bromoacetic acid, which is a very reactive acylating agent Activated bromoacetic acid is bis-reactive, in that it acylates by reacting with a nucleophile at the carbonyl carbon, or it can alkylate by reacting with a nucleophile at the neighboring ah-phatic carbon. Because acylation is approximately 1000 times faster than alkylation, acylation is exclusively observed. 

This method was effective for acylation of a hindered tertiary alcohol in the anticancer agent camptothecin by protected amino acids. 

Important prebiotic sequences, for example, the linking up of amino acids to form proteins, involve acylation reactions (see Sects. 5.1 and 5.2). Condensation agents are often not very efficient in aqueous phases condensation reactions may involve drastic conditions, such as high temperatures or an acidic environment. Activated amino acids, for example, thioester derivatives, can be considered as starting... 

HN Gopi, VV Suresh Babu. Zinc-promoted simple synthesis of oligomer-free N -Fmoc-amino acids using Fmoc-Cl as an acylating agent under neutral conditions. J Pept Res 55, 295, 2000. 

The symmetrical anhydride is prepared using dicyclohexylcarbodiimide in dichloromethane, the urea and solvent are removed, and the anhydride is dissolved in dimethylformamide and added to the peptide-resin (see Section 2.5). The anhydride is a more selective acylating agent than the 0-acylisourea and, thus, gives cleaner reactions than do carbodiimides, but twice as much amino-acid derivative is required, so the method is wasteful. It avoids the acid-catalyzed cyclization of terminal glutaminyl to the pyroglutamate (see Section 6.16) and is particularly effective for acylating secondary amines (see Section 8.15). 

LA Carpino, EME Mansour, D Sadat-Aalaee. lerl-WutoxycarbonyI and benzyloxy-carbonyl amino acid fluorides. New, stable rapid-acting acylating agents for peptide synthesis. J Org Chem 56, 2611, 1991. 

Aminoacyl adenylates (296), which are formed from protein amino acids and ATP, act as acylating agents towards t-RNAs, acylating their terminal 3 -hydroxy groups. These charged tRNAs are then used in protein synthesis. Little is known about the reactivity of aminoacyl adenylates (296), and studies are now reported of a model compound, alanyl ethyl phosphate (297). As expected, hydrolysis in both acid and base involves attack at the C=0 group of (297) with departure of ethyl phosphate. Metal ions (Cu +, Zn +) were found to act as catalysts of the hydrolysis. 

Another possible mechanism for the racemization of amino acid esters involves the in situ, transient, formation of Schiff s bases by reaction of the amine group of an amino acid ester with an aldehyde. Using this approach, DKR of the methyl esters of proline 5 and pipecolic acid 6 was achieved using lipase A from C. ant-arclica as the enantioselective hydrolytic enzyme and acetaldehyde as the racemiz-ing agent (Scheme 2.4). Interestingly, the acetaldehyde was released in situ from vinyl butanoate, which acted as the acyl donor, in the presence of triethylamine. The use of other reaction additives was also investigated. Yields of up to 97% and up to 97% e.e. were obtained [6]. 

Halotriazoles can act as halogenating agents and A-acyltriazoles can act as acyl transfer reagents. Triazole can be used for the synthesis of peptide bonds and is superior to imidazole in that less racemization is observed. It can also be used to transfer the t-butyloxycarbonyl (t-Boc) protecting group to the nitrogen of amino acids. For details see Polya <84CHEC-I(5)733, p. 786). 

It was shown previously that saturated 5(4//)-oxazolones or 2-oxazolm-5-ones with only one substituent at C-4 can be considered as the tautomeric form of saturated 5(2//)-oxazolones or 3-oxazolin-5-ones. These compounds can also be considered as amino acid derivatives and, indeed, cyclization procedures are the most commonly used to prepare these compounds. The cyclization reaction employs a variety of cyclodehydrating agents and the general method is shown in Scheme 7.23, with an A-acyl-a-amino acid being the most typical starting material used. In this way, 5(4//)-oxazolones derived from most natural amino acids 99 (R3 = H) have been obtained by heating the corresponding A-acyl derivatives in the presence of acetic anhydride. 

Cyclization of A-acyl-oc-amino acids under acidic reaction conditions is sometimes problematic due to the difficulty in separation of the desired oxazolone from by-products while avoiding decomposition of the reactive oxazolone. This finding is particularly true in the case of 2-phenyl-5(47i)-oxazolone, an interesting compound that is a very useful intermediate to prepare a variety of novel products. The use of carbodiimides as dehydrating agents has been described as a means to improve the results. In particular, treatment of an A-acyl-a-amino acid with A-cyclohexyl-A -2-(A-methylmorpholinio)ethylcarbodiimide p-toluensulfo-nate (Scheme 7.25) is especially useful as a general synthesis of the desired saturated 5(47i)-oxazolones 101 in excellent yields.This same carbodiimide was used to study the kinetics of the formation of saturated 5(47i)-oxazolones from N-protected dipeptides... 

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