Carbodiimides acid anhydride synthesis

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 ... 

Carbodiimides, in particular dicyclohexylcarbodiimide, have been applied in many syntheses where dehydration had to be performed under mild conditions. It is therefore no surprise that this reagent was also introduced for the synthesis of acid anhydrides from carboxylic acids." " In order to avoid N-acylation the reactions are carried out at low temperature. First 0-acylisoureas are formed, which then react further with free acid to the acid anhydride (equation 34). The reaction has been exploited in particular for the preparation of peptides." )V-alkoxycarbonyl-protected amino acids can be transformed in high yield to the corresponding anhydrides, which themselves are activated acid derivatives and may be converted to peptides. As in many other examples polymer-bound carbodiimides may prove superior sometimes, as the isolation of the products is facilitated. Easy preparation of acid anhydrides is possible in this way." ... 

The synthesis of larger rings has also been accomplished including the fully unsaturated azolo-fused 1,3-diazepines (222) from bis(iminophosphoranes) (221) and novel cyclic carbodiimides (e.g. 223). Iminophosphoranes are also intermediates in the synthesis of macrolactams (e.g. 225) from the reaction of co-azido acid anhydrides (e.g. 224) with tributylphosphine. The synthesis of iminophosphorane-containing cryptands and a spherand-type structure have been reported. 

In peptide chemistry two methods are used frequently. The reaction of phosgene with protected amino acids leads to symmetric anhydrides (equation 4), after disproportionation and release of carbon dioxide, which can be readily used to build up a growing peptide chain. - More recently, symmetrical amino acid anhydrides have been generated by carbodiimides like DCC, water soluble caibodiimide and diisopropylcarbodiimides in situ. They are extensively applied to autmnated solid phase peptide synthesis. Attention has to be paid to the proper solvent system, as eq)rotic dipolar solvents tend to slow down reactions and increase formation of side products. ... 

Reaction of the carbodiimide with the acid then provides a means for the synthesis of a biologically high-energy acid anhydride. This suggests a potential route for the synthesis of a peptide bond. For example, it has already been pointed out that amines will react with acid anhydrides to form peptide bonds. Further, under the mild conditions (i.e., room temperature) that carbodiimide will react with carboxylic acids, competing reactions will not occur. For example, carbodiimides will only undergo nucleophilic attack by alcohols under refluxing conditions. 

For the solid-phase synthesis of amides, it makes a significant difference whether the amine or the acid is linked to the support. Resin-bound amines are readily acy-lated by adding first a carboxylic acid and then a carbodiimide (Table 13.3). The acid/ carbodiimide ratio is not critical, because both the O-acylisourea (ratio 1 1) and the symmetric anhydride (ratio 2 1) will lead to N-acylation. It should, however, be borne in mind that the half-lives of O-acylisoureas are shorter than those of anhydrides, and for difficult couplings it might be advantageous to acylate with a symmetric anhydride (two equivalents of acid and one of carbodiimide). 

The combination of carboxyl activation by a carbodiimide and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols.10 The reaction proceeds at room temperature. Carbodiimides are widely applied in the synthesis of polypeptides from amino acids. The proposed mechanism for this esterification reaction involves activation of the acid via isourea 28 followed by reaction with another acid molecule to form anhydride... 

In connection with synthesis of quinomycin model systems, Chen and Olsen found that diethylphosphoryl cyanide is the reagent of choice for coupling amino acid derivatives to cis- or rra/ 5-4-aminocyclohexanecarboxylic acid. Other procedures, including the carbodiimide, p-nitrophenyl active ester, and symmetrical anhydride methods, were less satisfactory. 

Kemp et al have now published complete details on the use of this reagent for peptide synthesis. The second step is best carried out with a tetraalkylam-monium salt of an amino acid or with an amino acid (or peptide) in DMSO containing 1 eq. of tetramethylguanidine, [(CH3)2N]2C=NH. The method has been shown to be useful with all the common amino acids except arginine and histidine. Medium-sized peptides have been prepared. Kemp concludes that this method is comparable to the azide, carbodiimide, and mixed-anhydride methods of peptide synthesis. Difficulties with yield and purification have been observed with fairly large peptides. 

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