1.3- Dicyclohexylcarbodiimide anhydride formation

The subsequent binding of peptides, however, is not possible via symmetric anhydride formation. Even by dicyclohexylcarbodiimide and carbonylbisimidazol condensation with lipophilic tripeptides it is scarcely possible to bind more than 0.2 mmole/g of support. In those cases the attachment to bromoacetyl sites on polystyrene via caesium salts is highly recommended [85]. 

When the reagent is dicyclohexylcarbodiimide, the reaction is carried out in dichloromethane, the /V,/V -dicyclohcxylurca is removed by filtration after 15-30 minutes, the solvent is sometimes replaced by dimethylformamide, and the solution is then added to the /V-nucleophile. The /V,/V -dicyclohcxylurca is removed to help drive the coupling reaction to completion. The symmetrical anhydride is not prepared directly in the polar solvent because the latter suppresses its formation. 

The favored formation of a nucleoside 3 -(alkyl phosphate) was observed on treating the diphenyl phosphate anhydride of uridine 2, 3 -cyclic phosphate with benzyl alcohol.273 In a somewhat related reaction, on treatment with dicyclohexylcarbodiimide in aqueous pyridine, adenosine 2 (3 )-phosphate gave, initially, the 2, 3 -cyclic phosphate, which, on further reaction with the diimide, gave a mixture of the N-phosphonourea nucleoside 44 and its 2 -isomer, in unequal amounts.269 This type of reaction does not seem to occur with... 

As discussed before, the strategy to synthesize catenanes is not necessarily restricted to olefin metathesis as the ring closing reaction. Any reaction which can be carried out under conditions where the hydrogen-bonded dimers exist should be appropriate. A first example was realized by the formation of anhydride linkages with dicyclohexylcarbodiimide as the reagent in benzene as the solvent [57], as schematically illustrated in Scheme 5.19. 

Scheme 6 Formation of Symmetrical Anhydrides as a Side Reaction in iV,iV -Dicyclohexylcarbodiimide Coupling Reactionsl l...

The attempted formation of an anhydride from 7 using dicyclohexylcarbodiimide gave a dimeric anhydride 8. ... 

The most frequently used approaches for derivatizing carboxylic acids are esterification with a variety of single-enantiomer alcohols, or formation of amides with single-enantiomer amines [234,252]. The formation of amide derivatives requires activation of the carboxylic acid by formation of the acid chloride with thionyl chloride, mixed anhydrides with chloroformates, N-acylimidazoles with 1,1 -carbonyldiimidazole or N-acylureas with dicyclohexylcarbodiimide. Esterification reactions generally re-... 

The second reagent, dicyclohexylcarbodiimide (DCC, DCCI), introduced by J.C. Sheehan (Plate 41) and G.P. Hess for the formation of the peptide bond [40] brought about a revolution in synthesis. Carbodiimides (R—N=C=N—R) had been known for a long time [41] and their reactivity had been exploited before for the preparation of esters and anhydrides. According to H.G. Khorana [42] the condensation reaction starts with the addition of the carboxyl component to one of the double bonds in the carbodiimide to yield the reactive... 

A very useful group of procedures for oxidation of alcohols to ketones have been developed that involve dimethyl sulfoxide (DMSO) and any one of a number of electrophilic molecules, particularly dicyclohexylcarbodiimide, acetic anhydride, and sulfur trioxide. The initial work involved the DMSO-dicyclo-hexylcarbodiimide system. The utility of the method has been greatest in the oxidation of molecules that are highly sensitive to more powerful oxidants and therefore cannot tolerate alternative methods. The mechanism of the oxidation involves formation of intermediate A by nucleophilic attack of DMSO on the carbodiimide, followed by reaction of this species with the alcohol. A major portion... 

Dicyclohexylcarbodiimide is often used as a coupling reagent. The mechanism of activation is believed to involve formation of phosphoric anhydrides. 

To circumvent this uncertainty without use of the caesium salt procedure, hydroxymethyl [87] or aminomethyl functions on the polymer can be reacted with carboxylic partners in an esterification reaction [207] or peptide bond formation with the aid of condensing agents like carbonylbisimidazole [88], dicyclohexylcarbodiimide [89] or others. For this purpose in the author s laboratory the use of symmetric anhydrides [3] of the N-protected amino acids to be attached to the support was found to be most effective [90], especially in the formation of activated esters on the gel phase with phenolic hydroxyl functions [38]. By this procedure, on 0.5% cross-linked polystyrenes, load levels up to 1.5 millimoles/g of the support are reached. 

The amino functions on polymer in a nucleophilic attack react with this acylating intermediate from the moment of its formation. In contrast to the situation in real solution, the reactivity of the amino groups in the gel phase is lowered, leaving time for a branched pathway of side reactions of the 0-acyl isourea. It is attacked by another carboxylic partner forming the symmetric anhydride as a second highly reactive intermediate, which acylates the amino groups on polymer. In both the direct and the indirect acylation, dicyclohexylcarbodiimide loses its condensation potency by transformation into the dicyclohexylurea, which in most of the solvents employed in the synthesis step of the Merrifield procedure is only slightly soluble (Fig. 41). 

As already mentioned, one of the acylating species formed by activation with dicyclohexylcarbodiimide has been known for a long time to be the symmetric anhydride of the carboxylic component. Its formation can be favored by admixture of two equivalents of the N-protected amino acid with one of the diimide. Since the major portion of the dicyclohexylurea is precipitated, if dichloromethane is used as solvent, the byproduct can be filtered off before mixing of the anhydride solution with the polymer phase [ 141 ]. In this way, in the actual peptide synthesis the chance for side reactions is diminished, since only the dissolved part of the urea by-product, small amounts of the 0-acyl lactim, and traces of the diimide initially are still present. Though in most cases the peptides obtained by this procedure obviously are purer than those from the original method of activation with equivalent amounts of the components, the in situ formation of symmetric anhydrides with dicyclohexylcarbodiimide does not entirely overcome diimide dependent side reactions and the wash-out problem of the dicyclohexylurea. 

Although dicyclohexylcarbodiimide activation to date is still the widely used coupling method on polymer phase, we searched for an alternate to circumvent all the problems combined with diimide side reactions and the formation of the scarcely soluble dicyclohexylurea. For this purpose we reinvestigated the direct synthesis of synunetric anhydrides from N-protected amino acids with phosgene [142-145] (Fig. 43). 

The reagent most commonly used to bring about peptide bond formation is 1,3-dicyclohexylcarbodiimide (DCC). This reagent is the anhydride of a disubstituted urea, and when treated with water, it is converted to N,N -dicyclohexylurea (DCU). 

The use of the newer condensing reagents trifluoroacetic anhydride or dicyclohexylcarbodiimide has streamlined the synthesis of the depside linkage from the appropriately substituted benzoic acid and phenol. Where necessary the phenolic and carboxyl groups of the precursors are protected by O-benzylation until after depside-ester bond formation has been achieved. Catalytic hydrogenolysis of the so-formed 0-benzyldepside esters subsequently gives the natural depsides. 

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