1.3- Dicyclohexylcarbodiimide ester formation

Scheme 7 Side Reaction of Ai-Succinimidooxycarbonyl-p-alanine Succinimido Ester Formation by Reaction of One Molecule of Ai,Ai -Dicyclohexylcarbodiimide with Three Molecules of Ai-HydroxysuccinimideP l...

Of great importance in peptide chemistry are the f-butyl, benzyl and substituted benzyl es-ters. 226 They are more stable to acids than the corresponding urethanes. Benzyl and substituted benzyl esters can be prepared by azeotropic esterification with the respective benzyl alcohol, by activating the carboxy group, e.g. with dicyclohexylcarbodiimide (DCC) or by reacting a carboxylate with a benzyl halide (Scheme 65). The latter 5N2-type ester formation is particularly efficient if cesium carbox-ylates are employed. Under the conditions required for this reaction the racemization of a-chiral car-... 

The last two items of Table 9.6 are related. The seventh item shows that the techniques already discussed that employ dicyclohexylcarbodiimide and carbonyl-diimidazole to activate a carboxylic acid for attack by primary and secondary amines in order to forge the bond between the carbon of the carbonyl and the nitrogen of the amine to yield amide (vide supra. Scheme 9.119) can also be employed in ester formation (Scheme 9.122). The particular alcohol chosen, 3-(hydroxymethyl)-3-methyloxetane, although typical in its reactivity for primary alcohols in general and thus capable of serving as a prototype for ester, was also chosen because, as shown in item 8 of Table 9.6, it can subsequently be used to convert the ester to an orthoester of the corresponding carboxylic acid (Scheme 9.123). Such orthoesters are used to protect the carboxylic acid function and preserve it, while manipulations... 

Schemes are available, however, that start from the free carboxylic acid, plus an activator . Dicyclohexylcarbodiimide, DCC, has been extensively employed as a promoter in esterification reactions, and in protein chemistry for peptide bond formation [187]. Although the reagent is toxic, and a stoichiometric concentration or more is necessary, this procedure is very useful, especially when a new derivative is targeted. The reaction usually proceeds at room temperature, is not subject to steric hindrance, and the conditions are mild, so that several types of functional groups can be employed, including acid-sensitive unsaturated acyl groups. In combination with 4-pyrrolidinonepyridine, this reagent has been employed for the preparation of long-chain fatty esters of cellulose from carboxylic acids, as depicted in Fig. 5 [166,185,188] ...

Thus unsubstituted (R=H) and substituted (R = alkyl) non-stabilized diyiides 1 react with phenylisocyanate and dicyclohexylcarbodiimide (R NCX), leading to the formation of new monoylide type intermediates. These last ones react in situ with carbonyl compounds through a Wittig type reaction leading respectively to a,)8-unsaturated amides 2 and amidines 3, with a high E stereoselectivity, the double bond being di- or tri-substituted [48,49]. By a similar reactional pathway, diyiides also react with carbonic acid derivatives, with the synthesis as final products of -a,/l-unsaturated esters 4 and acids 5 [50]. 

Inversion of configuration.1 The configuration of a secondary alcohol (2) can be inverted by reaction with dicyclohexylcarbodiimide (1) to form an isourea ether (3), which is allowed to react, without isolation, with formic acid with formation of the ester 4 with inverted configuration. 

A reagent which allows both CGA and HGA esterifications is DCC (dicyclohexylcarbodiimide 53 R = cyclohexyl). CGA esterifications are accomplished by treating a mixture of the carboxylic acid and the alcohol with DCC in hexane or pyridine with a catalytic amount of p-TsOH. The O-acylisourea (54) is postulated as intermediate, which reacts with the alcohol under elimination of the urea (56) and formation of the desired ester. The urea is removed by filtration (equation 22). This method is highly recom-mendable if both the carboxylic acid and the alcohol are valuable and bear sensitive functional groups. Numerous applications in natural product synthesis have been reported. ... 

Hoskins and Crout have synthesized C-9 monoesters of retronecine (127) in reasonable yields by using iV,N -dicyclohexylcarbodiimide as the coupling reagent.The use of AT,JV -carbonyldiimidazole, with prior formation of the acylimidazole, was necessary with aj8-unsaturated acids and bulky a-trisubstituted acids. Subsequent esterification at C-7 of the retronecine ester with a suitable acid chloride produced unsymmetrical diesters of retronecine. 

Scheme 3. The Role of A jAf -Dicyclohexylcarbodiimide in the Formation of an Active Phosphorylating Species [Metaphosphates (76) or (76), or both] from Phosphoric Ester (69). (Dotted arrows indicate electronic shifts associated with metaphosphate formation.)...

Coupling of the two amino acids is achieved by A. A -dicyclohexylcarbodiimide (DCCl)-promoted amide bond formation between the free amino group of leucine benzyl ester and the free carboxyl group of Z-protected alanine. 

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... 

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. 

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