Carbonyldiimidazole with peptides

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

The broad use of A -carbonyldiimidazole (CDI) for the synthesis of amide and peptide linkages became a routine method only in the early sixties. JV-Protected amino acids were treated at room temperature with an equimolar amount of CDI to give imidazolides. Anhydrous tetrahydrofuran, dimethoxyethane, dichloromethane, pyridine, dimethylfor-mamide, and diethyl phosphite were utilized as solvents. In the second step the esters of amino acids, their hydrochlorides, or sodium salts were added to yield the peptide after several minutes or hours of reaction time. 

Carbonyldiimidazole does certainly stand out as one of the most remarkable reagents for peptide coupling. Carboxylic acids react readily with this reagent to yield acyl imidazoles which in turn couple with the amino group of a peptide to produce a new acyl-nitrogen linkage with very little racemization. Reaction of the acylimidazolide with other nucleophiles can lead to a variety of carbonyl derivatives (62AG(E)35l). 

Paul R, Anderson GW. N,N -carbonyldiimidazole, a new peptide forming reagent. J. Am. Chem. Soc. 1960 82 4596-4600. Bethell GS, Ayers JS, Hancock WS, Hearn MTW. Novel method of activation of cross-linked agaroses with 1,1 -carbonyldiimidazole which gives a matrix for affinity chromatography devoid of additional charged groups. J. Biol. Chem. 1979 254 2572-2574. 

Activation of carboxylic acids with carbonyldiimidazole (equation 12) and subsequent reaction with amines gives amides and peptides in good yield. " Through the same intermediate, the activation also occurs with the more stable AA -oxalyldiimidazole and the mixture of triphenyl phosphite and imidazole. "... 

Double amidation of phosgene, to give symmetrical ureas, is considerably easier to perform. Considerable interest is attached to the recent reaction of imidazole with phosgene, which led to l,T-carbonyldiimidazole, an extremely reactive compound on account of the lability of its amide bonds 597 The ease with which the imidazole group can be replaced by other groups offers the widest possibilities for synthesis of other carbonic acid derivatives, carboxylic esters, amides, and hydrazides, peptides, phosphoric esters, etc., all under the mildest conditions.598 Since l,T-carbonyldiimidazole is hydrolysed even by atmospheric moisture, it must be prepared under the most strictly anhydrous conditions. 

Carbonyldiimidazole was first used for peptide activation in conjunction with the solid-phase Edman degradation because of its reported high yields and the absence of side reactions (Paul and Anderson, 1960). Activation occurs by way of the imidazolide (Fig. 3). Although this reagent does seem... 

Figure 4. Cyclic imide formation at aspartic acid during activation of peptides with carbonyldiimidazole.

Several reports have dealt with the use of phosphinic pseudodipeptide building blocks in peptide couplings where both phosphinic and carboxylic acids are unprotected. Among the coupling reagents used successfully for such transformations are W,W -carbonyldiimidazole (CDl) [66-68], (benzotriazol-l-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP) [69, 70],... 

Carbonyldiimidazole (GDI) is a crystalline phosgene substitute (mp 117-122 °C) and a preferred reagent for carboxyl activation. Salts (triflate or sulfate) of GDI are also used as activating agents in peptide and ester formation with retention of optical activity [104, 105]. 

N,N -carbonyldiimidazole orgchem C7H6N4O Crystals with a melting point of 115.5-116°C hydrolyzed by water very quickly used in the synthesis of peptides. en en,prTm kar ba.nil.dT i mid a.zol ... 

Trimethylsilyl can be used in peptide synthesis for blocking of carboxyl as well as for protection of hydroxyl and sulfhydryl. It can be easily removed by treatment with water or alcohol.—E N-Carbobenzoxyglycine warmed 1 hr. at ca. 50° with 10% excess N,N -carbonyldiimidazole in anhydrous tetrahydro-furan, cooled, shaken and treated dropwise with a soln. of N,0-bis (trimethylsilyl) -DL-serine trimethylsilyl ester, refluxed ca. 1 hr., tetrahydrofuran removed by distillation at 12 mm, and treated with water N-carbobenzoxyglycyl-DL-serine. Y 80%. F. e., also with POCI3 (cf. Synth. Meth. 13, 450), s. L. Birkofer, W. Konkol, and A. Ritter, B. 94, 1263 (1961) N.N -carbonyldiimidazole method s. Synth. Meth. 14, 452. 

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