Amide formation with DCC

Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexyl-carbodiimide (DCC). 

We ll see in Section 26.7 that this DCC-induced method of amide formation is the key step in the laboratory synthesis of small proteins, or peptides. For instance, when one amino acid with its NH2 rendered unreactive and a second... 

Peptide synthesis requires the use of selective protecting groups. An N-protected amino acid with a free carboxyl group is coupled to an O-protected amino acid with a free amino group in the presence of dicydohexvlcarbodi-imide (DCC). Amide formation occurs, the protecting groups are removed, and the sequence is repeated. Amines are usually protected as their teit-butoxy-carbonyl (Boc) derivatives, and acids are protected as esters. This synthetic sequence is often carried out by the Merrifield solid-phase method, in which the peptide is esterified to an insoluble polymeric support. 

In search of a convenient procedure for preparing diazo substrates for the cycloaddition to Cgg, Wudl introduced the base-induced decomposition of tosyl-hydrazones [116]. This procedure allows the in situ generation of the diazo compoimd without the requirement of its purification prior to addition to Cgg. Since they are rapidly trapped by the fullerene, even unstable diazo compounds can be successfully used in the 1,3-dipolar cycloaddition. In a one-pot reaction the tosyUiydrazone is converted into its anion with bases such as sodium methoxide or butylHfhium, which after decomposition readily adds to Cgg (at about 70 °C). This method was first proven to be successful with substrate 142. Some more reactions that indicate the versatility of this procedure are shown in Table 4.4. Reaction of 142 with CgQ under the previously described conditions and subsequent deprotection of the tert-butyl ester leads to [6,6]-phenyl-C5j-butyric acid (PCBA) that can easily be functionalized by esterification or amide-formation [116]. PCBA was used to obtain the already described binaphthyl-dimer (obtained from 149 by twofold addition) in a DCC-coupling reaction [122]. 

The carbodiimide method has been employed in several syntheses of depsipeptides. However, direct application of DCC for the formation of the ester bond between the amino acid and hydroxy acid components under the usual conditions of amide coupling affords the desired depsipeptides in acceptable yields only in the case of unhindered co-hydroxy units [54] or an active hydroxy group, such as in TV-benzoyl-u-hydroxyglycine benzyl ester. For example, Ravdel et al.[55 have performed the esterification of various benzyloxycarbonyl- and phthalylamino acids with /V-benzoyl-a-hydroxyglycine benzyl ester with DCC in 50-65% yield. On the other hand, Shemyakin et all21 failed to obtain the expected depsipeptide products on condensation of bulky benzyloxycarbonyl- or phthalylvaline with a-hydroxy-isovaleric acid benzyl ester. The main product was acylurea in the first case and phthalylvaline anhydride in the second. Thus, the classical carbodiimide procedure could not be applied in practical depsipeptide preparation. 

The mechanism for amide formation promoted by DCC is shown in Figure 26.4. The carboxylic acid first reacts with DCC to form an intermediate that resembles an anhydride, but with a carbon-nitrogen double bond in place of one of the carbonyl groups. 

Amide formation from carboxylic acids 480 with O-subsituted hydroxylamine hydrochlorides also proceeds in the presence of DCC to give the substituted hydroxamic acid 481 in 91 % yield.451... 

Following thorough washes with DMF, amide formation was carried out for 24 h under standard carbodiimide coupling conditions (DCC, 4 equiv., H0Bt/H20, 4 equiv.) using an excess of a primary amine (4 equiv.) in DMF. Intermediate 15 was obtained after exhaustive washing, first with DMF and then with MeOH. 

The above mentioned methods for preparation of cyclic bis-amides were patterned after peptide chemistry reactions where amide bonds dominate. Also in peptide chemistry, DCC, and DCC plus 1-hydroxybenzotriazole (HOBT) have been used in amide formation reactions. Using this procedure, 16-membered peraza-crowns have been prepared in 50-55% yields for the cyclization step (Vellacio et al., 1977). The carboxyl group can also condense with secondary amines in DMF in the presence of 1.1 mol of DCC and 1.2 mol of HOBT per mole of the dicarboxylic acid (Krakowiak et al., 1989). 

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