DCC coupling

Developed as a carboxyl protective group for peptide synthesis because of its stability to hydrogenolysis and acidic conditions, the acetol (hydroxy acetone) ester is prepared by DCC coupling (68-92% yield) of the acid with acetol. It is cleaved with TBAF in THF. ... 

Formation of this ester proceeds under standard DCC coupling conditions (DMAP, THF, 28-93%). The ester is cleaved with 1% TFA or dichloroacetic acid in CH2CI2 by DDQ (reflux, CH2CI2, H2O, 5-15 h, 47-92% yield). Hydrogenolysis (Pd/C, EtOAc, MeOH) cleaves the ester in 23 h, whereas a benzyl ester is cleaved in 10 min under these conditions. ... 

This ester, developed for peptide synthesis, is prepared by the standard DCC coupling protocol and is cleaved reductively with SnCl2 (MeOH, 25°, 5 h) followed by treatment with mild base to effect quinonemethide formation with release of the acid in 75-95% yield. ... 

These derivatives, used for 5 -phosphate protection, are prepared by using the DCC coupling protocol and are cleaved with 2 N NaOH at The protected phosphates can be purified using benzoylated DEAE-Cellulose. 

The reaction of 5a-bromo-a-tocopherol (46) with amines was further elaborated into a procedure to use this compound as a protecting group Toe for amines and amino acids (Fig. 6.35).62 The protection effect was due to a steric blocking of the amino function by the bulky tocopheryl moiety rather than due to conversion into a non-nucleophilic amide derivative, and the Toc-protected amino acids were employed in the synthesis of dipeptides according to the dicyclohexylcarbodiimide (DCC) coupling method.64 The overall yield of the reaction sequence was reported to be largely dependent on the coupling reaction, since both installation and removal of the... 

A potential undesirable effect of DCC coupling reactions is the spontaneous rearrangement of the o-acylisourea to an inactive N-acylurea (Stewart and Young, 1984) (Figure 3.6). The rate of this rearrangement is dramatically increased in aprotic organic solvents, such as DMF. 

LCB polymers can be formed by chemically linking preformed polymers (arm first or polymer first method) or by growing polymer chains from a multifunctional initiatior (core first method). In both cases living polymerization techniques are preferred because they provide better control over MW, MW distribution and the final branching architecture. However, highly selective coupling reactions e.g. with multifunctional isocyanates, or dicyclohexylcar-bodiimide (DCC) coupling, have also been successful. 

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 utility of carbodiimide reagents was too important to consider abandoning them. Instead, it rapidly became obvious that carbodiimide activation could be used to prepare in situ active esters. Numerous nucleophilic additives were discovered and prepared for use in these reactions. The most important of these additives was 1,2,3-benzotriazol-l-ol (HOBt, 1), first reported for use in peptide synthesis by Konig and Geiger in 1970.[2(l As an example of a typical result, 1.2 equivalents of HOBt was added to the DCC coupling of Boc-Leu-Phe-OH to H-Val-OtBu in DMF as a solvent. Less than 1% of the l-d-l epimerized tripeptide was formed. When the reaction was carried out in the absence of HOBt, the amount of l-d-l product formed was 14.3%. Addition of HOBt to DCC reactions converts the intermediate G-acylisourea (2) (and any symmetrical anhydride) into the HOBt active ester 3 (Scheme 8). 

The first glycodendrimer was pepared by Roy et al. [49]. Access to dendrimers bearing carbohydrate terminal groups is provided by the triglycosylated trihy-droxyamine 3 [50] obtained in a several-stage synthesis, which can serve as dendron. The amino dendrons could be attached to the tricarboxylic acid core by DCC coupling (dicyclohexylcarbodiimide) (Fig. 4.28) [51]. 

The mechanism for DCC coupling is not as complicated as it may seem. The car-boxylate ion adds to the strongly electrophilic carbon of the diimide, giving an activated acyl derivative of the acid. This activated derivative reacts readily with the amine to give the amide. In the final step, DCU serves as an excellent leaving group. The cyclohexane rings are miniaturized for clarity. 

The second amino acid (valine) is added in its N-protected Boc form so that it cannot couple with itself. Addition of DCC couples the valine carboxyl group with the free —NH2 group of phenylalanine. 

The synthesis of compound (88) is outlined in Scheme 3.13. DCC coupling of enantiomerically pure (1. S, 2.V)-(+)-tra i-2-pyrrolidinyl-(V-methylcy-clohexylamine (92) with 2-nitrophenylacetic acid gave the nitro derivative (93). Catalytic hydrogenation over Pd-C catalyst afforded amine (94) which was treated with thiophosgene to yield (88). 

Asymmetric Peptide Synthesis. The reagent activates amino acids through 1,3-Dicyclohexylcarbodiimide (DCC) coupling to the N-hydroximide for subsequent coupling with chiral amino acids. The asymmetric center induces preferential reaction with L-amino acids and high optical purities of L-L-dipeptides can be achieved (eq 2). Enantioselectivity is improved if the 5-methyl group is replaced by isobutyl. ... 

Preparative Methods can be prepared by DCC coupling of iV-Boc-(S)-proline and isoindoline followed by LiAlH4 reduction. ... 

Table 3 Schedule for DCC Coupling in Solid-phase Synthesis of Somatostatin-14 ...

Table 1 Schedule of Operations for One Step of Chain Elongation by DCC Coupling ...

Figure 4. Preparation of the methoprene immunogen (Structure 15) by two methods a. The NHS-ester of methoprene (Structure 14) was conjugated to human serum albumin (H2N-HSA) in organic/aqueous solution, b. A water soluble active ester of methoprene (Structure 16) was prepared by the DCC coupling of methoprene-spacer acid (Structure 13) with l-hydroxy-2-nitro-4-benzene sulfonate. Reaction of compound 16 with H2N-HSA was carried out in aqueous phosphate buffered saline (PBS).

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