Polymer-bound DCC

Very recently more comprehensive research on the solid-supported preparation of substituted oxadiazoles and thiadiazoles was reported [108], Initially, a set of ten oxadiazoles was prepared by microwave-mediated cyclization of semicarba-zides. In the presence of polymer-bound DCC the desired compounds were obtained within 1 h at 140 °C (Scheme 16.70a). To find a different pathway a set of nine polymer-bound bases was used in an optimization sequence employing sul-fonyl acid chlorides. If the reactions were performed in THF under the action of microwave irradiation for 1 h, PS-BEMP was found to be the most effective base. A set of twenty sulfonyl acid chlorides was used in this microwave procedure to afford the corresponding compounds in moderate to good yields and excellent purity... 

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

Dehydration of fi-nitro alcohols using DCC gives a mixnire of E/Z nitroaikenes. The pure fE -isomers are obtained on treatment with catalytic amounts of triethylamine or polymer-bound triphenylphosphme (TPP fEq. 3.281. When (Z) nitroaikenes are desired, the addition of PhSeNa to the E/Z mixnire and protonadon at -78 "C fohowed by oxidadon with gives fZi-nitroalkenes fEq. 3.29. ... 

The desired polymer-bound tryptophan was rapidly generated under microwave irradiation, employing a classical esterification protocol using N,N -dicydohexylcar-bodiimide (DCC) and a catalytic amount of N,N-dimethylaminopyridine (DMAP), followed by subsequent Fmoc deprotection (Scheme 7.68). Cyclocondensations with various carbonyl compounds were performed with catalytic amounts of p-toluene-... 

The details of the reaction mechanism with DCC were given in Chapter 43, p. 1172, and can be shown more easily if we mark the polymer and spacer as P and the cyclohexyl groups as CR The DCC is protonated by the free carboxylic acid and is then attacked by the carboxylate anion. The intermediate is rather like an anhydride with a C=NR group replacing one of the carbonyl groups. It is attacked by the amino group of the polymer-bound amino acid. The by-product is dicyclohexy-... 

Step 4 A Boc-protected Ala is coupled to the polymer-bound valine by reaction with DCC. The polymer is washed. 

In the solid phase reaction the anhydride formation is the predominant pathway. Reaction with radioactive DCC has shown that less than 0.2 % of the polymer-bound amine reacts directly with the reagent. ... 

The mechanism of DCC coupling involves conversion of the carboxyl group of the acid to a good acylating agent (steps 1 and 2) followed by acylation of the free amino group of the polymer-bound amino acid (steps 3 and 4). 

Af,Af -diisopropylcarbodiimide (DIC), A, A -dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-A -ethylcarbodiimide (EDCI), and TsCl (p-toluenesnlfonyl chloride), and found that the addition of DIC markedly increased the yield of the desired resin 32. This intermediate is subsequently cyclized to yield 2-mercaptobenzoxazole 34, which combines with the Merriheld resin 1 to afford the polymer-bound benzoxazole 32 (Scheme 10.6, path c). 

The DCC peptide coupling method can be improved both in terms of yield and suppression of racemization by the addition of Lewis acids, especially zinc chloride. A promising pilot study on the use of polymer-bound carbonic-carboxylic anhydride functions for the preparation of amides has been reported. It has been suggested in two reports that peptide bond formation is more rapid when soluble polymers are used, specifically a, >-diaminopolyethyl-ene glycol ( amino PEG ) and chloromethylated polystyrene. ... 

Functionalisation with bulky hydrophobic carboxylic acids/DCC was studied for the synthesis of amphiphilic polymers based on dextran. Bile acid is covalently bound to dextran (Fig. 27) through ester linkage in the presence of DCC/DMAP (added in dichloromethane) as coupling reagent. 

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