Polymer-bound carbodiimides

Scheme 7.103 Amide synthesis utilizing polymer-bound carbodiimide.

An advantage of polymer-based reagents is that both the excess and the spent reagent are easily separated from the product. Bruno Linclau of the University of Southampton has reported J. Org. Client. 2004, 69,5897) the preparation of a polymer-bound carbodiimide. Exposure of the polymer to alcohol gives a family of O-alkylisoureas that smoothly convert carboxylic acids to the corresponding esters. Methyl, benzyl, ally and p-nitrobenzyl transfer smoothly. The polymeric (-butyl reagent could not be prepared. 

Carbodiimides, in particular dicyclohexylcarbodiimide, have been applied in many syntheses where dehydration had to be performed under mild conditions. It is therefore no surprise that this reagent was also introduced for the synthesis of acid anhydrides from carboxylic acids." " In order to avoid N-acylation the reactions are carried out at low temperature. First 0-acylisoureas are formed, which then react further with free acid to the acid anhydride (equation 34). The reaction has been exploited in particular for the preparation of peptides." )V-alkoxycarbonyl-protected amino acids can be transformed in high yield to the corresponding anhydrides, which themselves are activated acid derivatives and may be converted to peptides. As in many other examples polymer-bound carbodiimides may prove superior sometimes, as the isolation of the products is facilitated. Easy preparation of acid anhydrides is possible in this way." ... 

Keck, G. E., Sanchez, C., Wager, C. A. Macrolactonization of hydroxy acids using a polymer-bound carbodiimide. Tetrahedron Lett. 2000, 41, 8673-8676. 

Scheme 16.77. Amide synthesis using polymer-bound carbodiimide.

Aminomethylated, crosslinked polystyrenes constitute very valuable and versatile resins for a variety of applications. The amino group can be easily acylated for the introduction of spacer and linker molecules and it was also used for the synthesis of polymer-bound carbodiimides. - In Scheme 1 S.4.4, some of the most common synthetic accesses to aminomethylated polystyrenes are summarised. 

Also, reaction of the aminomethyl polystyrene with cyclohexylisocyanate affords a polymer bound urea, which is converted into the carbodiimide using Ph3PBr2. Reaction of the polycarbodiimide with methanol affords an 0-alkylisourea which is used in the 0-alkylation of carboxylic acids. ... 

Also, polymer bound thioureas 29 are converted into carbodiimides 30 using Mukaiyama s reagent (2-chloro-l-methylpyridinium iodide) in the presence of triethy-lamine. This polymer is used in the solid phase synthesis of 2-aminoimidazolinones. °... 

Enzymes can be readily bound to these activated polymers using carbodiimides. 

On reviewing the couphng methods proposed for application in solid phase peptide synthesis one finds that most known methods of peptide bond formation have been tried but no new approach was designed specially for the acylation of the polymer bound amine component. Therefore we will limit the discussion in this section to two well established procedures, coupling with the help of carbodiimides and acylation via active esters. 

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