Diphenolic monomers derived from the natural amino acid alpha-L-tyrosine: An evaluation of peptide coupling techniques

Tyrosine-derived polycarbonates and polyarylates have recently been recognized as promising biomaterials. In these novel polymers, non-toxic desaminotyrosyl-tyrosine alkyl esters are being used as monomers in place of industrial diphenols such as Bisphenol A. The high cost and limited availability of desaminotyrosyl-tyrosine alkyl esters have prevented the large-scale preparation of these polymers. To address this problem, the following four peptide coupling techniques were explored: dicyclohexylcarbodiimide with 1-hydroxybenzotriazole hydrate (DCC/HOBt), ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride salt (EDCI . HCl), N-hydroxysuccinimide (NHS) active ester, and p-nitrophenol (pNP) active ester. Desaminotyrosyl-tyrosine hexyl ester (DTH) was used as a model compound. DCC/HOBt led to a crude product that required column chromatography for purification. The water soluble coupling agent EDCI HCl made it possible to replace column chromatography by precipitation/extraction in aqueous media. This alleviated possible environmental concerns about the use of organic solvents. Furthermore, EDCI . HCl did not require the addition of an auxiliary nucleophile such as HOBt in the reaction mixture. The use of the NHS active ester of Dat also produced DTH of sufficient purity, but was less cost effective than EDCI . HCl. The pNP active ester produced DTH which could not be easily purified. Based on these results, the effectiveness of EDCI . HCl was verified by the 100 g synthesis of the ethyl, butyl, hexyl and octyl esters of desaminotyrosyl-tyrosine. All of these monomers could be polymerized to high polymers. Overall, the EDCI . HCl mediated coupling of Bat and tyrosine alkyl esters was identified as the best method for the large-scale synthesis of the desaminotyrosyl-tyrosine alkyl esters in a cost efficient and environmentally acceptable manner.