Development of transition metal mediated biocompatible reactions

Abstract

1. Betaine-catalyzed triazole formation reation As the CuAAC reaction which is a powerful tool for the facile, convenient synthesis of triazoles is highly efficient and regioselective, it has been extensively applied to several reactions in organic synthesis and biological chemistry, as well as material science. Recently, for biological application, highly efficient Cu(I) catalysts have been developed for the synthesis of triazoles to minimize the amount of Cu(I) catalyst used. In this thesis, the CuAAC reaction in aqueous medium was dramatically accelerated by a simple zwitterionic additive, betaine, at ambient temperature. In the presence of betaine, 1,4-disubstituted-1,2,3-triazoles were obtained in excellent yields under 2.5–200 ppm levels of Cu(I) in water. This efficient Cu-betaine catalyst system is expected to be applied in the field of biological applications and materials science.

2. C-C bond formation reaction of dehydroalanine unit Chemical modification of proteins has emerged as an invaluable tool for biochemical research. To facilitate the reaction, it is challenging to satisfy the mild reaction conditions applicable to proteins, namely, aqueous media, ambient temperature, a narrow pH range, shorter reaction time, functional group tolerance and high efficiency. In this thesis, Zn/Cu(OTf)2 mediated addition of alkyl bromides to Dha derivatives including dipeptides and tripeptides in good to high yields under aqueous medium was introduced. Moreover, Rh catalyzed 1,4-addition of arylboronic acids to Dha units was also successfully demonstrated under buffer system at 37 °C within 3 h.

3. β-elimination reaction of phosphoserine The β-elimination reaction of phosphoserine generates Dha which plays a versatile precursor for diverse PTM moieties. In general, the conversion of phosphoserine to Dha was performed with treatment of various alkaline solutions up to pH 13, and it can cause hydrolysis or denaturation of proteins, which is difficult to apply to a wide range of proteins. In this thesis, we study various reaction conditions to improve the leaving group ability of phosphate, by the pyrophosphorylation of phosphate or introducing one or two Rs in the hydroxyl group of phosphate or using various metals such as Mg, Zn and La, which can be easily coordinated with phosphate. Through the coordination between LaCl3 and phosphate, phosphoserine derivative was successfully converted to Dha at pH 9.7 under Tris buffer at 37 °C within 3 h.