Development of Oxime Palladacycle Resin, Ionic Liquid Resin, and CoreShell-Type Resin Designed for Efficient C-C Coupling and Peptide Synthesis

Abstract

Polymer support is a very useful tool for organic synthesis and chemical process. A polymer support on which metal or organic catalyst are immobilized has been used as a heterogeneous catalyst and a functionalized polymer support with linker has been used in SPPS and SPOS. Because the polymer support is mostly insoluble in solvents, it can be easily isolated from the reaction media by simple filtration and reused many times. Furthermore, it is possible to design simple chemical processes through repeating reaction and filtration. Despite these advantages, there are several limitations in using polymer support because the reaction occurs between a solid and a liquid interface. Therefore, the development of highly efficient polymer supports still remains a challenge in SPPS and heterogeneous catalyst fields. In this thesis, three different types of polymer supports were developed for efficient Suzuki coupling reaction and SPPS: palladated oxime resins, ionic liquid resins, and coreshell-type resin. In the first part, various oxime derived palladacycle resins were prepared as a heterogeneous catalyst for Suzuki coupling reaction of aryl halide with arylboronic acid. Unlike Kaiser oxime resin, electron-rich oxime resins afforded efficient and stable environment to form a palladium complex. The electron-richness of oxime ligand could be controlled by the number of methoxy group. The electronic effect of oxime ligand on C-C coupling reactions of activated and deactivated aryl halide (Cl, Br, I) with arylboronic acid were studied with the oxime palladacycle resins. The most electron-rich oxime resin catalyzed Suzuki coupling reaction in high yield and displayed high turnover number without severe leaching of palladium. In reusability test, two methoxy substituted oxime palladacycle resin could be reused during 5 cycles maintaining good catalytic activity for C-C coupling. In the second part, ionic liquid (IL) resins with an ionic liquid environment on polymer support were prepared by immobilizing ionic liquid spacers on polystyrene (PS) resin. The properties of IL resins were dramatically changed as the anions of IL were exchanged. The performance of IL resins for solid-phase peptide synthesis (SPPS) was evaluated by measuring coupling kinetics of the first amino acid and synthesizing several peptides on IL resins. Initial loading of amino acids were performed very efficiently on IL resins with PF6- and TFSI- anions. They also achieved higher purity in the synthesis of difficult sequences peptide than that of AM PS resin. In the third part, a simple, mild and inexpensive bi-phasic functionalization approach is attempted for preparing an ideal coreshell-type resin. The coreshell-type architecture was constructed by coupling Fmoc-OSu to the amino groups on the shell layer of an aminomethyl polystyrene (AM PS) resin. The shell layer thickness of the resin could be easily controlled under mild conditions. The efficiency of coreshell-type resin for solid-phase peptide synthesis (SPPS) was demonstrated by the synthesis of various peptides, and compared with commercially available non-coreshell-type resins, such as AM PS and poly(ethylene glycol)-based resins. The coreshell-type resin provided effective performance during the synthesis of hydrophobic peptide sequences, a disulfide-bridged cyclic peptide and a difficult PNA sequence. Furthermore, a highly aggregative peptide fragment, MoPrP 105–125, was synthesized more efficiently on the coreshell-type resin under microwave condition than AM PS and ChemMatrix resins.