Graham B. Jones
Michael P. Pollastri, David A. Forsyth
Date of Award
Master of Science
Department or Academic Unit
College of Arts and Sciences. Department of Chemistry and Chemical Biology.
flow chemistry, peptide, radiolabel, TFP-resin, wang resin
Chemical reactions--Analysis, Tomography
Increases in efficiency, reduction of turnaround time, and many other factors have long influenced the pursuit of new technologies in chemistry. With the goal of effective synthesis of previously unattainable compounds and the more efficient synthesis of libraries of compounds, these methods continue to evolve and have grown to include tandem orientation of various tools. Through the use of flow systems, many significant advances have been made in the field of organic synthesis: for example, unattended automation, resin tethered reagents, and extensive library production. New methodology and instrumentation of flow systems are constantly evolving and adapting to new developing research. The goal of this research project was to apply flow chemistry to various projects, produce novel syntheses of various compounds that, in the end, demonstrate the versatility of flow methodology.
The synthesis of amide libraries was explored in a project executed at Merck & Co., Inc. The goal of this project was to use the Syrris AFRICA system to decrease the turnaround time between synthesis and screening of libraries of compounds. With the improvement on the turnover time of libraries, the efficiency and throughput of the drug discovery process would largely improve by allowing the screening many additional extended libraries with ease. Also, the method included unattended synthesis of these libraries, with a carboxylic acid tethered to a macroporous (MP) resin via an activated tetrafluorophenol (TFP) ester linkage. In this project, a library of 20 pure amides was synthesized consecutively, and in dimethyl sulfoxide (DMSO), which provided the molecules a straight route to assay. The TFP-MP resin column was re-used over 36 times, with reproducible efficiency, in a coupling time of an hour.
A project was then initiated that extended this resin-bound reaction technology further to include methodology for efficient, high-throughput radiolabeling of many different substrates, ranging from small molecules to proteins and other biomolecules. Rapid and direct fluorination of biologically sensitive molecules is not possible. The use of a linker between the molecule and the radiolabel is needed and had to be chosen carefully. After exploring the use of 4-fluorobenzaldehyde as a fluorine source and boc-aminooxyacetic acid as a linker, a N-succinimidyl-4-fluorobenzoate moiety was chosen to fulfill both requirements. A synthetic route was developed to rapidly radiolabel proteins and peptides with ease. These labeled molecules may be used to develop new imaging agents for positron emission tomography (PET) imaging.
Lebed, Andrea, "Exploring new technologies in synthesis using flow chemistry" (2010). Chemistry Master's Theses. Paper 11. http://hdl.handle.net/2047/d20000129
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