Development and application of new methods for chemical synthesis

点击翻译按钮获取中文摘要

Amphoteric molecules – bifunctional structures equipped with orthogonal nodes of reactivity – are the main focus of our research program. The main operational principle of our work has been and will remain to develop new synthetic methods and apply them toward understanding how small-to-medium sized molecules interact with biological receptors. My lab provides superb training for highly qualified personnel, who receive employment and postdoctoral offers from top companies and labs throughout the world. Over the next five years, our program will address the following strategic directions.******We will develop new macrocyclization technologies and delineate the role of heterocyclic grafts on the properties of macrocycles. Building on the cooperative interplay of intramolecular hydrogen bonds and electrostatic interactions in macrocyclization mechanisms, we will develop new methods of cyclizing linear sequences with an emphasis on structural diversity of the resulting scaffolds.******We will pursue “hidden” conformations of macrocycles. We hypothesize that site-selective enforcement of cis-amide bonds in macrocycles will lead to the discovery of previously uncharted conformational space. We will resort to the thioamide functionality as the tool to investigate this idea.******We will develop new boron transfer processes. Encouraged by the discovery of boride/hydride analogy in polar reaction mechanisms, we will seek new reactions for the synthesis of hitherto inaccessible boron-based intermediates and endpoints of synthesis. ******We will modulate residence time of covalent serine protease inhibitors. We will use our recent success in co-crystal formation between small molecules and their protein targets as the foundation for the development of covalent inhibitors of proteases and will address the enduring challenge of modulating the residence time of boron-containing inhibitors. ******Our foundational papers are published in high impact journals (e.g. over the past year we published three key Nature Chemistry papers). The novelty and significance of our approaches is evidenced by the rapid adoption of our methods in industry and in academia. MilliporeSigma has created a special web portal exclusively dedicated to our methods of synthesis. This decision was largely based on the worldwide demand for our reagents. The ideas implemented by us and ultimately funded by NSERC over the past 5 years have led to tangible products that are on MilliporeSigma's best-selling list. These offerings include aziridine aldehydes, boryl aldehydes, acyl boronates, and Pinc technology for macrocyclization. Chemists throughout the world use our molecules, which makes it reasonable to assume that the plans outlined for 18 students in the present NSERC discovery grant will continue to provide transformative methods of synthesis with direct application to the discovery and development of biologically active compounds.