Reaction Development Using Amphoteric Reagents and Organocatalysts

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Most pharmaceuticals that cure diseases and improve our quality of life have emerged from intense medicinal chemistry efforts. Clinical candidates are selected from thousands of potential molecules, each of which has been designed, synthesized in an average of 8 steps, and thoroughly tested. Chemical innovation is at the core of this endeavour, and new technologies are rapidly adopted by industry in an effort to improve the efficiency of the drug discovery process. Our program is centred on the development of new reactions and catalysts for the synthesis of key structural subunits containing nitrogen atoms, which are present in >95% of drug candidates tested. Ultimately, these reactions provide more efficient formation of biologically-active molecules and enable the formation of new compounds for structure-activity relationship studies and drug development. These efforts are also important from a Green Chemistry perspective, as reactions that result in increased efficiency also inherently minimize the generation of “chemical waste”, which remains an important issue associated with the development and production of pharmaceuticals. The reactions developed and targeted in this research make use of inexpensive reagents and catalysts, allowing additional applications in the synthesis of agrochemicals and bulk chemicals. Building on momentum gained in the synthesis of nitrogen-containing molecules using hydroxylamines and hydrazines, the reactivity of new families of “unusual” isocyanates will be developed. This will provide new reagents and strategies in a field of significant industrial importance: millions of tons of isocyanates are used annually to form products that are worth >$ 10 billion. In parallel, reactions using aldehydes as simple catalysts will be developed, drawing inspiration from enzymes, and how they accelerate difficult intermolecular reactions. A special focus will be to show that these aldehydes catalyze a variety of difficult hydration and hydrolysis reactions through a proximity effect, mimicking the catalytic function of hydrolase and hydratase enzymes. Beyond providing much needed alternatives to the conditions currently used industrially (for example to form unnatural amino-acids in pharmaceuticals), these studies will show the importance of simple aldehydes as catalysts in the chemistry responsible for the “origin of life”. As part of this research, students will receive training that is ideally suited for future work in medicinal chemistry, agrochemistry and bulk chemistry (isocyanates) sectors. Business and technology transfer opportunities that could result from the discovery of the new technologies described above will also be pursued.