Grant: Discovery Grants Program - Individual

The overall focus of our program is the development of efficient protocols for asymmetric synthesis of compounds of medicinal importance and the investigation of new methods of environmentally benign manufacturing, or 'green', synthesis. The proposed research represents a well integrated approach to the synthesis of alkaloids of the Amaryllidaceae and morphine groups and the provision of new synthons, or building blocks, resulting from biotransformations of aromatic and sulfur-containing compounds.      Several interdependent streams have these objectives: BIOTRANSFORMATIONS: (1) Enzymes are used in the whole-cell fermentation protocols to identify synthons for pharmaceutical manufacturing. (2) Various fungal and bacterial strains metabolize sulfur-containing compounds to provide other valuable synthons. TOTAL SYNTHESIS OF ALKALOIDS: Two groups of alkaloids are targeted in this effort: pancratistatin, because of its potent antitumour activity, and morphine, with its C-14 oxygenated derivatives, important as analgesics and antagonists. As pancratistatin is not soluble and has poor bioavailability, a new approach has been developed to allow variations in the aromatic core that will increase solubility while maintaining activity. Several approaches to morphine synthesis are pursued in order to provide for preparations of morphine, codeine, or thebaine in fewer than 10 steps. Notably, a short synthesis of thebaine from thiophene depends on the oxidation of the sulfur atom in thiophenes. ASYMMETRIC CATALYSIS: New reagents will be designed for the synthesis of chiral amino alcohols, commonly used in medicinal and pharmaceutical chemistry.      Overall, this proposal will address focused investigations in asymmetric synthesis driven by the use of biocatalytic methods in order to increase the environmentally benign component in manufacturing on organic compounds of medicinal significance. Highly qualified personnel will be trained in biocatalysis and synthesis for employment in the Canadian pharmaceutical sector. New routes will be developed to make marketable medicinal agents.