Natural Product Synthesis and Development of Synthesis-Enabling Methodologies

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The ability to synthesize organic molecules rapidly and efficiently is inextricably linked to the success of R&D efforts and sustained profitability in the pharmaceutical, agrochemical and fine-chemical industries. Natural products have been refined over millions of years for biological interactions, and as such, they represent an unsurpassed source of life-saving drugs and drug leads. However, their limited availability from the natural source can hamper biological assessment. This is particularly common for compounds isolated from unculturable microbes and marine organisms, where recollection is often problematic or impossible. In such cases, chemical synthesis is the only option for supplying the material needed for pharmacological investigation. A practical and flexible synthesis can also serve as a blueprint for generating custom-designed analogues of superior therapeutic performance. Hence, the prime objective of our research is to develop new methods and strategies enabling rapid and efficient access to natural products of biological importance. Our target molecules include the marine terpenoids niphateolide A (anticancer) and hippolide J (antifungal), which have yet to succumb to chemical synthesis, and fungal butenolides such as aurantricholides A-B that have eluded biological investigation due to their scarcity in nature and inefficiency of their current synthesis (<1% yield). These molecules instill unique synthetic challenges, providing a strong impetus to invent new methodologies and expand upon the discoveries and creative contributions of my talented co-workers. The goal is to achieve maximum increase in target-relevant complexity while minimizing step count, cost and chemical waste. One way of accomplishing this is through strategic implementation of reaction cascades and one-pot procedures. Reaction cascades allow two or more bond-forming transformations to be performed under the same conditions sequentially without the need for work-up and product isolation between successive synthesis steps. Besides improving efficiency, this approach makes the synthesis substantially greener as it reduces the amount of solvents used in the synthesis, work-up and product isolation, and contaminated aqueous waste generated from cleaning equipment and glassware. The proposed research will have application in the synthesis of a variety of other biologically important natural products and small molecules. Collaborations are in place to evaluate the synthesized compounds as antimicrobial, anticancer and herbicidal agents. In the long term, this research may have an impact on the discovery of new healing drugs and agrochemicals. The target oriented nature of the work ensures that students will acquire broad-based training in organic synthesis and invaluable problem-solving skills. Such skills and expertise are of paramount importance to the rapidly growing pharmaceutical industry in Canada.