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| Organic Synthesis. Organophosphine Chemistry. Anticancer Drugs. Chemical Biology. Natural Products Isolation. |
| New Graduate students are welcome. See the Graduate Studies on-line application page for details on how to apply. |
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| Research in my group is focused on the development of new useful synthetic methods and their application to solve problems of importance at the chemical-biological interface. Students obtain significant practical experience in all aspects of synthetic and mechanistic organic chemistry as well as an appreciation of a variety of important biological targets available and how these two interact at the chemical-biological interface. |
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| Methodological research involves the exploration of routes to new useful, densely-functionalized chirons as well as routes to new catalysts and promoters for coupling reactions. |
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| Densely functionalzed chirons have been prepared from desymmetrization strategies using chiral-pool precursors such as tartaric acid derivatives. We have also recently demonstrated a new strategy that allows complete reversal in the regioselectivity of free-radical mediated benzilidene acetal fragmentation reactions. This process allows convenient access to an expanding range of monosaccharide derived functionalized chirons.. |
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| Catalysts and promoters being explored are of two types: Lewis acid and/or transition metal complexes as well as metal-free “organic catalysts”. Research in the former area involves the synthesis of new chiral and achiral ligands and the investigation of their value in metal-mediated C-C bond forming processes including Suzuki, Sonogashira and Heck couplings, metathesis processes as well as classic Diels-Alder, Michael and aldol-type reactions. We are also investigating methods for linking key ligands onto Merrifield and other polymer resins. New systems that allow for the linking of hindered trialkylphosphine residues (as opposed to arylphosphines) onto polymer resins is a central theme of this work. In terms of organic catalysts and promoters, we have developed a new class of phosphorane that effects Mitsunobu-type condensation processes but that allows for controlled retention or inversion of confuguration through choice of conditions. The mechanism of this process has been investigated in detail and new mechanistic insights into the compexities of the Mitsunobu reaction unravelled. Recently, we have been able to promote various reactions (Diels-Alder, Aldol, etc.) using a new unpublished organic catalyst systems. The use of chiral and solid-state versions of these promoters should allow for asymmetric versions of the reactions and these leads are being actively pursued. A new, fertile and very promising field of research has been opened up through this recent work. |
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| While fundamental development in organic synthesis is one underlying feature of our work, we are fully aware of the importance of applications development of these processes in chemical biology. The major interest here is in anticancer agents that exhibit new or unknown mechanisms of action. A major general problem exhibited in anticancer chemotherapeutic regimens is the non-selective cytotoxicity exhibited in such treatments. Our work in this area is focused on a new series of synthetic compounds that demonstrate very selective cytotoxicity and do not interact with DNA. We develop systematic approaches to reveal the pharmacophore through structure-activity correlations. This provides us with a solid understanding of the structural requirements for anticancer activity. Recent biological studies with two of our new analogs using animal and human tumor cell lines has demonstrated significant differential cytostatic behavior and allowed us to develop a very selective drug with a defined mechanism of action. In addition to the above “structural” based approach, we also undertake ”mechanistic” based approaches when a solid postulate as to the mode of action is in hand. This involves the chemical synthesis of biological probes that challenge and refine our understanding of the drug-target interaction. |
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| We are also exploring two Southern Ontario plant leads as potential sources of new bioactive Natural products. We have isolated two families of flavanoid and diterpene Natural product and are presently investigating the structure and biological properties of the purified compounds. |
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| Selected Publications: |
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| New entries to densely functionalized chirons. |
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| McNulty, J., Wilson, J., Rochon, A., J. Org. Chem., 69, 563 (2004). |
| McNulty, J., Mao, J., Tetrahedron Lett., 43, 3857 (2002). McNulty, J., Grunner, V., Mao, J., Tetrahedron Lett., 42, 5609 (2001). |
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| New fragment coupling methodology. |
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| McNulty, J., Capretta, A., Robertson, A.J., Larichev, V., Dyck, J., Angew. Chem. Int. Ed., 42, 4051 (2003). McNulty, J., Capretta, A., Robertson, A.J., Larichev, V., Dyck, J., J. Org. Chem., 68, 1597 (2003). Adjabeng, G., Brenstrum, T., Dyck, J., Wilson, J., Frampton, C., Robertson, A.J., McNulty, J., Capretta, A., Organic Lett., 5, 953 (2003). J. McNulty, A. Capretta, J. Wilson, J. Dyck, A. Robertson, Chem. Commun., 1986 (2002). McNulty, J.; Mo, R.; Frampton, C.S.; Capretta, A., Chem. Commun., 2384 (2001). |
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| Chemical Biology of Pancratistatin Alkaloids. |
| McNulty, J., Mao, J., Gibe, R., Mo, R., Wolf, S., Pettit, G.R., Herald, D., Boyd, M.R., Bioorg. Med. Chem. Lett., 11, 169 (2001). McNulty, J., Mo, R., Chem. Commun., 933 (1998). |
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