Gleason, James - McGill University - Department of Chemistry

个人简介

Jim Gleason was born in Montreal in 1967, but was raised mostly in the United States. He returned to Canada for undergraduate studies and completed his B.Sc. (Honours) from McGill University in 1989. He then attended the University of Virginia for graduate studies and obtained his Ph.D. in 1994 under the supervision of Prof. Robert E. Ireland. While there, he completed the total synthesis of FK-506 and developed methodology for the synthesis of alpha,beta-diketoamides from masked enediols. After completing his studies at Virginia, he moved to the California Institute of Technology where he was an NIH postdoctoral fellow in the labs of Prof. Andrew G. Myers. While at Caltech, he developed highly practical methodology for the synthesis of unnatural amino acids through the alkylation of glycine amides of psuedoephedrine. In 1996, he took up an academic position at McGill and was promoted to Associate Professor in 2002. His research focuses on several areas of organic chemistry including synthetic methods development, total synthesis of natural products and the development of novel hybrid molecules for cancer research. In his spare time, he enjoys skiing, backpacking, running, squash and hockey.

研究领域

Our research program encompasses many areas of organic chemistry including synthetic methods development, total synthesis of natural products and medicinal chemistry. Projects in the group provide excellent training in organic synthesis and provide graduate students the opportunity to develop their creativity and critical thinking skills. In many cases, research in the group is aided significantly by computer modeling studies including DFT methods to predict reactivity/selectivity in methods projects and small-molecule docking for medicinal chemistry. Examples of areas of current interest are below. Organocatalysis of Pericyclic Reactions Catalysis of the Cope and Claisen rearrangements typically involves the use of transition metals which activate the involved olefins or the use of Lewis and Bronstead acids in the Claisen to activate the allylic ether. We are investigating the use of small-molecule catalysts to accelerate the Cope and Claisen rearrangements via LUMO-lowering catalysis. Specific catalysts being developed are being extended to other reactions of interest including the Diels-Alder and Michael addition. Total Synthesis of Natural Products The total synthesis of natural products is a highly challenging endeavour which allows one to develop novel strategies, develop new chemistry and test developed methodology. We take on targets that either have unique structural features and/or possess functional arrays which allow us to examine novel methods developed within the group. A few targets of interest are shown below. Multi-Action Drugs Traditionally, medicinal chemistry has focused on developing small-molecules which are selective for a single biological target and thus will be useful for treating a disease with a minimum of side-effects. In recent years, however, many clinical therapies have used combinations of drugs to treat a disease by focusing on several complimentary disease pathways. The best known example of this is using combinations of protease inhibitors and reverse transcriptase inhibitors to treat HIV. In a collaborative effort with groups in Physiology (McGill) and Biochemistry (University of Montreal), we are attempting to develop multi-action drugs which simultaneously target two synergistic biochemical pathways. This presents a significant challenge as we attempt to target two separate receptors and/or enzymes which have very different natural substrates and functions. However, through careful design, we have been able to develop small-molecules which can simultaneously target a nuclear receptor and a transcription regulator and are examining their effects on cellular models of cancer and autoimmune disorders. Chiral auxiliaries for stereoselective quaternary carbon formation The formation of quaternary carbon stereocenters is a significant challenge in organic synthesis. When attempting to form quaternary carbon stereocenters through enolate alkylation reactions, a key problem to be addressed is enolate stereochemistry (E vs. Z isomers).While this is easily addressed in cyclic systems, E/Z enolate stereocontrol in acyclic enolates is very difficult. We have developed a method based on stereoselective reduction of alpha,alphas-disubstituted bicyclic thioglycolate lactams. Enolate stereochemistry is influenced by the conformation and stereochemistry of the bicyclic lactams. Our first system, developed as a proof-of-concept, was based on proline and has been improved upon in a second generation auxiliary which is formed readily from valinol, methyl thioglycolate and an acrolein equivalent. The auxiliary is currently available for purchase through Aldrich. The enolates from this second generation auxiliary may be alkylated to form simple quaternary carbon containing substrates and we are currently examining their use in aldol and Mannich reactions. This method has been successfully applied towards a highly efficient enantioselective synthesis of puraquinonic acid (see above).

近期论文

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Krikor Bijian, Dainis Kaldre, Tian-Tian Wang, Manuella Bouttier, Annie Boucher, Moulay Alaoui-Jamali, John. H. White and James L. Gleason Efficacy of Hybrid Vitamin D Receptor Agonist/Histone Deacetylase Inhibitors in Vitamin D-Resistant Triple-Negative 4T1 Breast Cancer J. Steroid Biochem. Mol. Biol. in press Johnathan M. E. Hughes and James L. Gleason A Concise, Enantioselctive Total Synthesis of (–)-Virosaine A Angew. Chem. Int. Ed., in press. Florent Larnaud, Adamo Sulpizi, Nicklas O. Häggman, Jonathan M.E. Hughes, Damien F. Dewez and James L. Gleason Organocatalytic Michael Addition of Indoles to alpha-Substituted Enals Using a Diazepane Carboxylate Catalyst Eur. J. Org. Chem. 2017, 18, 2637-2640 Dainis Kaldre and James L. Gleason An Organocatalytic Cope Rearrangement Angew. Chem., 2016, 55, 11557-115561 James L. Gleason and John H. White Bifunctional Vitamin D. Hybrid Molecules Vitamin D: 4th edition. Feldmen, Pike, Bouillon, Givannucci, Goltzman, Hewison, eds. in press Tatiana Traboulsi, Mohamed El Ezzy, James L. Gleason, Sylvie Mader Mechanisms of Action of Antiestrogens: Impact on Clinical Use J. Mol. Endo., 2017, 58, R15-31 Lee D. Fader, Martine Brault, Jessica Desjardins, Nathalie Dansereau, Louie Lamorte, Sonia Tremblay, François Bilodeau, Josée Bordeleau, Martin Duplessis, Vida Gorys, James R. Gillard, James L Gleason, Clint James, Marc-André Joly, Cyrille Kuhn, Montse Llinas-Brunet, Laibin Luo, Louis Morency, Sébastien Morin, Mathieu Parisien, Maude Poirier, Carl Thibeault, Thao Trinh, Claudio Sturino, Sanjay Srivastava, Christiane Yoakim, and Michael Franti Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus ACS Med. Chem. Lett., 2016, 7, 525-530 Rodrigo Mendoza-Sanchez, David Cotnoir-White, Justyna Kulpa, Isabel Jutras, Joshua Pottel, Nicolas Moitessier, Sylvie Mader and James L. Gleason Design, Synthesis and Evaluation of Antiestrogen and Histone Deacetylase Inhibitor Molecular Hybrids Bioorg. Med. Chem. 2015, 24, 7597-7606 Dainis Kaldre, Tian-Tian Wang, Joshua Fischer, John H. White and James L. Gleason Optimization of Histone Deacetylase Inhibitor Activity in Non-Secosteroidal Vitamin D Receptor Agonist Hybrids Bioorg. Med. Chem., 2015, 23, 5035-5049 Shuo Xing and James L. Gleason A Robust Synthesis of N-Glycolyl Muramyl Dipeptide via Azidonitration/Reduction Org. Biomol. Chem. 2015, 13, 1515-1520