Research in the Leighton group is focused on the development of new asymmetric synthetic methods and their application to the synthesis of complex natural and unnatural targets that are possessed of useful and important functionality.
In one major program we are developing a suite of methods for the synthesis of polyketide natural products with extraordinary bioactivity that are in many cases not available in quantity from natural sources, and applying those methods to develop highly step-economical and at the same time practical and scalable syntheses of the natural products. The combination of step-economy and scalability is a powerful one, and is enabling us to pursue some novel approaches to the development of these compounds as anti-cancer chemotherapeutic agents. One current focus is the synthesis and evaluation of analogs of the natural product targets that have been modified to carry a linking functionality, with no loss in activity or potency. This in turn is allowing us to evaluate the potential of these compounds to serve effectively as the drug component of antibody-drug conjugates and other selective delivery vehicles. Validated linker strategies for these natural products is also putting us in a position to carry out chemical biology and mechanism of action studies, as well as explore other more novel linked constructs wherein useful functionality is designed into the linker group.
Our emphasis on the practicality and ready scalability of the synthetic methods we develop means that they often have applicability beyond the natural product syntheses for which they were developed. Our methods have in several cases been utilized by researchers in the pharmaceutical industry, and in one notable case, one of our allylsilane reagents has been used in the process scale (more than 120 kg to date) synthesis of a compound (veledimex) that is currently being evaluated in several different clinical trials. We continue to pursue the further development and commercialization of these reaction chemistries, reagents, and catalysts.
In another line of investigation in the group, we are, in collaboration with the Nuckolls and Venkataraman groups, exploring the impact of ring-strain on the electrical conductance properties (oligo)silanes in single molecule measurements using the scanning tunneling microscope break-junction (STM-BJ) technique.
Selected Recent Publications:
“A ‘Methyl Extension’ Strategy for Polyketide Natural Product Linker Site Validation and its Application to the Microtubule-Stabilizing Agent Dictyostatin” Ho, S.; Sackett, D. L.; Leighton, J. L. J. Am. Chem. Soc. 2015, 137, 14047-14050.
“Design, Development, Mechanistic Elucidation, and Rational Optimization of a Tandem Ireland Claisen/Cope Rearrangement Reaction for Rapid Access to the (Iso)Cyclocitrinol Core” Plummer, C. W.; Wei, C. S.; Yozwiak, C. E.; Soheili, A.; Smithback, S. O.; Leighton, J. L. J. Am. Chem. Soc. 2014, 136, 9878-9881.
“Beyond the Roche Ester: A New Approach to Polypropionate Stereotriad Synthesis” Foley, C. N.; Leighton, J. L. Org. Lett. 2014, 16, 1180-1183.
“Silicon Ring Strain Creates High-Conductance Pathways in Single-Molecule Circuits” Su, T. A.; Widawsky, J. R.; Li, H.; Klausen, R. S.; Leighton, J. L.; Steigerwald, M. L.; Venkataraman, L.; Nuckolls, C. J. Am. Chem. Soc. 2013, 135, 18331-18334.
“A Highly Step-Economical Synthesis of Dictyostatin” Ho, S.; Bucher, C.; Leighton, J. L. Angew. Chem. Int. Ed. 2013, 52, 6757-6761.
“A New and More Powerfully Activating Diamine for Practical and Scalable Enantioselective Aldehyde Crotylsilylation Reactions” Suen, L. M.; Steigerwald, M. L.; Leighton, J. L. Chem. Sci. 2013, 4, 2413-2417.
“Toward a More Step-Economical and Scalable Synthesis of Spongistatin 1 to Facilitate Cancer Drug Development Efforts” Reznik, S. K.; Leighton, J. L. Chem. Sci. 2013, 4, 1497-1501.
“Direct and Highly Regioselective and Enantioselective Allylation of b-Diketones” Chalifoux, W. A.; Reznik, S. K.; Leighton, J. L. Nature 2012, 487, 86-89.
“Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester” Harrison, T. J.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 7308-7311.
“A More Comprehensive and Highly Practical Solution to Enantioselective Aldehyde Crotylation” Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517-6520.