James L. Leighton
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 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 targeted delivery constructs. 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.
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 of silanes in single molecule measurements using the scanning tunneling microscope break-junction (STM-BJ) technique. We have shown how a bipodal anchoring strategy allows a stable junction formed from a direct Au-Si contact, and have begun to elucidate and explore the mechanism of high bias-induced Si-Si bond rupture in the 1,2-disilaacenaphthene system.
Selected recent publications:
“Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1” Suen, L. M.; Tekle-Smith, M. A.; Williamson, K. S.; Infantine, J. R.; Reznik, S. K.; Tanis, P. S.; Casselman, T. D.; Sackett, D. L.; Leighton, J. L. Nature Communications 2018, 9, 4710.
“Direct, Mild, and General n-Bu4NBr-Catalyzed Aldehyde Allylsilylation with Allyl Chlorides” Tekle-Smith, M. A.; Williamson, K. S.; Hughes, I. F.; Leighton, J. L. Org. Lett. 2017, 19, 6024-6027.
“Synthesis and Evaluation of a Linkable Functional Group-Equipped Analog of the Epothilones” Foley, C. N.; Chen, L.-A.; Sackett, D. L.; Leighton, J. L. ACS Med. Chem. Lett. 2017, 8, 701-704.
“Evolution of an Efficient and Scalable Nine Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester” Chen, L.-A.; Ashley, M. A.; Leighton, J. L. J. Am. Chem. Soc. 2017, 139, 4568-4573.
“Mechanism for Si–Si Bond Rupture in Single Molecule Junctions” Li, H.; Kim, N. T.; Su, T. A.; Steigerwald, M. L.; Nuckolls, C.; Darancet, P.; Leighton, J. L.; Venkataraman, L. J. Am. Chem. Soc. 2016, 138, 16159-16164.
“High-Conductance Pathways in Ring-Strained Disilanes by Way of Direct s-Si–Si to Au Coordination” Kim, N. T.; Li, H.; Venkataraman, L.; Leighton, J. L. J. Am. Chem. Soc. 2016, 138, 11505-11508.
“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.