Iterative Cyclization Strategies for Complex Molecule Synthesis - Project Summary/ Abstract In order to do a better job identifying complex molecules with novel bioactivity and suitable bioavailability profiles, chemists need a larger supply of promising small molecules, which requires new methods for their efficient synthesis. However, there are many molecules of interest, both natural and non-natural, that are still difficult to prepare with high efficiency and selectivity. Synthetic chemists are constantly searching for versatile new methods for building densely functionalized molecules that contain vicinal chiral centers and quaternary centers. The development of efficient, stereoselective carbon-carbon bond-forming methods will enable chemists to more effectively prepare biologically relevant target molecules, and enable more detailed study of these compounds for applications as chemical therapies. During this project, strategies will be developed to enable efficient, convenient, and stereocontrolled synthesis of highly functionalized cyclic carbocycles and heterocycles from simple precursors, with the formation of two or more carbon-carbon bonds. The new methods are expected to deliver differentially functionalized ring systems with useful synthetic handles for further transformations. The chemistry of various cationic intermediates will be exploited to access a series of bioactive complex molecules, including the natural products tubingensins A and B, and polycyclic intermediates related to Daphniphyllum alkaloid natural products. Modern public health challenges demand a drug pipeline full of promising compounds that represent the entire spectrum of biologically relevant small molecules. This project is expected to make an impact at the very inception of the drug discovery process. Successful development of this versatile new method will enable for the synthesis of small, drug-like molecules with unique shapes, and help chemists expand the catalog of compounds available for biological evaluation. Over the course of the project, novel molecules with drug-like properties will be synthesized, characterized, and submitted for biological evaluation through agreements with different screening programs (NCI (both DTP and MTP), HTS facility at Roswell Cancer Center, BU-CMD (Center for Molecular Discovery). In this way, the two- and three step methods that will be developed during these projects, as well as the intermediates prepared during synthetic efforts toward natural product targets, will become tools for chemists and biologists to use in their efforts to discover effective new medicines.
