Wednesday, March 12, 2025
3/12/2025
Project Summary/Abstract: The invention of new methods to access chiral organic molecules is a critical objective in modern organic chemistry as it is essential for the efficient synthesis of pharmaceutical agents. This is especially relevant as the pharmaceutical industry is making efforts to increase the 3D complexity of drug candidates. Despite substantial progress in the field of stereoselective chemical synthesis, many structures remain challenging to prepare in useful quantities. Therefore, development of new methods and strategies for the chemical synthesis of stereochemically and topologically complex molecules is of contemporary interest. The long-term goals of our research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult- to-access molecular frameworks found in important bioactive molecules. Towards this end, we are interested in the conversion of abundant and readily available alkenes to more complex structures through difunctionalization reactions. This approach is attractive because the rapid buildup of complexity can be achieved as two new bonds and two new stereocenters are generated in a single operation. The studies described in this application focus on three distinct programs. The first is the development of stereoselective cross-coupling reactions of Csp3- nucleophiles that are catalytically generated in situ from simple alkenes. Our rationale for development of these reactions is that widely available alkenes, diboron reagents, and organohalides are converted to synthetically versatile intermediates. We will develop new Pd/Cu-catalyzed and Ni-catalyzed systems with a particular emphasis placed on saturated heterocycle synthesis. In addition, with the advent of new catalytic systems we will engage Csp3-electrophiles for the generation of multiple stereogenic centers. In the second program of research, we are developing methods for the stereoselective synthesis of cyclobutanes by [2+2] cycloadditions of alkenes that are enabled by boron. Our rationale for the development of these reactions is that due to the unique feature of boron, a broad range of borylated cyclobutanes can be prepared. Finally, we are introducing new classes of novel building blocks to enable drug discovery, such as bicyclo[2.2.0]hexanes as isosteres for meta-substituted aromatic rings. Within this program, we are also developing novel strain release reactions initiated by energy transfer. Overall, these studies in reaction development will introduce new concepts and strategies, as well as provide access to new building blocks for chemical synthesis by exploring new cross- coupling paradigms and cycloaddition reactions.
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