Exploiting Unconventional Building Blocks in Chemical Synthesis

Project Summary/Abstract The central objective of this application is to harness unconventional synthetic building blocks for the development of new, reliable, and efficient, methodologies. These methodologies are intended to enable the construction of stereochemically-rich scaffolds, including those seen in naturally occurring small molecules and medicines. The development of new methods and the syntheses of complex small molecules continues to be vital areas of research. Most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past several decades. The chemical structures of new drug entities are becoming increasingly complex, providing an increased need for chemists to develop new methods that can reliably build intricate structures. Our proposal involves strained intermediate chemistry, with a particular focus on pi-bond containing compounds that are geometrically distorted. The distortion leads to heightened reactivity, which we ultimately leverage to access complex scaffolds and provide new synthetic strategies. We will develop methods associated with transient intermediates that display bent geometries, such as cyclic allenes and cyclic 1,2,3- trienes, that otherwise prefer linear geometries in the acyclic form. Alkenes that are geometrically distorted from an ordinary trigonal planar geometry due to twisting or pyramidalization, including anti-Bredt olefins, will be pursued. Lastly, the scope and limitations of these methodologies will be probed in the context of enantioselective natural product synthesis. Collectively, our efforts will establish the concept that historically avoided strained intermediates that possess geometrically-distorted structures can be strategically exploited to assemble complex molecular architectures.