Development and Applications of Reactions to Enable Molecular Rigidification

PROJECT SUMMARY Rigidity is an important property of molecules that increases the likelihood of their success as drugs. Our goal with support of this MIRA grant is to develop reactions that enable molecular rigidification. We describe a research program that enables access to rigid small and medium sized-strained rings. Our innovative approach to obtaining rigid molecules is to use sulfone anions as carbene surrogates. We will also develop new methods to stabilize highly reactive alkylidene units using palladium catalysis. The knowledge gained from these studies using reactive carbenes will also be used to enable skeletal editing of heterocycles. We will apply the reactions developed in this proposal to synthesize complex natural products and their derivatives with tubulin binding properties and antifungal properties.