New Methods for Nitrogen and Oxygen Heterocycle Synthesis

New reactions for the synthesis of saturated oxygen and nitrogen heterocycles based on copper-catalyzed additions to readily available alkenes are being developed. The use of chiral copper complexes for stereocontrolled Csp3-O and Csp3-N bond formation is being explored. Based on our mechanistic work in this area, we have found that both polar and radical reaction mechanisms are involved, and judicious selection of substrate and reaction conditions can enable the concise and enantioselective synthesis of otherwise challenging complex molecules from simple alkenol and alkenylamine substrates. In this project, an enantioselective alkene carboetherification scope is expanded to useful oxygen heterocycles such as phthalans, compounds that have shown activity as ?1 receptor ligands (relevant to CNS disorder therapy). The first highly enantioselective hydroalkoxylation of unactivated alkenes for the synthesis of chiral oxygen heterocycles is being developed. A diverse collection of novel chiral spirocyclic compounds is accessible from 1,1-disubstituted alkenes using a suite of copper-catalyzed intramolecular alkene difunctionalization reactions. In this context new copper-catalyzed enantioselective alkene dioxygenation and oxyamination reactions will be explored. Potentially powerful aerobic alkene oxidative difunctionalizations are also being explored. Copper-catalyzed intermolecular couplings between vinylarenes and alkyl radicals, formed in situ, are being explored for the synthesis of oxygen and nitrogen heterocycles. Lastly, an elusive catalytic enantioselective Mannich reaction with phenols is being pursued. The concise, enantioselective synthesis of bioactive saturated oxygen and nitrogen heterocyclic small molecules will be performed as a demonstration of the biomedical relevance of these reactions.