New Directions in Alkene Difunctionalization Reactions

Project Summary/Abstract Catalytic difunctionalization of alkenes with two carbon sources is a powerful method to create two carbon- carbon bonds in one synthetic step. Achievement of this objective will establish new techniques for the rapid, concise and cost-effective construction of the cores of many biologically important molecules. Our long-term goal is to devise and create such catalytic reactions that will allow us to add one or both alkyl sources to unactivated alkenes. However, these are exceptionally challenging reactions to develop largely because of two critical problems – a) low reactivity of unactivated alkenes, and b) difficulty in intercepting catalytic intermediates generated upon the addition of the first carbon source. To remedy these challenges, strongly metal-binding groups, such as imines, pyridines and aminoquinolines, are currently employed, which can both activate alkenes by proximity effects and promote migratory insertion, and stabilize alkylmetal intermediates as metallacycles, thereby decelerating -H elimination and enabling subsequent interception. However, serious limitations exist with this approach, particularly with the requirement for the installation and removal of coordinating groups. These reactions are also mainly successful for incorporating two C(sp2) coupling reagents, such aryls and alkenyls. In addition, the coordination-assisted strategy is not applicable for alkenes that don’t have heteroatoms proximal to the alkenes. To remedy these limitations, we are adopting two substrate-dependent strategies. We will develop transition metal catalysis for alkenyl substrates containing simple FGs, a universal scenario in organic synthesis. A key challenge in implementing simple FGs for coordination is their weak binding to metals and the low stability of their metallacycles since they are fluxional. We will develop a combination of electron deficient alkenes (EDAs) and organic nitriles (RCN) as a dual ligand system for transition metals to promote simple FG-assisted alkene difunctionalization in non-coordinating reaction media through the stabilization of reaction intermediates and promotion of C(sp3)/C(sp3) reductive elimination. For alkenes where no FGs are present for coordination, we will develop photoredox catalysis. Photoredox catalysis enables the generation of carbon-centered radicals, which are most amenable intermediates to react with alkenes. A key challenge to apply this strategy for alkene difunctionalization is the interception of the resultant second carbon-centered radicals with organo-reagents. We are developing a novel photoredox catalytic process with photoexcited dioxygen and catalytic iodine. We propose to implement this catalytic protocol for alkene difunctionalization reactions, including generating strained ring systems such as cyclopropanes. Our ultimate goal is to transform catalytic alkene difunctionalization with two carbonaceous reagents into its enantioselective version. We will design and develop TADOL-phosphoramidites, PyOx and BOX ligand systems to realize this goal. The catalytic alkene difunctionalization reactions and their enantioselective variants proposed, for which we have strong preliminary results, are unique transformations that cannot be achieved with using other methodology.