Carbon-hydrogen bond functionalization via hydride transfer: Development of catalytic carbon-carbon bond forming reactions via intramolecular coupling of sp3 carbon hydrogen bonds and activated alkenes

This thesis describes a general approach for the intramolecular coupling of sp3 C-H bonds and activated alkenes under mild conditions using Lewis acid catalysts. This transformation is proposed to involve an intramolecular through-space hydride transfer-cyclization (HT-cyclization). The first chapter describes our initial investigation of HT-cyclizations involving alpha,beta-unsaturated aldehyde, ketone and malonate substrates with several Lewis acid catalysts. This cyclization allows for the direct functionalization of sterically hindered sp3 C-H bonds leading to the formation of bicyclic and spirocyclic products.;The second chapter explores the scope of HT-cyclization reactions using homoallylic ether derived substrates. The substrate scope and reactivity of various C-H bonds and functional groups are examined. An efficient synthetic route to HT-cyclization substrates is outlined and the resulting cyclization reactions provide access to diversely substituted tetrahydropyran, an important structural motif found in many biologically active natural products.;Chapter three presents an alternative activation strategy for HT-cyclization reactions involving hydride transfer to alkenyl oxocarbenium intermediates. Lewis acid catalyzed opening of cyclic acetal and ketal substrates generates a highly electrophilic olefin species that readily initiates the hydride transfer cascade at room temperature. An additional activation protocol using ethylene glycol as a co-catalyst is described. This in situ activation protocol greatly improves the efficiency and selectivity of HT-cyclization reactions.;The final chapter demonstrates the cyclization of aromatic ether substrates via HT-cyclization reactions. This type of reactivity had previously only been observed in amine-derived substrates. The substrates in this chapter were easily prepared in two steps from readily available salicyl aldehydes. Subsequent cyclization provides highly substituted dihydrobenzopyran products, an important class of heterocycles frequently found in biologically active compounds.