Asymmetric cyclization of nitrogen-containing heterocyles via catalytic carbon-hydrogen bond activation

Chapter 1. By exploiting a chemical functionality ubiquitous in nature, carbon-hydrogen (C-H) bond activation has the potential to become a powerful tool in total synthesis. The greatest challenge, however, is selectivity; with multiple carbon-hydrogen bonds of similar energy in a given small organic molecule, a transition metal catalyst must be able to choose a single one to cleave and functionalize. Previous work in our group has shown that this problem may be circumvented by use of an imine directing group, allowing functionalization of aryl imines at only the ortho position. This chapter describes the application of this strategy to the syntheses of two biologically active molecules possessing dihydropyrroloindole cores, with the second of these molecules containing a stereocenter that can be set with high enantioselectivity during the C-H activation reaction.;Chapter 2. Having successfully employed enantioselective imine-directed cyclization in the total synthesis of a biologically active molecule, we next chose to explore acyclic stereocontrol in the context of another total synthesis. With one stereocenter already present in the alkene tether of our substrate, we hoped to diastereoselectively set a second via catalytic C-H bond activation. After vinyl ethers failed to cyclize, it was shown that vinyl silanes, which can be oxidized following cyclization, undergo dehydrosilylation to give the corresponding 2H-chromene. With the lack of desired reactivity observed for both of these substrate classes, this project was concluded.;Chapter 3. Despite the fact that C-H bond activation has been an extensively studied process over the last two decades, there exist only a handful of examples in which this important synthetic transformation can be performed asymmetrically. While enantioselective reactions usually exhibit higher selectively at lower temperatures, this chapter reports the development of a cyclization that proceeds with up to 99% ee at an unprecedented 135°C. Adding to the novelty of this discovery is the mechanism by which the C-H bond activation occurs; rather than a simple, direct C-H oxidative addition, previous work in our group has implicated the intermediacy of an N-heterocyclic carbene intermediate.