Since the inception of organic chemistry more than a 200 years ago, halogenation of olefins has been a mainstay reaction. Yet, this venerable reaction had not succumbed to an enantioselective process. Two major issues that have thwarted the development of asymmetric alkene halogenations are the rapid stereochemical degradation of chiral halonium ions by olefin-to-olefin halonium transfer, and by isomerization of halonium ions to the open β-halocarbenium ions. The latter scenario changed in 2010, when our lab, among others, successfully demonstrated stereoselective reactions for the intramolecular halocyclization of alkenes with tethered nucleophiles. Not surprisingly, most early examples reported on the intramolecular capture of halonium ions via tethered nucleophiles; the proximity-driven rate enhancement of the cyclization step presumably outcompetes any stereorandomizing event. Enantioselectivities of >95:5 are routinely obtained with a variety of halonium precursors and nucleophiles. In contrast, enantioselective intermolecular halofunctionalizations have been more difficult to achieve due to reduced reaction rates, limited choice of compatible nucleophiles, and lack of regiochemical control. This dissertation highlights my efforts towards optimizing a variety of intermolecular halofunctionalization methodologies. First, our results that show excellent control of stereo and enantioselectivity in haloetherification and haloesterification of both activated and non-activated olefins will be discussed. The resulting lessons from the latter were parlayed into developing a highly selective olefin dihalogenation, demonstrating the ability to overcome regiochemical scrambling through catalyst controlled process, as opposed to substrate control selectivity, which limits the chemistry to activated olefins. Most recently, the chemistry has been extended to enantioselective haloamination of olefins, setting the stage for the synthesis of privileged moieties found in natural products, bioactive reagents, and pharmaceuticals. Finally, our preliminary mechanistic investigations suggest that a concerted mechanistic pathway is responsible for product formation. The dependence of the course of the reaction on the nature of the nucleophile leads to a suggested explanation for the observed divergence in product facial selectivity.
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