Development of catalytic, enantioselective halofunctionalization reactions of olefins and the investigation of cyclic orthoesters as synthetic building blocks for chiral molecules

This thesis details the efforts to discover and develop novel asymmetric halofunctionalization reaction of olefins. Chapter 1 describes the numerous challenges associated with this transformation and the current state of the art in enantioselective alkene halogenation reactions.Chapter 2 describes the development of the first asymmetric halocyclization reaction of unsaturated amides. This reaction has uncovered an unprecedented route to chiral heterocyclic compounds such as oxazolines and dihydro-oxazines. The optimized reaction conditions that employed 1--2 mol% of the commercially available (DHQD)2PHAL catalyst and chlorohydantoins as terminal chlorenium sources gave the cyclized products in >95% ee for a wide variety of substrates. A more practical and scalable second-generation protocol that affords comparable or better enantioselectivities was also developed. Chapter 2 also discloses preliminary results for the enantioselective chlorocyclization of unsaturated carbamates; this related transformation was eventually optimized to afford either enantiomer of the oxazolidinone product by a judicious choice of the reaction solvent while employing the same catalyst.;Chapter 3 details the development of the first kinetic resolution in a chlorocyclization reaction. The different hydrogen-bonding affinity of the two enantiomers of racemic unsaturated amides for protonated (DHQD)2PHAL catalyst was exploited for enabling this transformation. The same catalyst was shown to mediate two highly enantioselective events in a synergistic fashion---the stereodiscrimination of the two enantiomers and a highly face selective alkene chlorination. Excellent diastereoselectivity (up to 99:1) and enantioselectivities (typically greater than 95% ee) was obtained for the products with 0.5 mol% catalyst loading with selectivity factors of >50 for many substrates. Slight modifications to the optimized conditions could be used for the desymmetrization of meso-dienes and kinetic resolution of racemic propargyl amides via chlorocyclization. Preliminary optimizations for these related transformations are also provided in Chapter 3.;Efforts to expand this chemistry to enantioselective C-C bond forming reactions are presented in Chapter 4. A Friedel-Crafts reaction initiated by a chiral chloronium ion was used as a test-bed for developing such a reaction. Extensive optimizations studies that have focused on reaction variables, catalyst structures and substrate structures have led to up to 83% ee for this reaction. A preliminary substrate scope evaluation and kinetic studies are provided for this transformation.;Chapter 5 discloses efforts to expand the utility of cyclic orthoesters as synthetic building blocks for the construction of chiral molecules. Although these efforts were met with limited success, reactivity that was hitherto unknown for cyclic orthoesters was discovered. An unprecedented semi-pinacol rearrangement of cyclic acetoxonium ions was discovered.