Complexity-Building Deracemization and Desymmetrization Methodologies

I. Deracemization and Desymmetrization: A Primer - An overview of the principles of deracemization and desymmetrization techniques applied in modern asymmetric catalysis. II. Base-Catalyzed Direct Aldolization of alpha-Hydroxy Trialkyl Phosphonoacetates - A catalytic direct aldolization of racemic alpha-hydroxy trialkyl phosphonoacetates to access alpha-hydroxy-beta-phosphonyloxy esters is described. The fully-substituted glycolate enolate was generated in situ via [1,2]-phosphonate-phosphate rearrangement under mild proton-transfer conditions. An asymmetric variant was realized upon application of a chiral iminophosphorane providing excellent levels of diastereo- and enantiocontrol in the aldolization. III. Asymmetric Synthesis of Chlorohydrins via Dynamic Kinetic Reduction - A dynamic kinetic resolution via asymmetric transfer hydrogenation (DKR-ATH) of racemic beta-chloro-alpha-keto esters to provide access to optically active halohydrins is presented. The requisite beta-chloro-alpha-keto esters were prepared via Ni-catalyzed direct chlorination of alpha-keto esters. A Ru(II)-amido complex bearing a bulky m-terphenylsulfonamide ligand provided a remarkable ligand-controlled switch in diastereoselectivity in the reduction affording anti-chlorohydrins with high levels of diastereo- and enantiocontrol. IV. Dynamic Kinetic Reduction of Racemic Acyl Phosphonates - A strategy for the preparation of beta-stereogenic-alpha-hydroxy phosphonic acid derivatives via DKR-ATH of racemic alpha-aryl acyl phosphonates is discussed. A (arene)RuCl(monosulfonamide) complex featuring a bulky m-terphenylsulfonamide ligand provided excellent levels of diastereo- and enantiocontrol in the reduction. Interestingly, this reduction was determined to be proceeding from the opposite face of the ketone providing pseudo-diastereomeric products from those obtained in the reduction of alpha-keto esters. V. Dynamic Kinetic Aldolization of Configurationally Labile Electrophiles - Dynamic kinetic asymmetric transformations (DyKAT) of racemic beta-bromo-alpha-keto esters through direct aldolization of nitromethane and acetone are described. Cinchona alkaloid-derived catalysts effectively catalyzed the aldolizations providing access to fully substituted alpha-glycolic acid derivatives bearing a beta-stereocenter. Mechanistic studies revealed that the reactions proceed via facile catalyst-mediated racemization of the beta-bromo-alpha-keto esters under a DyKAT Type I manifold. VI. Enantioselective Synthesis of Hindered Cyclic Dialkyl Ethers via Organocatalytic Oxa-Michael/Michael Desymmetrization - An oxa-Michael/Michael desymmetrization strategy for the rapid construction of cyclic dialkyl ethers where both alpha-stereocenters of the ether linkage are set in a single step is presented. Employing a Jørgensen-Hayashi catalyst, the annulation of alkyl p-quinols and alpha,beta-unsaturated aldehydes provided access to densely functionalized bicyclic frameworks bearing four contiguous stereocenters.Doctor of Philosoph