Development of zinc- and palladium-catalyzed asymmetric transformations for total synthesis of alkaloids and other bioactive compounds

Since the enantiopurity of an organic molecule can have a profound impact on its unique biochemical and physical properties, the development of atom- and step-economical methods for constructing chiral chemical bonds is highly important and valuable. Besides asymmetric oxidation and reduction, recent advances have been made in reactions involving enantioselective carbon-carbon bond formation, enabling the synthesis of chiral complex molecules. This thesis describes the development of five novel and highly selective catalytic asymmetric transformations to construct chiral C-C bonds. Moreover, many of these methods have been applied to the total syntheses of alkaloids and other bioactive molecules. The first chapter of this thesis describes in detail the development and synthetic applications of dinuclear metal-ProPhenol catalysts. The ProPhenol ligand is a member of the chiral aza-crown family that forms bimetallic complexes upon treatment with alkyl metal reagents, such as Et2Zn and Bu2Mg. The resulting complexes can simultaneously activate both a nucleophile and an electrophile in the same chiral environment, enabling a broad range of asymmetric transformations, including aldol, Mannich, Henry reactions, alkynylations and conjugate additions. The second chapter details the development of the pseudo-C2-symmetric ProPhenol ligands, which enable a highly enantioselective vinylation of N-Boc aldimines using readily available vinylzirconocenes as nucleophiles. This asymmetric process led to the discovery of an unprecedented catalytic transmetallation between organozirconium reagents and Zn-ProPhenol, and also led to a short synthesis of (-)-dapoxetine. The next four chapters deal with asymmetric Mannich reactions catalyzed by the Zn-ProPhenol catalysts. The third chapter describes a Mannich reaction between alkynyl ketones and N-Boc imines. Alkynyl ketones are attractive yet challenging nucleophiles due to their intrinsic susceptibility to Michael additions and the difficulty of controlling the enolate geometry. Nonetheless, this method produces β-amino ynones with excellent chemo-, diastereo-, and enantioselectivity, and the products can be transformed into a broad range of structural scaffolds upon simple modifications. The fourth and fifth chapter describe the construction of quaternary stereocenters utilizing the Zn-ProPhenol Mannich reactions. Nonactivated enolate precursors that have either rarely or never been employed previously -- including α-branched aldehydes, enones, and ynones -- were successfully utilized to generate adducts featuring a quaternary stereocenter. The process involving α-branched aldehydes later led to the total syntheses of seven different isoqunioline alkaloids from the Genus Corydalis, discussed in the sixth chapter. The final chapter describes a unique way to utilize α-trifluoromethyl carbanions in palladium-catalyzed asymmetric cycloadditions. Although the electron-withdrawing nature of the CF3 group does increase the acidity of the neighboring protons, β-fluorocarbanions have rarely been utilized as nucleophiles due to their intrinsic propensity to undergo β-fluoro eliminations. Nonetheless, such elimination processes were successfully prevented by the presence of a neighboring cationic Pd-allyl motif. The resulting palladium-stabilized zwitterions can participate in asymmetric [3+2] cycloadditions with a broad range of acceptors, generating valuable di- and trifluoromethylated cyclopentanes, pyrrolidines, and tetrahaydrofurans.

Keywords: Chemistry.
Advisor: Trost Barry M. 
Burns Noah
Waymouth Robert M.