Chiral Lewis Acid and Organocatalytic Methods for the Asymmetric Synthesis and Functionalization of 3,3'-oxindoles and 3,3'-spirocyclic Oxindoles

Download or read book Chiral Lewis Acid and Organocatalytic Methods for the Asymmetric Synthesis and Functionalization of 3,3'-oxindoles and 3,3'-spirocyclic Oxindoles written by Joseph Jesse Badillo and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The development of regio- and stereoselective methods for the synthesis of oxindoles and spirocyclic oxindoles is important due to the prevalence of these structures in natural products and medicinal agents. This dissertation describes both Lewis acid and organocatalytic strategies for the regio-, diastereo-, and enantioselective synthesis of several classes of 3,3'-oxindoles and 3,3'-spirooxindoles. These strategies are applied to several synthetic transformations including allylsilane annulations, Friedel-Crafts alkylations, and Pictet-Spengler reactions. Chapter one describes an overview of recent methods for the enantioselective synthesis of oxindoles and spirooxindoles with a particular focus on scaffolds relevant to drug discovery. This overview is organized by type of catalyst and strategy in order to compare traditional organometallic and Lewis acid methods with recent organocatalytic methods. This chapter also features a section on multicomponent and cascade reaction strategies. Chapter two describes the development of synthetic methodology using titanium(IV)-catalysis for the selective synthesis of two new classes of spirocyclic oxindoles. In the first section, I present a highly regio- and diastereoselective method for the synthesis of spiro[3,3'oxindoleoxazolines] upon addition of 5-methoxy-2-oxazoles to isatins. In the second section, I present a method for the addition of 5-methoxy-2-aryloxazoles to [alpha],[beta]-unsaturated alkylidene oxindoles to provide access to spiro[3,3'oxindole-1-pyrrolines] with excellent yields and diastereoselectivities. This methodology is also effective for the diastereoselective synthesis of 1-pyrrolines derived from coumarins and simple malonates. Chapter three describes the condensation cyclization between isatins and 5-methoxytryptamine catalyzed by chiral phosphoric acids to provide spirooxindole tetrahydro-[beta]-carboline products in excellent yields and enantioselectivity. A comparison of catalysts provides insight for the reaction scope and factors responsible for efficient catalytic activity and selectivity in these Pictet-Spengler type spirocyclization reactions. In addition I show that chiral phosphoric acids with different 3,3'-substitution on the binaphthyl system and opposite axial chirality afford the spiroindolone product with the same absolute configuration. Chapter four describes a strategy for the efficient two-step synthesis of triazole derivatives of oxindoles and spirooxindoles. Using a common set of N-propargylated isatins, a series of mechanistically distinct stereoselective reactions with different combinations of nucleophiles and catalysts provides access to diverse hydroxy-oxindoles, spiroindolones, and spirocyclic oxazoline structures. The resulting N-propargylated oxindoles are then converted to triazoles using copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. This strategy is used for the synthesis of a 64-member pilot-scale library of diverse oxindoles and spirooxindoles. Chapter five describes the first catalytic asymmetric [3+2] allylsilane annulation for the synthesis of cyclopentanes containing an all-carbon quaternary spirocenter. The annulation reaction is catalyzed with a chiral scandium(III)-indapybox complex where a sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) anion is essential for catalytic activity and stereoselectivity. Lactone formation affords evidence for an ester stabilized [beta]-silyl carbocation. Further transformations provide access to N-H spirooxindoles and allow transformation of the silyl group to a hydroxyl moiety. This catalyst complex is also effective for the asymmetric Friedel-Crafts conjugate addition of variety of additional pi-nucleophiles (i.e. indoles, pyrroles, anilines) to [alpha],[beta]-unsaturated alkylidene oxindoles. This methodology is also effective for the diastereoselective synthesis of coumarin and simple malonate derivatives.