Abstract

This dissertation describes our efforts toward the total synthesis of welwitindolinone natural products, as well as the development of reactions involving the nickel-catalyzed activation of amide C–N bonds. The welwitindolinones have been long-standing targets in total synthesis for over two decades, and this dissertation describes two completed total syntheses of these alkaloids. In addition, several nickel-catalyzed transformations of amides are outlined, each of which demonstrate the powerful reactivity of nickel and highlight the utility of amides as synthetic building blocks. Chapters one and two present our enantiospecific total syntheses of the welwitindolinone alkaloids N-methylwelwitindolinone D isonitrile and N-methylwelwitindolinone B isothiocyanate. Our approach to these natural products features an aryne cyclization to construct the bicyclo[4.3.1]decane core of the molecules, as well as a C–H nitrene insertion reaction to introduce the bridgehead nitrogen substituent. In chapter one, a dual C–H functionalization event installs the challenging ether linkage and allows for completion of -N-methylwelwitindolinone D isonitrile. In chapter two, a regio- and diastereoselective chlorinative oxabicyclic opening is detailed, which enables the first total synthesis of N-methylwelwitindolinone B isothiocyanate. Chapters three, four, and five describe the development of nickel-catalyzed carbon–carbon bond-forming reactions of amides. More specifically, chapters three and four outline the Suzuki–Miyaura couplings of aromatic and aliphatic amides, respectively, whereas chapter five details the alkylation of amide derivatives. These methodologies represent mild and complementary tools to the Weinreb ketone synthesis, proceeding through the nickel-catalyzed activation of the amide C–N bond. It is shown that amides, which were traditionally thought of as inert functionalities, can be utilized as synthons in C–C bond-forming reactions. Chapter six describes a method for the benchtop delivery of Ni2 involving the encapsulation of Ni2 in paraffin wax. Due to air- and moisture-sensitivity, Ni2 is normally handled under an inert atmosphere. Using our method of wax encapsulation, several nickel-catalyzed transformations are performed without the use of a glove box, including various amide C–N bond cleavage reactions. These studies are aimed at promoting the widespread use of nickel in transition metal catalysis. Chapter seven illustrates the kinetic modeling of the nickel-catalyzed esterification of amides. By developing a kinetic model, an optimization is undertaken that allows for the employment of catalyst loadings as low as 0.4 mol% nickel. This demonstration is intended to foster the advancement of kinetic modeling as a powerful tool in methodology development.