Advances in Heterocyclic Synthesis through Ring Expansions and Flow Chemistry

Abstract

This dissertation comprises three chapters, which focus on the development of new synthetic methodologies and the construction of a screening collection. An Application of the Schmidt Reaction: Construction of an Azasteroid Library. Ring expansion chemistry is a powerful way of introducing a heteroatom substituent into carbocyclic frameworks. However, such reactions are limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve selectivity at all. These limitations may prove critical when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this chapter, a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from commercial or readily synthesized steroidal substrates of the A- and D-rings is described. A requisite intermediate in the reaction was leveraged to afford over one hundred isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to effect regiocontrol in chiral natural products, adds value to late-stage natural product diversification programs. New Variations of the Schmidt Reaction: A strong hydrogen-bond-donating solvent, hexafluoro-2-propanol (HFIP), was found improve the intermolecular reaction of ketones with trimethylsilyl azide and hydroxyalkyl azides. This study prompted the hypothesis for interrupting the classic Schmidt reaction with an added nucleophile reagent in HFIP. An extensive acid screen identified aluminum tribromide as a promoter for intercepting the Schmidt reaction iminium ion intermediate and combining it with subsequent reaction with 1,3,5-trimethoxybenzene to form substituted imines, enamides, and amines. This new variation of the Schmidt reaction provided access to unique heterocycles. Enabling Chemistry Technologies: High-Temperature and High-Pressure Continuous Flow Chemistry. The synthetic applications of a high-temperature and high-pressure flow reactor were investigated. The Gould-Jacobs reaction, nucleophilic aromatic substitution reaction with amine nucleophiles, and tert-butyloxycarbonyl deprotection in flow were explored. The protocols developed were applied to the high-throughput preparation of small-molecule libraries, as well as reaction telescoping, automation, and scaling.