A. Biosynthesis-Inspired Studies Toward Melonine B. Concise Total Syntheses of Fontonamide and Dechlorofontonamide with Synthetic Studies Toward Hapalonamide G and V

This dissertation describes biosynthesis-inspired synthetic studies toward complex indole alkaloids, with a particular focus on the monoterpene indole alkaloid melonine and members of the hapalindole-derived hapalonamide family, including fontonamide and dechlorofontonamide. These natural products exhibit significant structural complexity, dense stereochemical content, and diverse biological activities, making them compelling targets for chemical synthesis and methodological development. Initial efforts centered on the total synthesis of melonine, guided by a revised structural assignment and a biosynthetic hypothesis invoking formation of a macrocyclic iminium intermediate. A biomimetic strategy was designed in which transannular cyclization of a nine-membered macrocycle would construct the pentacyclic core in a single cascade event. Although efficient routes to key coupling partners were developed and advanced intermediates were accessed, multiple strategies for macrocycle formation—including macrolactamization, reductive amination, and intramolecular substitution—were unsuccessful, highlighting significant conformational and steric barriers associated with this approach. These studies provided important insight into the structural constraints of the melonine framework and informed subsequent strategic redirection. Building on these findings, the research focus shifted toward the synthesis of hapalonamide natural products, a structurally distinct oxidized subclass of hapalindole alkaloids characterized by a unique formanilide–benzylic ketone motif. Early work in the group established a first-generation route to fontonamide and dechlorofontonamide; however, this approach suffered from low yields and poor reproducibility. To address these limitations, a second-generation synthetic strategy was developed featuring a concise and modular design. Key innovations include a one-step directed α-vinylation of a carbonyl compound via a hydrazone intermediate, efficient construction of an enone intermediate through reduction–elimination sequences, and a late-stage carbonyl-directed C–H amidation enabling installation of the nitrogen functionality. This streamlined route provided improved reliability and significantly enhanced synthetic efficiency while delivering versatile intermediates for accessing additional members of the hapalonamide family. Further studies explored refinements to this strategy, including alternative approaches to chlorine installation and late-stage functionalization, enabling continued progress toward target molecules and related analogs. Collectively, the work presented in this dissertation demonstrates the power of biosynthesis-inspired design in guiding synthetic strategy, highlights the challenges associated with complex macrocycle formation, and establishes concise and generalizable routes to structurally intricate hapalonamide natural products.