Methods and Strategies for Concise Syntheses of Intricate Bioactive Compounds

PROJECT SUMMARY, ABSTRACT This proposal outlines a comprehensive strategy for advancing novel methodologies and innovative strategies for the chemical synthesis of intricate, bioactive alkaloid natural products derived from Veratrum and Hapalindole families, among others. The research plan is divided into three distinct projects, each providing access to unique classes of natural products. Project 1 focuses on the development of novel synthetic strategies for Veratrum alkaloids, a group of bioactive alkaloid natural products. This project has been inspired by the structural challenges posed by these alkaloids and aims to develop concise syntheses of several members. Project 2 details the further exploration of dearomative-Claisen rearrangement, which allows functionalization of the C2 position of indoles, enabling the stereocontrolled, asymmetric synthesis of 2,2- disubstituted indoline derivatives. Project 3 outlines our continued study and application of two [4+3]- cycloaddition-based routes for the synthesis of indole-fused cycloheptanes and their application to the synthesis of the complex, bioactive ambiguine natural products. The research plan is backed by compelling preliminary results and aims to maximally utilize the proposed methodology while addressing unmet synthetic challenges posed by the complex targets. The resulting chemistry is expected to be broadly beneficial to chemists involved in drug development, chemical synthesis, and natural product research. Over the next five years, we will especially focus on solving the key structural challenges presented by jervine-type alkaloids (Veratrum family) and ambiguines (Hapalindole family), providing unique solutions, and recording their synthesis using methods developed in our laboratory. The proposed projects will provide excellent training to graduate students and postdoctoral associates in chemical synthesis and problem-solving, preparing them for successful careers in the pharmaceutical industry and academia.