Total Synthesis of Indole Alkaloids Sharing Bicyclo-[2.2.2]-diazaoctane Skeleton

Nandy, Monosij (2026) Total Synthesis of Indole Alkaloids Sharing Bicyclo-[2.2.2]-diazaoctane Skeleton. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Monosij Nandy (21RS008)) 21RS008.pdf - Submitted Version Restricted to Repository staff only Download (30MB)

Abstract

Diketopiperazine-derived indole alkaloids containing the bicyclo[2.2.2]diazaoctane framework represent one of the most structurally intriguing families of fungal natural products. To date, numerous members belonging to the brevianamide, stephacidin, notoamide, avrainvillamide and related alkaloid families have been isolated from diverse fungal sources. Beyond their architectural complexity, these molecules exhibit a wide range of biological activities, including antimicrobial, cytotoxic, antitumor, and anthelmintic properties, highlighting their significance as both biological probes and potential therapeutic leads. The dense stereochemical complexity and polycyclic architectures of these alkaloids have inspired extensive synthetic efforts over the past several decades. Traditionally, total synthesis has largely been pursued in a target-oriented manner, wherein individual natural products are accessed through substrate-specific synthetic sequences. While highly successful, such approaches often provide limited insight into the broader biosynthetic logic connecting structurally related members of a natural product family. In contrast, Nature constructs these alkaloids through common biosynthetic intermediates and divergent reaction pathways, enabling the generation of remarkable structural diversity from a relatively small set of precursors. Understanding these biosynthetic principles offers an opportunity not only to access individual targets more efficiently but also to develop unified synthetic strategies capable of producing multiple natural products from common intermediates. Such an approach transforms total synthesis from a target-specific exercise into a platform for understanding and emulating Nature's molecular design principles. The central objective of my doctoral research was therefore to investigate how Nature assembles bicyclo[2.2.2]diazaoctane alkaloids and to translate these biosynthetic insights into practical synthetic strategies. Through the development of biomimetic cascade reactions, biosynthetically inspired retrosynthetic analyses, and mechanistic investigations, this work seeks to bridge the gap between natural product biosynthesis and chemical synthesis. In doing so, it not only provides efficient access to several architecturally complex members of this alkaloid family but also reveals fundamental principles governing their formation, diversification, and molecular recognition. Particular emphasis was placed on understanding the origin and reactivity of key biosynthetic intermediates responsible for the construction of the bicyclo[2.2.2]diazaoctane framework. These studies ultimately led to unified synthetic approaches to multiple alkaloid subclasses and culminated in the discovery of an unusual self-sorting phenomenon embedded within the bicyclo[2.2.2]diazaoctane scaffold, revealing an unexpected stereochemical feature that may contribute to the selective formation of dimeric alkaloids in Nature.

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