Research Projects

The exploration of marine natural products has highlighted the Pyrrolo[2,1-a]isoquinoline framework, a bicyclic structure integrating pyrrole and isoquinoline rings, as a significant scaffold for drug discovery. This core existing in two forms; possesses its own biological significance throughout the medicinal field. They also exist as a main core in various natural products such as Lamellarin marine alkaloids with significant biological properties. Our project proposes a unified synthetic strategy to create both the pyrrolo[2,1-a]isoquinoline and dihydro pyrrolo[2,1-a]isoquinoline core which and thereby demonstrated the synthesis of Type Ia and Ib lamellarin alkaloids. These types differ in saturation levels; Type Ia has a partially saturated core, while Type Ib is fully unsaturated. We aim to develop a streamlined approach utilizing copper-mediated aerobic oxidation, Paal-Knorr synthesis, double annulation and C-H activation. The foundation of this proposal builds on recent advancements in pyrrole synthesis. For example, we adapted Kim’s method, which uses Michael addition of ethyl cyanoacetate to chalcones followed by copper iodide-mediated oxidation to create a 1,4-dicarbonyl intermediate, ultimately converted into pyrroles via the Paal-Knorr reaction. Expanding upon this, in our recently accepted research article we synthesized over twenty pyrrole derivatives catalysed by proline with varying substituents, achieving significant yields and setting the stage for Lamellarin synthesis. Our recently published review article explores these synthetic methodologies, providing a comprehensive outlook on the construction of Lamellarin D analogues. The synthetic plan includes creating the Pyrrolo[2,1-a]isoquinoline core via a double annulation approach to produce both saturated and unsaturated variants. We will systematically introduce electron-donating and electron-withdrawing groups on the scaffold, allowing us to explore structure-activity relationships (SAR) and optimize biological efficacy. To complete the lamellarin synthesis, we will perform oxidative lactonization, C-H arylation, including the protection and deprotection steps. This sequence is designed to maximize efficiency and adaptability, offering a versatile pathway for producing Lamellarin analogues. Through this unified synthetic approach, we aim to provide an efficient, scalable solution to access lamellarins and evaluate their potential for further biological studies. This project will enhance the toolkit for synthesizing complex marine alkaloids, thus advancing research in therapeutic development.