Application of Branching Double Annulation Cascade (BDAC) and Ring Opening Cyclization (ROC) Strategies: Access to Diverse fused Tetrahydroisoquinoline, Quinazolinone derivatives and Rutaecarpine Alkaloid

MaliPatel, Srilaxmi and D S, Sharada (2019) Application of Branching Double Annulation Cascade (BDAC) and Ring Opening Cyclization (ROC) Strategies: Access to Diverse fused Tetrahydroisoquinoline, Quinazolinone derivatives and Rutaecarpine Alkaloid. PhD thesis, Indian institute of technology Hyderabad.

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Abstract

Nitrogen-containing compounds are the most common structural architectures in drug candidates, natural and biological products, and small-molecule therapeutics. Nheterocyclic containing natural product synthesis has been a very challenging area due to the structural complexity inherent in these molecules. The nitrogen atoms contained in these molecules are essential for their biological activity, as nitrogen can hold a positive charge as well as act as both hydrogen-bond donor and hydrogen-bond acceptor. These features are significant for the interaction between medicinal agents and their molecular targets. Although synthetic chemists have long been fascinated by natural products, for the most part they have focused on developing the chemistry in order to make precise replicates of the compounds purified from natural sources. Recently, synthetic targets concerning natural products have not been limited to precise replication of the naturally occurring compounds. The accumulation of insights and learning in total synthesis over the last few decades should enable organic chemists to “aim higher” to integrate natural products more closely with advance in biomedical research. Today, chemists can develop synthetic strategies to make both natural products and natural product-like compounds that are comparable to true natural products in size and complexity. The ability to synthesize in vitro complex natural products, combined with strategy of diversity-oriented synthesis (DOS) of natural product-like molecules, which allows very large numbers of natural product-based compound libraries to be made quickly, has made it possible for chemists to accelerate evolution in vitro in this process. Herein, we report a novel BDAC strategy for rapid access to diverse molecular library containing unprecedented THIQ fused skeletons by using 2-(2-bromoethyl)benzaldehyde 19 as a common substrate and variety of N,C-, N,O- and N,N-1,5-bisnucleophiles as SBAs. Apart from that we also successfully developed a facile methodology for Copper-catalyzed intramolecular α-C‒H amination via ring-opening cyclization strategy to quinazolin-4-one derivatives and application in Rutaecarpine synthesis.

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