Stereoselective Late-Stage Transformations of Indolo[2,3-a]quinolizines Skeleta to Nature-Inspired Scaffolds

Abstract

The indolo­[2,3-a]­quinolizines, canthines, and arborescidines natural products exhibit a wide range of bioactivities including anticancer, antiviral, antibacterial, and anti-inflammatory, among others. Therefore, the development of modular and efficient strategies to access the core scaffolds of these classes of natural products is a remarkable achievement. The Complexity-to-Diversity (CtD) strategy has become a powerful tool that transforms natural products into skeletal and stereochemical diversity. However, many of the reactions that could be utilized in this process are limited by the type of functional groups present in the starting material, which restrict transformations into a variety of products to achieve the desired diversity. In the course of employing a (CtD) strategy en route to the synthesis of nature-inspired compounds, unexpected stereoelectronic-driven rearrangement reactions have been discovered. These reactions provided a rapid access to indolo­[2,3-a]­quinolizines-, canthines-, and arborescidines-inspired alkaloids in a modular and diastereoselective manner. The disclosed strategies will be widely applicable to other late-stage natural product transformation programs and drug discovery initiatives.

Recent Advances in Divergent Synthetic Strategies for Indole-Based Natural Product Libraries

“…More recently, the Al-Tel group reported a new Ctd strategy for the nature-inspired indole monoterpenoid compounds 36 and 37 [ 45 ], prepared from compounds 34 and 35 [ 46 ] ( Scheme 3 ). The compounds 36 and 37 have inherent complexity and transformable moieties such as cyclohexanone, piperidine, and indole rings, which makes them efficient starting points for the Ctd strategy.…”

“…In contrast, natural product biosynthesis in living organisms allows facile access to structurally complex and distinct skeletons from relatively simple common intermediates through enzyme-catalyzed processes. This tremendous efficiency and diversity-generating power of the biosynthetic pathways allows for the rapid generation of diverse natural products and related compounds, including indole-based compounds [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds

“…Inspired by these reports, our group has recently reported a multidirectional desymmetrization protocol using the oxidative dearomatization products of phenols to access a diverse collection of enantiopure natural products-inspired architectures (Figure ). − …”

Stereodivergent Transformation of Azepino[3,4,5‐cd]indoles En Route to Nature‐Inspired Scaffolds

“…Prior work by our group investigated a late‐stage stereodivergent transformation of a diverse collection of complex indolo‐monoterpenoids into stereochemically and structurally complex nature‐inspired compounds (Scheme 1). [12e,13] This has led to the development of a diverse collection of chemical space endowed with functional synthetic handles with which to device our present CtD strategy [12d,e,13] …”