Total Synthesis of Complex Cyclotryptamine Alkaloids: Stereocontrolled Construction of Quaternary Carbon Stereocenters

Graphical Abstract

Filling the void: Efficient and flexible syntheses of many complex cyclotryptamine alkaloids are now possible because of the development of a set of stereocontrolled methods for accessing their multiple quaternary carbon stereocenters. The key steps include a cascade of Heck reactions or asymmetric dialkylation followed by an asymmetric Heck reaction (see scheme).

Abstract

Our ability to access the more complex members of the cyclotryptamine family of alkaloids, and to exploit their disparate biological activities, is limited by the synthetic challenge posed by their oligomeric, polyindoline structures. A recurring structural theme within these molecules is the presence of multiple quaternary stereocenters in close proximity to one another. Over the last decade, we have developed a set of transformations that allow rapid access to polyindolines, a number of which exploit the ability of catalytic levels of palladium to orchestrate carbon–carbon bond formation with impressive levels of regio- and stereocontrol. This review tells the story behind the development of this toolbox of synthetic methods, and their validation through the total synthesis of a number of structurally complex cyclotryptamine alkaloids. It also highlights an aspect of asymmetric catalysis that has received little attention, the ability of catalytic asymmetric reactions to selectively elaborate complex, polyfunctional molecules.