Palladium-Catalyzed Cascade Cyclizations in Natural Product Synthesis: Synthetic Studies of Noraugustamine and Falcatin A

Author: Holman, Karli Rose

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Fu, Gregory C.; Reisman, Sarah E.; Stoltz, Brian M.; Hsieh-Wilson, Linda C.

Option: Chemistry

Abstract

Palladium-catalyzed cascade cyclizations present a powerful strategy for the rapid assembly of polycyclic skeletal frameworks, enabling the efficient synthesis of bioactive and structurally complex natural products. Herein, we review the field of palladium-catalyzed cascade cyclizations in natural product synthesis and describe our application of these transformations toward the total syntheses of noraugustamine and falcatin A.

Our approach to the Amaryllidaceae alkaloid noraugustamine was driven by the simultaneous disconnection of a C–C and a C–N bond, with the aim of forming both bonds and two of the target’s six rings in a single step. A radical cascade cyclization delivered noraugustamine but displayed poor regioselectivity for 6-exo-trig versus 7-endo-trig cyclization. Improved regioselectivity was achieved using a palladium-catalyzed Heck cyclization, leading to the development of a novel oxidative Heck/aza-Wacker cascade forming both of the desired bonds with good yield and selectivity. This transformation and the general lessons taken from this work should find broad utility in the design of cascade cyclizations toward alkaloids of similar complexity.

We also investigated a palladium-catalyzed carboetherification cascade toward the synthesis of the central five- and seven-membered rings of the myrsinane diterpene falcatin A. In this case, competitive C–O coupling, olefin insertion, and cyclopropanation hindered our efforts to develop the proposed transformation in a simplified model system. A stereoselective bromoetherification and a nickel-catalyzed Nozaki–Hiyama–Kishi reaction were ultimately successful, forming the targeted rings. Efforts to synthesize a fully elaborated cyclization substrate, translate the key steps from the model system, and complete the synthesis of falcatin A are ongoing.