Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (−)‐Nitidasin

Abstract

Astellatol and nitidasin belong to a subset of sesterterpenoids that share a sterically encumbered trans-hydrindane motif with an isopropyl substituent. In addition, these natural products feature intriguing polycyclic ring systems posing significant challenges for chemical synthesis. Herein, we detail the evolution of our stereoselective strategy for isopropyl trans-hydrindane sesterterpenoids. Our endeavors included the synthesis of several building blocks, enabling studies toward all molecules of this terpenoid subclass, and of advanced intermediates of our initial route toward a biomimetic synthesis of astellatol. These findings provided the basis for a second-generation and a third-generation approach toward astellatol that eventually culminated in the enantioselective total synthesis of (−)-nitidasin. In particular, we orchestrated a series of substrate-controlled transformations to install the ten stereogenic centers of the target molecule and forged the carbocyclic backbone in a convergent fashion. Furthermore, we disclose our progress toward the synthesis of astellatol and provide insights into some observed yet unexpected diastereoselectivities by detailed quantum-mechanical calculations.

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis

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