A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

Abstract

The application of the Nazarov photocyclization as a mild and efficient method for access to the basic core of novel indoloditerpenoid derivatives is reported. The detailed synthesis of these new analogues of terpendole E, as well as their evaluation as potential inhibitors of KSP, is described.

Synthesis of (±)-terpendole E

“…5) Alkylation of the bis-TBS ether 8 with bromide 9 followed by chemoselective hydrolysis of the enol ether moiety of the resulting product gave phosphonate 10 as an epimeric mixture at the C16 position.…”

“…5,6) We have also addressed the total synthesis of terpendole E, and recently succeeded in a diastereoselective synthesis of (±)-3 from known WielandMiescher ketone analog (±)-2. 7,8) In this article, we describe the first synthesis of terpendole E as its racemate from (±)-3.…”

3,3-Dimethyl-1,2,3,4-tetrahydrocyclopenta[b]indole-1,2-dione (bruceolline E)

“…For examples of similar tandem acylation/Nazarov cyclization with pyrroles, see: Song et al (2006). For examples of Nazarov cyclizations with indoles, see: Bergman & Venemalm (1992); Cheng & Cheung (1996); Ishikura et al (2000); Miki et al (2001); Churruca et al (2010). For examples of -diketone oxidations using selenium dioxide, see: Gribble et al (1988); Xu et al (2002); Belsey et al (2006).…”

Asymmetric Synthesis and in vivo Biological Inactivity of the Right‐Hand Terpenoid Fragment of Terpendole E

“…[8] In spite of the intriguing biological activity, no synthetic study has been reported except for a recent study of an analog synthesis by the Giannis group. [9] This could be attributed to several synthetic difficulties in the selective construction of a hexacyclic molecular skeleton with eight asymmetric carbons, as can be anticipated from other indoloditerpene syntheses. [8c,10] The synthetically challenging structure, as well as the interesting biological activity, prompted us to study the chemical synthesis.…”