Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification

Abstract

We report a novel reductive interrupted Fischer indolization process for the concise assembly of the 20-oxoaspidospermidine framework. This rapid complexity generating route paves the way toward various dihydroindole Aspidosperma alkaloids with different C-5 side chain redox patterns. The end-game redox modulations were accomplished by modified Wolff–Kishner reaction and photo-Wolff rearrangement, enabling the total synthesis of (−)-aspidospermidine, (−)-limaspermidine, and (+)-17-demethoxy- N -acetylcylindrocarine and the formal total synthesis of (−)-1-acetylaspidoalbidine.

Synthesis of indole derivatives as prevalent moieties present in selected alkaloids

“…The end-game redox modulations were performed by using a modied Wolff-Kishner reaction and also a photo-Wolff rearrangement, allowing the total synthesis of (À)-aspidospermidine ( 229), (À)-limaspermidine (232), and also (+)-17-demethoxy-N-acetylcylindrocarine (231). 239 The total synthesis of (À)-aspidospermidine ( 229), (À)-limaspermidine (232), and (+)-17-demethoxy-N-acetylcylindrocarine (231) were Scheme 27 The formal synthesis of (À)-tubifolidine (210).…”

“…In 2020, Varga et al demonstrated 239 a unique reductive interrupted Fischer indolization method for the short synthesis of the 20-oxoaspidospermidine scaffold. This fast complexity producing pathway covers the route towards different dihydroindole Aspidosperma alkaloids having various C-5 side chain redox patterns.…”

“…The end-game redox modulations were performed by using a modified Wolff–Kishner reaction and also a photo-Wolff rearrangement, allowing the total synthesis of (−)-aspidospermidine (229), (−)-limaspermidine (232), and also (+)-17-demethoxy- N -acetylcylindrocarine (231). 239 The total synthesis of (−)-aspidospermidine (229), (−)-limaspermidine (232), and (+)-17-demethoxy- N -acetylcylindrocarine (231) were started from the reaction of tert -butyl 3-oxopent-4-enoate (221) and methyl 5-chloro-2-formylpentanoate (222), that afforded 1,3-dicarboxylate 223. The latter, after three steps, gave the stereochemically complex intermediate 225.…”

“…Moreover, the total synthesis of (+)-17-demethoxy- N -acetylcylindrocarine (231) was accomplished in 12 steps with a 5% overall yield ( Scheme 29 ). 239 …”

Preparation of Hexahydrocarbazole Derivatives by Reductive Indolization

“…The concept of “reductive indolization” has been applied in the past for the synthesis of dihydroindole derivatives, [ 11 ] and very recently for Aspidosperma alkaloids. [ 12 ] It can be regarded as the reductive case of an interrupted Fischer indolization, as introduced by Garg and co‐workers. [ 13 ] We now report our efforts to extend the reductive indolization towards hexahydrocarbazole derivatives 10 with a C 3 ‐side chain at the position 4a, thus, accessing the carbon skeleton of compound 4 (Figure 1).…”