Divergent Total Synthesis of Four Kopsane Alkaloids: N‐Carbomethoxy‐10,22‐dioxokopsane, Epikopsanol‐10‐lactam, 10,22‐Dioxokopsane, and N‐Methylkopsanone

Abstract

We have achieved the divergent total synthesis of four kopsane alkaloids which share a complex heptacyclic caged ring system. Key transformations include an asymmetric Diels–Alder reaction to assemble the central bicyclo[2.2.2]octane moiety and the quaternary stereocenter at C20, a SmI2‐mediated cascade reduction/aldol reaction to construct the five‐membered ring and the quaternary stereocenter at C7, and a late‐stage cascade reductive amination/cyclization to establish the highly strained caged ring system.

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

“…19 20 21 Only the group of Nishida investigated exo -selective [4+2] cycloaddition of conjugated enolates under catalysis of chiral Ho complexes (Scheme 1, b ), 22 and Jia very recently investigated endo -selective reaction of indole-derived chlorinated dienes, which resulted in a series of synthesized kopsane alkaloids. 23 The latter work demonstrates high efficiency of set-up of Diels–Alder step early in synthetic strategy, which can be further employed for other representatives of Kopsia alkaloids.…”

Aza-Achmatowicz rearrangement coupled with intermolecular aza-Friedel–Crafts enables total syntheses of uleine and aspidosperma alkaloids

“…1–7 They continue to influence the research fields of natural products, drug discovery, biochemistry, and especially organic chemistry (total synthesis and methodology development). 8,9 Structurally, the direct covalent C3–C2′ linkage of indole (in blue) with piperidine (in red) characterizes this subclass of alkaloids and thus has sparked great interest from generations of organic chemists in developing novel and efficient synthetic strategies 10–40 (Scheme 1c). For example, many innovative synthetic strategies for aspidosperma alkaloids have been developed, most of which can be classified into three categories: (i) intermolecular or intramolecular indolization of anilines with piperidine derivatives, 41–50 (ii) late-stage piperidine formation from 1,2,3,4-tetrahydrocarbazoles, 51–62 and (iii) intramolecular (or transannular) Mannich reaction of indoles with tethered piperidinium.…”