Echinopines A and B:  Sesquiterpenoids Possessing an Unprecedented Skeleton from Echinops spinosus

Abstract

Echinopines A (1) and B (2), novel sesquiterpenoids with an unprecedented rearranged skeleton named echinopane, were isolated from the roots of Echinops spinosus. The structures were elucidated by extensive spectroscopic analysis. The relative configuration of 1 was assigned by a combination of NOESY correlations and a simulation analysis. A plausible biosynthetic pathway for echinopane was discussed.

Formal Asymmetric Synthesis of Echinopine A and B

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In 2008, Shi, Kiyotam, and co-workers reported the isolation and structural elucidation of two novel sesquiterpenoids from the root of Echinops spinosus and subsequently named them echinopines A and B (1 and 2; Scheme 1).[1] Their unique carbocyclic framework, characterized by a [3,5,5,7] ring system, has been suggested to originate biosynthetically from a guaiane-type precursor (3; Scheme 1).[1] Although not noted for their biological properties, the unprecedented architectures of echinopines A (1) and B (2) presented an enticing challenge to the synthetic community.[2] Herein, we disclose a conceptually contrasting approach to the recently disclosed total synthesis of echinopine A (1) and B (2), [2] by using a novel strategy that intercepted the reported late-stage intermediate 5, [2a] and thereby constitutes a formal synthesis of these structurally intriguing natural products.Inspired by the biosynthetic proposal, [1] we speculated on the possibility of transforming a late-stage [5,6,7] tricyclic ring system, that has a carbocyclic framework represented by the hypothetical biosynthetic intermediate 4 (Scheme 1), to access echinopines A (1) and B (2). Along these lines, the alkenyl methyl ester 6 was identified as a plausible synthetic precursor that would require a late-stage C4ÀC13 bond formation to give 5.

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“…[1] Their unique carbocyclic framework, characterized by a [3,5,5,7] ring system, has been suggested to originate biosynthetically from a guaiane-type precursor (3; Scheme 1). [1] Although not noted for their biological properties, the unprecedented architectures of echinopines A (1) and B (2) presented an enticing challenge to the synthetic community.…”

Total syntheses of echinopines A and B, sesquiterpenes with a unique tetracyclic [3-5-5-7] skeleton

“…In 2010, inspired by the bond forming sequence suggested by the biosynthetic proposal of Shi and Kiyota, 1 Nicolaou and Chen considered a chemically equivalent intramolecular cyclopropanation process ,i.e., a late stage transformation of the [5-6-7] tricyclic ring system 5 into [3-5-5-7] echinopane skeleton of 1 and 2. Unfortunately, this strategy met with failure primarily due to difficulties associated with the preparation of a suitable intramolecular cyclopropanation precursor.…”

“…1 These minor metabolites (0.12% yield) are characterized by an unprecedented tetracyclic [3-5-5-7] skeleton. This complex architecture features five contiguous stereogenic centers, two of them being quaternary; noteworthy, the seven-membered cycle adopts a chair-like form (Fig.…”

Formal Total Synthesis of Echinopines A and B via Cr(0)-Promoted [6π + 2π] Cycloaddition

“…It was proposed that the echinopines A (1) and B (2) can be biosynthesized from a guanine type precursor, through a series of rearrangements. 1 The unprecedented tetracyclic structure of these molecules had attracted considerable attention from the synthetic community. In 2009, Mulzer and co-workers reported the first enantioselective total synthesis of 1 and 2 and determined the absolute configurations of these two natural products.…”