A Synthesis of Echinopine B

Abstract

The synthesis of natural products of unprecedented structure can drive innovation in strategy and provide opportunities to test the limits of new methodology; therefore, it remains a worthy venture even when the targets are not yet known to possess important biological activity. In that context, we felt that the synthesis of the structurally unusual echinopines (Scheme 1) was warranted for the opportunity to evaluate metal-catalyzed polycyclizations in complex settings, and to access these natural products and structural analogues for a broader evaluation of their biological properties.Echinopines A and B (1 and 2) are sesquiterpenes isolated by Kiyota and co-workers from the root of the plant Echinops spinosus [1] and they probably originate from biosynthetic modification of the guaiane framework (see 3). In spite of the lack of reported biological activity, their novel structure inspired several research groups to embark upon and complete syntheses of these compounds. First, in 2009, Magauer, Mulzer, and Tiefenbacher reported a clever enantioselective route beginning from 1,5-cyclooctadiene; this work served to determine the absolute configuration of these natural products. [2] Shortly thereafter in 2010, Nicolaou, Chen, and co-workers in Singapore reported an asymmetric synthesis of these targets. [3] A formal synthesis followed later that year from Chen and co-workers. [4] We felt that a strategy related to the presumed biogenesis of the echinopines might yield a more direct synthesis than these previous routes. We posited that a bioinspired conversion of a suitably functionalized cis-fused guaiane-like precursor into the tetracyclic core of the echinopines might take place through a transitionmetal catalyzed bicyclization reaction; the cyclopropane acetic acid/ester functional group would then be introduced directly, thus avoiding the multi-step homologation of cyclopropane carboxylate ester intermediates that was employed in previous syntheses. In a third-generation route to the echinopines, Chen and co-workers recently reported the successful execution of a related strategy, providing echinopine B in 25 steps. [5] Herein, we report our synthesis of echinopine B, which proceeds through a concise sequence featuring a one-step conversion of a guaiane-like intermediate to the natural product.Initially, much effort was put forth to generate the fused tricyclic motif, which consisted of the cyclopropane and two cyclopentane rings, and involved either a carbonylative Heck cascade (4!5, Scheme 2a) or a Heck bicyclization terminating in b-hydride elimination (6!7); unfortunately, these approaches were never successful. [6] In late 2009, we were inspired by a PtCl 2 -catalyzed reaction of alkene-tethered propargylic ethers that was disclosed by Michelet and coworkers. [7] In the simple enyne model system 8 (Scheme 2 b), Scheme 1. The echinopines and the related guaiane framework.Scheme 2. a) Attempted Heck cascades to access tricycles relevant to the echinopines. b) Successful enyne cycloisomerization. Bn = benzyl,...

Ready Access to the Echinopines Skeleton via Gold(I)-Catalyzed Alkoxycyclizations of Enynes

“…This result further illustrates the influence of the cyclopropane functionality on the reaction pathways followed in the gold(I)-catalyzed cyclizations of cyclopropane-tethered 1,5-enynes 23 and underscores the propensity of the strained tetracyclic system of echinopines to undergo rearrangements. 6 …”

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

“…7 The strategy was inspired by a PtCl 2 -catalyzed reaction of alkene-tethered propargylic ethers described by Michelet,22 to efficiently prepare tricyclic [3-5-5] architectures. The propargylic ether precursor (AE)-51 arose from ester (AE)-50 and this cis-bicyclic structure was accessible from cycloheptenone (AE)-49, by annulation reaction onto C5 and C1 (Scheme 12).…”

“…19 Therefore, compared to the formerly reported formal synthesis, a readily more straightforward access to 35 has been developed (Scheme 11). At this stage, an Eschenmoser fragmentation (treatment with TsNHNH 2 followed by acidic work-up) of the corresponding [5-6-7] epoxy ketone 36 allowed for the formation of the [5][6][7] alkynylketone 47 through rupture of the six-membered cyclohexane ring at C4eC11. 20 The final objective, i.e., the bioinspired [5][6][7]/ [3-5-5-7] skeletal conversion with intramolecular cyclopropanation, was achieved from 40 under Trost's conditions [CpRu(PPh 3 ) 2 Cl, CSA, In(OTf) 3 ] to deliver aldehyde 48 in 32% yield.…”

Small rings in the bigger picture: ring expansion of three- and four-membered rings to access larger all-carbon cyclic systems

“…20 It relies on the well-known Saegusa one-carbon ring expansion protocol 21 of [4.1.0] bicyclic structures (Scheme 5). Accordingly, the corresponding sevenmembered ring found in the intricated unusual structure of echinopine B (13) 22 and the cytotoxic terpenoid (À)-hortonone C ( 14) 23 was satisfyingly delivered thanks to this approach. Parented examples were also described in the literature and allowed the total synthesis of (AE)-schindilactone A ( 15) 24 (eqn (1)) and rameswaralide (16) (eqn ( 2)) (Scheme 6).…”