Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (e.g. plumarellide, verrillin, and bielschowskysin). These architecturally complex metabolites are thought to originate from site-selective oxidation of the macrocycle backbone and a series of intricate transannular reactions. Yet the development of a common biomimetic route has been hampered by a lack of synthetic methods for the pivotal furan dearomatization in a regio- and stereoselective manner. To address these shortcomings, a concise strategy of epoxidation followed by a kinetically controlled furan dearomatization is reported. The surprising switch of facial α:β-discrimination observed in the epoxidation of the most strained E-acerosolide versus E-deoxypukalide and E-bipinnatin J derived macrocycles has been rationalized by the variation of the 3D conformational landscape between macrocyclic scaffolds. A careful conformational analysis of these macrocycles by VT-NMR and NOESY experiments at low temperature was supported by DFT calculations to characterize these equilibrating macrocyclic conformers. The shift in conformational topology associated with a swing of the butenolide ring in E-deoxypukalide is in general agreement with the reversal of β-selectivity observed in the epoxidation. We also describe the downstream functionalization of FBC-macrocycles and how the C-7 epoxide configuration is retentively translated to the C-3 stereogenicity in dearomatized products under kinetic control to secure the requisite 3S,7S,8S configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a E-(Δ7,8)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.
Bielschowskysin (1), the flagship of the furanocembranoid diterpene family,has attracted attention from chemists owingtoits intriguing and daunting polycyclic architecture and medicinal potential against lung cancer.T he high level of functionalization of 1 poses ac onsiderable challenge to synthesis.H erein, as tereoselective furan dearomatization strategy of furanocembranoids was achieved via the intermediacy of chlorohydrins.T he stereochemical course of the kinetic dearomatization was established, and the C3 configuration of the resulting exo-enol ether intermediates proved to be essential to complete the late-stage transannular [2+ +2] photocycloaddition. Overall, this biomimetic strategy starting from the natural product acerosolide (9)f eatured an unprecedented regio-and highly stereoselective furan dearomatization, whichprovided rapid access to the pivotal exo-enol ethers en route to the intricate bielschowskyane skeleton.Gorgonian corals continue to supply an array of fascinating bioactive diterpenes,w hich are biosynthetically proposed to be derived from ac ommon fourteen-membered-ring cembrane skeleton. [1] Among them, furanocembranoids are an intriguing class of macrocycles that contain af uran and ab utenolide moiety. [2] These heterocycles are often further oxidized and undergo numerous transannular reactions to generate natural products with astonishing structural diversity. [2] Bielschowskysin (1), isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos,i sa ne xciting synthetic target owing to its architectural complexity and biological activity. [3] This natural product contains an intricate tricyclo[9.3.0.0]tetradecane skeleton with 11 stereogenic centers,a nd was reported to have high potency and selectivity against EKVX non-small lung cancer cells (GI 50 < 10 nm)and CAKI-1 renal cancer cells (GI 50 = 510 nm). Thes keleton of 1 has been ad aunting challenge to the synthesis community, and while elegant approaches have been reported by the groups of Mulzer, [4] Trauner, [5] and Pattenden, [6] Nicolaou [7] and co-workers were the first to assemble the tricyclo-[9.3.0.0]tetradecane core.H owever,t he straightforward biosynthetic pathway,involving adearomatization-cycloaddition sequence,remained elusive in the laboratory setting.Thes ynthesis of complex natural products utilizing biomimetic dearomatization strategies inspired our route to 1 (Scheme 1a). [8] Our retrosynthetic analysis of 1 relies on two key transformations:1)The tricyclo[9.3.0.0]tetradecane skeleton could originate from atransannular [2+ +2] cycloaddition; at actic that has been validated by others; [7,9] and 2) the pivotal exo-enol ether intermediate 2 could be generated from an oxidative dearomatization of ab iosynthetic furanocembranoid precursor.N ot surprisingly,t his approach has been previously tested by other groups but the lack of success in developing ad earomatization route via exo-enol ethers such as 2 prohibited the total synthesis of 1. [4b, 5, 6] A dearomatized furanocembranoid was first reporte...
Bielschowskysin (1), the flagship of the furanocembranoid diterpene family,has attracted attention from chemists owingtoits intriguing and daunting polycyclic architecture and medicinal potential against lung cancer.T he high level of functionalization of 1 poses ac onsiderable challenge to synthesis.H erein, as tereoselective furan dearomatization strategy of furanocembranoids was achieved via the intermediacy of chlorohydrins.T he stereochemical course of the kinetic dearomatization was established, and the C3 configuration of the resulting exo-enol ether intermediates proved to be essential to complete the late-stage transannular [2+ +2] photocycloaddition. Overall, this biomimetic strategy starting from the natural product acerosolide (9)f eatured an unprecedented regio-and highly stereoselective furan dearomatization, whichprovided rapid access to the pivotal exo-enol ethers en route to the intricate bielschowskyane skeleton.
Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (<i>e.g.</i> plumarellide, verrillin or bielschowskysin). These architecturally complex metabolites are thought to originate from site-selective oxidation of the macrocycles’ backbone and a series of intricate transannular reactions. Yet the development of a common biomimetic route has been hampered by a lack of synthetic methods for the pivotal furan dearomatization in a regio- and stereoselective manner. To address these shortcomings, a concise strategy of chemo- and stereoselective epoxidation followed by a kinetically-controlled furan dearomatization is reported. The surprising switch of facial <i>a</i>:<i>b</i>-discrimination observed in the epoxidations of the most strained <i>E</i>-acerosolide <i>versus</i> <i>E</i>-deoxypukalide and <i>E</i>-bipinnatin J derived macrocycles has been rationalized by the 3D-conformational preferences of the macrocyclic scaffolds. The downstream functionalization of FBC-macrocycles was also studied, and how the C-7 epoxide configuration was retentively translated to the C-3 stereogenicity in dearomatized products under kinetic control to secure the requisite (3<i>S</i>,7<i>S</i>,8<i>S</i>)-configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a <i>E</i>-(D<sup>7,8</sup>)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.
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