Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States.
J Am Chem Soc. 2021 May 19;143(19):7566-7577. doi: 10.1021/jacs.1c03336. Epub 2021 May 4.
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 -acerosolide versus -deoxypukalide and -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 -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 3,7,8 configurations for the bielschowskysin synthesis. Unlike previously speculated, our results suggest that the most strained FBC-macrocycles bearing a -(Δ)-alkene moiety may stand as the true biosynthetic precursors to bielschowskysin and several other polycyclic natural products of this class.
大环呋喃丁烯醇衍生的 cembranoids（FBCs）是广泛存在的高度拥挤和含氧多环（nor）二萜类化合物（如 plumarellide、verrillin 和 bielschowskysin）的生物合成前体。这些结构复杂的代谢物被认为源自大环骨架的选择性氧化和一系列复杂的跨环反应。然而，由于缺乏区域和立体选择性地实现关键呋喃去芳构化的合成方法，因此通用仿生途径的发展受到了阻碍。为了解决这些缺点，报道了一种简洁的环氧化策略，随后是动力学控制的呋喃去芳构化。在最紧张的 -acerosolide 与 -deoxypukalide 和 -bipinnatin J 衍生的大环环氧化反应中观察到的面 α:β-识别的惊人转变，通过大环骨架之间的 3D 构象景观的变化得到了合理化。通过 VT-NMR 和低温下的 NOESY 实验对这些大环进行仔细的构象分析，并通过 DFT 计算得到支持，以表征这些平衡的大环构象。与 -deoxypukalide 中环丁烯醇环摆动相关的构象拓扑变化通常与观察到的环氧化反应中 β-选择性的反转一致。我们还描述了 FBC-大环的下游官能化，以及在动力学控制下 C-7 环氧化物构型如何保留地转化为去芳构化产物中的 C-3 立体化学，以确保 bielschowskysin 合成所需的 3,7,8 构型。与之前的推测不同，我们的结果表明，具有 -（Δ）-烯烃部分的最紧张的 FBC-大环可能是 bielschowskysin 和该类别的其他几种多环天然产物的真正生物合成前体。
