Plangger Immanuel, Mühlsteiger Alex, Berger Julia, Feilner Julian, Wurst Klaus, Koeberle Andreas, Koeberle Solveigh C, Magauer Thomas
Department of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria.
Michael Popp Institute, University of Innsbruck, Mitterweg 24, 6020, Innsbruck, Austria.
Chemistry. 2025 Feb 3;31(7):e202403811. doi: 10.1002/chem.202403811. Epub 2024 Dec 19.
We present a comprehensive account on the evolution of a synthetic platform for a subfamily of ent-pimaranes. For the most complex member, norflickinflimiod C, five distinct strategies relying on either cationic or radical polyene cyclizations to construct the requisite tricyclic carbon scaffold were explored. Insights from early and late stage oxidative and reductive dearomatization studies ultimately led to a mild, rhodium-catalyzed arene hydrogenation for the final synthetic route. A Sharpless asymmetric dihydroxylation was found to be suitable to render the platform enantioselective and diversification of a late-stage key intermediate culminated in the total synthesis of eight ent-pimaranes in 11-16 steps. These compounds were found to inhibit the formation of pro-inflammatory leukotrienes and other 5-lipoxygenase products. Notably, three ent-pimaranes exhibited low micromolar, non-redox active ferroptosis inhibition with remarkable structural specificity.
我们全面阐述了一种用于对映-海松烷亚家族的合成平台的演变。对于最复杂的成员诺弗利克弗利米奥多 C，探索了五种不同的策略，这些策略依靠阳离子或自由基多烯环化来构建所需的三环碳骨架。早期和晚期氧化及还原脱芳构化研究的见解最终促成了一条温和的、铑催化的芳烃氢化最终合成路线。发现夏普莱斯不对称双羟基化适合使该平台具有对映选择性，并且一个后期关键中间体的多样化最终实现了以11至16步全合成8种对映-海松烷。发现这些化合物可抑制促炎性白三烯和其他5-脂氧合酶产物的形成。值得注意的是，三种对映-海松烷表现出低微摩尔浓度、非氧化还原活性的铁死亡抑制作用，且具有显著的结构特异性。
