Müller Nicolas, Kováč Ondřej, Rode Alexander, Atzl Daniel, Magauer Thomas
Department of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, 6020 Innsbruck, Austria.
Department of Organic Chemistry, Palacký University Olomouc, 77900 Olomouc, Czech Republic.
J Am Chem Soc. 2024 Aug 21;146(33):22937-22942. doi: 10.1021/jacs.4c08291. Epub 2024 Aug 7.
The total synthesis of the meroterpenoid ganoapplanin, an inhibitor of T-type voltage-gated calcium channels, is reported. Our synthetic approach is based on the convergent coupling of a readily available aromatic polyketide scaffold with a bicyclic terpenoid fragment. The three contiguous stereocenters of the terpenoid fragment, two of which are quaternary, were constructed by a diastereoselective, titanium-mediated iodolactonization. For the fusion of the two fragments and to simultaneously install the crucial biaryl bond, we devised a highly effective two-component coupling strategy. This event involves an intramolecular 6--trig radical addition of a quinone monoacetal followed by an intermolecular aldol reaction. A strategic late-stage oxidation sequence allowed the selective installation of the remaining oxygen functionalities and the introduction of the characteristic spiro bisacetal structure of ganoapplanin.
报道了T型电压门控钙通道抑制剂meroterpenoid ganoapplanin的全合成。我们的合成方法基于一个易于获得的芳香族聚酮支架与一个双环萜类片段的汇聚偶联。萜类片段的三个相邻立体中心，其中两个是季碳中心，通过非对映选择性的钛介导的碘内酯化反应构建。为了融合这两个片段并同时安装关键的联芳基键，我们设计了一种高效的双组分偶联策略。该反应涉及醌单缩醛的分子内6-三自由基加成，随后是分子间羟醛反应。一个策略性的后期氧化序列允许选择性地安装其余的氧官能团，并引入ganoapplanin的特征性螺双缩醛结构。
