Total Synthesis of Sporolide B and 9-epi-Sporolide B

The total synthesis of the structurally unique secondary metabolite sporolide B (1b) is described. The total synthesis of 1b was developed on the basis of preliminary studies that revealed the reactivity of an appropriate o-quinone as a diene system toward a number of indene derivatives as dienophiles, first in intermolecular and thence intramolecular settings. Thus, substrates were devised (37 and 75) that underwent exquisite intramolecular [4+2] cycloaddition reactions under thermal conditions to provide primitive sporolide-type structures that were subsequently elaborated to a sporolide model system, 9-epi-sporolide B, and 1b. The requisite indene o-quinone precursor 75 was synthesized through a ruthenium-catalyzed [2+2+2] cycloaddition reaction between a propargylic alcohol and a chloroacetylenic cyclopentenyne, followed by elaboration and silver-promoted oxidation of the resulting chloroindene derivative. In addition to the total synthesis of 1b, this work demonstrated, for the first time, the power of the intramolecular hetero [4+2] cycloaddition reaction in the total synthesis of complex molecules and the application of the ruthenium-catalyzed [2+2+2] cycloaddition reaction to highly substituted indene systems possessing a chlorine residue on the aromatic nucleus.

本论文详细阐述了结构独特的次级代谢物孢子菌素B（1b）的全合成过程。1b的全合成研究建立在初步研究的基础之上，初步研究发现，一种适宜的邻醌类化合物作为共轭双烯体系中的亲双烯体，与多种茚满衍生物发生反应，首先在分子间，随后在分子内环境中表现出高度的反应活性。因此，设计了（37和75）两种底物，在热力学条件下通过精湛的分子内[4+2]环加成反应，生成孢子菌素型初级结构，进而发展至孢子菌素模型系统，9-表-孢子菌素B，以及1b。所需的茚满邻醌前体75通过钯催化下的[2+2+2]环加成反应合成，该反应涉及丙炔醇与氯代乙酰基环戊烯的交联，随后对生成的氯代茚满衍生物进行后续修饰和银催化氧化。除了1b的全合成之外，本研究首次展示了分子内杂环[4+2]环加成反应在复杂分子全合成中的强大作用，以及将钯催化下的[2+2+2]环加成反应应用于具有氯原子残留在芳环核上的高度取代茚满体系的应用。