Frick Chemistry Laboratory, Department of Chemistry, Princeton University , Princeton, New Jersey, 08544, United States.
J Org Chem. 2013 Oct 4;78(19):9584-607. doi: 10.1021/jo401799f. Epub 2013 Sep 23.
This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring-forming, nucleophilic capture of a transient acylketene and an intramolecular Diels-Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced "double cyclization" cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B.
这篇报道描述了一种通过新颖的环化级联反应直接形成聚酮天然产物毛喉萜酮 B 中 6 个环中的 3 个的策略。我们方法中的关键步骤包括两个转化：瞬态酰基炔的大环形成和亲核捕获，以及通过适当官能化的多不饱和二氧杂环庚酮的热解串联发生的分子内 Diels-Alder 反应。这些热诱导的“双环化”级联反应生成了三个新键、四个连续的立体中心和毛喉萜酮 B 的多环结构的重要部分。通过该过程合成的先进的大环内酰胺和大环内酯中间体具有毛喉萜酮骨架的关键特征，包括立体密集的十氢化芴核心和应变的对环丙烯环。然而，通过形成反环碳-碳键来完成毛喉萜酮 B 的碳骨架的尝试因竞争性 O-烷基化反应而受到破坏。该报道还记录了我们如何通过评估几种不同的合成策略以及最终实现毛喉萜酮 B 的正式全合成来适应这种不理想的结果。
