In this report, we detail two distinct synthetic approaches to calyciphylline A-type Daphniphyllum alkaloids himalensine A and daphenylline, which are inspired by our analysis of the structural complexity of these compounds. Using MolComplex, a Python-based web application that we have developed, we quantified the structural complexity of all possible precursors resulting from one-bond retrosynthetic disconnections. This led to the identification of transannular bonds as especially simplifying to the molecular graph, and, based on this analysis, we pursued a total synthesis of himalensine A from macrocyclic intermediates with planned late-stage transannular ring formations. Despite initial setbacks in accessing an originally designed macrocycle, targeting a simplified macrocycle ultimately enabled investigation of this intermediate’s unique transannular reactivity. Given the lack of success to access himalensine A based solely on molecular graph analysis, we revised our approach to the related alkaloid, daphenylline. Herein, we also provide the details of the various synthetic challenges that we encountered and overcame en route to a total synthesis of daphenylline. First, optimization of a Rh-mediated intramolecular Buchner/6π-electrocyclic ring-opening sequence enabled construction of the pentacyclic core. We then describe various attempts to install a key quaternary methyl group and, ultimately, our solution to leverage a [2 + 2] photocycloaddition/bond cleavage sequence to achieve this elusive goal. Finally, a late-stage Friedel–Crafts cyclization and deoxygenation facilitated the 11-step total synthesis, which was made formally enantioselective by a Rh-mediated dihydropyridone conjugate arylation. Complexity analysis of the daphenylline synthesis highlights how complexity-building/C–C cleavage combinations can be uniquely effective in achieving synthetic outcomes.

中文翻译：

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分子复杂性启发的针对 Calyciphylline A 型 Daphniphyllum 生物碱 Himalensine A 和 Daphenylline 的合成策略


在本报告中，我们详细介绍了毛萼碱 A 型 Daphniphyllum 生物碱 himalensine A 和 daphenylline 的两种不同的合成方法，这些方法的灵感来自我们对这些化合物结构复杂性的分析。使用我们开发的基于 Python 的 Web 应用程序 MolComplex，我们量化了由单键逆合成断开导致的所有可能前驱体的结构复杂性。这导致跨环键的鉴定特别简化了分子图，并且，基于此分析，我们追求从大环中间体中完全合成 himalensine A，并计划形成晚期跨环形成。尽管在访问最初设计的大环方面最初遇到了挫折，但靶向简化的大环最终使研究该中间体独特的跨环反应性成为可能。鉴于仅基于分子图分析无法成功获得 himalensine A，我们修改了对相关生物碱 daphenylline 的方法。在本文中，我们还提供了我们在完全合成达芬碱的过程中遇到和克服的各种合成挑战的详细信息。首先，Rh 介导的分子内 Buchner/6π 电环开环序列的优化使五环核心的构建成为可能。然后，我们描述了安装关键季铵甲基的各种尝试，并最终描述了我们利用 [2 + 2] 光环加成/键切割序列来实现这个难以捉摸的目标的解决方案。最后，晚期 Friedel-Crafts 环化和脱氧促进了 11 步总合成，其通过 Rh 介导的二氢吡啶酮偶联芳基化正式成为对映选择性。 达芬碱合成的复杂性分析强调了复杂性构建/C-C 切割组合如何在实现合成结果方面发挥独特作用。