Wright Brandon A, Okada Taku, Regni Alessio, Luchini Guilian, Sowndarya S V Shree, Chaisan Nattawadee, Kölbl Sebastian, Kim Sojung F, Paton Robert S, Sarpong Richmond
Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
J Am Chem Soc. 2024 Dec 4;146(48):33130-33148. doi: 10.1021/jacs.4c11252. Epub 2024 Nov 20.
In this report, we detail two distinct synthetic approaches to calyciphylline A-type 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.
在本报告中，我们详细阐述了两种截然不同的合成方法，用于制备隐叶豆碱 A 型生物碱喜马拉宁 A 和达芬叶碱，这两种方法的灵感来源于我们对这些化合物结构复杂性的分析。我们使用自己开发的基于 Python 的网络应用程序 MolComplex，对单键逆合成断开产生的所有可能前体的结构复杂性进行了量化。这使得我们确定了跨环键对分子图具有特别的简化作用，并基于此分析，我们从大环中间体出发，通过计划中的后期跨环成环反应，对喜马拉宁 A 进行了全合成。尽管在获取最初设计的大环时遇到了挫折，但以简化的大环为目标最终使我们能够研究该中间体独特的跨环反应性。鉴于仅基于分子图分析未能成功合成喜马拉宁 A，我们调整了对相关生物碱达芬叶碱的合成方法。在此，我们还详细介绍了在达芬叶碱全合成过程中遇到并克服的各种合成挑战。首先，对铑介导的分子内布赫纳/6π-电环化开环序列进行优化，实现了五环核心的构建。然后，我们描述了安装关键季甲基的各种尝试，最终我们采用了[2 + 2]光环加成/键裂解序列来实现这一难以捉摸的目标。最后，后期的傅克环化和脱氧反应促进了 11 步全合成，通过铑介导的二氢吡啶共轭芳基化反应使该合成正式具有对映选择性。达芬叶碱合成的复杂性分析突出了复杂性构建/C-C 裂解组合在实现合成结果方面如何能具有独特的有效性。
