Institute of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Institute of General, Inorganic & Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
J Am Chem Soc. 2023 May 31;145(21):11811-11817. doi: 10.1021/jacs.3c03366. Epub 2023 May 16.
The first asymmetric total synthesis of the diterpenoid waixenicin A, a potent and highly selective TRPM7 inhibitor, is reported. The characteristic -fused oxabicyclo[7.4.0]tridecane ring system was constructed via a diastereoselective conjugate addition/trapping sequence, followed by an intramolecular alkylation to forge the 9-membered ring. While a β-keto sulfone motif enabled efficient ring-closure, the subsequent radical desulfonylation suffered from ()/()-isomerization of the C7/C8-alkene. Conducting the sequence with a trimethylsilylethyl ester allowed for a fluoride-mediated decarboxylation that proceeded without detectable isomerization. The acid-labile enol acetal of the delicate dihydropyran core was introduced at an early stage and temporarily deactivated by a triflate function. The latter was critical for the introduction of the side chain. Diverting from a common late-stage intermediate provided access to waixenicin A and 9-deacetoxy-14,15-deepoxyxeniculin. A high-yielding base-mediated dihydropyran-cyclohexene rearrangement of 9-deacetoxy-14,15-deepoxyxeniculin led to xeniafaraunol A in one step.
首次不对称全合成了强效且高选择性的瞬时受体电位阳离子通道 M7（TRPM7）抑制剂二萜类化合物 waixenicin A。通过非对映选择性共轭加成/捕获序列构建了特征性的 -稠合氧杂双环[7.4.0]十三烷环系，随后进行分子内烷基化以形成 9 元环。虽然 β-酮砜基可以实现有效的闭环，但随后的自由基脱磺化反应会受到 C7/C8-烯烃的（）/（）-异构化的影响。用三甲基硅基乙基酯进行该序列反应可以进行氟介导的脱羧反应，而不会发生可检测的异构化。脆弱的二氢吡喃核的酸不稳定烯醇缩醛在早期引入，并暂时通过三氟甲磺酸酯官能团失活。后者对于引入侧链至关重要。从常见的晚期中间体出发，可以分别得到 waixenicin A 和 9-去乙酰氧基-14,15-去氧木贼碱。9-去乙酰氧基-14,15-去氧木贼碱的高产碱介导的二氢吡喃-环己烯重排可以一步得到 xeniafaraunol A。
