Cassane 類雙萜化合物與麥角生物鹼 (−)-Chanoclavine-I 之全合成；雜環萜類天然物 Meleagrin B 與蕈類天然物(−)-Antrocin 的生物合成途徑研究

Abstract

本論文第一章敘述 (±)-pikrosalvin、(+)-simplexene C、(+)-simplexene D 和 (±)-swartziarboreol G 之全合成。合成關鍵步驟為仿生多烯環化與內酯化反應，此仿生合成途逕來自於Stork–Eschenmoser 的假說啟發，可以有效地構建這些天然物特有的A/B環結構、芳香族C環以及內酯D環。以香草酸與香葉醇為起始物，經官能基轉換與保護後引入三甲基矽基團，並利用一鍋化反應生成二烯中間體。此中間體經碘化鋅或三氟甲磺酸鋅搭配對甲苯磺酸催化多烯環化，建構反式十氫萘骨架。三甲基矽基團轉換為碘化物後，經偶聯反應生成苯乙烯衍生物，再進行內酯化反應形成甲基內酯，並在水解甲基芳基醚後完成 (±)-pikrosalvin 之合成，此部分研究成果已發表。 以同樣苯乙烯衍生物經氧化內酯化、去保護及層析分離獲得四個異構物，其中一個為 (+)-simplexene C，另一異構物經水解甲基芳基醚後得到 (+)-simplexene D。此外，將苯乙烯衍生物中的醯胺轉為羧酸，經乙酰氧基內酯化建構六環後，獲得四個同分異構物，經結晶與 X 光單晶繞射確認結構，最終去保護得到 (±)-swartziarboreol G。此全合成共歷經十一至十四步。 第二章探討麥角生物鹼 (−)-chanoclavine-I 之合成研究。因其六環的生合成機制至今仍未明確，我們提出一種仿生合成策略，嘗試以氨基酸合成 (−)-chanoclavine-I。關鍵步驟包括環氧化的合成及光催化去羧基環化反應，本研究仍在進行中。 第三章探討一種結合 (−)-conidiogenone 與 meleagrin 的特殊萜烯–生物鹼混合型天然物 meleagrin B 之生物合成途徑。林曉青老師發現 (−)-conidiogenone B 可經雙萜合酶與 P450 單加氧酶催化生成，隨後與咪唑在 α,β-水解酶（Con-ABH）催化下進行 aza-Michael 加成反應，形成 3S-imidazolyl conidiogenone B。我們以化學合成方式獲得該化合物，並藉X光單晶繞射確認其絕對立體結構，提供給林老師做更進一步研究，此研究成果已發表。 第四章探討一種蕈類次級代謝物 (−)-antrocin，其被推測由法尼基焦磷酸 (FPP) 經萜烯環化酶催化生成，但其生合成機制尚未完全明瞭。在林曉青老師的研究中，發現 (+)-albicanol 為FPP轉化為 (−)-antrocin的中間體。為探討此轉化過程中萜烯環化酶的作用，我們以化學合成方法 (+)-albicanyl pyrophosphate，利用(+)-sclareolide 為起始物，經六步反應成功獲得 (+)-albicanyl pyrophosphate，並將其提供給林老師作為生合成中間體做測試，證實酵素 AncC 在此合成機制中具有兩個功能區域：萜類環化酶 (terpene cyclase, TC) 與焦磷酸酶(pyrophosphatase, PPase)。其中，TC 區域可將 FPP 環化生成 (+)-albicanyl pyrophosphate，接著由 PPase 區域催化去除焦磷酸基團，產生 (+)-albicanol。此研究成果已發表。

The total synthesis of four cassane-type diterpenoids, pikrosalvin, simplexene C, simplexene D, and (±)-swartziarboreol G, was accomplished via a biomimetic polyene cyclization strategy followed by a late-stage lactonization, completed in 11–14 steps from commercially available vanillic acid and geraniol. This synthetic approach, inspired by the Stork–Eschenmoser hypothesis, enabled the efficient construction of the decalin A/B rings, the aromatic C ring, and the lactone D ring characteristic of these natural products. This part of the study has been published. Chapter two explores the synthetic studies of the ergot alkaloid (−)-chanoclavine-I. Since the biosynthetic mechanism of its 6-membered ring remains unclear, we propose a biomimetic synthetic strategy that attempts to access (−)-chanoclavine-I from amino acid precursors. Key steps include the construction of the epoxide intermediate and a photoredox-catalyzed decarboxylative cyclization. This research is still ongoing. In chapter three, the biosynthesis of Meleagrin B, a unique terpene–alkaloid hybrid natural product combining (−)-conidiogenone and meleagrin scaffolds, was investigated. We characterized the enzyme-mediated pathway in which a diterpene synthase and a P450 monooxygenase generate (−)-conidiogenone B, followed by an α,β-hydrolase (Con-ABH)-catalyzed aza-Michael addition with imidazole to form 3S-imidazolyl conidiogenone B. This hybrid compound was chemically synthesized, and its absolute configuration was confirmed by X-ray crystallography. This work has been published. Chapter four investigates the biosynthesis of a fungal secondary metabolite, (−)-antrocin. Its biosynthetic mechanism has not yet been fully elucidated. In this study, we identified (+)-albicanol as an intermediate in the conversion of FPP to (−)-antrocin. To investigate the role of the terpene cyclase involved in this transformation, we chemically synthesized (+)-albicanyl pyrophosphate from (+)-sclareolide in six steps. This compound was then tested as a biosynthetic intermediate, confirming that the enzyme AncC possesses two functional domains in the biosynthetic mechanism: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to form (+)-albicanyl pyrophosphate, which is subsequently dephosphorylated by the PPase domain to yield (+)-albicanol. This work has been published.