Ruspolinone及Tilivalline之合成研究

Abstract

本論文分為兩個部分，第一部分為Tilivalline的合成研究。9-Deoxytilivalline作為Tilivalline合成研究的模型化合物，建立以Tilivalline骨架為目標的合成路徑。第二個部分為Ruspolinone的合成研究，利用N-allylproline作為起始物進行脫羰基反應後，接續利用Mannich反應合成N-allylruspolinone。再透過deallyation獲得天然物Ruspolinoen。Tilivalline為PBDs天然物，具有連續的6-7-5三環核心骨架，並且在C-11、C-11a兩個連續的掌性中心皆為S組態，其中結構特色在於在C-11有indole取代，為PBDs天然物中少數於C-11具有芳香基取代的天然物。本論文將以9-deoxytilivalline作為Tilivalline的合成模型進行研究，利用proline作為反應起始物，經由一系列的修飾，proline被修飾為prolinal衍生物，再和氮上具保護的indole 3號位Grignard reagent進行加成反應，得到高選擇性的單一非鏡像化合物。利用此單一非鏡像化合物可經由兩個不同的合成路徑得到目標化合物9-deoxytilivalline。第二部分: 透過N-allylproline進行本實驗室所開發的脫羰基反應後和3',4'-dimethoxyacetophenone一鍋化地進行Mannich反應，得到N-allylruspolinone。接著進行deallylation得到天然物Ruspolinone。經由純化後，得到兩個化合物皆可在NMR光譜上被合理解釋為Ruspolinone，透過一系列酸鹼中和反應後，我們確定了主產物為free base的Ruspolinone，副產物為被質子化的Ruspolinone。同時，所合成的Ruspolinone可作為其他天然物像是Septicine的合成先驅物。This thesis is divided into two parts. The first part is the synthetic study of Tilivalline. 9-Deoxytilivalline is used as the model compound of Tilivalline in the study to establish a feasible synthetic pathway for the structural skeleton of Tilivalline. The second part is the synthetic study of Ruspolinone. N-Allylproline was used as a precursor to carry out decarbonylation reaction followed by Mannich reaction to form N-allylruspolinone. Subsequently, deallylation affords the natural product Ruspolinone.Tilivalline is a natural product of PBDs with a continuous 6-7-5 tricyclic core skeleton. And there are two continuous chiral centers at C-11 and C-11a, both of which are the S configuration. The structure features an indole substituent at C-11, which is rare in natural PBDs. In this thesis, 9-deoxytilivalline is used as the synthetic model of Tilivalline. Proline is used as the starting material in the synthesis. After a series of modifications, proline was converted to prolinal derivative and then underwent an addition reaction with the Grignard reagent at the 3-position of N-protected indole to give exclusively a single diastereomer. Through this diastereomer, 9-deoxytilivalline would be prepared via two different synthetic pathways.Part 2: N-Allylproline underwent the decarbonylation reaction developed by our laboratory followed by the Mannich reaction with 3',4'-dimethoxyacetophenone to form N-allylruspolinone in one pot. Subsequent deallylation afforded the natural product Ruspolinone. After purification, two products were obtained and can be interpreted as Ruspolinone by NMR spectra. Though a series of acid-base neutralization reactions, we determined that the major isolated product is the free base form of Ruspolinone. In addition, the minor product was shown to be the protonated form of Ruspolinone. We also demonstrated the synthesized Ruspolinone can be used as a synthetic precursor for other natural products such as Septicine.