臺灣博碩士論文加值系統

由於 Stellettoside B1－B4 混合物對於子宮頸癌的海拉細胞 (HeLa cells) 表現出中等的細胞毒殺活性 (cytotoxic activity)，其 IC50 值為 9 μM，然而文獻報導並沒有分別針對這四種化合物進行活性測試，所以並不知道這四種化合物對於海拉細胞是否具有甚麼樣的生物活性，而此化合物目前也尚未成功合成。因此，為了合成非還原端之全乙醯基醣體 Stellettoside 的三醣體骨架，本篇論文將說明我們如何利用本實驗室開發之正交性保護基策略應用在以L-阿拉伯糖為起始物來合成建構組元，與解決在合成過程中前人所沒有說明的問題，進而去合成 Stellettoside 三醣體。
在合成醣體建構組元的部分，其合成策略面臨的挑戰是如何選擇性在三號或四號位置上保護和探討選擇去保護後將非還原端之乙醯基保留下來的方法開發。本論文中，我們開發出兩種不同方法，一種是在鑭系金屬催化下選擇性在三號位置引入 ASMB 保護基，而另一種是在硫代硫酸鈉的催化下選擇性在四號位置引入 ASMB 保護基。而在其醣基化反應的部分，則是目前利用 NIS 和鑭系金屬的催化下經由醣基化反應將 PMB 成功接於醣苷予體，我們期望未來也可將其應用於建構組元與三醣體的醣基化反應。

We report a highly efficient strategy to synthesize the building blocks of stellettosides B, of use for biological and medicinal structure activity studies. The synthesis of Stellettoside glycosides is a challenge due to the need of multiple synthetic steps including regioselective protection and deprotection, which is used for the keeping peracetylated sugar unit of the non-reducing end after complete deprotection. By our retrosynthetic strategy, compound 1 served as a glycosyl donor starting from L-arabinose was synthesized by our recent report,9 We developed two methods for regioselective installation of orthogonal protecting group, namely ASMB, to prepare the building blocks of 10 and 11 served as glycosyl acceptors for glycosylation. We used lanthanide triflates as catalyst to get the compound 10, and used sodium thiosulfate as catalyst to get the compound 11. Model study of glycosylation between thioglycoside 5a and PMBOH was successfully achieved to obtain the desired product. Based on our experimental results, the installation of PMB group on anomeric center can be prevented the occurrence of aglycone transfer in glycosylation. Consequently, this work is still under process.

第一章、前言 1
1.1 Stellettosides 系列天然物的來源、結構組成與生物活性 1
1.2 阿拉伯糖的介紹 2
1.2.1 含五員環阿拉伯糖的天然物及其醣基化方法 3
1.2.2 含 L-Arap 的天然物 5
1.3 L-arap 醣基化方法和位向選擇性上保護之文獻回顧 7
1.3.1 L-arap 之醣基化方法 7
1.3.1.1 在 L-Arap 一號及二號碳進行醣基化的方法 7
1.3.1.2 在 L-Arap 之三號碳上進行醣基化反應的方法 9
1.3.1.3 含 L-Arap 雙醣片段之醣基化反應方法 11
1.3.2 L-Arabinose building block設計策略之文獻回顧 13
1.3.2.1 露出二號碳上羥基之方法 13
1.3.2.2 露出三號碳上羥基之方法 13
1.4 研究動機 16
第二章、結果與討論 17
2.1 三醣體的設計 17
2.1.1 影響醣基化立體位向的因素 17
2.1.1.1 變旋異構效應 17
2.1.1.2 鄰基效應 18
2.1.2 逆合成分析 18
2.1.3 非還原端化合物 4 的合成 20
2.1.4 選擇性保護二號位之 building block 化合物 9 的合成 22
2.1.5 選擇性在三號或是四號位置上保護的方法 27
2.1.5.1 在三號或是四號位選擇性上三甲基矽保護基的方法 27
2.1.5.2 利用實驗室開發的 ASMB 做選擇性上保護和去保護 28
2.1.5.2.1 ASMBOH 的製備方法 28
2.1.5.2.2 利用耦合方法進行選擇性上 ASMB 保護基 30
2.1.5.2.3 (ASMB)2O 的製備方法 32
2.1.5.2.4 利用鑭系金屬進行選擇性上 ASMB 保護基 33
2.1.5.2.5 選擇性去 ASMB 保護 37
2.1.5.2.6 利用硫代硫酸鈉進行選擇性上 ASMB 保護基 40
2.1.6 醣基化反應 41
第三章、結論 50
第四章、未來展望 52
第五章、實驗步驟與光譜數據 53
第六章、參考文獻 77
第七章、附錄 83

[1] Peddie, V.; Takada, K.; Okuda, S.; Ise, Y.; Morii, Y.; Yamawaki, N.; Takatani, T.; Arakawa, O.; Okada, S.; Matsunaga, S., Cytotoxic glycosylated fatty acid amides from a Stelletta sp. Marine Sponge. J. Nat. Prod. 2015, 78, 2808–2813.
[2] (a) Houseknecht, J. B.; Lowary, T. L., Chemistry and biology of arabinofuranosyl- and galactofuranosyl-containing polysaccharides. Curr. Opin. Chem. Biol, 2001, 5, 677–682. (b) Crich, D.; Pedersen, C. M.; Bowers, A .A.; Wink, D. J., On the use of 3,5-O-benzylidene and 3,5-O-(di-tert-butylsilylene)-2-O-benzylarabinothiofuranosides and Their Sulfoxides as glycosyl donors for the synthesis of β-arabinofuranosides: importance of the activation method. J. Org. Chem. 2007, 72, 1553–1565. (c) Konishi, T.; Ishii, T., The origin and functions of arabinofuranosyl residues in plant cell walls. Trends in Glycoscience and Glycotechnology. 2012, 24, 13–23. (d) Kotake, T.; Yamanashi, Y.; Imaizumi, C, Tsumuraya, Y., Metabolism of L-arabinose in plants. J. Plant. Res. 2016, 129, 781–792. (e) Shinohara, H.;Matsubayashi, Y., Chemical synthesis of Arabidopsis CLV3 glycopeptide reveals the impact of hydroxyproline arabinosylation on peptide conformation and activity. Plant and Cell Physiol. 2013, 54, 369–374. (f) Wu, Y.; Xiong, D.-C.; Chen, S.-C.; Wang, Y.-S.; Ye, X.-S., Total synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units. Nat. Commun. 2017, 8, 14851. (g) Kinnaert, C.; Daugaard, M.; Nami, F.; Clausen, M. H., Chemical synthesis of oligosaccharides related to the cell walls of plants and algae. Chem. Rev. 2017, 117, 11337–11405.
[3] (a) Fusetani, N.; Sata, N.; Asai, N.; Matsunaga S., Isolation and Sstructure elucidation of Erylusamine B, a new class of Marine natural products, which blocked an IL-6 receptor, from the Marine sponge Erylus placenta thielet. Tetrahedron Lett. 1993, 34, 4067–4070. (b) Zheng, D.; Zhou, L.; Guan, Y.; Chen, X.-Z.; Zhou, W.-Q.; Chen, X.-G.; Lei, P.-S., Synthesis of cholestane glycosides bearing OSW-1 disaccharide or its 1→4-linked analogue and their antitumor activities. Bioorg. Med. Chem. Lett. 2010, 20, 5439–5442. (c) Rao, Y.; Buskas, T.; Albert, A.; O’Neill, M. A.; Hahn, M. G.; Boons, G.-J. Synthesis and immunological properties of a tetrasaccharide portion of the B side chain of rhamnogalacturonan II (RG-II). Chem. BioChem. 2008, 9, 381–388. (d) Sun, J.; Han, X.; Yub, B., Synthesis of a typical N-acetylglucosamine-containing saponin, oleanolic acid 3-yl α-L-arabinopyranosyl-(1→2)-β-L-arabinopyranosyl-(1→6)-2-acetamido-2-deoxy-β-D-glucopyranoside. Carbohydr.Res. 2003, 338, 827–833. (e) Mandal, S.; Das, R.; Mukhopadhyay, B., Synthesis of two trisaccharides related to the triterpenoid saponineryloside isolated from the sponge Erylus nobilis. Tetrahedron: Asymm. 2011, 22, 1108–1113.
[4] (a) Valiullina, Z. R.; Khasanova, L. S.; Gimalova, F. A.; Selezneva, N. K.; Spirikhin, L. V.; Miftakhov, M. S., Synthesis of vespertilin conjugates with OSW-1 disaccharide blocks. Russ. J. Org. Chem. 2014, 10, 1538–1543. (b) Liu, Q.-C.; Guo, T.-T.; Zhao, C.; Sun, J.; Li, W.-H., synthesis of a trisaccharide related to the cytotoxic triterpenoid saponins isolated from the bark of Albizia procera. Helv. Chim. Acta. 2014, 97, 361–368.
[5] (a) Yu, W.-S.; Jin, Z.-D., A new strategy for the stereoselective introduction of steroid side chain via α-alkoxy vinyl cuprates: total synthesis of a highly potent antitumor natural product OSW-1. J. Am. Chem. Soc. 2001, 123, 3369–3370. (b) Xue, J.; Liu, P.; Pan, Y.-B.; Guo, Z.-W., A total synthesis of OSW-1. J. Org. Chem. 2008, 73, 157–161. (c) Rao, Y.; Boons, G.-J., A highly convergent chemical synthesis of conformational epitopes of rhamnogalacturonan II. Angew. Chem. Int. Ed. 2007, 46, 6148–6151. (d) Khasanova, L. S.; Gimalova, F. A.; Valiullina, Z. R.; Selezneva, N. K.; Ganieva, R. M.; Spirikhin, L. V.; Miftakhov, M. S., New disaccharide blocks for OSW-1 and its analogs. Russ. J. Org. Chem. 2012, 48, 1238–1244. (e) Kongkathip, B.; Kongkathip, N.; Rujirawanich, J., New srategy for synthesis of the disaccaride moiety of the highly Potent anticancer natural product OSW-1. Synth. Commun. 2014, 44, 2248–2255. (f) Mancini, R. S.; McClary, C. A.; Anthonipillai, S.; Taylor, M. S., Organoboron-promoted regioselective glycosylations in the synthesis of a saponin-derived pentasaccharide from Spergularia ramose. J. Org. Chem. 2015, 80, 8501–8510.
[6] (a) Wang, P.; Li, C.-X.; Zang, J.; Song, N.; Zhang, X.; Li, Y.-X., Synthesis of two bidesmosidic ursolic acid saponins bearing a 2,3-branched trisaccharide residue. Carbohydr. Res. 2005, 340, 2086–2096. (b) Wang, P.; Li, C.-X.; Wang, G.-F.; Li, Y.-X., Synthesis of an ursolic acid saponin with N-acetylglucosamine-containing trisaccharide Residue. Chin. J. Chem. 2006, 24, 1421–1426.
[7] Miljkovic, M., Carbohydrides: synthesis, mechanisms, and stereoelectronic effects; Springer Science + Business Media, LLC, 2009.
[8] 顏翊凌 《利用三價鑭系金屬催化醣類分子正交性保護基之設計》，2017 年。(國立中興大學化學研究所，碩士學位論文)
[9] Yan, Y.-L.; Guo, J.-R.; Liang, C.-F., Sequential Dy(OTf)3-catalyzed solvent-free per-O-acetylation and regioselective anomer de-O-acetylation of carbohydrates. Chem. Asian. J. 2017, 12, 2471–2479.
[10] Mukhopadhyay, B.; Kartha, K. P. R.; Russel, D. A.; Field, R. A., Streamlined synthesis of per-O-acetylated sugar, glycosyl iodides, or thio glycosides from unprotected reducing sugars. J. Org. Chem. 2004, 69, 7758 –7760.
[11] (a) Khan, K. M.; Hayat, S.; Zia-Ullah; Atta-ur-Rahman; Choudhary, M. I.; Mafarvi, G. M.; Bayer, E., An alternative method for the synthesis of γ-lactones by using cesium fluoride-celite/acetonitrile combination. Synth. Commun. 2003, 33, 3435–3453. (b) Hughes, T. V.; Emanuel, S. L.; Grady, H. R. O’; Connolly, P. J.; Rugg, C.; Fuentes-Pesquera, A. R.; Karnachi, P.; Alexander, R.; Middleton, S. A., 7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-ones as dual Aurora-A/VEGF-R2 kinase inhibitors: design, synthesis, and biological activity. Bioorg. Med. Chem. Lett. 2008, 18, 5130–5133. (c) Malwal, S. R.; Chakrapani, H., Benzosulfones as photochemically activated sulfur dioxide (SO2) donors. Org. Biomol. Chem. 2015, 13, 2399–2406.
[12] McNulty, J.; Keskar, K., Phthalide: a direct building-block toward P,O and P,N hemilabile ligands. Application in the palladium-catalysed Suzuki-Miyaura cross-coupling of aryl chlorides. Org. Biomol. Chem. 2013, 11, 2404–2407.
[13] Daskiewicz, J.-B.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-Sarrazin, G.; Comte, G.; Gee, J. M.; Johnson, I. T.; Ndjoko, K.; Hostettmann, K.; Barron, D., Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29: an SAR study. J. Med. Chem. 2005, 48, 2790–2804.
[14] Huang, H.-Y.; Liang, C.-F., Sequential Ytterbium(III) triflate catalyzed one-pot three-component thia-michael addition. Asian J. Org. Chem. 2018, 7, 955–963.
[15] 郭峻榕 《利用三價鑭系金屬催化醣類分子正交性保護基之設計》，2017 年。(國立中興大學化學研究所，碩士學位論文)
[16] Codée, J. D. C.; Litjens, R. E. J. N.; Bos, L. J. V. D.; Overkleeft, H. S.; Marel, G. A. V. D. Thiglycosides in sequential glycosylation strategies. Chem. Soc. Rev. 2005, 34, 769–782.
[17] (a) Timmons, S. C.; Jakeman, D. L., Stereospecific synthesis of sugar-1-phosphates and their conversion to sugar nucleotides. Carbohy. Res. 2008, 343, 865–874. (b) Zhang, J.-B.; Zhou, J.-F.; Li, J.; Shi, C.-J.; Huang, T.; Wang, Z.-F.; Tang, J., H2SO4-SiO2: Highly efficient and reusable catalyst for per-O-acetylation of carbohydrates under solvent-free conditions. J. Carbohydr. Chem. 2011, 30, 165–177.
[18] Morotii, A. L. M.; Lang, K. L.; Carvalho, I.; Schenkel, E. P.; Bemardes. L. S. C., Semi-synthesis of new glycosidic triazole derivatives of dihydrocucurbitacin B. Tetrahedron Lett. 2015, 56, 303–307.
[19] Murakami, T.; Matsuda, H.; Inadzuki, M.; Hirano, K.; Yoshikawa, M., Medicinal Foodstuffs. XVI. Sugar Beet. (3): Absolute Stereostructures of Betavulgarosides II and IV, Hypoglycemic Saponins Having a Unique Substituent, from the Roots of Beta vulgaris L. Chem. Pharm. Bull. 1999, 47, 1717–1721.
[20] Liu, C.; Wang, A.-P.; Jin, L.-L.; Guo, Y.-S.; Li, Y.; Zhao, Z.-H.; Lei, P.-S., Synthesis, conformational analysis and SAR research of OSW-1 analogues. Tetrahedron 2016, 72, 4091–4102.