成功大學博碩士論文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	鄭力維 Cheng, Li-Wei
論文名稱：	設計及合成具有雜環取代之亞胺醣 Design and synthesis of heterocyclyl-azasugars
指導教授：	鄭偉杰 Cheng, Wei-Chieh
共同指導教授:	黃福永 Huang, Fu-Yung
學位類別：	碩士 Master
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	181
中文關鍵詞：	雜環、亞胺醣、1,3-偶極環加成反應、半自動化的儀器、氮雜核苷、環狀亞胺
外文關鍵詞：	Heterocyclic, azasugars, 1,3-dipolar cycloaddition, semiautomatic equipments, aza-C-nucleoside, cyclic imine
相關次數：	點閱：140 下載：1
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

具有雜環取代的亞胺醣分子(HHAs)，在與醣相關的反應酵素以及藥物開發方面，具有很多的應用。基於這些分子具有十分廣泛的生物活性，其製備方式就成為一個值得討論的議題。但是由於雜環亞胺醣的結構複雜，導致這類分子的合成方法在文獻中不是很完善，而本篇論文則分兩個部份來研究這類分子的合成方法：(1) 利用對掌性cyclic nitrone為起始物來設計及合成具有異噁唑及三唑雜環的亞胺醣分子。(2) 合成氮雜核苷類的分子。
在第一部分，對掌性的cyclic nitrone和乙烯格林那試劑或三甲基矽烷鋰試劑進行高選擇性的親核性加成反應，再經過一些化學的轉換之後，得到具有炔基或肟基的亞胺醣來做為重要的中間物，結合中間物以及相對應的試劑，例如：炔類、肟氯代以及三疊氮等試劑，藉由1,3-偶極環加成反應來得到具有異噁唑及三唑雜環的亞胺醣分子，並且利用半自動化的技術，例如：合成反應器，自動劑液處理系統，真空離心濃縮，以及固相萃取等等的技術; 來更有效率的合成這些分子。最後我們合成出了70個這類化合物分子的衍生物，並且具有三種變異性，其中包含：立體組態變異性、雜環及其取代基之變異性、和氮上的取代基的變異性。
第二部分則是合成氮雜核苷分子，我們結合環狀亞胺以及2,4-雙甲基嘧啶鋰試劑，藉由高選擇性的親核性加成反應來得到很好的β-選擇性產物。值得注意的是，連續式史陶丁格(Staudinger) /氮雜维蒂希(aza-wittig)反應是環狀亞胺的制備中最重要步驟。

Heterocyclyl hybrid azasugars (HHAs) are biologically interesting molecules for the manupulication of various sugar processing enzymes and for the potential therapeutic applications. Because of their wide spectrum of biological activity, the preparation has become a very attractive and important subject. Due to the structural complexity and diversity of HHAs, preparation of HHAs still is a synthetic challenge and has not yet been explored completely. In this study, the research was divided into two parts: (1) design and synthesis of isoxazolyl-/triazolyl- azasugars from chiral cyclic nitrones; (2) synthesis for aza-C-nucleoside–based molecules
In the first part, chiral cyclic nitrones were reacted with vinyl magnesium bromide or lithiated[2-(trimethylsilyl)ethynyl] via a highly diastereoselective nucleophilic addition, followed by proper transformations to give the corresponding intermediates, the protected azasugars bearing an alkyne or oxime moiety. The desired heterocyclic ring such as the isoxazole or triazole ring, was generated by the conjugation of intermediates with various oxime chlorides or azides via 1,3-dipolar cycloaddition. With the assistance of semiautomatic equipments, such as synthesizer, liquid handler, speed-vac , and solid-phase extraction technique, the preparation of the triazole/isoxazole-azasugar hybride-based molecule library becomes convenient and efficient. 70 compound of HHAs have been synthesized, which were categorized into three characteric type: configuration diversity, heterocyclic ring diversity, and substituent diversity
In the second part, the preparation of aza-C-nucleoside-based HHAs was achieved by the conjugation of a chiral cyclic imine with lithiated 2,4-dimethoxypyrimidine via a highly diastereoselective nucleophilic addition with an excellent β-position stereoselectivity. Notably, the chiral cyclic imine was prepared using the tandem Staudinger/aza-Wittig reaction as a key step via an intramolecular cyclization.

Table of Content
摘要.......................................................I
Abstract..................................................II
Acknowledgement...........................................IV
Table of Content..........................................VI
Index of Figures........................................VIII
Index of Schemes...........................................X
Abbreviations.............................................XI
Chapter 1. Introduction....................................1
1.1 Introduction of aryl- and heterocyclyl-azasugars.......1
1.1.1 Mechanism for glycosidases or glycosyltransferases involved processes11.......................................2
1.1.2 Relationship between azasugars and transition state mimics.....................................................4
1.2 Synthesis of aryl-azasugars............................5
1.2.1 D. Correia method for preparaed aryl-azasugars.......5
1.2.2 Synthesis of aryl-azasugar from solution phase combinatorial approach.....................................6
1.3 Synthesis and biological applications of HHAs..........8
1.3.1 Synthesis of the Immucillin from D-gulonolactone.....8
1.3.2 Synthesis of the pseudouridine’s aza-nucleoside analogue...................................................9
1.4 Motivation............................................12
Chapter 2. Results and Discussion.........................13
2.1 Design and synthesis of isoxazolyl-/triazolyl- azasugars from chiral cyclic nitrones...............................13
2.1.1 Strategy of synthesizing azasugars from chiral cyclic nitrones..................................................13
2.1.2 Preparation of chiral tri-O-benzyl cyclic nitrones.14	..........................................................14
2.1.3 Preliminary Model Studies...........................15
2.1.3.1 Preparation of C5’-isoxazolyl azasugars...........15
2.1.3.2 Preparation of 1,2,3-triazolyl azasugars..........19
2.1.3.3 Preparation of C3’-isoxazolyl azasugars...........21
2.1.4 Library design......................................23
2.1.4.1 Library generation................................25
2.2 Synthesis for aza-C-nucleoside–based molecules........30
2.2.1 Synthesis of the 5-bromo-2,4-dimethoxy-pyrimidine...30
2.2.2 Synthesis of C-4-aminouridines from cyclic nitrone..30
2.2.3 New strategy of synthesis of C-4-aminouridines from cyclic imine..............................................31
2.2.4 Development of new synthesis method for cyclic imine 43........................................................33
2.2.4.1 Retrosynthetic analysis...........................33
2.2.4.2 Preparation of cyclic imine 43....................33
2.2.5 Conjugation between cyclic imine and lithiated 2,4-dimethoxy- pyrimidine.....................................37
2.3 Chemical space analysis of the library................38
2.4 Biological evaluation.................................40
2.5 Conclusion............................................44
Chapter 3. Experimental Section...........................45
3.1 General experimental procedure........................45
3.2  Procedures and experimental data.....................46
References................................................81
Appendix..................................................87


Index of Figures
Figure 1.1. Structures of aryl and heterocyclyl-azasugar	...........................................................1
Figure 1.2. Mechanisms of retaining and inverting enzymatic hydrolysis.................................................3
Figure 1.3. The relationship of a sugar with an oxocarbenium TS.........................................................4
Figure 1.4. Aryl-azasugar 3 mimicking the transition state structure for a nucleoside hydrolase.......................4
Figure 2.1. Set of intermediate for the library...........23
Figure 2.2. Set of alkyne 12{1-10} for the library........23
Figure 2.3. Set of azide 22{1-4} for the library..........24
Figure 2.4. Set of oxime chlorides 26{1-7} for the library	..........................................................24
Figure 2.5. General workup procedure for the synthesis of HHAs......................................................25
Figure 2.6. Operation principles for our liquid-liquid extraction................................................26
Figure 2.7. Proposed transition state with the ketone reduction of 51...........................................35
Figure 2.8. Analysis of Lipinski’s “rule of five”.........39
Figure 2.9. Chaperone effect of Library on cellular N370S GC activity at 10 μM.........................................40
Figure 2.10. Chaperone effect of Library on cellular N370S GC activity at 50 μM......................................41
Figure 2.11. Structures of entry 35{10,3}, 35{10,2}, 14{4,1}	..........................................................41
Figure 2.12. Structures of the 27{7,2}, 36{7,2}, 36{7,2}, 27{7,1}...................................................43


Index of Tables
Table 2.1. Model study for the preparation of C5’-isoxazole 11{1}.....................................................16
Table 2.2. Study of the Suzuki coupling reaction of 11{10}	..........................................................18
Table 2.3. Study on debenzylation of 25{1,1}..............22
Table 2.4. Yield and purity of the HHAs library...........27
Table 2.5. Preparation of cyclic imine 43 from cyclic nitrone...................................................32
Table 2.6. Selective reduction of ketone 50...............35
Table 2.7. Preparation of azide 51 from alcohol 50........36
Table 2.8. MICs of the Mycobacterium smegmatis............41


Index of Schemes
Scheme 1.1. Synthesis of aryl-azasugars 9 by Heck reactions	...........................................................5
Scheme 1.2. Preparation of cyclic nitrones 12a and 12b.....6
Scheme 1.3. General synthetic route toward aryl-azasugars	...........................................................7
Scheme 1.4. Preparation of immucillin-H from D-gulonolactone	...........................................................8
Scheme 1.5. Preparation of the aza-C-nucleoside 17 reported by Yokoyama................................................9
Scheme 1.6. Preparation of pseudourindine analogues 28a and 28b.......................................................10
Scheme 2.1. General synthetic route of isoxazolyl-/triazolyl azasugars.................................................13
Scheme 2.2. Preparation of chiral tri-O-benzyl cyclic nitrone 6.................................................14
Scheme 2.3. Preparation of oxime 10 from cyclic nitrone 6	..........................................................15
Scheme 2.4. Diversity improvement of the C5’-isoxazolyl azasugars.................................................17
Scheme 2.5. Preparation of 14{9,1} by hydrogenation.......18
Scheme 2.6. Preparation of 1,2,3-triazolyl azasugars 16a and 16b.......................................................19
Scheme 2.7. Proposed mechanism for the preparation of cyclic nitrones 16a and 16b......................................20
Scheme 2.8. Nitrogen-Oxygen bond cleavage by 15...........20
Scheme 2.9. Preparation of 1,2,3-triazolyl azasugars 24{2,1}...................................................21
Scheme 2.10. Preparation of C3’-isoxazolyl azasugars 25{1,1} from alkyne 21............................................22
Scheme 2.11. Solution-phase combinatorial synthesis of HHAs	..........................................................24
Scheme 2.12. Preparation of the 5-bromo-2,4-dimethoxy-pyrimidine 39.............................................30
Scheme 2.13. Preparation of 42 from cyclic nitrone 41.....30
Scheme 2.14. Retrosynthetic analysis of cyclic imine 43...33
Scheme 2.15. Preparation of alcohol 49 form 2,3,5-tri-O-benzyl-D-ribofuranose 47..................................33
Scheme 2.16. Epimerization of alcohol 49..................34
Scheme 2.17. Preparation of cyclic imine 43 from azide 51	..........................................................37
Scheme 2.18. Preparation of C-4-aminouridines and analogues	..........................................................37

                                    

1. Ribes, C.; Falomir, E.; Murga, J.; Carda, M.; Alberto Marco, J., Convergent, stereoselective syntheses of the glycosidase inhibitors broussonetines D and M. Org. Biomol. Chem. 2009, 7, 1355-1360.
2. Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King, C. H. R.; Liu, P. S., A facile, practical synthesis of 2,6-dideoxy-2,6-imino-7-O-.beta.-D-glucopyranosyl-D-glycero -L-gulo-heptitol (MDL 25,637). J. Org. Chem. 1989, 54, 2539-2542.
3. Mehta, A.; Zitzmann, N.; Rudd, P. M.; Block, T. M.; Dwek, R. A., α-Glucosidase inhibitors as potential broad based anti-viral agents. FEBS lett. 1998, 430, 17-22.
4. Winchester, B. G., Iminosugars: from botanical curiosities to licensed drugs. Tetrahedron: Asymmetry 2009, 20, 645-651.
5. Tsou, E.-L.; Chen, S.-Y.; Yang, M.-H.; Wang, S.-C.; Cheng, T.-R. R.; Cheng, W.-C., Synthesis and biological evaluation of a 2-aryl polyhydroxylated pyrrolidine alkaloid-based library. Bioorg. Med. Chem. 2008, 16, 10198-10204.
6. Shankaraiah, G.; Sateesh Chandra Kumar, R.; Poornima, B.; Babu, K. S., Stereoselective synthesis of (+)-radicamine B. Tetrahedron Lett. 2011, 52, 4885-4887.
7. Just, G.; Donnini, G. P., C-Nucleosides and related compounds. XIV. The synthesis of a nitrogen analogue of showdomycin. Can. J. Chem. 1977, 55, 2998-3006.
8. Roy-Burman, S.; Roy-Burman, P.; Visser, D. W., Showdomycin, a new nucleoside antibiotic. Cancer Research 1968, 28, 1605-1610.
9. (a) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L., Synthesis of transition state inhibitors for N-riboside hydrolases and transferases. Tetrahedron 1997, 53, 2915-2930; (b) Evans, G. B.; Furneaux, R. H.; Hutchison, T. L.; Kezar, H. S.; Morris, P. E.; Schramm, V. L.; Tyler, P. C., Addition of lithiated 9-deazapurine derivatives to a carbohydrate cyclic Imine: Convergent Synthesis of the aza-C-nucleoside immucillins. J. Org. Chem. 2001, 66, 5723-5730; (c) Merino, P.; Tejero, T.; Delso, I., Current Developments in the synthesis and biological activity of aza-C-nucleosides: Immucillins and related compounds. Curr. Med. Chem. 2008, 15, 954-967; (d) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Schramm, V. L.; Tyler, P. C., Synthesis of transition state analogue inhibitors for purine nucleoside phosphorylase and N-riboside hydrolases. Tetrahedron 2000, 56, 3053-3062; (e) Braunheim, B. B.; Miles, R. W.; Schramm, V. L.; Schwartz, S. D., Prediction of inhibitor binding free energies by quantum neural networks. nucleoside analogues binding to trypanosomal nucleoside hydrolase. Biochemistry 1999, 38, 16076-16083.
10. (a) Bzowska, A.; Kulikowska, E.; Shugar, D., Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol. Ther. 2000, 88, 349-425; (b) Wang, F.; Miles, R. W.; Kicska, G.; Nieves, E.; Schramm, V. L.; Angeletti, R. H., Immucillin-H binding to purine nucleoside phosphorylase reduces dynamic solvent exchange. Protein Sci. 2000, 9, 1660-1668.
11. Pearson, M. S. M.; Mathé-Allainmat, M.; Fargeas, V.; Lebreton, J., Recent advances in the total synthesis of piperidine azasugars. Eur. J. Org. Chem. 2005, 2159-2191.
12. Zechel, D. L.; Withers, S. G., Glycosidase mechanisms: anatomy of a finely tuned catalyst. Acc. Chem. Res. 1999, 33, 11-18.
13. Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D., Probing the stereoselectivity of the heck arylation of endocyclic enecarbamates with diazonium salts. concise syntheses of (2S,5R)-phenylproline methyl ester and Schramm's C-azanucleoside. Org. Lett. 2003, 5, 305-308.
14. Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C., A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP. Tetrahedron 2009, 65, 93-100.
15. Evans, G. B., The synthesis of N-ribosyl transferase inhibitors based on a transition state blueprint. Aust. J. Chem. 2004, 57, 837-854.
16. (a) Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Yokoyama, M., synthesis and properties of C-azalyxonucleosides. J. Org. Chem. 1998, 63, 7207-7212; (b) Yokoyama, M.; Ikenogami, T.; Togo, H., Stereoselective synthesis of C-4’-aminouridines (uracil C-4-amino-D-ribonucleosides). J. Chem. Soc. Perkin Trans 1. 2000, 13, 2067-2071.
17. Grohar, P. J.; Chow, C. S., A practical synthesis of the modified RNA nucleoside pseudouridine. Tetrahedron Lett. 1999, 40, 2049-2052.
18. (a) Bookser, B. C.; Zhu, S., Solid phase extraction purification of carboxylic acid products from 96-well format solution phase synthesis with DOWEX 1×8-400 formate anion exchange resin. J. Comb. Chem. 2001, 3, 205-215; (b) Shih, H.-W.; Guo, C.-W.; Lo, K.-H.; Huang, M.-Y.; Cheng, W.-C., Solution-phase parallel synthesis of novel spirooxazolinoisoxazolines. J. Comb. Chem. 2009, 11, 281-287; (c) Boger, D. L.; Desharnais, J.; Capps, K., Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein–protein or protein–DNA interactions. Angew. Chem. Int. Ed. 2003, 42, 4138-4176.
19. Delso, I.; Marca, E.; Mannucci, V.; Tejero, T.; Goti, A.; Merino, P., Tunable diastereoselection of biased rigid systems by lewis acid induced conformational effects: a rationalization of the vinylation of cyclic nitrones en route to polyhydroxylated pyrrolidines. Chem. Eur. J. 2010, 16, 9910-9919.
20. Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Franco, F.; Sánchez-Cantalejo, F., Total synthesis of natural (+)-hyacinthacine A6 and non-natural (+)-7a-epi-hyacinthacine A1 and (+)-5,7a-diepi-hyacinthacine A6. Tetrahedron 2010, 66, 3788-3794.
21. Padwa, A.; Pearson, W. H.; Editors, Synthetic applications of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products. [In: Chem. Heterocycl. Comp. (Chichester, U. K.), 2002; 59]. Wiley: 2002; p 940 pp.
22. Desvergnes, S.; Desvergnes, V.; Martin, O. R.; Itoh, K.; Liu, H.-w.; Py, S., Stereoselective synthesis of β-1-C-substituted 1,4-dideoxy-1,4-imino-d-galactitols and evaluation as UDP-galactopyranose mutase inhibitors. Bioorg. Med. Chem. 2007, 15, 6443-6449.
23. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L., Catalysts for Suzuki−Miyaura coupling processes: scope and studies of the effect of ligand structure. J. Am. Chem. Soc. 2005, 127, 4685-4696.
24. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596-2599.
25. Shibata, T.; Uemae, K.; Yamamoto, Y., Highly stereoselective synthesis of C2-chiral and meso nitroxides from an optically active pyrrolidine. Tetrahedron:Asymmetry 2000, 11, 2339-2346.
26. (a) Roy, B.; Pérez-Luna, A.; Ferreira, F.; Botuha, C.; Chemla, F., Addition of a 3-alkoxy allenylzinc to N-acyliminium ions: new entry to propargyl syn-1,2-aminoalcohol units. Tetrahedron Lett. 2008, 49, 1534-1537; (b) Alexakis, A.; Croset, K., Tandem copper-catalyzed enantioselective allylation−metathesis. Org. Lett. 2003, 5, 4239-4239.
27. (a) Lee, C. K. Y.; Easton, C. J.; Gebara-Coghlan, M.; Radom, L.; Scott, A. P.; Simpson, G. W.; Willis, A. C., Substituent effects in isoxazoles: identification of 4-substituted isoxazoles as Michael acceptors. J. Chem. Soc. Perkin Trans 2. 2002, 12, 2031-2038; (b) Akhrem, A.; Lakhvich, F.; Khripach, V., Isoxazole derivatives in the synthesis of bifunctional compounds by cleavage of the heteroring (review). Chem. Heterocycl. Compd. 1981, 17, 853-868; (c) Saxena, R.; Singh, V.; Batra, S., Studies on the catalytic hydrogenation of Baylis–Hillman derivatives of substituted isoxazolecarbaldehydes. Unusual retention of isoxazole ring during Pd–C-promoted hydrogenation of Baylis–Hillman adducts. Tetrahedron 2004, 60, 10311-10320.
28. Mukherjee, S.; Ghorai, B. K., Metallation of 2,4-Dialkoxy-5-bromopyrimidine and f ormylation with dimethylformamide: Isolation of 2,6-Dialkoxy-5-dimethylamino- pyrimidine-4-carboxaldehyde. Synth. Commun. 2010, 40, 1939-1943.
29. Koszytkowska-Stawińska, M.; Mironiuk-Puchalska, E.; Sas, W., Synthesis of 1-pyrroline 1-oxides analogous to pseudouridine. Tetrahedron Lett. 2011, 52, 1866-1870.
30. Cividino, P.; Dheu-Andries, M.-L.; Ou, J.; Milet, A.; Py, S.; Toy, P. H., Mechanistic investigations of the phosphine-mediated nitrone deoxygenation reaction and its application in cyclic imine synthesis. Tetrahedron Lett. 2009, 50, 7038-7042.
31. (a) Ilias, M.; Barman, D. C.; Prajapati, D.; Sandhu, J. S., An indium mediated efficient chemoselective deoxygenation of N-oxides and nitrones. Tetrahedron Lett. 2002, 43, 1877-1879; (b) Balicki, R., TiCl4/NaI - A novel, efficient reagent for mild reduction of the N-O bond in amine N-oxides and nitrones. Chem. Ber. 1990, 123, 647-648.
32. Li, Y.; Zhou, Y.; Ma, Y.; Li, X., Design and synthesis of novel cell wall inhibitors of Mycobacterium tuberculosis GlmM and GlmU. Carbohydr. Res. 2011, 346, 1714-1720.
33. (a) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J. M., The aza-Wittig reaction: an efficient tool for the construction of carbon–nitrogen double bonds. Tetrahedron 2007, 63, 523-575; (b) Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P., Synthesis of enantiopure 1,2-didehydropyrrolidine, D-proline, and oxazoline derivatives via Staudinger-aza-Wittig cyclization of γ-azido aldehydes. Synthesis 1996, 1, 123-132; (c) Cossío, F. P.; Alonso, C.; Lecea, B.; Ayerbe, M.; Rubiales, G.; Palacios, F., Mechanism and stereoselectivity of the aza-Wittig reaction between phosphazenes and aldehydes. J. Org. Chem. 2006, 71, 2839-2847.

校內：2017-09-06公開
校外：2017-09-06公開

簡易檢索 / 詳目顯示

相關論文