簡易檢索 / 詳目顯示

回結果列表
研究生： 納堤士
Verma, Nitish
論文名稱： 利用硫醣苷及噁唑啉醣予體合成含有Gal β1→3 GlcNAc重覆單位之寡醣
Synthesis of Galβ1→3GlcNAc Repeating Oligosaccharides by Using Thioglycoside and Oxazoline Donors
指導教授： 林俊宏
Lin, Chun-Hung
林俊成
Lin, Chun-Cheng
口試委員: 蒙國光
Mong, Kwok Kong
王正中
Wang, Cheng-Chung
梁健夫
Liang, Chien-Fu
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 321
中文關鍵詞： 寡糖
外文關鍵詞： Oligosaccharide synthesis
相關次數： 點閱：1  下載：0 
分享至:
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

    • 第一型N-乙醯乳醣胺(Galβ1→3GlcNAc)的寡醣合成是一個繁瑣且充滿挑戰性的工作。而本論文主要闡述如何通過系統性的研究以及利用化學選擇性醣基化反應，並找出對第一型N-乙醯乳醣胺(Galβ1→3GlcNAc)寡醣最有效率的合成方式。首先，我們利用對十六個含有硫代甲苯基的醣受體與醣予體所測得的RRV（相對反應值），來獲得其化學選擇性醣基化反應的最佳條件。從這些反應中，我們發現當醣予體與醣受體的RRV差值必須大於6311，才能在醣苷配基轉移(aglycon transfer)最小程度的情況下，以72-86％的產率獲得第一型N-乙醯乳醣胺四醣。而此RRV的差異閾值也在更長的寡醣合成上扮演重要的角色。但由於量測四醣的RRV難度甚高，因此我們利用1號氫的氫譜化學位移來預測其RRV大小，從而解釋了合成第一型N-乙醯乳醣六醣的結果。此結果也進一步支持了聚醣鏈的延伸必須從還原端開始進行到非還原端，才能獲得較高產率的想法。
    在本論文的第二章中，描述了如何利用醣予體所產生的副產物—噁唑啉來作為新的醣予體，並有效地合成第一型N-乙醯乳醣胺寡醣。首先，我們使用經由優化過的條件合成出第一型N-乙醯乳醣胺雙醣噁唑啉。接著，我們針對噁唑啉為醣予體時的醣基化反應來篩選出最佳的酸性活化試劑。然而，為了有效避免醣苷配基轉移的現象發生，我們開發了一個全新的雙二苄醚保護的三氯噁唑啉雙醣醣予體，並用它來和具有硫苷的第一型N-乙醯乳醣胺雙醣醣受體進行醣基化反應。此外，通過對溫度以及活化試劑當量的調控，我們利用此優化過的反應條件成功進行[4 + 2]的醣基化反應，並成功得到第一型N-乙醯乳醣胺六醣，產率為77%。此硫苷六醣也更進一步以67%的產率活化為六醣噁唑啉，並最終以一鍋化的方式，合成出第一型N-乙醯乳醣胺六醣以及八醣化合物。

    Synthesis of type I LacNAc (Galβ1→3GlcNAc) oligosaccharides is often tedious and challenging. Chapter 2 of this thesis details the systematic studies for efficient synthesis of type I LacNAc oligosaccharides by chemoselective glycosylation. The RRVs (relative reactivity values) of sixteen thiotoluenyl-linked disaccharide donors and acceptors were measured, and chemoselective glycosylations were investigated to achieve optimal conditions. In these reactions, the RRV difference between donor and acceptor had to be more than 6311 to obtain type I LacNAc tetrasaccharides in 72%-86% yields, with minimal occurrence of aglycon transfer. The threshold of RRV difference was further applied to synthesize longer glycans. Because it is challenging to measure the RRVs of tetrasaccharides, the chemical shifts of anomeric proton were utilized to predict the corresponding RRVs, which consequently explained the outcome of glycosylations for synthesis of type I LacNAc hexasaccharides. The results support the hypothesis that the elongation of a glycan chain has to proceed from the reducing to non-reducing end.
    Interestingly, in chapter 3, formation of oxazoline as donor side product laid the foundation for efficient synthesis of type I oligosaccharides by using oxazoline as a donor. First, reactive type I LacNAc disaccharide oxazoline was synthesized by using an optimized activation condition. This was followed by screening of various acid promoters for activation of oxazoline donors. Novel reactive di-OBn protected trichloro oxazoline donor was discovered, which was demonstrated to be useful to prevent aglycon transfer during glycosylation with thioglycoside type I LacNAc disaccharide acceptors in an unprecedented manner. The activation conditions were then optimized by adjusting the activation temperature and amount of the promoter for preparation of tetrasaccharide oxazoline donor, which was successfully applied for [4 + 2] glycosylation with thioglycoside disaccharide acceptor to afford the type I LacNAc thioglycoside hexasaccharide in 77% yield. The synthesized thioglycoside hexasaccharide was further activated to hexasaccharide oxazoline in an acceptable yield (67%). Finally, one-pot glycosylation was performed for the synthesis of type I LacNAc hexa- and octasaccharides by using reactive oxazoline donor.

    Table of Contents 摘要 i Abstract ii Acknowledgments iv List of Abbreviations vi List of Figures xix List of Schemes xx List of Tables xxv Chapter 1. Introduction 1 1.1. General Introduction of Carbohydrates 1 1.2. Tumor Associated Carbohydrate Antigens (TACA’s) 2 1.3. Enzymatic Approaches to Synthesize Type I Repeating Oligomers 5 1.4. Chemical Synthesis and Challenges 7 1.5 Aglycon Transfer 9 1.6. Concept of Relative Reactivity Value (RRV) 11 1.7. Synthesis of LacNAc Related Oligosaccharides 16 1.8. Methods to Prevent Aglycon Transfer 24 1.9. Oxazoline Formation as Donor Side Product 27 1.10. Reported Methods to Synthesize Oxazoline 29 1.11. Research Goal of Thesis 37 Chapter 2. 40 Threshold of Thioglycoside Reactivity Difference Is Critical for Efficient Synthesis of Type I Oligosaccharides by Chemoselective Glycosylation 40 2.1. Synthesis of Type I LacNAc Thioglycoside Disaccharide Donors and Acceptors 41 2.2. Determination of RRVs of Type I LacNAc Thioglycoside Disaccharides 44 2.3. [2 + 2] Chemoselective Glycosylations Between Type I LacNAc Disaccharide Donors and Acceptors 47 2.4. Correlation Between Obtained Yield of Tetrasaccharide and ln(RRV Difference) 52 2.5. Correlation Between Obtained Yield of Tetrasaccharide and Estimated ln(RRV Difference) 53 2.6. Synthesis of Type I LacNAc Hexasaccharides by Chemoselective Glycosylations 56 2.7. Correlation Between RRV vs. H-1 Chemical Shift of Type I LacNAc Thioglycoside Disaccharides 58 2.8. Synthesis of Type I LacNAc Hexa- and Octasaccharides by Using Anomeric-OTBS Protected Acceptors 61 2.9. Conclusions 64 Chapter 3. 65 Preventing Aglycon Transfer by Reactive Oxazoline Donor for Efficient Synthesis of Type I Oligosaccharides 65 3.1. Synthesis of Type I LacNAc Disaccharide Oxazoline 66 3.2. Glycosylation of Type I LacNAc Disaccharide Oxazoline Donors with Cyclohexanol 67 3.3. [2 + 2] Glycosylations of Type I LacNAc Disaccharide Oxazoline Donors with Thioglycoside Disaccharide Acceptors 71 3.4. Synthesis of Type I LacNAc Tetrasaccharide Oxazoline 76 3.5. Synthesis of Type I LacNAc Hexasaccharide by Using Tetrasaccharide Oxazoline Donor Through [4 + 2] Glycosylation 78 3.6. Synthesis of Type I LacNAc Hexasaccharide Oxazoline 82 3.7. One-Pot Synthesis of Type I LacNAc Hexa- and Octasaccharides 84 3.8. Conclusions 85 4. Conclusions and Perspective 86 4.1. Conclusions 86 4.2. Future Direction 90 4.2.1. Discussion for Replacement of Nap-Protecting Group 90 4.2.2. Remaining Challenge in Using Oxazoline Donor 90 Chapter 5. Materials and Methods 92 5.1. General Experimental Procedure 92 5.2. General Procedure to Determine RRVs of Thioglycoside Disaccharides (Tables 2.1 and 2.2 in Chapter 2) 93 5.3. General Procedure for [2 + 2] Glycosylations in Table 2.3 in Chapter 2 94 5.4. General Procedure to Synthesize Di- (33) and Tetrasaccharide (45) Oxazoline Donors by Ph2SO/Tf2O Method (Entries 1-3, Table 3.1; and Entry 1, Table 3.5 in Chapter 3) 94 5.5. General Procedure to Synthesize Di- (33), Tetra- (45), and Hexasaccharide (47) Oxazoline Donors by NIS/TMSOTf Method (Entry 4, Table 3.1; Entries 2-9, Table 3.5; and Entries 1-3, Table 3.6 in Chapter 3). 95 5.6. General Procedure for Glycosylation of Disaccharide Oxazoline 33 with Cyclohexanol by Using Different Promoters (Entries 1-12, Table 3.2 in Chapter 3) 95 5.7. General Procedure for Glycosylation of Disaccharide Oxazoline 42 with Cyclohexanol by Using Different Promoters (Entries 13-19, Table 3.2 in Chapter 3) 96 5.8. General Procedure for [2 + 2] Glycosylations Between Disaccharide Oxazoline Donor 33 and Thioglycoside Acceptors (10, 11, and 13) (Table 3.3) 96 5.9. Reaction Procedures of [2 + 2] Glycosylations Between Disaccharide Oxazoline Donor 33 and Thioglycoside Acceptor 10 in Table 3.4 97 5.10. Synthetic Procedures 99 References 184 Publication 193 Appendix: NMR Spectra 194 1H NMR spectrum of compound DI-1 195 13C NMR spectrum of compound DI-1 196 1H NMR spectrum of compound DI-2 197 13C NMR spectrum of compound DI-2 198 1H NMR spectrum of compound 1 199 13C NMR spectrum of compound 1 200 1H NMR spectrum of compound 2 201 13C NMR spectrum of compound 2 202 1H NMR spectrum of compound 3 203 13C NMR spectrum of compound 3 204 1H NMR spectrum of compound 4 205 13C NMR spectrum of compound 4 206 1H NMR spectrum of compound 5 207 13C NMR spectrum of compound 5 208 1H NMR spectrum of compound 6 209 13C NMR spectrum of compound 6 210 1H NMR spectrum of compound 7 211 13C NMR spectrum of compound 7 212 1H NMR spectrum of compound 8 213 13C NMR spectrum of compound 8 214 1H NMR spectrum of compound 9 215 13C NMR spectrum of compound 9 216 1H NMR spectrum of compound 10 217 13C NMR spectrum of compound 10 218 1H NMR spectrum of compound 11 219 13C NMR spectrum of compound 11 220 1H NMR spectrum of compound 12 221 13C NMR spectrum of compound 12 222 1H NMR spectrum of compound 13 223 13C NMR spectrum of compound 13 224 1H NMR spectrum of compound 14 225 13C NMR spectrum of compound 14 226 1H NMR spectrum of compound 15 227 13C NMR spectrum of compound 15 228 1H NMR spectrum of compound 16 229 13C NMR spectrum of compound 16 230 1H NMR spectrum of compound 17 231 13C NMR spectrum of compound 17 232 1H NMR spectrum of compound 18 233 13C NMR spectrum of compound 18 234 1H NMR spectrum of compound 19 235 13C NMR spectrum of compound 19 236 1H NMR spectrum of compound 20 237 13C NMR spectrum of compound 20 238 1H NMR spectrum of compound 21 239 13C NMR spectrum of compound 21 240 1H NMR spectrum of compound 22 241 13C NMR spectrum of compound 22 242 1H NMR spectrum of compound 22a 243 13C NMR spectrum of compound 22a 244 1H NMR spectrum of compound 23 245 13C NMR spectrum of compound 23 246 1H NMR spectrum of compound 24 247 13C NMR spectrum of compound 24 248 1H NMR spectrum of compound 25 249 13C NMR spectrum of compound 25 250 1H NMR spectrum of compound 26 251 13C NMR spectrum of compound 26 252 1H NMR spectrum of compound 27 253 13C NMR spectra of compound 27 254 1D-Selective TOCSY NMR spectra of compound 27 255 1H-1H 2D COSY NMR spectrum of compound 27 256 1H-1H 2D COSY NMR spectrum of compound 27 257 1H-13C 2D HMQC NMR spectrum of compound 27 258 1H-13C 2D HMBC NMR spectrum of compound 27 259 1H NMR spectrum of compound 28 260 13C NMR spectrum of compound 28 261 1H NMR spectrum of compound 29 262 13C NMR spectrum of compound 29 263 1H NMR spectrum of compound 30 264 13C NMR spectrum of compound 30 265 1H NMR spectrum of compound 31 266 13C NMR spectrum of compound 31 267 1H NMR spectrum of compound 32 268 13C NMR spectrum of compound 32 269 13C DEPT NMR spectra of compound 32 270 1D-Selective TOCSY NMR spectrum of compound 32 271 1D-Selective TOCSY NMR spectrum of compound 32 272 1H-1H 2D COSY NMR spectrum of compound 32 273 1H-1H 2D COSY NMR spectrum of compound 32 274 1H-1H 2D COSY NMR spectrum of compound 32 275 1H-13C 2D HMQC NMR spectrum of compound 32 276 1H-13C 2D HMQC NMR spectrum of compound 32 277 1H-13C 2D HMBC NMR spectrum of compound 32. 278 1H NMR spectrum of compound 33 281 13C NMR spectrum of compound 33 282 1H NMR spectrum of compound 33a 283 13C NMR spectrum of compound 33a 284 1H NMR spectrum of compound 34 285 13C NMR spectrum of compound 34 286 1H NMR spectrum of compound 34a 287 13C NMR spectrum of compound 34a 288 1H NMR spectrum of compound 36 289 13C NMR spectrum of compound 36 290 1H-1H 2D COSY NMR spectrum of compound 36 291 1H-13C 2D HMQC NMR spectrum of compound 36 292 1H-13C 2D HMBC NMR spectrum of compound 36 293 1H NMR spectrum of compound 38 294 13C NMR spectrum of compound 38 295 1H NMR spectrum of compound 39 296 13C NMR spectrum of compound 39 297 1H-1H 2D COSY NMR spectrum of compound 39 298 1H-13C 2D HMQC NMR spectrum of compound 39 299 1H-13C 2D HMBC NMR spectrum of compound 39 300 1H NMR spectrum of compound 40 301 13C NMR spectrum of compound 40 302 1H NMR spectrum of compound 41 303 13C NMR spectrum of compound 41 304 1H-1H 2D COSY NMR spectrum of compound 41 305 1H-13C 2D HMQC NMR spectrum of compound 41 306 1H-13C 2D HMBC NMR spectrum of compound 41 307 1H NMR spectrum of compound 42 308 13C NMR spectrum of compound 42 309 1H NMR spectrum of compound 43 310 13C NMR spectrum of compound 43 311 1H NMR spectrum of compound 44 312 13C NMR spectrum of compound 44 313 1H NMR spectrum of compound 45 314 13C NMR spectrum of compound 45 315 1H NMR spectrum of compound 46 316 13C NMR spectrum of compound 46 317 1H NMR spectrum of compound 47 318 13C NMR spectrum of compound 47 319 1H NMR spectrum of compound 48 320 13C NMR spectrum of compound 48 321

    1. Astronomo, R. D.; Burton, D. R., Carbohydrate vaccines: developing sweet solutions to sticky situations? Nat. Rev. Drug Discov. 2010, 9 (4), 308-324.
    2. Dube, D. H.; Bertozzi, C. R., Glycans in cancer and inflammation — potential for therapeutics and diagnostics. Nat. Rev. Drug Discov. 2005, 4 (6), 477-488.
    3. Gilewski, T.; Ragupathi, G.; Bhuta, S.; Williams, L. J.; Musselli, C.; Zhang, X.-F.; Bornmann, W. G.; Spassova, M.; Bencsath, K. P.; Panageas, K. S.; Chin, J.; Hudis, C. A.; Norton, L.; Houghton, A. N.; Livingston, P. O.; Danishefsky, S. J., Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: a phase I trial. Proc. Natl. Acad. Sci. U.S.A. 2001, 98 (6), 3270-3275.
    4. Stroud, M. R.; Levery, S. B.; Nudelman, E. D.; Salyan, M. E.; Towell, J. A.; Roberts, C. E.; Watanabe, M.; Hakomori, S., Extended type 1 chain glycosphingolipids: dimeric Lea (III4V4Fuc2Lc6) as human tumor-associated antigen. J. Biol. Chem. 1991, 266 (13), 8439-8446.
    5. Kawasaki, N.; Lin, C.-W.; Inoue, R.; Khoo, K.-H.; Kawasaki, N.; Ma, B. Y.; Oka, S.; Ishiguro, M.; Sawada, T.; Ishida, H.; Hashimoto, T.; Kawasaki, T., Highly fucosylated N-glycan ligands for mannan-binding protein expressed specifically on CD26 (DPPVI) isolated from a human colorectal carcinoma cell line, SW1116. Glycobiology 2009, 19 (4), 437-450.
    6. Park, S. Y.; Yoon, S. J.; Hakomori, S. I.; Kim, J. M.; Kim, J. Y.; Bernert, B.; Ullman, T.; Itzkowitz, S. H.; Kim, J. H., Dimeric Le(a) (Le(a)-on-Le(a)) status of beta-haptoglobin in sera of colon cancer, chronic inflammatory disease and normal subjects. Int. J. Oncol. 2010, 36 (5), 1291-1297.
    7. Kawasaki, N.; Kawasaki, T., Recognition of endogenous ligands by C-type lectins: interaction of serum mannan-binding protein with tumor-associated oligosaccharide epitopes. Trends Glycosci. Glycotechnol. 2010, 22 (125), 141-151.
    8. Fischoder, T.; Laaf, D.; Dey, C.; Elling, L., Enzymatic synthesis of N-acetyllactosamine (LacNAc) type 1 oligomers and characterization as multivalent galectin ligands. Molecules 2017, 22 (8).
    9. Markowska, A. I.; Liu, F.-T.; Panjwani, N., Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J. Exp. Med. 2010, 207 (9), 1981-1993.
    10. Elola, María T.; Blidner, Ada G.; Ferragut, F.; Bracalente, C.; Rabinovich, Gabriel A., Assembly, organization and regulation of cell-surface receptors by lectin–glycan complexes. Biochem. J. 2015, 469 (1), 1-16.
    11. Dumic, J.; Dabelic, S.; Flögel, M., Galectin-3: An open-ended story. Biochimica et Biophysica Acta - General Subjects 2006, 1760 (4), 616-635.
    12. Guévremont, M.; Martel-Pelletier, J.; Boileau, C.; Liu, F. T.; Richard, M.; Fernandes, J. C.; Pelletier, J. P.; Reboul, P., Galectin-3 surface expression on human adult chondrocytes: a potential substrate for collagenase-3. Ann. Rheum. Dis. 2004, 63 (6), 636.
    13. Ochieng, J.; Green, B.; Evans, S.; James, O.; Warfield, P., Modulation of the biological functions of galectin-3 by matrix metalloproteinases. Biochimica et Biophysica Acta - General Subjects 1998, 1379 (1), 97-106.
    14. John, C. M.; Leffler, H.; Kahl-Knutsson, B.; Svensson, I.; Jarvis, G. A., Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer. Clin. Cancer. Res. 2003, 9 (6), 2374-2383.
    15. Bandara, M. D.; Stine, K. J.; Demchenko, A. V., Chemical synthesis of human milk oligosaccharides: lacto-N-hexaose Galβ1→3GlcNAcβ1→3 [Galβ1→4GlcNAcβ1→6] Galβ1→4Glc. J. Org. Chem. 2019, 84 (24), 16192-16198.
    16. Henze, M.; Schmidtke, S.; Hoffmann, N.; Steffens, H.; Pietruszka, J.; Elling, L., Combination of glycosyltransferases and a glycosynthase in sequential and one-pot reactions for the synthesis of type 1 and type 2 N-acetyllactosamine oligomers. ChemCatChem 2015, 7 (19), 3131-3139.
    17. Tu, Z.; Hsieh, H.-W.; Tsai, C.-M.; Hsu, C.-W.; Wang, S.-G.; Wu, K.-J.; Lin, K.-I.; Lin, C.-H., Synthesis and characterization of sulfated Gal-beta-1,3/4-GlcNAc disaccharides through consecutive protection/glycosylation steps. Chem. Asian. J. 2013, 8 (7), 1536-1550.
    18. Arboe Jennum, C.; Hauch Fenger, T.; Bruun, L. M.; Madsen, R., One-pot glycosylations in the synthesis of human milk oligosaccharides. Eur. J. Org. Chem. 2014, 2014 (15), 3232-3241.
    19. Santra, A.; Yu, H.; Tasnima, N.; Muthana, M. M.; Li, Y.; Zeng, J.; Kenyond, N. J.; Louie, A. Y.; Chen, X., Systematic chemoenzymatic synthesis of O-sulfated sialyl lewis x antigens. Chem. Sci. 2016, 7 (4), 2827-2831.
    20. Mukherjee, C.; Liu, L.; Pohl, N. L., Regioselective benzylation of 2-deoxy-2-aminosugars using crown ethers: application to a shortened synthesis of hyaluronic acid oligomers. Adv. Synth. Catal. 2014, 356 (10), 2247-2256.
    21. Kobayashi, D.; Ueki, A.; Yamaji, T.; Nagao, K.; Imamura, A.; Ando, H.; Kiso, M.; Ishida, H., Efficient synthesis of the lewis a tandem repeat. Molecules 2016, 21 (5).
    22. Tu, Z.; Liu, P.-K.; Wu, M.-C.; Lin, C.-H., Expeditious synthesis of orthogonally protected saccharides through consecutive protection/glycosylation Steps. Isr. J. Chem. 2015, 55 (3‐4), 325-335.
    23. Li, Z.; Gildersleeve, J. C., Mechanistic studies and methods to prevent aglycon transfer of thioglycosides. J. Am. Chem. Soc. 2006, 128 (35), 11612-11619.
    24. Dinkelaar, J.; Codee, J. D.; van den Bos, L. J.; Overkleeft, H. S.; van der Marel, G. A., Synthesis of hyaluronic acid oligomers using Ph2SO/Tf2O-mediated glycosylations. J. Org. Chem. 2007, 72 (15), 5737-5742.
    25. Lu, X.; Kamat, M. N.; Huang, L.; Huang, X., Chemical synthesis of a hyaluronic acid decasaccharide. J. Org. Chem. 2009, 74 (20), 7608-7617.
    26. Lu, X.; Kovac, P., Chemical synthesis of the galacturonic acid containing pentasaccharide antigen of the O-specific polysaccharide of vibrio cholerae O139 and its five fragments. J. Org. Chem. 2016, 81 (15), 6374-6394.
    27. Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H., Programmable one-pot oligosaccharide synthesis. J. Am. Chem. Soc. 1999, 121 (4), 734-753.
    28. Huang, L.; Wang, Z.; Huang, X., One-pot oligosaccharide synthesis: reactivity tuning by post-synthetic modification of aglycon. Chem. Commun. 2004, (17), 1960-1961.
    29. Chang, C.-W.; Wu, C.-H.; Lin, M.-H.; Liao, P.-H.; Chang, C.-C.; Chuang, H.-H.; Lin, S.-C.; Lam, S.; Verma, V. P.; Hsu, C.-P.; Wang, C.-C., Establishment of guidelines for the control of glycosylation reactions and intermediates by quantitative assessment of reactivity. Angew. Chem. Int. Ed. 2019, 58 (47), 16775-16779.
    30. Mong, T. K.; Huang, C.-Y.; Wong, C.-H., A new reactivity-based one-pot synthesis of N-acetyllactosamine oligomers. J. Org. Chem. 2003, 68 (6), 2135-2142.
    31. Ting, C.-Y.; Lin, Y.-W.; Wu, C.-Y.; Wong, C.-H., Design of disaccharide modules for a programmable one-pot synthesis of building blocks with LacNAc repeating units for asymmetric N-glycans. Asian J. Org. Chem. 2017, 6 (12), 1800-1807.
    32. Li, Q.; Guo, Z., Synthesis of the cancer-associated KH-1 antigen by block assembly of its backbone structure followed by one-step grafting of three fucose residues. Org. Lett. 2017, 19 (24), 6558-6561.
    33. Huang, X.; Huang, L.; Wang, H.; Ye, X.-S., Iterative one-pot synthesis of oligosaccharides. Angew. Chem. Int. Ed. 2004, 43 (39), 5221-5224.
    34. Hsu, Y.; Lu, X.-A.; Zulueta, M. M. L.; Tsai, C.-M.; Lin, K.-I.; Hung, S.-C.; Wong, C.-H., Acyl and silyl group effects in reactivity-based one-pot glycosylation: synthesis of embryonic stem cell surface carbohydrates Lc4 and IV2Fuc-Lc4. J. Am. Chem. Soc. 2012, 134 (10), 4549-4552.
    35. Bandara, M. D.; Stine, K. J.; Demchenko, A. V., The chemical synthesis of human milk oligosaccharides: lacto-N-tetraose (Galβ1→3GlcNAcβ1→3Galβ1→4Glc). Carbohydr. Res. 2019, 486, 107824.
    36. Crich, D.; Jayalath, P., 2-O-Propargyl ethers: readily cleavable, minimally intrusive protecting groups for β-mannosyl donors. Org. Lett. 2005, 7 (11), 2277-2280.
    37. Cheshev, P. E.; Kononov, L. O.; Tsvetkov, Y. E.; Shashkov, A. S.; Nifantiev, N. E., Syntheses of α- and β-glycosyl donors with a disaccharide β-D-Gal-(1→3)-D-GalNAc backbone. Russ. J. Bioorg. Chem. 2002, 28 (5), 419-429.
    38. Geurtsen, R.; Boons, G.-J., Chemoselective glycosylations of sterically hindered glycosyl acceptors. Tetrahedron Lett. 2002, 43 (51), 9429-9431.
    39. Yu, F.; Nguyen, H. M., Studies on the selectivity between nickel-catalyzed 1,2-cis-2-amino glycosylation of hydroxyl groups of thioglycoside acceptors with C2-substituted benzylidene N-phenyl trifluoroacetimidates and intermolecular aglycon transfer of the sulfide group. J. Org. Chem. 2012, 77 (17), 7330-7343.
    40. Peng, P.; Xiong, D.-C.; Ye, X.-S., ortho-Methylphenylthioglycosides as glycosyl building blocks for preactivation-based oligosaccharide synthesis. Carbohydr. Res. 2014, 384, 1-8.
    41. Nakabayashi, S.; Warren, C. D.; Jeanloz, R. W., A new procedure for the preparation of oligosaccharide oxazolines. Carbohydr. Res. 1986, 150, C7-10.
    42. Colon, M.; Staveski, M. M.; Davis, J. T., Mild conditions for the preparation of high-mannose oligosaccharide oxazolines: entry point for β-glycoside and neoglycoprotein syntheses. Tetrahedron Lett. 1991, 32 (35), 4447-4450.
    43. Blatter, G.; Beau, J. M.; Jacquinet, J. C., The use of 2-deoxy-2-trichloroacetamido-D-glucopyranose derivatives in syntheses of oligosaccharides. Carbohydr. Res. 1994, 260 (2), 189-202.
    44. Shrader, W. D.; Imperiali, B., Synthesis of the glucoallosamidin pseudo-disaccharide: use of an efficient Hg(II) mediated cyclization. Tetrahedron Lett. 1996, 37 (5), 599-602.
    45. Donohoe, T. J.; Logan, J. G.; Laffan, D. D., Trichloro-oxazolines as activated donors for aminosugar coupling. Org. Lett. 2003, 5 (26), 4995-4998.
    46. Despras, G.; Alix, A.; Urban, D.; Vauzeilles, B.; Beau, J. M., From chitin to bioactive chitooligosaccharides and conjugates: access to lipochitooligosaccharides and the TMG-chitotriomycin. Angew. Chem. Int. Ed. 2014, 53 (44), 11912-11916.
    47. Fujita, M.; Shoda, S.-i.; Haneda, K.; Inazu, T.; Takegawa, K.; Yamamoto, K., A novel disaccharide substrate having 1,2-oxazoline moiety for detection of transglycosylating activity of endoglycosidases. Biochimica et Biophysica Acta - General Subjects 2001, 1528 (1), 9-14.
    48. Noguchi, M.; Tanaka, T.; Gyakushi, H.; Kobayashi, A.; Shoda, S.-I., Efficient synthesis of sugar oxazolines from unprotected N-acetyl-2-amino sugars by using chloroformamidinium reagent in water. J. Org. Chem. 2009, 74 (5), 2210-2212.
    49. Li, H.; Li, B.; Song, H.; Breydo, L.; Baskakov, I. V.; Wang, L.-X., Chemoenzymatic synthesis of HIV-1 V3 glycopeptides carrying two N-glycans and effects of glycosylation on the peptide domain. J. Org. Chem. 2005, 70 (24), 9990-9996.
    50. Huang, W.; Li, C.; Li, B.; Umekawa, M.; Yamamoto, K.; Zhang, X.; Wang, L.-X., Glycosynthases enable a highly efficient chemoenzymatic synthesis of N-glycoproteins carrying intact natural N-glycans. J. Am. Chem. Soc. 2009, 131 (6), 2214-2223.
    51. McIntosh, J. D.; Brimble, M. A.; Brooks, A. E. S.; Dunbar, P. R.; Kowalczyk, R.; Tomabechi, Y.; Fairbanks, A. J., Convergent chemo-enzymatic synthesis of mannosylated glycopeptides; targeting of putative vaccine candidates to antigen presenting cells. Chem. Sci. 2015, 6 (8), 4636-4642.
    52. Fairbanks, A. J., The ENGases: versatile biocatalysts for the production of homogeneous N-linked glycopeptides and glycoproteins. Chem. Soc. Rev. 2017, 46 (16), 5128-5146.
    53. Fairbanks, A. J., Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines. Beilstein J. Org. Chem. 2018, 14, 416-429.
    54. Crich, D.; Cai, W., Chemistry of 4,6-O-benzylidene-d-glycopyranosyl triflates: contrasting behavior between the gluco and manno series. J. Org. Chem. 1999, 64 (13), 4926-4930.
    55. Burkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C.-H., Synthesis of the globo H hexasaccharide using the programmable reactivity-based one-pot strategy. Angew. Chem. Int. Ed. 2001, 40 (7), 1274-1277.
    56. Mong, T. K.; Lee, H. K.; Duron, S. G.; Wong, C.-H., Reactivity-based one-pot total synthesis of fucose GM1 oligosaccharide: a sialylated antigenic epitope of small-cell lung cancer. Proc. Natl. Acad. Sci. U.S.A. 2003, 100 (3), 797-802.
    57. Cheng, C.-W.; Zhou, Y.; Pan, W.-H.; Dey, S.; Wu, C.-Y.; Hsu, W.-L.; Wong, C.-H., Hierarchical and programmable one-pot synthesis of oligosaccharides. Nat. Commun. 2018, 9 (1), 5202.
    58. Hsu, C.-H.; Hung, S.-C.; Wu, C.-Y.; Wong, C.-H., Toward automated oligosaccharide synthesis. Angew. Chem. Int. Ed. 2011, 50 (50), 11872-11923.
    59. Pedersen, C. M.; Marinescu, L. G.; Bols, M., Conformationally armed glycosyl donors: reactivity quantification, new donors and one pot reactions. Chem. Commun. 2008, (21), 2465-2467.
    60. Aglycon transfer was calculated based on the acceptor decomposition. Out of initially 1.2 equiv acceptor taken, 0.66 equiv was recovered after column. Therefore, from the consumed 0.54 equiv (1.2-0.66) acceptor, 0.28 equiv was used for hexasaccharide formation. Hence, remaining consumed 0.26 equiv acceptor was attributed to aglycon transfer from acceptor to donor, resulting in acceptor decomposition. This was also evident from TLC of reaction during which little donor spot was visible after the reaction.
    61. Verma, N.; Tu, Z.; Lu, M.-S.; Liu, S.-H.; Renata, S.; Phang, R.; Liu, P.-K.; Ghosh, B.; Lin, C.-H., Threshold of thioglycoside reactivity difference is critical for efficient synthesis of type I oligosaccharides by chemoselective glycosylation. J. Org. Chem. 2021, 86 (1), 892-916.
    62. Hesek, D.; Lee, M.; Yamaguchi, T.; Noll, B. C.; Mobashery, S., Facile preparation of a highly functionalized tetrahydropyran by catalytic hydrogenation of an oxazoline. J. Org. Chem. 2008, 73 (18), 7349-7352.
    63. Minuth, T.; Irmak, M.; Groschner, A.; Lehnert, T.; Boysen, M. M. K., Sweets for catalysis – facile optimisation of carbohydrate-based bis(oxazoline) ligands. Eur. J. Org. Chem. 2009, 2009 (7), 997-1008.
    64. Huang, L.; Huang, X., Highly efficient syntheses of hyaluronic acid oligosaccharides. Chem. Eur. J. 2007, 13 (2), 529-540.

    QR CODE