臺灣博碩士論文加值系統

LLG-5為Higuchi研究團隊於2005年從海星Linckia laevigata純化分離之神經節苷脂，亦被證實在神經生長因子的輔助之下，LLG-5可刺激大鼠嗜鉻細胞瘤分化為類神經細胞，因具有此特殊的生物活性，此化合物為開發治療神經退化相關疾病之重要來源。
然而從天然物純化之神經節苷脂通常為非勻相的混合物，且含量較為稀少，無法提供足夠量的化合物進行生理作用機制研究，因此本研究希望利用有機合成及酵素催化之策略取得相對大量的LLG-5及其衍生物。首先利用唾液酸轉移酶Cst-I建構植物神經鞘乳糖脂質與Neu5Cbz之a(2,3)唾液酸苷鍵結，接著與飽和脂肪醯鏈進行耦合反應得到GM3衍生物，雙唾液酸進一步與GM3衍生物進行[2+3]耦合反應鍵結至非還原端五號氮位置，移除保護基後首次完成LLG-5及其衍生物之全合成。

Ganglioside LLG-5 was first isolated from the starfish Linckia laevigata by Higuchi group in 2005 and it shows the activity of stimulating neurogenesis in the rat pheochromocytoma cell line PC-12 in the presence of nerve growth factor. Consequently, LLG-5 was considered as a potential source for the development of carbohydrate-based drugs for curing neurodegenerative diseases.
Since the mechanism of action remains unclear due to non-sufficient amount and structurally heterogeneous compounds isolated from the natural resource. We developed an efficient che-moenzymatic strategy to synthesize LLG-5 and its analogues. The synthesis was first performed by using a(2,3)-sialyltransferase Cst-I to couple lactosyl phytosphingosine acceptor with CMP-Neu5Cbz donor. Subsequently, chemical N-acylation with saturated fatty acids yielded GM3 ganglioside derivatives. Finally, the a-2,5-linked Neu5Gc dimers were attached to the amine of C-5 position of GM3 derivatives by amide bond formation. After global removal of all protecting groups, the first total synthesis of the targeted LLG-5 and its analogues were accom-plished.

目錄
謝誌 I
中文摘要 II
Abstract III
縮寫對照表 IV
圖目錄 X
表目錄 XIII
流程目錄 XIV
第一章 緒論 1
1-1 前言 1
1-2 唾液酸 (sialic acids) 1
1-3 神經節苷酯 (gangliosides) 2
1-4 神經節苷脂誘導PC-12細胞分化 4
1-4-1 PC-12細胞 4
1-4-2 神經節苷脂誘導分化神經細胞途徑 5
1-5 海洋棘皮動物分離之神經節苷脂 7
1-6 →Neu5Gc唾液酸合成分析 9
1-7神經節苷脂GM3之合成研究 12
1-7-1 化學合成策略 13
1-7-2 Chen Xi教授的方法 14
1-7-3 Tuchinsky教授的方法 15
1-7-4 本實驗室的方法 16
1-8 神經節苷酯LLG-3之合成研究 17
1-8-1 Kiso教授的方法 18
1-8-2 Withers教授的方法 19
1-9 光敏感保護基 20
1-10 研究動機 22
第二章 結果與討論 24
2-1 LLG-5及其類似物之合成溯徑分析 24
2-2 雙唾液酸之合成 25
2-3乳醣脂質之建構 30
2-4 以酵素進行(2,3)唾液酸醣基化 40
2-5 [2+3]合成策略 44
2-6 核磁共振光譜鑑定各醣體之討論 55
2-7 結論 57
第三章 實驗部份 59
3-1 Reagents and Solvents 59
3-2 Spectra Notes 59
3-3 Synthetic Procedures and Characterization 61
第四章 參考文獻與資料 111

1. Blix, F. G.; Gottschalk, A.; Klenk, E. Proposed nomenclature in the field of neuraminic and sialic Acids. Nature 1957, 179, 1088-1088.
2. (a) Schauer, R.; Tipson, R. S.; Derek, H. Chemistry, metabolism, and biological functions of sialic acids. Adv. Carbohydr. Chem. Biochem. 1982, 40, 131-234; (b) Chen, X.; Varki, A. Advances in the biology and chemistry of sialic acids. ACS Chem. Biol. 2010, 5, 163-176.
3. Angata, T.; Varki, A. Chemical diversity in the sialic acids and related a-keto acids: An evolutionary perspective. Chem. Rev. 2002, 102, 439-469.
4. (a) Sonnino, S.; Chigorno, V. Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures. Biochim. Biophy. Acta 2000, 1469, 63-77; (b) Kracun, I.; Rosner, H.; Drnovsek, V.; Vukelic, Z.; Cosovic, C.; Trbojeviccepe, M.; Kubat, M. Gangliosides in the human brain development and aging. Neurochem. Int. 1992, 20, 421-431.
5. Hakomori, S.; Zhang, Y. M. Glycosphingolipid antigens and cancer therapy. Chem. Biol. 1997, 4, 97-104.
6. (a) Fleming, F. E.; Böhm, R.; Dang, V.; Holloway, G.; Haselhorst, T.; Madge, P. D.; Deveryshetty, J.; Yu, X.; Blanchard, H.; Itzstein, M.; Coulson, B. S. Relative roles of GM1 ganglioside, N-acylneuraminic acids, and a2b1 integrin in mediating rotavirus infection. J. Virol. 2014, 88, 4558-4571; (b) Smith, D. C.; Lord, J. M.; Roberts, L. M.; Johannes, L. Glycosphingolipids as toxin receptors. Semin. Cell Dev. Biol. 2004, 15, 397-408.
7. Coskun, Ü.; Grzybek, M.; Drechsel, D.; Simons, K. Regulation of human EGF receptor by lipids. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 9044-9048.
8. Tagami, S.; Inokuchi, J.; Kabayama, K.; Yoshimura, H.; Kitamura, F.; Uemura, S.; Ogawa, C.; Ishii, A.; Saito, M.; Ohtsuka, Y.; Sakaue, S.; Igarashi, Y. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 2002, 277, 3085-3092.
9. Kuhn, R.; Wiegandt, H. Die Konstitution der Ganglio-N-tetraose und des Gangliosides GI. Chemische Berichte 1963, 96, 866-880.
10. Svennerholm, L. Gangliosides - A new therapeutic agent against stroke and Alzheimer's disease. Life Sci. 1994, 55, 2125-2134.
11. Schneider, J. S.; Gollomp, S. M.; Sendek, S.; Colcher, A.; Cambi, F.; Du, W. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson's disease patients. J. Neurol. Sci. 2013, 324, 140-148.
12. Greene, L. A.; Tischler, A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. U. S. A. 1976, 73, 2424-2428.
13. (a) Encinas, M.; Iglesias, M.; Liu, Y.; Wang, H.; Muhaisen, A.; Cena, V.; Gallego, C.; Comella, J. X. Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J. Neurochem. 2000, 75, 991-1003; (b) Chen, J.; Chattopadhyay, B.; Venkatakrishnan, G.; Ross, A. H. Nerve growth factor-induced differentiation of human neuroblastoma and neuroepithelioma cell line. Cell Growth Differ. 1990, 1, 79-85.
14. Segal, R. A.; Greenberg, M. E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 1996, 19, 463-489.
15. (a) Hafner, A.; Obermajer, N.; Kos, J. g -Enolase C-terminal peptide promotes cell survival and neurite outgrowth by activation of the PI3K/Akt and MAPK/ERK signalling pathways. Biochem. J. 2012, 443, 439-450; (b) Cheung, W. M.; Hui, W. S.; Chu, P. W.; Chiu, S. W.; Ip, N. Y. Ganoderma extract activates MAP kinases and induces the neuronal differentiation of rat pheochromocytoma PC12 cells. FEBS Lett. 2000, 486, 291-296; (c) Liu, J. H.; Bo, J.; Bao, Y. M.; An, L. J. Effect of Cuscuta chinensis glycoside on the neuronal differentiation of rat pheochromocytoma PC12 cells. Int. J. Dev. Neurosci. 2003, 21, 277-281; (d) Gundimeda, U.; McNeill, T. H.; Schiffman, J. E.; Hinton, D. R.; Gopalakrishna, R. Green tea polyphenols potentiate the action of nerve growth factor to induce neuritogenesis: Possible role of reactive oxygen species. J. Neurosci. Res. 2010, 88, 277-281; (e) More, S. V.; Koppula, S.; Kim, I. S.; Kumar, H.; Kim, B. W.; Choi, D. K. The role of bioactive compounds on the promotion of neurite outgrowth. Molecules 2012, 17, 6728-6753.
16. (a) Yao, R.; Cooper, G. M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 1995, 267, 2003-2006; (b) Hagemann, C.; Rapp, U. R. Isotype-specific functions of Raf kinases. Exp. Cell Res. 1999, 253, 34-46; (c) Bilderback, T. R.; Gazula, V. R.; Dobrowsky, R. T. Phosphoinositide 3-kinase regulates crosstalk between Trk Atyrosine kinase and p75NTR-dependent sphingolipid signalingpathways. J. Neurochem. 2001, 76, 1540-1551; (d) Huang, E. J.; Reichardt, L. F. Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 2003, 72, 609-642.
17. Sofroniew, M. V.; Howe, C. L.; Mobley, W. C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 2001, 24, 1217-1281.
18. Mutoh, T.; Tokuda, A.; Miyadai, T.; Hamaguchi, M.; Fujiki, N. Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 5087-5091.
19. Miljan, E. A.; Meuillet, E. J.; Mania-Farnell, B.; George, D.; Yamamoto, H.; Simon, H. G.; Bremer, E. G. Interaction of the extracellular domain of the epidermal growth factor receptor with gangliosides. J. Biol. Chem. 2002, 277, 10108-10113.
20. Li, R.; Liu, Y.; Ladisch, S. Enhancement of epidermal growth factor signaling and activation of Src kinase by gangliosides. J. Biol. Chem. 2001, 276, 42782-42792.
21. Kaneko, M.; Yamada, K.; Miyamoto, T.; Inagaki, M.; Higuchi, R. Neuritogenic activity of gangliosides from echinoderms and their structure–activity relationship. Chem. Pharm. Bull. 2007, 55, 462-463.
22. Inagaki, M. Structure and biological activity of glycosphingolipids from starfish and feather stars. Yakugaku Zasshi 2008, 128, 1187-1194.
23. Maruta, T.; Saito, T.; Inagaki, M.; Shibata, O.; Higuchi, R. Biologically active glycosides from asteroidea, 41. Isolation and structure determination of glucocerebrosides from the starfish Linckia laevigata. Chem. Pharm. Bull. 2005, 53, 1255-1258.
24. (a) Inagaki, M.; Isobe, R.; Higuchi, R. Biologically active glycosides from asteroidea. Part 39. Glycosphingolipids from the starfish Linckia laevigata. Part 1. Isolation and structure of new ganglioside molecular species. Eur. J. Org. Chem. 1999, 771-774; (b) Inagaki, M.; Miyamoto, T.; Isobe, R.; Higuchi, R. Biologically active glycosides from asteroidea,43. Isolation and structure of a new neuritogenic-active ganglioside molecular species from the starfish Linckia laevigata. Chem. Pharm. Bull. 2005, 53, 1551-1554; (c) Inagaki, M.; Saito, M.; Miyamoto, T.; Higuchi, R. Isolation and structure of hematoside-type ganglioside from the starfish linckia laevigata. Chem. Pharm. Bull. 2009, 57, 204-206.
25. Yamagishi, M.; Hosoda‐Yabe, R.; Tamai, H.; Konishi, M.; Imamura, A.; Ishida, H.; Yabe, T.; Ando, H.; Kiso, M. Structure‐activity relationship study of the neuritogenic potential of the glycan of starfish ganglioside LLG‐3. Mar. Drug 2015, 13, 7250-7274.
26. Brinkman-Van der Linden, E. C. M.; Sjoberg, E. R.; Juneja, L. R.; Crocker, P. R.; Varki, N.; Varki, A. Loss of N-glycolylneuraminic acid in human evolution. J. Biol. Chem. 2000, 275, 8633-8640.
27. McAuliffe, J. C.; Rabuka, D.; Hindsgaul, O. Synthesis of O-glycolyl-linked neuraminic acids through a spirocyclic intermediate. Org. Lett. 2002, 4, 3067-3069.
28. Ren, C. T.; Chen, C. S.; Yu, Y. P.; Tsai, Y. F.; Lin, P. Y.; Chen, Y. J.; Zou, W.; Wu, S. H. Synthesis of a-(2→5)Neu5Gc Oligomers. Chem. Eur. J. 2003, 9, 1085-1095.
29. Shi, M.; Kleski, K. A.; Trabbic, K. R.; Bourgault, J. P.; Andreana, P. R. Sialyl-Tn polysaccharide A1 as an entirely carbohydrate immunogen: synthesis and immunological evaluation. J. Am. Chem. Soc. 2016, 138, 14264-14272.
30. Schnaar, R. L.; Gerardy-Schahn, R.; Hildebrandt, H. Sialic acids in the brain: Gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 2014, 94, 461-518.
31. Mufuse, M.; Ishida, M.; Kiso, M.; Hasegawa, A. A facile, regio- and stereo-selective synthesis of ganglioside GM3. Carbohydr. Res. 1989, 188, 71-80.
32. Liu, Y.; Wen, L.; Li, L.; Gadi, M. R.; Guan, W.; Huang, K.; Xiao, Z.; Wei, M.; Ma, C.; Zhang, Q.; Yu, H.; Chen, X.; Wang, P. G.; Fang, J. A general chemoenzymatic strategy for the synthesis of glycosphingolipids. Eur. J. Org. Chem. 2016, 4315-4320.
33. Zehavi, U.; Tuchinsky, A. Enzymic glycosphingolipid synthesis on polymer supports. III. Synthesis of GM3 , its analog [NeuNAca(2-3)Galb(1-4)Glc (1-3)Cer] and their lyso-derivatives. Glycoconj. J. 1998, 15, 657-662.
34. 陳安宜，國立清華大學化學研究所 碩士論文，民國104年。
35. Tamai, H.; Ando, H.; Tanaka, H. N.; Hosoda-Yabe, R.; Yabe, T.; Ishida, H.; Kiso, M. The total synthesis of the neurogenic ganglioside LLG-3 isolated from the starfish Linckia laevigata. Angew. Chem. Int. Ed. 2011, 50, 2330-2333.
36. Withers, S. G.; Rich, J. R. A chemoenzymatic total synthesis of the neurogenic starfish ganglioside LLG-3 using an engineered and evolved synthase. Angew. Chem. Int. Ed. 2012, 51, 8640-8643.
37. Barltrop, J. A.; Schofield, P., Photosensitive protecting groups. Tetrahedron Lett. 1962, 16, 697-699.
38. Bochet, C. G. Photolabile protecting groups and linkers. J. Chem. Soc., Perkin Trans. I 2002, 2, 125-142.
39. (a) Wieboldt, R.; Ramesh, D.; Jabri, E.; Karplus, P. A.; Carpenter, B. K.; Hess, G. P. Synthesis and characterization of photolabile o-nitrobenzyl derivatives of urea. J. Org. Chem. 2002, 67, 8827-8831; (b) Schaper, K.; Mobarekeh, S. A. M.; Grewer, C. Synthesis and photophysical characterization of a new, highly hydrophilic caging group. Eur. J. Org. Chem. 2002, 1037-1046; (c) Russell, A. G.; Ragoussi, M.-E.; Ramalho, R.; Wharton, C. W.; Carteau, D.; Bassani, D. M.; Snaith, J. S. a-Carboxy-6-nitroveratryl: A photolabile protecting group for carboxylic acids. J. Org. Chem. 2010, 75, 4648-4651; (d) Kotzur, N.; Briand, B.; Beyermann, M.; Hagen, V. Wavelength-selective photoactivatable protecting groups for thiols. J. Am. Chem. Soc. 2009, 131, 12927-12931.
40. Fan, G. T.; Lee, C. C.; Lin, C. C.; Fang, J. M. Stereoselective synthesis of Neu5Acα(2→5)Neu5Gc: The building block of oligo/poly(→5-OglycolylNeu5Gcα2→) chains in sea urchin egg cell surface glycoprotein. J. Org. Chem. 2002, 67, 7565-7568.
41. Okamoto, K.; Goto, T. Glycosidation of sialic acid. Tetrahedron 1990, 46, 5835-5857.
42. Dodds, C. A.; Hobday, C. L.; Kennedy, A. R.; McKellar, S. C.; Smillie, K.; Walls, A., Ag(I) bipyridyl coordination polymers containing functional anions. New J. Chem. 2017, 41, 1574-1581.
43. (a) Roy, R.; Laferriere, C. A. Synthesis of protein conjugates and analogues of N-acetylneuraminic acid. Can. J. Chem. 1990, 68, 2045-2054; (b) Orlova, A. V.; Shpirt, A. M.; Kulikova, N. Y.; Kononov, L. O. N,N-Diacetylsialyl chloride - A novel readily accessible sialyl donor in reactions with neutral and charged nucleophiles in the absence of a promoter. Carbohydr. Res. 2010, 345, 721-730.
44. Boons, G. J.; Demchenko, A. V. Recent advances in O-sialylation. Chem. Rev. 2000, 100, 4539-4565.
45. Hori, H.; Nakajuma, T.; Nishida, Y.; Ohrui, H.; Meguro, H. A simple method to determine the anomeric configuration of sialic acid and its derivatives by 13C-NMR. Tetrahedron Lett. 1988, 29, 6317-6320.
46. Plietker, B.; Niggemann, M.; Pollrich, A. The acid accelerated ruthenium-catalysed dihydroxylation. Scope and limitations. Org. Biomol. Chem. 2004, 2, 1116-11124.
47. (a) Goff, R. D.; Gao, Y.; Mattner, J.; Zhou, D.; Yin, N.; Cantu, C.; Teyton, L.; Bendelac, A.; Savage, P. B. Effects of lipid chain lengths in α-galactosylceramides on cytokine release by natural killer T cells. J. Am. Chem. Soc. 2004, 126, 13602-13603; (b) Azuma, H.; Tamagaki, S.; Ogino, K. Stereospecific total syntheses of sphingosine and its analogues from L-serine. J. Org. Chem. 2000, 65, 3538-3541; (c) Cheng, J. M. S.; Chee, S. H.; Knight, D. A.; Acha-Orbea, H.; Hermans, I. F.; Timmer, M. S. M.; Stocker, B. L. An improved synthesis of dansylated α-galactosylceramide and its use as a fluorescent probe for the monitoring of glycolipid uptake by cells. Carbohydr. Res. 2011, 346, 914-926; (d) Nakamura, T.; Shiozaki, M. Stereoselective synthesis of D-erythro-sphingosine and L-lyxo-phytosphingosine. Tetrahedron 2001, 57, 9087-9092.
48. Fan, G. T.; Pan, Y. S.; Lu, K. C.; Cheng, Y. P.; Lin, W. C.; Lin, S.; Lin, C. H.; Wong, C. H.; Fang, J. M.; Lin, C. C. Synthesis of a-galactosyl ceramide and the related glycolipids for evaluation of their activities on mouse splenocytes. Tetrahedron 2005, 61, 1855–1862.
49. Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Preparation of esters of phosphoric acid by the reaction of trivalent phosphorus compounds with diethyl azodicarboxylate in the presence of alcohols. Bull. Chem. Soc. Jpn. 1967, 40, 935-939.
50. Lee, J. H.; Domaille, D. W.; Noh, H.; Oh, T.; Choi, C.; Jin, S.; Cha, J. N. High-yielding and photolabile approaches to the covalent attachment of biomolecules to surfaces via hydrazone chemistry. Langmuir 2014, 30, 8452-8460.
51. Rosowsky, A.; Forsch, R. A.; Freisheim, J. H.; Moran, R. G.; Wick, M. Methotrexate analogs. 19. Replacement of the glutamate side-chain in classical antifolates by L-homocysteic acid and L-cysteic acid: Effect on enzyme inhibition and antitumor activity. J. Med. Chem. 1984, 27, 600-604.
52. Sandbhor, M. S.; Soya, N.; Albohy, A.; Zheng, R. B.; Cartmell, J.; Bundle, D. R.; Klassen, J. S.; Cairo, C. W. Substrate recognition of the membrane-associated sialidase NEU3 requires a hydrophobic aglycone. Biochem. 2011, 50, 6753-6762.
53. Angelino, N. J.; Bernacki, R. J.; Sharma, M.; Dodson-Simmons, O.; Korytnyk, W. Versatile intermediates in the selective modification of the amino function of 2-amino-2-deoxy-D-mannopyranose and the 3-position of 2-acetamido-2-deoxy-D-mannose: Potential membrane modifiers in neoplastic control. Carbohydr. Res. 1995, 276, 99-115.
54. Yu, H.; Chokhawala, H.; Karpel, R.; Yu, H.; Wu, B.; Zhang, J.; Zhang, Y.; Jia, Q.; Chen, X. Multifunctional Pasteurella multocida sialyltransferase: A powerful tool for the synthesis of sialoside libraries. J. Am. Chem. Soc. 2005, 127, 17618-17619.
55. Gilbert, M.; Brisson, J. R.; Karwaski, M. F.; Michniewicz, J.; Cunningham, A. M.; Wu, Y.; Young, N. M.; Wakarchuk, W. W. Biosynthesis of ganglioside mimics in Campylobacter jejuni OH4384: Identificatin of the glycosyltransferase genes, enzymatic synthesis of model compounds, and characterization of nanomole amounts by 600-MHz 1H and 13C NMR analysis. J. Biol. Chem. 2000, 275, 3896-3906.
56. Zheng, M.; Ye, X. S. Synthesis of N-modified ganglioside GM3 derivatives. Tetrahedron 2012, 68, 1475-1482.
57. Otsubo, N.; Ishida, H.; Kiso, M. Synthesis of novel ganglioside GM4 analogues containing N-deacetylated and lactamized sialic acid: Probes for searching new ligand structures for human L-selectin. Carbohydr. Res. 2001, 330, 1-5.
58. 張婷崴，國立清華大學化學研究所 碩士論文，民國105年。
59. Bartholomew, C. V., Mechanisms of catalyst deactivation. Applied Catalysis A: General 2001, 212, 17-60.
60. Hossain, M. I.; Hanashima, S.; Nomura, T.; Lethu, S.; Tsuchikawa, H.; Murata, H.; Kusaka, H.; Kita, S.; Maenaka, K. Synthesis and Th1-immunostimulatory activity of a-galactosylceramide analogues bearing a halogen-containing or selenium-containing acyl chain. Bioorg. Med. Chem. 2016, 24, 3687-3695.
61. Kim, S.; Lee, S.; Lee, T.; Ko, H.; Kim, D. Efficient synthesis of D-erythro-sphingosine and D-erythro-azidosphingosine from D-ribo-phytosphingosine via a cyclic sulfate intermediate. J. Org. Chem. 2006, 71, 8661-8664.
62. Akimoto, K.; Natori, T.; Morita, M. Synthesis and stereochemistry of agelasphin-9b. Tetrahedron Lett. 1993, 34, 5593-5594.
63. Loka, R. S.; Sadek, C. M.; Romaniuk, N. A.; Cairo, C. W. Conjugation of synthetic N-acetyl-lactosamine to azide-containing proteins using the Staudinger ligation. Bioconjugate Chem. 2010, 21, 1842-1849.
64. Fusz, S.; Srivatsan, S. G.; Ackermann, D.; Famulok, M. Photocleavable initiator nucleotide substrates for an aldolase ribozyme. J. Org. Chem. 2008, 73, 5069-5077.
65. (a) Chappell, M. D.; Halcomb, R. L. Synthesis of CMP-sialic acid conjugates: Substrates for the enzymatic synthesis of natural and designed sialyl oligosaccharides. Tetrahedron 1997, 53, 11109-11120; (b) Knorst, M.; Fessner, W.-D. CMP-Sialate synthetase from neisseria meningitidis -Overexpression and application to the synthesis of oligosaccharides containing modified sialic acids. Adv. Synth. Catal. 2001, 343, 698-710.
66. Chen, X.; Wu, Y.-L.; Chen, D. Structure determination and synthesis of a new cerebroside isolated from the traditional chinese medicine Typhonium Giganteum Engl. Tetrahedron Lett. 2002, 3529-3532.