在抗流感藥物瑞樂沙之活性物質Zanamivir合成研究中，我們以tri-O-acetyl-D-glucal (57)為起始物進行C-糖苷化反應(C-glycosidation)，得到具有 Zanamivir 基本骨架之加成產物48。我們首先進行光學異構化反應(epimerization)的研究。將加成產物48與Co2(CO)8進行錯合反應後，得到具有兩個活性中心之鈷錯合物63。在路易士酸及醋酸的環境下，化合物63
成功地進行光學異構化反應，且同時進行保護基轉換得到產物67。
在取得加成產物67後，經由七步合成，可成功地引入含氮之官能基並合成氮丙環化合物73與53。應用先前所發展的方法，進行光學異構化反應之研究：發現化合物73在光學異構化反應中矽醚基被水解，並攻擊至為路易士酸活化
之氮丙環，得到開環產物，接著進行hydrosilation得到化合物89；而化合物53，在光學異構化反應中得到了保護基轉換之產物80，並在hydrosilation完後取得化合物83，經NOESY實驗鑑定，發現其
未進行光學異構化反應。

Contents

中文摘要 i
Abstract ii
Acknowledgements iii
Index v
Figure index viii
Table index ix
Scheme index x
Abbreviations xii

Chapter 1 Introduction 1
1.1 General introduction 1
1.2 Synthetic approaches to Zanamivir 2
1.2.1 von Itzstein group - first design and synthesis of Zanamivir 2
1.2.2 Merck Frosst Centre - synthesis of Zanamivir from sialic acid 3
1.2.3 Glaxo - scalable route to Zanamivir 4
1.2.4 Yao’s group - synthesis of Zanamivir from D-glucono-δ-lactone 5
1.3 Methodologies developed by our group 7
1.3.1 C-glycosidation with silylacetylenes to D-glucals 7
1.3.2 Cobalt mediated C-1 alkynyl pyranose ring system functionalization 8
1.3.3 Strategies for the removal of cobalt complex 10
1.4 Retrosynthetic plan 11

Chapter 2 Results and Discussion 14
2.1 Construction of basic carbon skeleton 14
2.1.1 Nucleophile preparation 14
2.1.2 C-glycosidation of tri-O-acetyl-D-glucal 15
2.2 Model study of cobalt mediated epimerization 15
2.3 Synthesize the aziridine intermediate 20
2.4 Epimerization of the alkynyl aziridine 23


Chapter 3 Conclusion 30

Chapter 4 Proposal of Next Generation Zanamivir Synthesis 32
4.1 Proposal A: epimerization and aziridine formation as key steps 32
4.2 Proposal B: reductive amination and aziridine formation as key steps 34

Chapter 5 Experimental Section 36
5.1 General method 36
5.2 Experimental section of chapter 2 38
5.2.1 Methylalcohol formation YCL02023 (60) 38
5.2.2 OTBDPS protection YCL02024 (58) 39
5.2.3 C-glycosidation YCL02104 (48) 40
5.2.4 Cobalt complexation YCL02013 (64) 41
5.2.5 Epimerization YCL02077 (67) 42
5.2.6 Hydrolysis of diacetate YCL02076 (69) 43
5.2.7 Selective OTBS protection YCL03006 (70) 44
5.2.8 Preparation of trichloriacetimidate YCL03038 (56) 45
5.2.9 Iodo-oxazoline formation YCL03012 (55) 46
5.2.10 Oxazoline ring opening YCL03063 (54) 47
5.2.11 O-acetylation YCL03026 (72) 48
5.2.12 Aziridine formation YCL03094 (53) 49
5.2.13 Aziridine formation YCL03112 (73) 50
5.2.14 Oxazoline formation YCL03088 (74) 51
5.2.15 Cobalt complexation YCL03096 (78) 52
5.2.16 Aziridine opening YCL03136 (79) 52
5.2.17 Hydrosilation YCL03136 (80) 53
5.2.18 Cobalt complexation YCL03096 (52) 54
5.2.19 Cobalt mediated epimerization YCL03098 (81, 82) 54
5.2.20 Hydrosilation YCL03150 (83) 55
5.2.21 Hydrosilation YCL03122 (84) 56
5.2.22 Hydrolysis of trichloracetamide YCL03124 (85) 57
5.2.23 Hydrolysis of trichloracetamide YCL03128 (85) 58
5.3 Reference 59

Supporting information I: crystal data of compound YCL03136 (80) 61
Supporting information II: NMR spectra of synthesized compounds 65
Supporting information III: the PPT slides of final defence 101

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