本實驗室已發展出一套新合成方法，並成功合成出具有屈公熱病毒活性的的「咪唑烷」（imidzolidine）。利用「1,3-偶極環化加成」（1,3-cycloaddition）反應的策略，「希夫鹼」（Schiff base）會和芳炔生成「甲亞胺偶極體」（azomethine ylide）。反應中產生的偶極體會和第二當量的同一個「希夫鹼」（Schiff base）經由[3 + 2]環化加成而得到所需的「咪唑烷」（imidzolidine），產率為7085%。
「吡咯烷」（pyrrolidine）具有非常多的生物活性，包括抗癌、抗病毒、抗糖尿病的活性。為了延續之前不須使用金屬做催化的反應，我們將烯烴化合物引進為起始物來取代第二當量的「希夫鹼」（Schiff base）。在溫和的反應條件下當「偶極體」（dipole）形成後馬上與烯烴化合物進行「1,3-環化加成」反應，得到產率不錯的「吡咯烷」（pyrrolidine）。利用此新穎「1,2-加成/[3 + 2]環化加成串聯反應」（tandem 1,2-addition/[3 + 2] cycloaddition）可以更容易且更有效率地合成高產率與高立體專一性的「吡咯烷」（pyrrolidine）。由於不需要純化中間產物，所以這是一個非常高效率的新方法。
此反應很明顯不只可應用在A + 2 B 的系統，A + B + C的系統也適用。不同的「偶極體」（dipole）及「親偶極體」（dipolarophile）也可以適用於此新穎的方法。因此更多複雜的「五元雜環化合物」（five-membered heterocycles）及具有生物活性的化合物都可以藉由此方法而有效率得到。這是第一個利用「芳炔」（aryne）誘導環化來合成「五元雜環」（five-membered heterocycles）的報導。

Our research group has developed a new method for the synthesis of imidazolidine which possesses Chikungunya activity. By use of the 1,3-dipolar cycloaddition strategy, a Schiff base with an aryne gave an azomethine ylide in situ. This ylide reacted with a second equivalent of the same Schiff base through a [3 + 2] fashion to produce the desired imidazolidines in 70–85%.
Pyrrolidines impart a variety of biological activities, including anticancer activity, antiviral activity, and antidiabetic activity. To continue previous study of transition metal free aryne induced [3 + 2] cycloaddition, we applied alkenes as starting materials instead of the addition of the second equvilent of Schiff base. After the ylide formed, it subsequently underwent 1,3-dipolar cycloaddition with alkenes to give pyrrolidines in situ under mild conditions in good yields. The newly tandem 1,2-addition/[3 + 2] cycloaddition led to stereospecific pyrroidinesin high yields. This new method was efficient without identification of intermediates.
Our results indicate that not only A + 2B system worked out in this one-flaksystem, but also A + B + C system was also feasible. That is, different kinds of dipolarophiles and dipoles can be applied with our method. Therefore more complicated five-membered heterocycles and bioactive compounds could be obtained with high efficiency and high yields. This is the first aryne-induced cyclization reported in the synthesis of five-membered heterocycles.

Abstract i
Chinese Abstract iii
Acknowledgement v
Content vi
List of Figure xiii
List of Table xiv
List of Scheme xv
I. Introduction 1
1-1 Chikungunya Virus 1
1-2 Bioactivities of Imidazolidines 2
1-3 Modified Strategy for Pyrrolidine Synthesis 4
1-4 Bioactivities of Pyrrolidines 6
1-5 Methods for Synthesis of Pyrroidines 8
1-6 Tandem reaction 13
1-7 Benzynes 15
1-8 Azomethine Ylides 17
1-9 1,3-Dipolar Cycloaddition Reactions 19
II. Results 24
2-1 Synthetic Scheme of Pyrrolidines 24
2-2 Pyrrolidine as Final Products 25
2-3 Optimization of Reactions 27
2-4 X-ray Identification 30
2-5 Azomethine Ylide Formation 32
III. Discussion 33
3-1 Mechanistic Study and Structural identification of Pyrrolidines 33
3-2 Reaction Optimization 38
3-3 Discussion on Yield 40
3-4 Sequential tandem reaction 41
3-5 Competitive Reaction 42
3-6 Cycloreversion 43
3-7 Advantages 44
3-8 Lipinski’s Rule of Five 44
3-9 Future Application 45
IV. Conclusions 49
V. General Experimental 50
Standard Procedure 1 for the Synthesis of Arylpyrrolidines 92a–g. 52
Standard Procedure 2 for the Synthesis of Arylpyrrolidines 92a–g. 52
(2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5-diphenylpyrrolidine (92a). 53
(2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5-(4-methoxyphenyl)-1-phenylpyrrolidine (92b). 54
(2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2-methoxycarbonyl-1-phenylpyrrolidine (92c). 56
(2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl-5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 57
(2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e). 59
(2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5-(4-methylphenyl)-1-phenylpyrrolidine (92f). 60
(2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5-(4-methoxyphenyl)-1-phenylpyrrolidine (92g). 62
VI. References 64
VII. Spectra 78
1H NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5- diphenylpyrrolidine (92a) 79
13C NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5- diphenylpyrrolidine (92a) 79
Mass spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5- diphenylpyrrolidine (92a) 80
HPLC spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5- diphenylpyrrolidine (92a) 80
IR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-1,5- diphenylpyrrolidine (92a) 81
1H NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92b) 81
13C NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92b) 82
Mass spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92b) 82
HPLC spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92b) 83
IR spectrum of (2RS,4SR,5SR)-4-Acetyl-2-methoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92b) 83
1H NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2- methoxycarbonyl-1-phenylpyrrolidine (92c) 84
13C NMR spectrum of (2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2- methoxycarbonyl-1-phenylpyrrolidine (92c) 84
Mass spectrum of (2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2- methoxycarbonyl-1-phenylpyrrolidine (92c) 85
HPLC spectrum of (2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2- methoxycarbonyl-1-phenylpyrrolidine (92c) 85
IR spectrum of (2RS,4SR,5SR)-4-Acetyl-5-(4-fluorophenyl)-2- methoxycarbonyl-1-phenylpyrrolidine (92c) 86
1H NMR spectrum of (2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl- 5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 86
13C NMR spectrum of (2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl- 5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 87
Mass spectrum of (2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl- 5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 87
HPLC spectrum of (2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl- 5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 88
IR spectrum of (2RS,4SR,5SR)-4-tert-Butoxycarbonyl-2-methoxycarbonyl- 5-(4-methoxyphenyl)-phenylpyrrolidine (92d) 88
1H NMR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl- 5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e) 89
13C NMR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl- 5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e) 89
Mass spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl- 5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e) 90
HPLC spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl- 5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e) 90
IR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl- 5-(4-methoxyphenyl)-1-phenylpyrrolidine (92e) 91
1H NMR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5- (4-methylphenyl)-1-phenylpyrrolidine (92f) 91
13C NMR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5- (4-methylphenyl)-1-phenylpyrrolidine (92f) 92
Mass spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5- (4-methylphenyl)-1-phenylpyrrolidine (92f) 92
HPLC spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5- (4-methylphenyl)-1-phenylpyrrolidine (92f) 93
IR spectrum of (2RS,4SR,5SR)-4-cyano-2-methoxycarbonyl-5- (4-methylphenyl)-1-phenylpyrrolidine (92f) 93
1H NMR spectrum of (2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92g) 94
13C NMR spectrum of (2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92g) 94
Mass spectrum of (2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92g) 95
HPLC spectrum of (2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92g) 95
IR spectrum of (2RS,3RS,4SR,5SR)-2,3,4-Trimethoxycarbonyl-5- (4-methoxyphenyl)-1-phenylpyrrolidine (92g) 96

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