本論文內容共分為三個部分：第一部分乃是利用酯類的烯醇基陰離子 (enolate) 進行新合環方法的開發；第二部分主要探討將氰基丙烯酸酯如化合物 154－157 轉換為具多重取代基或具立體空間擁擠取代基的丙烯酸酯之對等物 (equivalent)，並進而應用於雙駢環骨架的建立；第三部分則是嘗試將掌性輔助基引入氰基丙烯酸酯中，期望能有利於 Diels−Alder 化學反應的選擇性。

第一部分：以市售的酯類化合物 76 利用二異丙胺鋰 (LDA) 去質子化後，與一系列氰基環烯酮化合物進行 1,4-加成反應並伴隨分子內親核性取代反應 (SN2) 的發生，可成功地合成出相對應之具環丙烷結構的新雙駢環骨架。化合物 80a 與 80b 互為非鏡像異構物 (diastereomer)，可藉由 X 射線繞射實驗或利用環丙烷相鄰二氫原子順向及反向偶合數值 (coupling constant, J) 差異的特性，證明兩化合物之間的相互關係來推定立體組態。

第二部分：以市售的對稱二烴基化合物 (diol) 如化合物 141 先以氯化第三丁基二苯矽基 (tert-butyldiphenylsilyl chloride, TBDPSCl) 做成單邊保護的化合物 145－148，再使用 PCC 氧化得到醛類化合物 149－152，並與市售之氰基甲酸乙酯化合物 153 進行 Knoevenagel 縮合反應，可製備出具氰基丙烯酸酯結構的親二烯基 (dienophile) 如化合物 154－157，藉由與不同的二烯基化合物 (diene) 進行 Diels−Alder 反應，生成環化產物 158－169，再運用本實驗室長年研究的□化鋰試劑 (lithium naphthlenide, L.N.) 進行還原去氰取代反應引入各式各樣的親電子基 (electrophile)，得到化合物 170－178，因此可成功地將氰基丙烯酸酯化合物154－157視為具多重取代基或具立體空間擁擠取代基的丙烯酸酯之對等物。
接下來，以氟化四丁胺溶液 (TBAF) 將經由還原取代反應後的化合物 170－178 去保護，在此步驟生成兩種不同的反應產物－(一)、當 n = 1 時，在去保護的同時亦進行分子內環化反應而生成一邊為內酯環的雙環骨架如化合物 179－181，且經 NOE 實驗鑑定，於雙環連接處 (ring junction) 為順向排列；(二)、若 n > 1 時，則僅單純得到醇類化合物 182－184。將醇類化合物繼續往下反應，使用 PDC 氧化成羧酸化合物，再經酯化反應可製備出二酯類化合物 189－191 (即為 Dieckmann 反應的前驅物)，最後以六甲基二矽胺化鋰試劑 (lithium hexamethyl-disilazide, LHMDS) 將二酯類化合物去質子化，進行分子內 Claisen 反應 (即 Dieckmann 反應)，便可順利建構出新的稠環 (fused ring) 骨架如化合物 192－195，且經 NOE 實驗鑑定，於雙環連接處 (ring junction) 亦為順向排列。

第三部分：以市售已具有固定位向掌性取代基的化合物 196 (即 (R)-(+)-pulegone) 經 1,4−加成反應、在鹼存在下進行差向異構化再經還原反應製備出所需的輔助基 205 (即 (-)-8-phenylmenthol)，與alpha−氰基羧酸化合物混合，進行酯化反應便可順利合成出親二烯基 197，因此部分只是嘗試是否能將掌性輔助基 (auxiliary) 引入氰基丙烯酸酯中而做的實驗研究，故僅與市售且結構簡單的醛、酮類化合物 (如：乙醛或丙酮等) 進行 Knoevenagel 縮合反應，得到縮合化合物 198。最後再與 2−甲基−1,3−丁二烯或 2,3−二甲基−1,3−丁二烯進行 Diels−Alder 反應，亦可順利得到環化產物 199。

Abstract
Chapter 1 of this thesis details a novel process in accessing bicyclic systems possessing a cyclopropane ring. Specifically, when ester 76 was treated with lithium diisopropylamide (LDA) followed by a doubly activated Michael acceptor (i.e. 2-cyano-2-cycloalkenones), a tandem process involving a 1,4-addition followed by an intramolecular SN2 displacement reaction ensues to furnish bicyclic systems 80a and 80b, the individual reative stereochemistry of which were determined by X-ray crystallography and/or detailed analysis of the coupling constant patterns found in their respective 1H-NMR spectra.

Chapter 2 expounds upon our investigation towards the construction of highly congested cyclohexenes via the Diels-Alder cycloaddition reaction. Towards this end, various glycols (i.e. 141) were mono-protected to give compounds 145-148 which were individually oxidized using pyridinium chlorochromate (PCC) to furnish aldehydes 149-152. The desired dienophiles 154-157 were then achieved by treating aldehydes 149-152 individually with malonate 153 under Knoevenagel conditions. Olefins 154-157 were found to be highly dienophilic and furnished the corresponding individual Diels-Alder cycloadducts 158-169 readily. The nitrile moiety present in the resulting cycloadducts could be replaced by an alkyl group using a reductive alkylation process mediated by lithium naphthalenide (LN) developed in our laboratories to give highly congested cyclohexenes 170-178. It was also discovered that, for cycloadducts generated starting from ethylene glycol and upon unmasking the hydroxyl by treatment with tetrabutylammonium fluoride (TBAF), □-lactones 179-181 was obtained apparently due to spontaneous cyclization of the ensuing alkoxide onto the adjacent methyl ester. The resulting □-lactones 179-181 were identified to possess a cis-ring junction as per extensive n.O.e. experiments. For cycloadducts 170-178 where n > 1, the TBAF mediated deprotection proceeded uneventfully to furnish alcohols 182-184. Subsequent oxidation using pyridinium dichromate (PDC) followed by esterification yielded diesters 189-191 which were then exposed to Dieckmann condensation reaction conditions to yield bicyclic keto esters 192-195.

Chapter 2 extends the Diels-Alder cycloaddition study by the incorporation of a chiral auxiliary on the ester present in the dienophile. Towards this end, optically active menthol derivative 205, arrived at starting from (R)-(+)-pulegone (i.e. 196), was acylated to give optically active ester 197. Knoevenagel reaction with ester 197 and a series of carbonyl containing building blocks then furnished the desired optically active dienophile 198 which was indeed found to be dienophilic and readily furnished cycloadducts 199.

1. Michael, A. J. Prakt. Chem. 1887, 35, 349.
2. (a) Yamaguchi, M.; Tsukamoto, M; Hirao, I. Chem. Lett. 1984, 25, 375. (b) Yamaguchi, M.; Tsukamoto, M; Tanaka, S.; Hirao, I. Chem. Lett. 1984, 25, 5661.
3. Jabin, I.; Revil, G.; Melloul, K.; Pfau, M. Tetrahedron: Asymmetrey 1997, 8, 1101
4. Oare, D. A.; Heathcock, C. H.; Tetrahedron Lett. 1986, 27, 6169.
5. (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207. (b) Posner, G. H.; Oh, C. H.; Gerena, L.; Milhous, W. K. J. Med. Chem. 1992, 35, 2459.
6. Truce, W. E.; Wellish, E. J. Am. Chem. Soc. 1952, 74, 2281.
7. Calderari, G.; Seebach, D. Helv. Chim. Acta. 1985, 68, 1592.
8. Enders, D.; Rendenbach, B. E. M. Tetrahedron 1986, 42, 2235.
9. tork, G.; Leong, A. Y. W.; Touzin, A. M. J. Org. Chem. 1976, 41, 3491.
10. Macquarrie, D. J. Tetrahedron Lett. 1998, 39, 4125.
11. Bartlett, P. D.; Woods, G. F. J. Am. Chem. Soc. 1940, 62, 2933.
12. Lee, P. H.; Seomoon, D.; Lee, K.; Heo, Y. J. Org. Chem. 2003, 68, 2510.
13. Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 15, 1223.
14. Rajanbabu, T. V. J. Org. Chem. 1984, 49, 2083.
15. Pereira, O. Z.; Chan, T. -H. J. Org. Chem. 1994, 59, 6710.
16. Shen, Z. L.; Ji, S. J.; Loh, T. P. Tetrahedron Lett. 2005, 46, 507.
17. Fleming, F. F.; Pu, Y.; Tercek, F. J. Org. Chem. 1997, 62, 4883.
18. 龔亮仁，博士論文，國立清華大學，2003年。
19. Wender, P. A.; Hillemann, C. L.; Szymonifka, M. J. Tetrahedron Lett. 1980, 21, 2205-2208.
20. Hudrlik, P. F.; Chou, D. T.; W, Stephenson, M. A. J. Org. Chem. 1982, 47, 2987-2993.
21. Chen, C.; Liao, Y.; Huang, Y. Z. Tetrahedron. 1989, 45, 3011-3020.
22. Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 111, 6691-6707.
23. 涂哲豪，博士論文，國立清華大學，2007年。
24. (a) Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726. (b) Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am. Chem. Soc. 1984, 106, 6006.
25. (a) Johnson, W. S.; Shelberg, W. E. J. Am. Chem. Soc. 1945, 67, 1745. (b) Yip, J. Ph. D. Thesis, Department of Chemistry, University of Alberta, Canada, 1998.
26. G□rtner, W.; Oesterhelt, D.; Seifert-Schiller, E.; Towner, P.; Hopf, H.; B□hm, I. J. Am. Chem. Soc. 1984, 106, 5654.
27. Chin, C. L.; Tran, D. P.; Shia, K. S.; Liu, H. J. Synlett. 2005, 3, 417.
28. Bergman, R.; Magnusson, G. J. Org. Chem.1986, 51, 212.
29. (a) Flaugh, M. E.; Crowell, T. A.; Farlow, D. S. J. Org. Chem. 1980, 45, 5399. (b) Schultz, A. G.; Sundararaman, P. J. Org. Chem. 1984, 49, 2455.
30. Chang, W. S., Ph.D. Thesis, National Tsing Hua University, Taiwan, 2005.
31. Walker, D.; Hebert, J. D. Chem. Rev. 1967, 67, 153.
32. Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887.
33. (a) Ikota, N.; Ganem, B. J. Org. Chem. 1978, 34, 1607. (b) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar, H. S. J. Org. Chem. 1981, 46, 2920.
34. (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265. (b) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883.
35. (a) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem Lett. 1976, 17, 163. (b) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673.
36. Demailly, G.; Solladie, G. J. Org. Chem. 1981, 46, 3102.
37. (a) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247. (b) Angle, S. R.; Turnbull, K. D. J. Am. Chem. Soc. 1989, 111, 1136.
38. Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98.
39. (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford, 1990. (b) Fringuelli, F.; Tatichi, A. Dienes in the Diels-Alder Reactions; Wiley: New York, 1990. (c) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 2023. (d) Li, C. J.; Chan, T. H.; Organic synthesis in Aqueous Media; John Wiley: New York, 1977. (e) Laschat, S. Angew. Chem. Int. Ed. Engl. 1996, 35, 289.
40. Kreiser, W.; Haumesser, W.; Thomas, A. F. Helv. Chim. Acta. 1974, 57, 164.
41. Onaka, M.; Hashimoto, N.; Yamasaki, R.; Kitabata, Y. Chem. Lett. 2002, 166.
42. Kagi, D. A.; Subrahmania, Ayyar. K.; Cookson, R. C.; Tuddenham,. Soap, R. M. Pergum and Cosmet. 1974, 47, 29.
43. Dauben, W. G.; Kozikowski, A. P.; Zimmerman, W. T. Tetrahedron Lett. 1975, 8, 515.
44. Chapuis, C. Tetrahedron Lett. 1991, 32, 355.
45. 郭俊徹，博士論文，國立清華大學，2006年。
46. Holy, N. L. Chem. Rev. 1974, 74, 243.
47. Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
48. Najera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155.
49. Yus, M. Chem. Soc. Revs. 1996, 155.
50. Racccanelli, S.; Pavoni, B.; Maroli, L.; Toxicol. Environ. Chem. 1994, 45, 1221.
51. (a) Ashby, E. C. Acc. Chem. Res. 1988, 21, 414. (b) Chanon, M.; Tobe, M. L. Angew. Chem. Int. Ed. Engl. 1982, 21, 1. (c) Pross, A. Acc. Chem. Res. 1985, 18, 212. (d) Chanon, M. Acc. Chem. Res. 1987, 201, 214.
52. (a) Harring, S. R.; Livinghouse, T. Tetrahedron Lett. 1989, 30, 1499. (b) Barluenga, J.; Fernandez-Simon, J. L.; Concellon, J. M.;Yus, M. Synthesis 1988, 234. (c) Komatsu, K.; Nishinaga, T.; Aonuma, S.; Hirosawa, C.; Takeuchi, K.; Lindner, H. J.; Richter, J. Tetrahedron Lett. 1991, 32, 6767. (d) Kondo, Y.; Muraata, N.; Sakamoto, T. Heterocycles 1994, 37, 1467. (e) Guijaro, A.; Yus, M. Tetrahedron 1994, 50, 13269. (f) Guijaro, A.; Romon, D. J.; Yus, M. Tetrahedron 1993, 49, 469.
53. Guijaro, A.; Yus, M. Tetrahedron 1994, 50, 3447.
54. Agawa, T.; Ishida, M.; Ohshiro, Y. Synthesis 1980, 933.
55. Pradhan, S. K.; Radhakrishnan, T. V.; Subramanian, R. J. Org. Chem. 1976, 41, 1943.
56. (a) Bartmann, E. Angew. Chem. Int. Ed. Engl. 1986, 25, 653. (b) Almena, J.; Foubeo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210.
57. Clive, D. L. J.; Keshava, Myrthy, K. S.; Zhang, C.; Hayward, W. D.; Daigneault, S. J. Chem. Soc., Chem. Commun. 1990, 509.
58. Philips, K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40, 1856.
59. (a) Rieke, R. D.; Dawson, B. T.; Stack, D. E.; Stinn, D. E. Synth. Commun. 1990, 20, 2771. (b) Jutzi, P.; Hielscher, B. Organometallica 1986, 5, 1201.
60. Shia, K. S.; Chang, N. Y.; Yip, J.; Liu, H. J. Tetrahedron Lett. 1997, 38, 7713.
61. Liu, H. J.; Shia, K. S.; Zhu, J. L. Tetrahedron Lett. 1998, 39, 4183.
62. (a) 吳仁達，博士論文，國立清華大學，2003年。(b) 廖志雄，博士論文，國立清華大學，2004年。
63. (a) Rychnovsky, S. D.; Swenson, S. S. J. Org. Chem. 1997, 62, 1333. (b) Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J. P.; Moient, C. Org. Biomol. Chem. 2003, 1, 547 (c) Savoia, D.; Taglivini, E.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1980, 45, 3227 (d) Shono, T.; Terauchi, J.; Kutayama, K.; Takeshima, Y. I.; Matsumura, Y. Tetrahedron 1992, 48, 8253. (e) Kang, H. Y.; Hong, W. S.; Cho, Y. S.; Koh, H. Y. Tetrahedron Lett. 1995, 36, 7661. (f) Black, D. St. C.; Doyle, J. E. Aust. J. Chem. 1978, 31, 2323. (g) Tamele, E. E.; Bjorklund, H. R. C. J. Am. Chem. Soc. 1971, 93, 7113.
64. 戴嘉良，碩士論文，國立清華大學，1999年。
65. 謝琬萍，碩士論文，國立清華大學，2001年。
66. Liu, H. J.; Ly, T. W.; Tai, C. L.; Wu, J. D.; Ling, J. K.; Guo, J. C.; Tseng, N. W.; Shia, K. S. Tetrahedron 2003, 59, 1209.
67. (a) Huang, M. J. Am. Chem. Soc. 1946, 68, 2487. (b) Huang, M. J. Am. Chem. Soc. 1949, 71, 3301.
68. Liu, H. J.; Tsai, T. Y.; Shia, K. S. Synlett. 2003, 1, 97.
69. 蔡廷岳，博士論文，國立清華大學，2004年。
70. For leading references, see (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063. (b) van Staden, L. F.; Gravestork, D.; Ager, D. Chem. Soc. Rev. 2002, 41, 195.
71. Kocienski, P. Chem Ind. (London) 1981, 548.
72. Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833.
73. Tietze, L. F.; Beifuss, U. in comprehensive Organic Synthesis (Trost, B. M.; Fleming, I., Eds.), Pergamon Press: Oxford, 1991, Vol. 2, Chap. 1.13.
74. Cope, A. C.; J. Am. Chem. Soc. 1937, 59, 2327.
75. Hein, R. W.; Astle, M. J.; Shelton, J. R. J. Org. Chem. 1961, 26, 4874.
76. Lehnert, W. Tetrahedron 1974, 30, 301.
77. (a) Texier-Boullet, F.; Foucaud, A. Tetrahedron Lett. 1982, 23, 4927. (b) Cabello, J. A.; Campelo, J. M.; Carcia, A.; Luna, D.; Marinas, M. J. Org. Chem.1984, 49, 5195.
78. Brillon, D.; Sauv□, G. J. Org. Chem. 1992, 57, 1838.
79. (a) Prout, F. S. J. Org. Chem.1953, 18, 928. (b) Rand, L.; Swisher, J. V.; Cronin, C. J. J. Org. Chem. 1962, 27, 3503. (c) Chalais, S.; Laszlo, P.; Mathy, A. Tetrahedron Lett. 1985, 26, 4453. (d) Reddy, T. I.; Varma, R. S. Tetrahedron Lett. 1997, 38, 1721.
80. Prajapati, D.; Lekhok, K. C.; Sandhu, T. S.; Ghosh, A. C. J. Chem. Soc., Perkin Trans. 1. 1996, 1.
81. (a) Watson, S. E.; Synth. Commun. 1998, 28(10), 1897-1895. (b) Watson, S. E.; Synth. Commun. 1998, 28(20), 3885-3894.
82. L. Y. -Q.; J. Chem. Res. 2000, 524-525.
83. ZHANG, M.; ZHANG, A.-Q.; DENG, Z. -H.; J. Chem. Res, 2005, (1), 69-70.
84. Hu. L. Tetrahedron Lett. 2000, 41, 4281-4285.
85. Ramachary, D. B.; Kishor, M.; Reddy, G. B. Org. Biomol. Chem. 2006, 4, 1641-1646.
86. Ramachary, D. B.; Reddy, G. B. Org. Biomol. Chem. 2006, 4, 4463-4468.
87. Wade, L. G. Organic Chemistry, Pearson Prentice Hall, 3rd edition, 1995, 691.
88. Brown, H. C.; Ramachandran, P. V. Tetrahedron: Asymmetry. 1999, 10, 11-15.
89. (a) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chemistry, Springer-Verlag: Berlin, 1984, Chap. IV. (b) Freeman, F. in Organic Syntheses by Oxidation with Metal Compounds (Mijs, W. J.; De Jonge, C. R. H. I., Eds.), Plenum Press: New York, 1986, Chap. 2. (c) Luzzio, F. A.; Guziec, F. S. Jr. Org. Prep. Proced. Int. 1988, 20, 533.
90. Ballini, R.;Carotti, A. SC 1983, 1197.
91. Paquette, L. A.; Wang, H. L. J. Org. Chem. 1996, 61, 5352.
92. Corey, E. J.; Ensley, H. E.; Suggs, J. W. J. Org. Chem. 1976, 41, 380.
93. Ort, O.; Jayasingh, R.; White, J. D. Org. Synth. 1987, 65, 203-214.
94. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
95. Ensley, H. E.; Corey, E. J.; Parnell, C. A. J. Org. Chem. 1978, 43, 1610-1612.
96. Garc□a-Mera, X.; Caama□o, O.; Fern□ndez, F.; Rodr□guez-Borges, J. E. Tetrahedron Lett. 2000, 41, 4123-4125.
97. Potin, D.; Dumas, F. Synth. Commun. 1990, 20, 2805.
98. Yang, D.; Xu, M. Org. Lett. 2001, 3, 1785-1788.
99. Liu, H. J.; Chan, W. H.; Lee, S. P. Tetrahedron Lett. 1978, 46, 4461-4464.
100. Melman, A.; Nahmany, M. Org. Lett. 2001, 3, 3733-3735.
101. Melman, A.; Shelkov, R.; Nahmany, M. J. Org. Chem. 2002, 67, 8975-8982.
102. Cativiela, C.; Diaz-de-Villegas, M. D.; G□lvez, J. A. Synth. Commum. 1990, 20, 3145-3152.