本論文所探討的合成研究可區分為三個部分，其中包含了一個新合成方法的開發，與兩個天然物的全合成研究，此三個實驗主題存在一個共通點，即是均利用萘化鋰試劑來進行還原去氰取代反應，用以建構所需之化合物骨架。
於第一章的新合成方法研究中，我們利用丙二腈的次烷基衍生物如化合物32與isoprene進行Diels-Alder反應，可取得六員環的加成化合物43，接著利用萘化鋰試劑進行還原去氰反應後立即與丙酮作用，合成β-羥基乙腈化合物64，將羥基轉化成較佳之離去基後再一次使用萘化鋰試劑，對化合物78進行還原消去反應，最終取得環外具雙鍵的化合物90；由實驗的成功可驗證，丙二腈的次烷基衍生物可有效地作為丙二烯對等物應用於Diels-Alder反應。
第二章為(±)-laurencenone C (103)的全合成研究，相同地利用萘化鋰試劑對Diels-Alder反應加成化合物134進行還原去氰反應，後與親電子化合物135進行取代反應而取得化合物136，利用TBAF試劑去除羥基的TBDMS保護後可直接環化生成關鍵的內酯化合物142；利用內酯化合物的特殊反應特性以甲基鋰試劑將化合物142開環取得醇酮化合物143，羥基氧化後之醛酮化合物144藉由aldol縮合反應後便可建構具天然物雙環結構之化合物147，再歷經1,2-加成反應引進甲基後氧化掉頭取得化合物149；將化合物149氧化成環己二烯酮化合物154後，對此對稱分子進行共軛加成反應引進甲基便完成了天然物(±)-laurencenone C (103)的合成。
第三章乃是(±)-blepharostol (245)的合成研究，雖然工作有待完成，但仍在此簡述我們的合成策略與目前之成果：以1,3-環己二酮為起始物歷經十一個實驗步驟可取得Michael accepter化合物255，而另一個Michael accepter化合物271則是由丙醛為始藉九個實驗步驟取得，將化合物263製備成cuprate後對化合物255與化合物271進行共軛加成反應，分別生成化合物264與化合物272，其中化合物272可藉由碘化鋅誘導之ω-矽炔-α-氰基環酮分子內環化反應合環，取得四個具十氫萘骨架之化合物273a、273b、274a、274b，而化合物264則因分子鋼性（rigid）較強無法成功環化；化合物273b以三氟醋酸去除TMS官能基可轉換為化合物274b，其具有合成目標化合物245之骨架，利用鈀金屬氧化的方法將化合物274b製備成烯酮化合物275b，至此為目前的實驗成果；接下來我們欲將化合物275b的環外雙鍵轉移至環內，並利用萘化鋰與甲基碘對化合物277進行還原取代反應，期望取得化合物278，而後進行共軛加成反應引進甲基合成化合物280，最後利用Wolff-Kishner反應還原酮基、三氯化鐵去除甲基苯保護，便可完成(±)-blepharostol (245)的合成。

Abstract

This thesis describes the work involved in 3 projects based on a common theme: the reductive alkylation of nitriles using lithium naphthalenide. The first chapter describes a methodology designed to access highly substituted cyclohexenes in a rapid and efficient manner. As a specific example, malononitrile derivative 32 was reacted with isoprene to furnish the Diels-Alder cycloadduct 43. Sequential treatment of cyclohexene 43 with lithium naphthalenide and acetone furnished tertiary alcohol 64, the hydroxy group of which was derivatized to give compound 78. Finally, exposure of compound 78 to lithium naphthalenide effected a reductive elimination process to furnish cyclohexene 90 bearing an exocyclic carbon-carbon double bond. This methodology proved to be extremely useful and widely applicable towards the facile and effective generation of highly congested cyclohexenes heretofore inaccessible in a convenient and high yielding manner.

Chapter 2 of this thesis deals with the total synthesis, in racemic form, of the natural product laurencenone C (103). Lithium naphthalenide treatment of cyclohexene 134, obtained as the Diels-Alder cycloadduct, followed by iodide 135 furnished cyclohexene 136. Unmasking of the primary alcohol function present in 136 by TBAF resulted in a concomitant ring closing process to yield □-lactone 142. Treating lactone 142 with methyllithium gave methyl ketone 143 which was oxidized to yield aldehyde 144. Aldol condensation of compound 144 gave enone 147, the carbonyl of which was subjected to a 1,2-addition reaction with methyllithium to give an hydroxyl intermediate which was further subjected to a 1,5-transpositioning process to give enone 149. Oxidation of enone 149 furnished symmetrical dienone 154 which yielded (±)-laurencenone C (103) after a 1,4-addition of a methyl nucleophile.

Chapter 3 continues the total synthesis theme and describes the efforts expended towards the total synthesis of blepharostol (245) in racemic form. Towards this end, enone 271, obtained in 9 synthetic steps starting from propionaldehyde, was treated with the higher order cuprate generated from chloride 263 to give Michael adduct 272. Subsequent ZnI2 mediated cyclization of compound 272 yielded, via a 6-exo-dig fashion, a mixture of cyclized adducts 273a, 273b, 274a, and 274b. Compound 273b was treated with trifluoroacetic acid to effect the removal of the trimethylsilyl function to yield ketone 274b which was subsequently oxidized to yield the advanced intermediate enone 275b. Incidentally, the suitability of enone 255, readily obtained in bulk quantities starting from 1,3-cyclohexanedione, as a feedstock to enone 275b was also investigated. Following the same synthetic pathway utilized for enone 271, Michael adduct 264 was obtained but all attempts at achieving the cyclization process were fruitless, presumably due to added rigidity of the molecule afforded by the presence of the extra carbon-carbon double bond. Future work in this project will entail the transpositioning of the exocyclic olefin in ketone 275b to an endocyclic position (i.e. compound 277), reductive alkylation of the bridgehead nitrile using lithium naphthalenide and methyl iodide to furnish compound 278, 1,4-addition of a methyl group onto the enone system (278 to 280), Wolff-Kishner reduction of the resulting carbonyl (280 to 281), and selective hydrogenolysis of the benzyl group will allow for the total synthesis of (±)-blepharostol.

參考文獻
1. Holy, N. L. Chem. Rev. 1974, 74, 243.
2. Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
3. Najera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155.
4. Yus, M. Chem. Soc. Revs. 1996,155.
5. Racccanelli, S.; Pavoni, B.; Maroli, L.; Toxicol. Environ. Chem. 1994, 45, 1221.
6. (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.
7. (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.
8. Guijaro, A.; Yus, M. Tetrahedron 1994, 50, 3447.
9. Agawa, T.; Ishida, M.; Ohshiro, Y. Synthesis 1980, 933
10. Pradhan, S. K.; Radhakrishnan, T. V.; Subramanian, R. J. Org. Chem. 1976, 41, 1943.
11. (a) Bartmann, E. Angew. Chem. Int. Ed. Engl. 1986, 25, 653. (b) Almena, J.; Foubeo, F.; Yus, M. J. Org. Chem. 1994, 59, 3210.
12. Clive, D. L. J.; Keshava, Myrthy, K. S.; Zhang, C.; Hayward, W. D.; Daigneault, S. J. Chem. Soc., Chem. Commun. 1990, 509.
13. Philips, K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40, 1856.
14. (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.
15. Shia, K. S.; Chang, N. Y.; Yip, J.; Liu, H. J. Tetrahedron Lett. 1997, 38, 7713.
16. Liu, H. J.; Shia, K. S.; Zhu, J. L.; Tetrahedron Lett. 1998, 39, 4183.
17. (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。
18. Rychnovsky, S. D.; Swenson, S. S. J. Org. Chem. 1997, 62, 1333. (b) Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J. P.; Moinet, 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.
19. 戴嘉良，碩士論文，國立清華大學，1999年。
20. 謝琬萍，碩士論文，國立清華大學，2001年。
21. 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.
22. Liu, H. J.; Tsai, T. Y.; Shia, K. S. Synlett. 2003, 1, 97.
23. 蔡廷岳，博士論文，國立清華大學，2004年。
24. 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.
25. Kocienski, P. Chem Ind. (London) 1981, 548.
26. Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833.
27. (a) Carruthers, W. Cycloaddition Reaction in Organic Synthesis; Pergamon: Oxford, 1990. (b) Feringuelli, 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.
28. (a) Staudinger, H. Die Ketene, F. Enke, Stuttgart, 1912. (b) Yamabe, S.; Tatsuo, D. J. Am. Chem. Soc. 1996, 118, 6518.
29. Ruden, R. A.; Bonjouklian, R. J. Org. Chem. 1977, 42, 4095.
30. Prajapati, D.; Lekhok, K. C.; Sandhu, T. S.; Ghosh, A. C. J. Chem. Soc. Perkin Trans 1, 1996, 959.
31. Cope, A. C. J. Am. Chem. Soc. 1937, 59, 2327.
32. Hein, R. W.; Astle, M. J.; Shelton, J. R. J. Org. Chem. 1961, 26, 4874.
33. Lehnert, W. Tetrahedron 1974, 30, 301.
34. (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.
35. Brillon, D.; Sauvé, G. J. Org. Chem. 1992, 57, 1838.
36. (a) Prout, F. S. J. Org. Chem. 1953, 18, 928. (b) Rand, L.; Swisher, J. V.; Cronin, C. J. J. Org. Chem. 1962, 27, 3505. (c) Chalais, S.; Laszlo, P.; Mathy, A. Tetrahedron Lett. 1985, 26, 4453. (d) Reddy, T. I.; Varma R. S. Tetrahedron Lett. 1997, 38, 1721.
37. Wade, L. G. Organic Chemistry, Pearson Prentice Hall, 3rd edition, 1995, 691.
38. 曹景博，博士論文，國立清華大學，2005年。
39. Hassner, A.; Stumer, C. Organic Syntheses Based on Name Reaction, Pergamon, 2nd edition, 2002, 253.
40. Keyser, J.-L. D.; Cock, C. J. C. D.; Poupaert, J. H.; Dumont, P. J. Org. Chem. 1988, 53, 4859.
41. Wothers, P.; Greeves, N.; Warren, S.; Clayden, J. Organic Chemistry, Oxford, 2001, 889.
42. Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, John Wiley & Sons, 3rd edition, 1999, 23.
43. Pojer, P. M.; Angyal, S. Tetrahedron Lett. 1976, 35, 3067.
44. Marshall, J. A.; Karas, L. J. J. Am. Chem. Soc. 1978, 100, 3615.
45. Marshall, J. A.; Karas, L. J.; Royce, R. D. J. Org, Chem. 1979, 44, 2994.
46. Cohen, T.; Kreethadumrongdat, T.; Liu, X.; Kulkarni, V. J. Am. Chem. Soc. 2001, 123, 3478.
47. Ito, S.; Endo, K.; Yoshida, T.; Yatagai, M.; Kodama, M. Chem. Commun. 1967, 186.
48. Ohta, Y.; Hirose, Y. Tetrahedron Lett. 1968, 9, 2483.
49. (a) Kennedy, D. J.; Selby, I. A.; Thomson, R. H. Phytochemistry 1988, 27, 1761. (b) Asakawa, Y.; Tori, M.; Masuya, T.; Frahm, J.-P. Phytochemistry 1990, 29, 7801.
50. Dias, T.; Brito, I.; Moujir, L.; Paiz, N.; Darias, J.; Cueto, M. J. Nat. Prod. 2005, 68, 1677.
51. Asakawa, Y.; Tori, M.; Masuya, T.; Frahm, J.-P. Phytochemistry 1990, 29, 1577.
52. Hatsui, T.; Wang, J.-J.; Takeshita, H. Bull. Chem. Soc. Jpn. 1994, 67, 2507.
53. Chen, Y.-J.; Wang, C.-Y.; Lin, W.-Y. Tetrahedron 1996, 41, 13181.
54. Srikrishna, A.; Lakshmi, B. V.; Mathews, M. Tetrahedron Lett. 2006, 47, 2103.
55. (a) Hobley, G.; Stuttle, K.; Wills, M. Tetrahedron 2003, 59, 4739. (b) Yefidoff, R.; Albeck, A. Tetrahedron 2004, 60, 8093.
56. (a) Manchand, P. S. Chem. Commun. 1971, 667. (b) Felix, A. M. J. Org. Chem. 1974, 39, 1427. (c) Fronza, G.; Fogliato, G.; Fuganti, C.; Grasselli, P.; Rigoni, R. Tetrahedron 1996, 45, 14281.
57. Rubottom, G. M.; Kim, C.-W. J. Org. Chem. 1983, 48, 1550.
58. Kamat, V. P.; Hagiwara, H.; Katsumi, T.; Hoshi, T.; Suzuki, T.; Ando, M. Tetrahedron 2000, 56, 4397.
59. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647.
60. (a) Bouchard, H.; Renard, P. Y.; Lallemand, J. Y. Tetrahedron Lett. 1991, 42, 5953. (b) Bouchard, H.; Soulie, J.; Lallemand, J. Y. Tetrahedron Lett. 1991, 42, 5957.
61. 郭俊徹，博士論文，國立清華大學，2005年。
62. (a) Liu, H. J.; Chan, W. H. Can. J. Chem. 1979, 57, 708. (b) Liu, H. J.; Chan, W. H. Can. J. Chem. 1982, 60, 1081. (c) Mehta, G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113.
63. Momose, T.; Toyooka, N.; Nishio, M.; Shinoda, H.; Fujii, H.; Yanagino, H. Heterocycles 1999, 51, 1321.
64. Mehta, G.; Nandakumar, J. Tetrahedron Lett. 2001, 42, 7667.
65. (a) Cook, K. L.; Waring, A. J. J. Chem. Soc. Perkin Trans. 1 1973, 529. (b) Paczkowski, R.; Maichle-Möessmer, C.; Maier, M. E. Org. Lett. 2000, 2, 3967.
66. (a) Rose, P. A.; Cutler, A. J.; Irvine, N. M.; Shaw, A. C., Squires, T. M.; Loewen, M. K.; Abrams, A. R. Bioorg. Med. Chem. Letter. 1997, 7, 2543. (b) Todoroki, Y.; Nakano, A.-I.; Hirai, N.; Mitsui, T.; Ohigashi, H. Biosci. Biotechnol. Biochem. 1997, 1872. (c) Hou, X.; Abrams, S. R.; Balsevich, J. J.; Irvine, N.; Norstrom, T.; Sikorski, M.; Sinha, H. K.; Steer, R. P. Can. J. Chem. 2000, 78, 963.