本論文內容共分為兩個部分：第一部份係具有光學活性之一倍半萜類(sesquiterpene)天然物(+)-ricciocarpin A (1)之全合成；第二部份則是具有光學活性之二萜類(diterpene)天然物(-)-pisiferin (68)與(-)-isopisiferin (70)之合成研究。

第一部份：以市售之4,4-二甲基-2-環己烯酮(53)為起始物，利用已知的方法來合成具有光學活性之(R)-2-碘基-4,4-二甲基-2-環己烯醇((+)-52)。於Johnson條件下，烯丙醇(allylic alcohol)化合物(+)-52可經由Claisen重排反應而得到α,β-不飽和酯化合物(-)-54。藉由該重排反應((+)-52→(-)-54)，我們非但完成構築天然物的δ-內酯環(δ-lactone ring)時至為關鍵之兩個碳單元的支鏈；同時化合物(+)-52之掌性(chirality)在重排過程中將被保留(retention)至產物(-)-54。為了促進3-呋喃鋰(3-lithiofuran)的加成效率，我們將化合物(-)-54的酯基轉換成醛基((-)-60)，加成反應後得到兩非對映異構物(-)-59與(-)-62 (比例為(-)-59：(-)-62＝1：2)。其中立體位向相反之化合物(-)-62可以經由Mitsunobu反應來修正其立體位向而得到化合物(-)-59。在零價的鈀金屬及一氧化碳的條件下進行分子內環化反應而建立δ-內酯環((+)-41)，最後將α,β-不飽和酯還原即可完成具有光學活性之天然物(+)-ricciocarpin A (1)之全合成。
第二部份：同樣以具有光學活性之醛基化合物(-)-60為中間體，芳香族化合物115進行金屬-鹵素交換反應產生有機鋰試劑，然後加成到化合物(-)-60的醛基而得到兩非對映異構物之混合物118，比例為1：2.2。在對甲苯磺酸(p-TsOH)作用下脫水而得到化合物(-)-114。將化合物(-)-114的乙烯基碘轉換成α,β-不飽和酯基((-)-120)，在Pd/C的催化下，選擇性氫化環外之雙取代雙鍵而得到化合物(-)-121，待將酯基水解成羧酸基後即完成Friedel-Crafts環化反應之前驅物(-)-113的製備。利用三氟醋酸與三氟醋酸酐促進環化反應而完成天然物骨架的建立((-)-112)。經由官能基轉換得到與二烯化合物127，選擇性氫化雙取代雙鍵後得到(-)-isopisiferin methyl ether ((-)-88)，去甲基醚保護後即可完成具有光學活性之天然物(-)-isopisiferin (70)之全合成。

The first part of this thesis describes the asymmetric total synthesis of naturally occurring sesquiterpene (+)-ricciocarpin A (1) in its native optical form. Starting with 4,4-dimethyl-2-cyclohexenone (53) and following precedented procedures alcohol (+)-52 was obtained. Under Johnson’s condition, optically active ester (-)-54 was arrived at via a Claisen rearrangement of (+)-52. Not only did this rearrangement process allowed for a complete retention of stereochemical integrity, but also established the ring junction stereochemistry found in the target molecule. To facilitate the installationof the 3-furyl moiety, ester (-)-54 was transformed to aldehyde (-)-60 followed by a 1,2-addition of 3-furyllithium across the aldehydic carbonyl. In this way, an epimeric mixture of alcohols (-)-59 and (-)-62 was obtained in a relative ratio of 1:2. The undesired epimer was converted to the desired (-)-59 via a Mitsunobu reaction and which was exposed to Pd(0) and carbon monoxide to furnish□δ-lactone (+)-41. Finally, the α,β-unsaturated enone system was reduced to yield (+)-ricciocarpin A (1).

The second part of this thesis details the investigation towards the asymmetric total synthesis of (-)-pisiferin (68) and (-)-isopisiferin (70) in their natural optical form. Starting from optically pure aldehyde (-)-60 and treating with the organometallic reagent resulting from metal -halogen exchange of bromide 115, an epimeric mixture of alcohol 118 was obtained in a ratio of 1:2.2. This was subsequently dehydrated to furnish compound (-)-114, the exocyclic olefin of which was selectively saturated via hydrogenation over palladium catalyst to yield ester (-)-121. Upon hydrolysis of the ester moiety of (-)-121, the resulting carboxylic acid (-)-113 was treated with trifluoroacetic acid and trifluoroacetic anhydride to achieve the desired Friedel-Crafts type cyclization process to yield tricyclic ketone (-)-112 bearing the skeletal core of the targeted natural products containing the correct stereochemistry in the ring junction. Towards natural product 70, ketone (-)-112 was reduced to ether 127, the less substituted olefin of which was selectively saturated to yield ether (-)-88. All that remains is to unveil the phenol functionality to arrive at naturally occurring (-)-isopisiferin (70).

1. Wurzel, G.; Becker, H. Phytochemistry 1990, 29, 2565.
2. (a) Wurzel, G.; Becker, H.; Eicher, T.; Tiefensee, K. Planta Med. 1990, 56, 444. (b) Zinsmeister, H. D.; Becker, H.; Eicher, T. Angew. Chem. Int. Ed. Engl. 1991, 30, 130. (c) Thiel, R.; Adam, K. P.; Zapp, J.; Becker, H. Pharm. Pharmacol. Lett. 1997, 7, 103.
3. Nabih, I.; Elwasimi, M. T. J. Pharm. Sci. 1968, 57, 1202.
4. Schreier, T. M.; Dawson, V. K.; Choi, Y.; Spanjers, N. J.; Boogaard, M. A. J. Agric. Food Chem. 2000, 48, 2212.
5. Eicher, T.; Massonne, K.; Herrmann, M. Synthesis 1991, 1173.
6. (a) Ihara, M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Chem. Commun. 1993, 755. (b) Ihara, M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1993, 2251.
7. Takeda, K.; Ohkawa, N.; Hori, K.; Koizumi, T.; Yoshii, E. Heterocycles 1998, 47, 277.
8. (a) Held, C.; Frohlich, R.; Metz, P. Angew. Chem. Int. Ed. 2001, 40, 1058. (b) Held, C.; Frohlich, R.; Metz, P. Adv. Synth. Catal. 2002, 344, 720.
9. Agapiou, K.; Krische, M. Org. Lett. 2003, 5, 1737.
10. Sibi, M. P.; He, L. Org. Lett. 2004, 6, 1749.
11. (a) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012. (b) Yet, L. Chem. Rev. 2000, 100, 2963.
12. Corey, E. J.; Wu, L. I. Tetrahedron Lett. 1994, 35, 663.
13. Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1981, 103, 5454.
14. Jackson, W. R.; Zuquiyah, A. J. Chem. Soc. 1965, 5280.
15. (a) Orita, A.; Nagano, Y.; Hirano, J.; Otera, J. Synlett. 2001, 637. (b) Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org. Lett. 2002, 4, 3343.
16. (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. (b) Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G. Tetrahedron Lett. 1997, 37, 2825.
17. (a) Negishi, E.-i.; Takahashi, T.; King, A. O. Org. Synth. 1988, 66, 67. (b) Xue, S.; Han, K.-Z.; He, L.; Guo, Q.-X. Synlett. 2003, 870.
18. (a) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem. 1998, 63, 228. (b) Cossy, J.; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett. 2002, 1595.
19. Overman, L. E.; Kamatani, A. Org. Lett. 2001, 3, 1229.
20. (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem. Commun. 1983, 469. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. J. Am. Chem. Soc. 1987, 109, 5551. (c) Itsuno, S. Org. React. 1998, 52, 395.
21. Knochel, P.; Soorukram, D. Org. Lett. 2004, 6, 2409.
22. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741.
23. Bovonsombat, P.; Angara, G. J.; McNelis, E. Tetrahedron Lett. 1994, 35, 6787.
24. Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron 1990, 46, 1199.
25. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
26. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
27. (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13. (c) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
28. Ly, T. W.; Liao, J. H.; Shia, K. S.; Liu, H. J. Synthesis 2004, 271.
29. Hagiwara, H.; Hamano, K.; Nozawa, M.; Hoshi, T.; Suzuki, T.; Kido, F. J. Org. Chem. 2005, 70, 2250.
30. Mitsunobu, O. Synthesis 1981, 1.
31. Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67, 2323.
32. Yatagai, M.; Takahashi, T. Phytochemistry 1980, 19, 1149.
33. Hasegawa, S.; Hirose, Y.; Yatagai, M.; Takahashi, T. Chem. Lett. 1984, 1837.
34. Hasegawa, S.; Kojima, T.; Hirose, Y. Phytochemistry 1985, 24, 1545.
35. Matsumoto, T.; Imai, S.; Yoshinari, T.; Matsuno, S. Bull. Chem. Soc. Jpn. 1986, 59, 3103.
36. Kametani, T.; Kondoh, H.; Tsubuki, M.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 5.
37. Deb, S.; Bhattachariee G.; Ghatak, U. R. J. Chem. Soc., Perkin Trans. 1 1990, 1453.
38. Majetich, G.; Hicks, R.; Zhang, Y.; Tian, X.; Feltman, T. L.; Fang, J.; Duncan, S. G., Jr. J. Org. Chem. 1996, 61, 8169.
39. Jan, N. W.; Liu, H. J. Org. Lett. 2006, 8, 151.
40. Tanaka, M.; Abe, Y.; Tokuyama, K. Chem. Pharm. Bull. 1978, 26, 1558.
41. Dhekne, V. V.; Rao, A. S. Synth. Commun. 1978, 8, 135.
42. (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
43. Tai, C. L.; Ly, T. W.; Wu, J. D.; Shia, K. S.; Liu, H. J. Synlett. 2001, 214.
44. Liu, H. J.; Yip, J.; Shia, K. S. Tetrahedron Lett. 1997, 38, 2253.
45. (a) Poigny, S.; Huor, T.; Guyot, M.; Samadi, M. J. Org. Chem. 1999, 64, 9318. (b) Liao, J. H., Ph.D. Thesis, National Tsing Hua University, 2004.
46. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
47. (a) Takano, M.; Umino, A.; Nakada, M. Org. Lett. 2004, 6, 4897. (b) Watanabe, K.; Iwasaki, K.; Abe, T.; Inoue, M.; Ohkubo, K.; Suzuki, T.; Katoh, T. Org. Lett. 2005, 7, 3745.
48. Srebnik, M.; Mechoulam, R.; Yona, I. J. Chem. Soc., Perkin Trans. 1 1987, 1423.
49. Chang, H. M.; Cheng, K. P.; Choang, T. F.; Chow, H. F.; Chui, K. Y.; Hon, P. M.; Tan, F. W. L.; Yang, Y.; Zhong, Z. P.; Lee, C. M.; Sham, H. L.; Chan, C. F.; Cui, Y. X.; Wong, H. N. C. J. Org. Chem. 1990, 55, 3537.
50. Yim, H. K.; Liao, Y.; Wong, H. N. C. Tetrahedron 2003, 59, 1877.
51. (a) Chakraborthy, A.; Kar, G. K.; Ray, J. K. Tetrahedron 1997, 53, 2989. (b) Doe, M.; Shibue, T.; Haraguchi, H.; Morimoto, Y. Org. Lett. 2005, 7, 1765.