本研究希望利用樟腦衍生物 126 作為掌性輔助基，與甘胺酸第三
丁酯 (128) 縮合形成的樟腦醯基亞胺 109 與 α,β-不飽和酸酯 118 經
由 1,4-加成反應來建立不對稱中心得到化合物 119；化合物 119 利用
胺轉換將掌性輔助基水解並進行合環反應，可建構出內醯胺(lactam)
結構的焦谷胺酯(Pyroglutamate) 120，且進行羥醛反應建構出 4 號碳
具有立體中心的中間體145，做為紅藻胺酸(+)-α-Allokainic acid (7) 合
成研究的重要前驅物。

This study is the application of camphor derivatives ketopinic amide
126 as a chiral auxiliary in the synthesis of pyrrolidine alkaloids.
Condensation of ketopinic amide 126 with tert-butyl glycinate (128)
provided imine 109. Compound 119 could be obtained via asymmetric
Michael addition of imine 109 with α,β-unsaturated ester 118. Hydrolysis
of compound 119 to remove the chiral auxiliary followed by cyclization
to afford lactam 120, and then via aldol reaction can construct the chiral
center to provide compound 145 which can be an important precursor for
the synthesis of (+)-α-Allokainic acid (7).

65

第四章 參考文獻
[1] Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026.
[2] Nitta, I.; Watase, H.; Tomiie, Y. Nature (London) 1958, 181, 761.
[3] Cantrell, B. E.; Zimmerman, D. M.; Monn, J. A.; Kamboj, R. K.; Hoo,
K. H.; Tizzano, J. P.; Pullar, I. A.; Farrell, L. N.; Bleakman, D. J. Med.
Chem. 1996, 39, 3617.
[4] (a) Takemoto, T. and Daigo, K. Chem. Pharm. Bull. 1958, 6, 578. (b)
Daigo, K. J. Pharm. Soc. Jpn. 1959, 79, 350.
[5] Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto, T.;
Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892.
[6] Watase, H.; Tomiie, Y.; Nitta, I. Bull. Chem. Soc. Jpn. 1958, 31, 714.
[7] Johnston, G. A. R.; Curtis, D. R.; Davies, J.; McCulloch, R. M. Nature,
1974, 248, 804.
[8] Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1-32.
[9] Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
[10] (a) McGeer, E.G.; Olney, J.W.; McGeer, P.L., Eds., Kainic Acid as a
Tool in Neurobiology, Raven Press, New York, 1978. (b) Simon, R.P.,
Ed., Excitatory Amino Acids, Thieme Medical Publishers, New York,
1992. (c) Wheal, H.V.; Thomson, A.M., Eds., Excitatory Amino
Acids and Synaptic Transmission, Academic Press, London, 1991.
[11] Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.
66

[12] (a) Oppolzer, W.; Robbiani, C.; Battig, K. Tetrahedron 1984, 40,
1391. (b) Baldwin, J. E.; Lee, C.-S. J. Chem. Soc. Chem. Commun.
1987, 166. (c) Barco, A.; Benetti, S.; Casolari, A.; Pollini, G. P.;
Spalluto, G. Tetrahedron Lett. 1990, 31, 4917. (d) Barco, A.; Benetti,
S.; Spalluto, G.; Casolari, A.; Pollini, G. P.; Zanirato, V. J. Org. Chem
. 1992, 57, 6279. (e) Hatakeyama, S.; Sugawara, K.; Takano, S. J.
Chem. Soc. Chem. Commun. 1993, 125. (f) Agami, C.; Cases, M.;
Couty, F. J. Org. Chem. 1994, 59, 7937. (g) Ezquerra, J.; Estibano,
A.; Rubio, A.; Remuinan, M. J.; Vaquero, J. J. Tetrahedron Lett. 1995,
36, 6149. (h) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 54
18. (i) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896.
(j) Bachi, M. D.; Melman, A. Pure Appl. Chem. 1998, 70, 259.
(k) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55, 6153.
(l) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc.
Perkin Trans. 1 2000, 3194. (m) Ma, D.; Deng, P. Tetrahedron Lett.
2001, 42, 6929. (n) Xia, Qian; Ganem, B. Org. Lett. 2001, 3, 485. (o)
Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem Commun. 2002, 38.
(p) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (q) Cook, G.
R.; Sun, L. Org. Lett. 2004, 6, 2481. (r) Morita, Y.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2005, 7, 4337. (s) Pandey, S. K.; Orellana,
A.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665. (t) Yung,
Y. C.; Yoon, C. H.; uros, E.; Yoo, K. S.; Yung, K. W. J. Org. Chem.
2007, 72, 10114. (u) Tomooka, K.; Akiyama, T.; Man, P.; Suzuki, M.
Tetrahedron Lett. 2008, 49, 6327. (v) Kitamoto, K.; Sampei, M.;
Nakayama, Y.; ato, T.; Chida, N. Org. Lett. 2010, 12, 5756. (w)
Lemière, G.; Sedehizadeh, S.; Toueg, J.; Fleary-Roberts, N.; Clayden,
J. Chem. Commun. 2011, 47, 3745. (x) Arena, G.; Chen, C. C.;
67

Leonori, D.; Aggarwal, V. K. Org. Lett. 2013, 15, 4250. (y) Vulovic,
B.; Pavlovic, M. G.; Matovic, R.; Saicic, R. M. Org. Lett. 2014, 16,
34.
[13] Oppolzer, W.; Robbiani, C.; Btittig, K. Tetrahedron 1984, 40,
1391.
[14] Murakami, M.; Hasegawa, N.; Hayashi, M.; Ito,Y. J. Org. Chem.
1991, 56, 7356.
[15] Barco, A.; Spalluto, G.; Benetti, S. J. Org. Chem. 1992, 57, 6279
[16] Agami, C.; Cases, M.; Couty, F. J. Org. Chem. 1994, 59, 7937.
[17] Rubio, A.; Ezquerra, J.; Escribano, A.; Remuiñán, M.J.; Vaquero,
J.J.; Tetrahedron Lett. 1998, 39, 2171.
[18] Scott, M. E.; Lautens, E. Org. Lett. 2005, 7, 3045.
[19] Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, Y. C.; Jung, K. W. J. Org.
Chem. 2007, 72, 10114.
[20] Achqar, A. E.; Boumzebra, M.; Roumestant, M. L.; Viallefont P.
Tetrahedron 1988, 44, 5319.
[21] Kanemasa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2739.
[22] Rolland, J. W.; Roumestant, M. L.; Martinez, J. Tetrahedron:
Asymmetry 2003, 14, 1123.
[23] Xu, P.-F.; Huang, Y.; Li, Q.; Liu, T.-L. J. Org. Chem. 2009, 74, 1252.
[24] 鍾權忠，清華大學博士論文，2010。
[25] (a) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. Tetrahedron:
68

Asymmetry 2001, 12, 1353. (b) Zampella, A.; D’Auria, M. V.;
Paloma, L. G.; Casapullo, A. Minale, L.; Debitus, C.; Henin, Y. J. Am.
Chem. Soc. 1996, 118, 6202. (c) Calimsiz, S.; Lipton, M. A. J. Org.
Chem. 2005, 70, 6218.
[26] (a) Somfia, P.; Ahman, J. Tetrahedron Lett. 1992, 33, 3791. (b)
Ahman, J.; Somfia, P. Tetrahedron Lett. 1992, 48, 9537. (c)
Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp , W. N.
Tetrahedron Lett. 1986 , 27, 4709.
[27] (a) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang, J.; Cai, C.;
Hruby, V. J. J. Org. Chem. 2002, 67, 6353. (b) Lim, S. H.; Ma, S.;
Beak, P. J. Org. Chem. 2001, 66, 9056.
[28] (a) Ezquerra, J.; Pedregal, C.; Collado, I.; Yruretagoyena, B.; Rubio,
A. Tetrahedron 1995, 51, 10107. (b) Ohta , T.; Hosoi, A.; Nozoe, S.
Tetrahedron Lett. 1988, 29, 329. (c) Attwood, M. R.; Carr, M. G.;
Jordan, S. Tetrahedron Lett. 1990, 31, 283.
[29] Lin, S.; Deiana, L.; Tseggai, A.; Córdova, A. Eur. J. Org. Chem.
2011, 398
[30] 許筑婷，清華大學博士論文，2010。
[31] Ezquerra, J.; Pedregal, C.; Yruretagoyena, B.; Rubio, A. J. Org.
Chem. 1995, 60, 2925.
[32] Tchabanenko, K.; Clayden, J. Chem. Commun. 2000, 317.
[33] 詹德品，清華大學博士論文，2004。

69

[34] Iwabuchi, Y.; Ogasawara, K.; Takano, S. J. Chem. Soc. Chem.
Commun. 1988, 1204.