English
往期目录
新闻公告
More
化学进展 2018, Vol. 30 Issue (12): 1827-1835 DOI: 10.7536/PC180227 前一篇   后一篇

• 综述 •

高三尖杉酯碱和三尖杉酯碱的合成研究

董玉, 李海波, 李津, 冯磊, 张志伟*   

  1. 河北科技大学化学与制药工程学院 河北省药用分子化学重点实验室 石家庄 050018
  • 收稿日期:2018-02-28 修回日期:2018-05-17 出版日期:2018-12-15 发布日期:2018-08-17
  • 通讯作者: 张志伟 E-mail:zhangzw@hebust.edu.cn
  • 基金资助:
    国家自然科学基金项目（No.21302039）和河北省自然科学基金项目（No.B2016208124）资助
下载PDF ( 498 ) 引用
导出

Synthesis of Homoharringtonine and Harringtonine

Yu Dong, Haibo Li, Jin Li, Lei Feng, Zhiwei Zhang*   

  1. College of Chemical and Pharmaceutical Engineering, Key Laboratory of Molecular Chemistry for Drug of Hebei Province, Hebei University of Science and Technology, Shijiazhuang 050018, China
  • Received:2018-02-28 Revised:2018-05-17 Online:2018-12-15 Published:2018-08-17
  • Supported by:
    The work was supported by the National Natural Science Foundation of China(No. 21302039) and the Natural Science Foundation of Hebei Province(No. B2016208124).
天然药物高三尖杉酯碱和三尖杉酯碱是从三尖杉植物的叶和茎中分离得到的微量生物碱，是手性化合物。结构上，二者不仅含有一个共同的母核三尖杉碱，酯基侧链的α位也均为手性叔醇。因母核三尖杉碱和酯基侧链较大的空间位阻，两个结构片段的酯化偶联具有较大的挑战性。设计合成位阻较小的侧链中间体是酯化反应发生的关键。因此，化学家们相继合成了结构多样的α-羰基羧酸侧链以及含有杂环的侧链中间体，如四元内酯杂环侧链、四氢呋喃杂环侧链、六氢吡喃杂环侧链、七元内酯杂环侧链，并成功地完成了高三尖杉酯碱、三尖杉酯碱和同属其他活性生物碱的合成。本文基于本课题组的相关研究，根据侧链片段的构建策略和方法，综述了天然药物高三尖杉酯碱、三尖杉酯碱以及其他天然产物的合成研究。不仅总结了近几年来的新进展，还对我国老一辈的科学家们在此方面作出的贡献进行了回顾。
关键词： 高三尖杉酯碱, 天然药物, 侧链中间体, 手性叔醇, 合成策略
Natural drugs homoharringtonine and harringtonine are minor alkaloids isolated from the leaves and stems of plum yew Cephalotaxus harringtonia, an evergreen tree native of the southern provinces of China. Structurally, two natural drugs are all chiral compounds and have a common skeleton cephalotaxine, and the ester side chains bear chiral tertiary alcohol at α position. Because of the formidable steric bulk of both the keleton cephalotaxine and ester side chain, the esterification of both sections is extremely challenging. A less hindered side chain intermediate is key element to success for this coupling reaction. Consequently, chemists continuously designed and synthesized structurally diverse side chain intermediates such as α-ketoacids, four-membered lactone heterocycles, tetrahydrofuran heterocycles, tetrahydropyran heterocycles, and seven-membered lactone heterocycles, enabling the completion of synthesis of homoharringtonine, harringtonine and other related natural products. Based on our studies toward the synthesis of Cephalotaxus alkaloids, this paper reviews the strategic development towards the synthesis of Cephalotaxus natural drugs and other products by the types of side chain intermediates, including not only recent strategy advances but also synthetic methods developed by respected older generation chemists.
Contents
1 Introduction
2 Synthesis of homoharringtonine
2.1 α-Ketoacids as coupling partners
2.2 Tetrahydropyran intermediate as coupling partner
2.3 Four-membered lactone intermediate as coupling partner
3 Synthesis of harringtonine
3.1 α-Ketoacid as coupling partner
3.2 Dihydrofuran intermediate as coupling partner
3.3 Seven-membered lactone intermediate as coupling partner
4 Synthesis of anhydroharringtonine
4.1 α-Ketoacid as coupling partner
4.2 Tetrahydrofuran intermediate as coupling partner
5 Synthesis of homodeoxyharringtone
5.1 α-Ketoacid as coupling partner
5.2 Four-membered lactone intermediate as coupling partner
6 Synthesis of deoxyharringtone
6.1 α-Ketoacids as coupling partners
6.2 Four-membered lactone intermediate as coupling partner
7 Synthesis of isoharringtonine, nordeoxyharringtonine and homoneoharringtonine
8 Conclusion
Key words: homoharringtonine, natural drug, side chain intermediate, chiral tertiary alcohol, synthetic strategy

中图分类号: 

()
[1] (a) Huang L, Xue Z. The Alkaloids. NY:Academic Press, 1984. 157; (b) Hudlicky T, Kwart L D, Reed J W. Alkaloids Chemical and Biological Perspectives. NY:John Wiley and Sons, 1987. 639; (c) Jalil Miah M A, Hudlicky T, Reed J W. The Alkaloids. NY:Academic Press, 1998. 199; (d)何子乐(He Z L), 吴毓林(Wu Y L), 洪永叁(Hong Y S), 伍贻康(Wu Y K), 姚祝军(Yao Z J). 天然产物全合成荟萃-生物碱(Collection of Natural Products Total Synthesis-Alkaloids). 北京:科学出版社(Beijing:Science Press), 2009. 331; (e)曾步兵(Zeng B B), 任江萌(Ren J M). 药用天然产物全合成-合成路线精选(Medicinal Natural Products-Total Synthetic Approaches). 上海:华东理工大学出版社(Shanghai:East China University of Science and Technology Press), 2016. 88; (f)陈洋(Chen Y), 李卫东(Li W D Z). 有机化学(Chin. J. Org. Chem.), 2017, 37(8):1885.
[2] (a)中国药典, 1990年版二部, 1990. 588.; (b)中国药典, 2005年版二部, 2005. 629.; (c)中国药典, 2015年版二部, 2015. 1176.
[3] (a) Kantarjian H M, O'Brien S, Cortes J. Clin. Lymphoma Myeloma Leuk., 2013, 13:530; (b) Heiblig M, Sobh M, Nicolini F E. Leuk Res., 2014, 38:1145; (c)杨楠(Yang N), 孙红哲(Sun H Z). 化学进展(Prog. Chem.), 2009, 21(05):856.
[4] Hiranuma S, Shibata M, Hudlicky T. J. Org. Chem., 1983, 48:5321.
[5] Li X, Wang S, Dai J, Yan L, Zhao S, Wang J, Sun Y. European Journal of Pharmacology, 2017, 815:437.
[6] Pérard-Viret J, Quteishat L, Alsalim R, Royer J, Dumas F. The Alkaloids:Chemistry and Biology. NY:Academic Press, 2017. 205.
[7] Abdelkafi H, Nay B. Nat. Prod. Rep., 2012, 29:845.
[8] (a) Zhang Z W, Zhang X F, Feng J, Yang H, Wang C C, Feng J C, Liu S X. J. Org. Chem., 2013, 78:786; (b) Zhang ZW, Wang CC, Xue H, Dong Y, Yang JH, Liu S X, Liu WQ, Li WD Z. Org. Lett., 2018, 20:1050.
[9] 赵知中(Zhao Z Z), 席与珪(Xi Y G), 赵翰飞(Zhao H F), 侯建英(Hou J Y), 张建友(Zhang J Y), 王子厚(Wang Z H). 药学学报(Acta Pharmaceutica Sinica), 1980, 15(1):46.
[10] (a)王永铿(Wang Y K), 李裕林(Li Y L), 潘鑫复(Pan X F), 李绍白(Li S B), 黄文魁(Huang W K). 科学通报(Chin. Sci. Bull.), 1980, 25(12):576; (b)王永铿(Wang Y K), 李裕林(Li Y L), 潘鑫复(Pan X F), 李绍白(Li S B), 黄文魁(Huang W K). 化学学报(Acta Chimica Sinica), 1985, 43(2):161.
[11] Hiranuma S, Hudlicky T. Tetrahedron Lett., 1982, 23:3431.
[12] 程家宪(Cheng J X), 张建华(Zhang J H), 张千兵(Zhang Q B), 杨晶(Yang J), 黄量(Huang L). 药学学报(Acta Pharmaceutica Sinica), 1984, 19(3):178.
[13] 陈莉(Chen L), 李卫东(Li W D). CN 201110193584, 2011.
[14] Ma G Z, Li P F, Liu L, Li W D Z, Chen L. Org. Lett., 2017, 19:2250.
[15] Robin JP, Dhal R, Dujardin G, Girodier L, Mevellec L, Poutot S. Tetrahedron Lett., 1999, 40:2931.
[16] Ancliff R A, Russell A T, Sanderson A J. Chem. Commun., 2006, 3243.
[17] Marguerit M, Little G, Wang Y, He L, Allwein S, Reif J, Rossi J, Roemmele R, Bakale R. Eur. J. Org. Chem., 2015, 8003.
[18] (a) Eckelbarger J D, Wilmot J T, Gin D Y. J. Am. Chem. Soc., 2006, 128:10370; (b) Eckelbarger J D, Wilmot J T, Epperson M T, Thakur C S, Shum D, Antczak C, Tarassishin L, Djaballah H, Gin D Y. Chem. Eur. J., 2008, 14:4293.
[19] Mikolajczak K L, Smith C R Jr. J. Org. Chem., 1978, 43:4762.
[20] Huang L, Xi Y G, Guo J Y, Liu D K, Xu S P, Wu K M, Cheng J X, Jiang Y Z, Gao Y S, Guo Z R, Li L M, Zhang M Y, Chu F M. Scientia Sinica, 1979, 22:1333.
[21] Kelly T R, McNutt R W Jr, Montury M, Tosches N P. J. Org. Chem., 1979, 44:63.
[22] Berhal F, Tardy S, Pérard-Viret J, Royer J. Eur. J. Org. Chem., 2009, 437.
[23] El Bialy S A A, Braun H, Tietze L F. Eur. J. Org. Chem., 2005, 2965.
[24] 王永铿(Wang Y K), 穆启运(Mu Q Y), 李裕林(Li Y L), 潘鑫复(Pan X F), 黄文魁(Huang W K). 科学通报(Chin. Sci. Bull.), 1982, 27(14):576.
[25] 潘鑫复(Pan X F), 李裕林(Li Y L), 李绍白(Li S B), 田军(Tian J), 张大男(Zhang D N), 崔育新(Cui Y X), 成培贵(Cheng P G), 王永铿(Wang Y K), 黄文魁(Huang W K). 科学通报(Chin. Sci. Bull.), 1982, 27(17):576.
[26] (a) Keller L, Dumas F, d'Angelo J. Tetrahedron Lett. 2001, 42:1911; (b) Keller L, Dumas F, d'Angelo J. Eur. J. Org. Chem., 2003, 2488.
[27] Kelly T R, McKenna J C, Christenson P A. Tetrahedron Lett., 1973, 14, 3501.
[28] (a) Yang H, Sun M R, Zhao S G, Zhu M, Xie Y L, Niu C L, Li C L. J. Org. Chem., 2013, 78:339; (b)孙默然(Sun M R), 周航(Zhou H), 曹其伟(Cao Q W), 高凯哥(Gao K G), 杨华(Yang H). 化学研究(Chemical Research), 2013, 24(4):416; (c) Sun M R, Jia X, Lai Y W, Yang H. J. Chem. Res., 2015, 39:26.
[1] 杨孟蕊, 谢雨欣, 朱敦如. 化学稳定金属有机框架的合成策略[J]. 化学进展, 2023, 35(5): 683-698.
[2] 陈振明,刘金华,陶军华. 生物催化在绿色化学和新药开发中的应用*[J]. 化学进展, 2007, 19(012): 1919-1927.