吗啡全合成
外观
吗啡全合成是指化学中吗啡样生物碱的合成,描述了天然吗啡喃类生物碱的全合成,其包括可待因,吗啡,奥利平,和蒂巴因及其密切相关的半合成类似物丁丙诺啡,氢可酮,异可待因,纳曲酮,纳洛酮,纳布啡和羟考酮[1][2]。
吗啡的结构并不是特别复杂,然而,相邻结合原子的静电极化在整个结构中不均匀交替。这种“不一致的连接性”使得键的形成更加困难,并且因此使应用于该分子家族的任何合成策略明显的复杂化[2]。
首次全合成由美國化學家马歇尔·D·盖茨于1952年完成,并被视为这个领域中的经典之作[3]。该合成总共用了31个步骤,并且总产率有0.06%。Kenner C. Rice的氢可酮合成是最有效的,用了14个步骤并且有30%的总产率[4]。
此后,许多化学家提出了新的合成路线,其中值得注意的有以下研究者率领的团队所提出的路线:赖斯、[5]埃文斯、[6]富克斯、[7]帕克、[8]奥尔曼、[9]木泽尔·特劳纳、[10]怀特、[11]泰伯、[12]特罗斯特、[13]福山、[14]吉尤[15]和斯托克。[16]
盖茨的合成路线
[编辑]盖茨的吗啡全合成路线是在全合成中运用Diels-Alder反应的首个例子。
Rice的合成路线
[编辑]Rice合成遵循仿生途径,并且是迄今为止已经被报道中最有效的。一个关键的步骤是Grewe环化,类似于发生在吗啡生物合成中的网状结构的环化 [4]。
参考文献
[编辑]- ^ Chida N. Recent advances in the synthesis of morphine and related alkaloids. Top Curr Chem. 2011, 299: 1–28. PMID 21630507. doi:10.1007/128_2010_73.
- ^ 2.0 2.1 Rinner U, Hudlicky T. Synthesis of morphine alkaloids and derivatives. Top Curr Chem. 2012, 309: 33–66. PMID 21547687. doi:10.1007/128_2011_133.
Morphine's synthesis remains a serious challenge to this day.
- ^ Gates, Marshall; Tschudi, Gilg. Journal of the American Chemical Society. 1956, 78 (7): 1380. doi:10.1021/ja01588a033. 缺少或
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为空 (帮助) - ^ 4.0 4.1 Rice KC. Synthetic opium alkaloids and derivatives. A short total synthesis of ( /-)-dihydrothebainone, ( /-)-dihydrocodeinone, and ( /-)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners. The Journal of Organic Chemistry. July 1980, 45 (15): 3135–3137. doi:10.1021/jo01303a045.
- ^ Rice, Kenner C. Synthetic opium alkaloids and derivatives. A short total synthesis of (. -.)-dihydrothebainone, (. -.)-dihydrocodeinone, and (. -.)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners. The Journal of Organic Chemistry. 1980, 45 (15): 3135. doi:10.1021/jo01303a045.
- ^ Evans, D.A.; Mitch, C.H. Studies directed towards the total synthesis of morphine alkaloids. Tetrahedron Letters. 1982, 23 (3): 285. doi:10.1016/S0040-4039(00)86810-0.
- ^ Toth, J. E.; Hamann, P. R.; Fuchs, P. L. Studies culminating in the total synthesis of (dl)-morphine. The Journal of Organic Chemistry. 1988, 53 (20): 4694. doi:10.1021/jo00255a008.
- ^ Parker, Kathlyn A.; Fokas, Demosthenes. Convergent synthesis of (. -.)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (. -.)-morphine. Journal of the American Chemical Society. 1992, 114 (24): 9688. doi:10.1021/ja00050a075.
- ^ Hong, Chang Y.; Kado, Noriyuki; Overman, Larry E. Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (-)- and ( )-dihydrocodeinone and (-)- and ( )-morphine. Journal of the American Chemical Society. 1993, 115 (23): 11028. doi:10.1021/ja00076a086.
- ^ Mulzer, Johann; Dürner, Gerd; Trauner, Dirk. Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition. Angewandte Chemie International Edition in English. 1996, 35 (2324): 2830. doi:10.1002/anie.199628301.
- ^ White, James D.; Hrnciar, Peter; Stappenbeck, Frank. Asymmetric Total Synthesis of ( )-Codeine via Intramolecular Carbenoid Insertion. The Journal of Organic Chemistry. 1999, 64 (21): 7871. doi:10.1021/jo990905z.
- ^ Taber, Douglass F.; Neubert, Timothy D.; Rheingold, Arnold L. Synthesis of (−)-Morphine. Journal of the American Chemical Society. 2002, 124 (42): 12416–7. PMID 12381175. doi:10.1021/ja027882h.
- ^ Trost, Barry M.; Tang, Weiping. Enantioselective Synthesis of (−)-Codeine and (−)-Morphine. Journal of the American Chemical Society. 2002, 124 (49): 14542–3. PMID 12465957. doi:10.1021/ja0283394.
- ^ Uchida, Kenji; Yokoshima, Satoshi; Kan, Toshiyuki; Fukuyama, Tohru. Total Synthesis of (±)-Morphine. Organic Letters. 2006, 8 (23): 5311–3. PMID 17078705. doi:10.1021/ol062112m.
- ^ Varin, Marie; Barré, Elvina; Iorga, Bogdan; Guillou, Catherine. Diastereoselective Total Synthesis of (±)-Codeine. Chemistry - A European Journal. 2008, 14 (22): 6606. doi:10.1002/chem.200800744.
- ^ Stork, Gilbert; Yamashita, Ayako; Adams, Julian; Schulte, Gary R.; Chesworth, Richard; Miyazaki, Yoji; Farmer, Jay J. Regiospecific and Stereoselective Syntheses of (±) Morphine, Codeine, and Thebaine via a Highly Stereocontrolled Intramolecular 4 2 Cycloaddition Leading to a Phenanthrofuran System. Journal of the American Chemical Society. 2009, 131 (32): 11402–6. PMID 19624126. doi:10.1021/ja9038505.