吗啡全合成

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（英语：Oripavine），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（英语：Isocodeine），纳曲酮（英语：Naltrexone），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]。

首次全合成由美国化学家马歇尔·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]。

[1]
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]
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.
[3]
Gates, Marshall; Tschudi, Gilg. Journal of the American Chemical Society. 1956, 78 (7): 1380. doi:10.1021/ja01588a033. 缺少或|title=为空 (帮助)
[4]
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.
[5]
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.
[6]
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.
[7]
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.
[8]
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.
[9]
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.
[10]
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.
[11]
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.
[12]
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.
[13]
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.
[14]
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.
[15]
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.
[16]
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.

Morphine Total Syntheses @ SynArchive.com（页面存档备份，存于互联网档案馆）

[pmid21630507-1] [1]
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.

[pmid21547687-2] [2]
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.

[Doijaa-3] [3]
Gates, Marshall; Tschudi, Gilg. Journal of the American Chemical Society. 1956, 78 (7): 1380. doi:10.1021/ja01588a033. 缺少或|title=为空 (帮助)

[Rice_1980-4] [4]
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.

[5] [5]
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.

[6] [6]
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.

[7] [7]
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.

[8] [8]
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.

[9] [9]
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.

[10] [10]
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.

[11] [11]
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.

[12] [12]
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.

[13] [13]
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.

[14] [14]
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.

[15] [15]
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.

[16] [16]
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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

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吗啡全合成

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盖茨的合成路线

Rice的合成路线

参考文献

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