嗎啡全合成

嗎啡全合成是指化學中嗎啡樣生物鹼的合成，描述了天然嗎啡喃類生物鹼的全合成，其包括可待因，嗎啡，奧利平（英語：Oripavine），和蒂巴因及其密切相關的半合成類似物丁丙諾啡，氫可酮，異可待因（英語：Isocodeine），納曲酮（英語：Naltrexone），納洛酮，納布啡和羥考酮^[1]^[2]。

嗎啡的結構並不是特別複雜，然而，相鄰結合原子的靜電極化在整個結構中不均勻交替。這種「不一致的連接性」使得鍵的形成更加困難，並且因此使應用於該分子家族的任何合成策略明顯的複雜化^[2]。

首次全合成由美國化學家馬歇爾·D·蓋茨於1952年完成，並被視為這個領域中的經典之作^[3]。該合成總共用了31個步驟，並且總產率有0.06％。Kenner C. Rice的氫可酮合成是最有效的，用了14個步驟並且有30％的總產率^[4]。

此後，許多化學家提出了新的合成路線，其中值得注意的有以下研究者率領的團隊所提出的路線：賴斯、^[5]埃文斯、^[6]富克斯、^[7]帕克、^[8]奧爾曼、^[9]木澤爾·特勞納、^[10]懷特、^[11]泰伯、^[12]特羅斯特、^[13]福山、^[14]吉尤^[15]和斯托克。^[16]

蓋茨的合成路線

蓋茨的嗎啡全合成路線是在全合成中運用Diels-Alder反應的首個例子。

Rice的合成路線

Rice合成遵循仿生途徑，並且是迄今為止已經被報道中最有效的。一個關鍵的步驟是Grewe環化，類似於發生在嗎啡生物合成中的網狀結構的環化 ^[4]。

參考文獻

^ 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|title=為空 (幫助)
^ ^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.

外部連結

Morphine Total Syntheses @ SynArchive.com（頁面存檔備份，存於網際網路檔案館）

[pmid21630507-1] 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] 2.0 ^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.

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

[Rice_1980-4] 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.

[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.

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