Total synthesis of morphine and related alkaloids explained

Synthesis of morphine-like alkaloids in chemistry describes the total synthesis of the natural morphinan class of alkaloids that includes codeine, morphine, oripavine, and thebaine and the closely related semisynthetic analogs methorphan, buprenorphine, hydromorphone, hydrocodone, isocodeine, naltrexone, nalbuphine, oxymorphone, oxycodone, and naloxone.^{[1] [2]}

The structure of morphine is not particularly complex, however the electrostatic polarization of adjacent bonded atoms does not alternate uniformly throughout the structure. This "dissonant connectivity" makes bond formation more difficult and therefore significantly complicates any synthetic strategy that is applied to this family of molecules.^[2]

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952 remains a widely used example of total synthesis.^[3] This synthesis took a total of 31 steps and proceeded in 0.06% overall yield. The hydrocodone synthesis of Kenner C. Rice is one of the most efficient and proceeds in 30% overall yield in 14 steps.^[4] At 9 steps, the Barriault route is the shortest to date, but contains a number of low-yielding steps and is racemic.^[5]

Several other syntheses were reported, notably by the research groups of Evans,^[6] Fuchs,^[7] Parker,^[8] Overman,^[9] Mulzer-Trauner,^[10] White,^[11] Taber,^[12] Trost,^[13] Fukuyama,^[14] Guillou,^[15] Stork,^[16] Magnus,^[17] Smith,^[18] and Barriault.

Gates synthesis

Gates' total synthesis of morphine^[3] provided a proof of the structure of morphine proposed by Robinson in 1925.^[19] This synthesis of morphine features one of the first examples of the Diels-Alder reaction in the context of total synthesis.^[3]

Rice synthesis

The Rice synthesis follows a biomimetic route and is the most efficient reported to date. A key step is the Grewe cyclization that is analogous to the cyclization of reticuline that occurs in morphine biosynthesis.^[4]

External links

• Morphine Total Syntheses @ SynArchive.com
• Web site: Synthesis of Morphine Alkaloids . Wilson T . 2006 . Professor Scott E. Denmark Research Group Presentations . University of Illinois at Urbana-Champaign . dead . https://web.archive.org/web/20130228131105/http://www.scs.illinois.edu/denmark/presentations/2006/gm-2006-01n31.pdf . 2013-02-28 .

Notes and References

1. Book: Chida N . Chemistry of Opioids . Recent advances in the synthesis of morphine and related alkaloids . Topics in Current Chemistry . 299 . 1–28 . 2011 . 21630507 . 10.1007/128_2010_73 . 978-3-642-18106-1 .
2. Book: Rinner U, Hudlicky T . Alkaloid Synthesis . Synthesis of morphine alkaloids and derivatives . Topics in Current Chemistry . 309 . 33–66 . 2012 . 21547687 . 10.1007/128_2011_133 . Morphine's synthesis remains a serious challenge to this day. . 978-3-642-25528-1 . 22715508 .
3. Gates M, Tschudi G . The Synthesis of Morphine . Journal of the American Chemical Society . April 1956 . 78 . 7 . 1380–1393 . 10.1021/ja01588a033 .
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 . 10.1021/jo01303a045 .
5. A Nine-Step Formal Synthesis of (±)-Morphine. Organic Letters. 21. 5. 1347–1349. en. 10.1021/acs.orglett.9b00044. 2019. Brousseau. Julie. Xolin. Amandine. Barriault. Louis. 30785291 .
6. Evans DA, Mitch CH . Studies directed towards the total synthesis of morphine alkaloids . Tetrahedron Letters . January 1982 . 23 . 3 . 285–288 . 10.1016/S0040-4039(00)86810-0 .
7. Toth JE, Hamann PR, Fuchs PL . Studies culminating in the total synthesis of (dl)-morphine . The Journal of Organic Chemistry . September 1988 . 53 . 20 . 4694–4708 . 10.1021/jo00255a008 .
8. Parker KA, Fokas D . 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 . November 1992 . 114 . 24 . 9688–9689 . 10.1021/ja00050a075 .
9. Hong CY, Kado N, Overman LE . Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (−)- and (+)-dihydrocodeinone and (−)- and (+)-morphine . Journal of the American Chemical Society . November 1993 . 115 . 23 . 11028–11029 . 10.1021/ja00076a086 .
10. Mulzer J, Dürner G, Trauner D . Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition . Angewandte Chemie International Edition in English . December 1996 . 35 . 2324 . 2830–2832 . 10.1002/anie.199628301 .
11. White JD, Hrnciar P, Stappenbeck F . Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion . The Journal of Organic Chemistry . October 1999 . 64 . 21 . 7871–7884 . 10.1021/jo990905z .
12. Taber DF, Neubert TD, Rheingold AL . Synthesis of (-)-morphine . Journal of the American Chemical Society . 124 . 42 . 12416–7 . October 2002 . 12381175 . 10.1021/ja027882h . 32048193 .
13. Trost BM, Tang W . Enantioselective synthesis of (-)-codeine and (-)-morphine . Journal of the American Chemical Society . 124 . 49 . 14542–3 . December 2002 . 12465957 . 10.1021/ja0283394 .
14. Uchida K, Yokoshima S, Kan T, Fukuyama T . Total synthesis of (+/-)-morphine . Organic Letters . 8 . 23 . 5311–3 . November 2006 . 17078705 . 10.1021/ol062112m .
15. Varin M, Barré E, Iorga B, Guillou C . Diastereoselective total synthesis of (+/-)-codeine . Chemistry: A European Journal . 14 . 22 . 6606–8 . 2008 . 18561354 . 10.1002/chem.200800744 .
16. Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ . 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 . 131 . 32 . 11402–6 . August 2009 . 19624126 . 10.1021/ja9038505 .
17. Magnus P, Sane N, Fauber BP, Lynch V . Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative . Journal of the American Chemical Society . 131 . 44 . 16045–7 . November 2009 . 19835379 . 10.1021/ja9085534 .
18. Chu S, Münster N, Balan T, Smith MD . A Cascade Strategy Enables a Total Synthesis of (±)-Morphine . Angewandte Chemie . 55 . 46 . 14306–14309 . November 2016 . 27735107 . 5129523 . 10.1002/anie.201608526 .
19. Gulland JM, Robinson R . Constitution of codeine and thebaine . Memoirs of the Literary and Philosophical Society of Manchester . 1925 . 69 . 79–86 .