total synthesis of morphine and related alkaloids

Image:Morphin - Morphine.svg

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.{{cite book | vauthors = Chida N | title = Chemistry of Opioids | chapter = Recent advances in the synthesis of morphine and related alkaloids | journal = Topics in Current Chemistry | volume = 299 | pages = 1–28 | year = 2011 | pmid = 21630507 | doi = 10.1007/128_2010_73 | isbn = 978-3-642-18106-1 }}{{cite book | vauthors = Rinner U, Hudlicky T | title = Alkaloid Synthesis | chapter = Synthesis of morphine alkaloids and derivatives | journal = Topics in Current Chemistry | volume = 309 | pages = 33–66 | year = 2012 | pmid = 21547687 | doi = 10.1007/128_2011_133 | quote = Morphine's synthesis remains a serious challenge to this day. | isbn = 978-3-642-25528-1 | s2cid = 22715508 }}

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.

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952 remains a widely used example of total synthesis.{{cite journal |vauthors=Gates M, Tschudi G | title = The Synthesis of Morphine | journal = Journal of the American Chemical Society |date=April 1956 | volume = 78 | issue = 7 | pages = 1380–1393 | doi = 10.1021/ja01588a033 }} 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.{{cite journal| author = Rice KC | title = 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 | journal = The Journal of Organic Chemistry |date=July 1980 | volume = 45 | issue = 15 | pages = 3135–3137 | doi = 10.1021/jo01303a045 }} At 9 steps, the Barriault route is the shortest to date, but contains a number of low-yielding steps and is racemic.{{Cite journal|title=A Nine-Step Formal Synthesis of (±)-Morphine|journal = Organic Letters|volume = 21|issue = 5|pages = 1347–1349|language=en|doi=10.1021/acs.orglett.9b00044|year = 2019|last1 = Brousseau|first1 = Julie|last2 = Xolin|first2 = Amandine|last3 = Barriault|first3 = Louis| pmid=30785291 |url = https://figshare.com/articles/A_Nine-Step_Formal_Synthesis_of_-Morphine/7745963|url-access = subscription}}

Several other syntheses were reported, notably by the research groups of Evans,{{cite journal |vauthors=Evans DA, Mitch CH | title = Studies directed towards the total synthesis of morphine alkaloids | journal = Tetrahedron Letters |date=January 1982 | volume = 23 | issue = 3 | pages = 285–288 | doi = 10.1016/S0040-4039(00)86810-0 }} Fuchs,{{cite journal |vauthors=Toth JE, Hamann PR, Fuchs PL | title = Studies culminating in the total synthesis of (dl)-morphine | journal = The Journal of Organic Chemistry |date=September 1988 | volume = 53 | issue = 20 | pages = 4694–4708 | doi = 10.1021/jo00255a008 }} Parker,{{cite journal |vauthors=Parker KA, Fokas D | title = Convergent synthesis of (+/-)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (+/-)-morphine | journal = Journal of the American Chemical Society |date=November 1992 | volume = 114 | issue = 24 | pages = 9688–9689 | doi = 10.1021/ja00050a075 }} Overman,{{cite journal |vauthors=Hong CY, Kado N, Overman LE | title = Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (−)- and (+)-dihydrocodeinone and (−)- and (+)-morphine | journal = Journal of the American Chemical Society |date=November 1993 | volume = 115 | issue = 23 | pages = 11028–11029 | doi = 10.1021/ja00076a086 }} Mulzer-Trauner,{{cite journal |vauthors=Mulzer J, Dürner G, Trauner D |title=Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition | journal = Angewandte Chemie International Edition in English |date=December 1996 | volume = 35 | issue = 2324 | pages = 2830–2832 | doi = 10.1002/anie.199628301 }} White,{{cite journal |vauthors=White JD, Hrnciar P, Stappenbeck F | title = Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion | journal = The Journal of Organic Chemistry |date=October 1999 | volume = 64 | issue = 21 | pages = 7871–7884 | doi = 10.1021/jo990905z }} Taber,{{cite journal | vauthors = Taber DF, Neubert TD, Rheingold AL | title = Synthesis of (-)-morphine | journal = Journal of the American Chemical Society | volume = 124 | issue = 42 | pages = 12416–7 | date = October 2002 | pmid = 12381175 | doi = 10.1021/ja027882h | s2cid = 32048193 }} Trost,{{cite journal | vauthors = Trost BM, Tang W | title = Enantioselective synthesis of (-)-codeine and (-)-morphine | journal = Journal of the American Chemical Society | volume = 124 | issue = 49 | pages = 14542–3 | date = December 2002 | pmid = 12465957 | doi = 10.1021/ja0283394 | url = https://figshare.com/articles/Enantioselective_Synthesis_of_-Codeine_and_-Morphine/3646293 | url-access = subscription }} Fukuyama,{{cite journal | vauthors = Uchida K, Yokoshima S, Kan T, Fukuyama T | title = Total synthesis of (+/-)-morphine | journal = Organic Letters | volume = 8 | issue = 23 | pages = 5311–3 | date = November 2006 | pmid = 17078705 | doi = 10.1021/ol062112m }} Guillou,{{cite journal | vauthors = Varin M, Barré E, Iorga B, Guillou C | title = Diastereoselective total synthesis of (+/-)-codeine | journal = Chemistry: A European Journal | volume = 14 | issue = 22 | pages = 6606–8 | year = 2008 | pmid = 18561354 | doi = 10.1002/chem.200800744 }} Stork,{{cite journal | vauthors = Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ | title = Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system | journal = Journal of the American Chemical Society | volume = 131 | issue = 32 | pages = 11402–6 | date = August 2009 | pmid = 19624126 | doi = 10.1021/ja9038505 | url = https://figshare.com/articles/Regiospecific_and_Stereoselective_Syntheses_of_Morphine_Codeine_and_Thebaine_via_a_Highly_Stereocontrolled_Intramolecular_4_2_Cycloaddition_Leading_to_a_Phenanthrofuran_System/2834536 | url-access = subscription }} Magnus,{{cite journal | vauthors = Magnus P, Sane N, Fauber BP, Lynch V | title = Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative | journal = Journal of the American Chemical Society | volume = 131 | issue = 44 | pages = 16045–7 | date = November 2009 | pmid = 19835379 | doi = 10.1021/ja9085534 | url = https://figshare.com/articles/Concise_Syntheses_of_Galanthamine_and_Codeine_via_Intramolecular_Alkylation_of_a_Phenol_Derivative/2813797 | url-access = subscription }} Smith,{{cite journal | vauthors = Chu S, Münster N, Balan T, Smith MD | title = A Cascade Strategy Enables a Total Synthesis of (±)-Morphine | journal = Angewandte Chemie | volume = 55 | issue = 46 | pages = 14306–14309 | date = November 2016 | pmid = 27735107 | pmc = 5129523 | doi = 10.1002/anie.201608526 }} and Barriault.