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Strychnine total synthesis

Strychnine ball-and-stick model based on X-ray data [1]

Strychnine total synthesis in chemistry describes the total synthesis of the complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954 is considered a classic in this research field.[2][3][4][5]

At the time it formed the natural conclusion to an elaborate process of molecular structure elucidation that started with the isolation of strychnine from the beans of Strychnos ignatii by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1818.[6] Major contributors to the entire effort were Sir Robert Robinson with over 250 publications and Hermann Leuchs with another 125 papers in a time span of 40 years. Robinson was awarded the Nobel Prize in Chemistry in 1947 for his work on alkaloids, strychnine included.

The process of chemical identification was completed with publications in 1946 by Robinson [7][8][9] and later confirmed by Woodward in 1947.[10] X-ray structures establishing the absolute configuration became available between 1947 and 1951 with publications from Johannes Martin Bijvoet[11][12] and J. H. Robertson[13][14]

Woodward published a very brief account on the strychnine synthesis in 1954 (just 3 pages)[15] and a lengthy one (42 pages) in 1963.[16]

Routes to Strychnine Many routes to Strychnine have been developed over the years. Some are chiral and some give racemic product.

Many more methods exist and reported by the research groups of Magnus,[17] Overman,[18] Kuehne,[19][20] Rawal,[21] Bosch,[22][23] Vollhardt,[24][25] Mori,[26][27] Shibasaki,[28] Li,[29] Fukuyama [30] Vanderwal [31] and MacMillan.[32] Synthetic (+)-strychnine is also known.[33][34] Racemic synthesises were published by Padwa in 2007 [35] and in 2010 by Andrade [36] and by Reissig.[37] In his 1963 publication Woodward quoted Sir Robert Robinson who said[38] for its molecular size it is the most complex substance known.

  1. ^ X-ray; Messerschmidt, M.; Scheins, S.; Luger, P. (2005). "Charge density of (−)-strychnine from 100 to 15 K, a comparison of four data sets". Acta Crystallogr B. 61 (1): 115–121. doi:10.1107/S0108768104032781. PMID 15659864.
  2. ^ Nicolaou, K. C.; Sorensen, E. J. (1996). Classics in Total Synthesis: Targets, Strategies, Methods. Wiley. ISBN 978-3-527-29231-8.
  3. ^ K. C. Nicolaou, Dionisios Vourloumis, Nicolas Winssinger, Phil S. Baran The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century Angewandte Chemie International Edition 2000; Volume 39, Issue 1, Pages: 44-122
  4. ^ Bonjoch, Josep; Sole, Daniel (2000). "Synthesis of Strychnine". Chem. Rev. 100 (9): 3455–3482. doi:10.1021/cr9902547. PMID 11777429.
  5. ^ Proudfoot, John R. (2013). "Reaction Schemes Visualized in Network Form: The Syntheses of Strychnine as an Example". Journal of Chemical Information and Modeling. 53 (5): 1035–1042. doi:10.1021/ci300556b. PMID 23597302.
  6. ^ Pelletier; Caventou (1818). "Note sur un nouvel alkalai (Note on a new alkali)". Annales de Chimie et de Physique. 8: 323–324. See also: Pelletier; Caventou (1819). "Mémoire sur un nouvel alcali vegetal (la strychnine) trouvé dans la feve de Saint-Ignace, la noix vomique, etc. (Memoir on a new vegetable alkali (strychnine) found in the St. Ignatius bean, the nux vomica, etc)". Annales de Chimie et de Physique. 10: 142–176.
  7. ^ Robinson, R. (1946). "The constitution of strychnine". Experientia. 2 (1): 1946. doi:10.1007/BF02154708. PMID 21012825.
  8. ^ Briggs, L. H.; Openshaw, H. T.; Robinson, Robert (1946). "Strychnine and brucine. Part XLII. Constitution of the neo-series of bases and their oxidation products". J. Chem. Soc. 1946: 903. doi:10.1039/JR9460000903.
  9. ^ Openshaw, H. T.; Robinson, R. (1946). "Constitution of Strychnine and the Biogenetic Relationship of Strychnine and Quinine". Nature. 157 (3988): 438. Bibcode:1946Natur.157..438O. doi:10.1038/157438a0. PMID 21024272.
  10. ^ Woodward, R. B.; Brehm, Warren J.; Nelson, A. L. (1947). "The Structure of Strychnine". J. Am. Chem. Soc. 69 (9): 2250. doi:10.1021/ja01201a526. PMID 20262753.
  11. ^ Bijvoet , Schoone and Bokhoven , Kon. Ned. Akad. Wet., 50, No 8, 51, No. 8, 52, No. 2 (1947–49)
  12. ^ Bokhoven, C.; Schoone, J. C.; Bijvoet, J. M. (1951). "The Fourier synthesis of the crystal structure of strychnine sulphate pentahydrate" (PDF). Acta Crystallogr. 4 (3): 275–280. doi:10.1107/S0365110X51000891.
  13. ^ Robertson, J. H.; Beevers, C. A. (1950). "Crystal Structure of Strychnine Hydrobromide". Nature. 165 (4200): 690–691. Bibcode:1950Natur.165..690R. doi:10.1038/165690a0. PMID 15416785.
  14. ^ Robertson, J. H.; Beevers, C. A. (1951). "The crystal structure of strychnine hydrogen bromide". Acta Crystallogr. 4 (3): 270–275. doi:10.1107/S0365110X5100088X.
  15. ^ Woodward, R. B.; Cava, Michael P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. (1954). "The Total Synthesis of Strychnine". J. Am. Chem. Soc. 76 (18): 4749–4751. doi:10.1021/ja01647a088.
  16. ^ Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. (1963). "The total synthesis of strychnine". Tetrahedron. 19 (2): 247–288. doi:10.1016/s0040-4020(01)98529-1.
  17. ^ Magnus, Philip; Giles, Melvyn; Bonnert, Roger; Kim, Chung S.; McQuire, Leslie; Merritt, Andrew; Vicker, Nigel (1992). "Synthesis of strychnine via the Wieland-Gumlich aldehyde". J. Am. Chem. Soc. 114 (11): 4403–4405. doi:10.1021/ja00037a058.
  18. ^ Knight, Steven D.; Overman, Larry E.; Pairaudeau, Garry (1993). "Synthesis applications of cationic aza-Cope rearrangements. 26. Enantioselective total synthesis of (−)-strychnine". J. Am. Chem. Soc. 115 (20): 9293–9294. doi:10.1021/ja00073a057.
  19. ^ Kuehne, Martin E.; Xu, Feng (1993). "Total synthesis of strychnan and aspidospermatan alkaloids. 3. The total synthesis of (+-)-strychnine". J. Org. Chem. 58 (26): 7490–7497. doi:10.1021/jo00078a030.
  20. ^ Kuehne, Martin E.; Xu, Feng (1998). "Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids. 10. An Enantioselective Synthesis of (−)-Strychnine through the Wieland−Gumlich Aldehyde". J. Org. Chem. 63 (25): 9427–9433. doi:10.1021/jo9813989.
  21. ^ Rawal, Viresh H.; Iwasa, Seiji (1994). "A Short, Stereocontrolled Synthesis of Strychnine". J. Org. Chem. 59 (10): 2685–2686. doi:10.1021/jo00089a008.
  22. ^ Total Synthesis of (−)-Strychnine via the Wieland-Gumlich Aldehyde Angewandte Chemie International Edition Volume 38, Issue 3, 1999, Pages: 395-397 Daniel Solé, Josep Bonjoch, Silvina García-Rubio, Emma Peidró, Joan Bosch
  23. ^ Solé, Daniel; Bonjoch, Josep; García-Rubio, Silvina; Peidró, Emma; Bosch, Joan (2000). "Enantioselective Total Synthesis of Wieland-Gumlich Aldehyde and (−)-Strychnine". Chemistry: A European Journal. 6 (4): 655–665. doi:10.1002/(SICI)1521-3765(20000218)6:4<655::AID-CHEM655>3.0.CO;2-6.
  24. ^ Eichberg, Michael J.; Dorta, Rosa L.; Lamottke, Kai; Vollhardt, K. Peter C. (2000). "The Formal Total Synthesis of (±)-Strychnine via a Cobalt-Mediated [2 + 2 + 2]Cycloaddition". Org. Lett. 2 (16): 2479–2481. doi:10.1021/ol006131m. PMID 10956526.
  25. ^ Eichberg, Michael J.; Dorta, Rosa L.; Grotjahn, Douglas B.; Lamottke, Kai; Schmidt, Martin; Vollhardt, K. Peter C. (2001). "Approaches to the Synthesis of (±)-Strychnine via the Cobalt-Mediated [2 + 2 + 2] Cycloaddition: Rapid Assembly of a Classic Framework". J. Am. Chem. Soc. 123 (38): 9324–9337. doi:10.1021/ja016333t. PMID 11562215.
  26. ^ Nakanishi, Masato; Mori, Miwako (2002). "Total Synthesis of (−)-Strychnine". Angewandte Chemie International Edition. 41 (11): 1934–1936. doi:10.1002/1521-3773(20020603)41:11<1934::AID-ANIE1934>3.0.CO;2-F. PMID 19750638.
  27. ^ Mori, Miwako; Nakanishi, Masato; Kajishima, Daisuke; Sato, Yoshihiro (2003). "A Novel and General Synthetic Pathway to Strychnos Indole Alkaloids: Total Syntheses of (−)-Tubifoline, (−)-Dehydrotubifoline, and (−)-Strychnine Using Palladium-Catalyzed Asymmetric Allylic Substitution". J. Am. Chem. Soc. 125 (32): 9801–9807. doi:10.1021/ja029382u. PMID 12904045.
  28. ^ Ohshima, Takashi; Xu, Youjun; Takita, Ryo; Shimizu, Satoshi; Zhong, Dafang; Shibasaki, Masakatsu (2002). "Enantioselective Total Synthesis of (−)-Strychnine Using the Catalytic Asymmetric Michael Reaction and Tandem Cyclization". J. Am. Chem. Soc. 124 (49): 14546–14547. doi:10.1021/ja028457r. PMID 12465959.
  29. ^ Bodwell, Graham J.; Li, Jiang (2002). "A Concise Formal Total Synthesis of (±)-Strychnine by Using a Transannular Inverse-Electron-Demand Diels–Alder Reaction of a [3](1,3)Indolo[3](3,6)pyridazinophane". Angewandte Chemie International Edition. 41 (17): 3261–3262. doi:10.1002/1521-3773(20020902)41:17<3261::AID-ANIE3261>3.0.CO;2-K.
  30. ^ Kaburagi, Y; Tokuyama, H; Fukuyama, T (2004). "Total synthesis of (−)-strychnine". J. Am. Chem. Soc. 126 (33): 10246–10247. doi:10.1021/ja046407b. PMID 15315428.
  31. ^ Martin, David B. C.; Vanderwal, Christopher D. (2011). "A synthesis of strychnine by a longest linear sequence of six steps". Chemical Science. 2 (4): 649. doi:10.1039/C1SC00009H.
  32. ^ Jones, Spencer B.; Simmons, Bryon; Mastracchio, Anthony; MacMillan, David W. C. (2011). "Collective synthesis of natural products by means of organocascade catalysis". Nature. 475 (7355): 183–188. doi:10.1038/nature10232. PMC 3439143. PMID 21753848.
  33. ^ Knight, Steven D.; Overman, Larry E.; Pairaudeau, Garry (1995). "Asymmetric Total Syntheses of (−)- and (+)-Strychnine and the Wieland-Gumlich Aldehyde". J. Am. Chem. Soc. 117 (21): 5776–5788. doi:10.1021/ja00126a017.
  34. ^ Not counted:an unpublished method by Gilbert Stork, Lecture at the Ischia School of Organic Chemistry, Ischia Porb, Italy, September 211992.
  35. ^ Zhang, Hongjun; Boonsombat, Jutatip; Padwa, Albert (2007). "Total Synthesis of (±)-Strychnine via a [4 + 2]-Cycloaddition/Rearrangement Cascade". Org. Lett. 9 (2): 279–282. doi:10.1021/ol062728b. PMC 2587098. PMID 17217284.
  36. ^ Sirasani, Gopal; Paul, Tapas; William Dougherty, Jr.; Kassel, Scott; Andrade, Rodrigo B. (2010). "Concise Total Syntheses of (±)-Strychnine and (±)-Akuammicine". The Journal of Organic Chemistry. 75 (10): 3529–3532. doi:10.1021/jo100516g. PMID 20408591.
  37. ^ Beemelmanns, C.; Reissig, H.-U. (2010). "A Short Formal Total Synthesis of Strychnine with a Samarium Diiodide Induced Cascade Reaction as the Key Step". Angewandte Chemie International Edition. 49 (43): 8021–8025. doi:10.1002/anie.201003320. PMID 20848626.
  38. ^ R. Robinson "Molecular structure of Strychnine, Brucine and Vomicine Prog. Org. Chem., 1952; 1 ,2

Strychnine total synthesis

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