Total Synthesis of Strychnine 1954 - 2004

1. André B. Charette Tuesday, January 23, 2007 Total Synthesis of Strychnine1954 - 2004 “For its molecular size it is the most complex substance known”

2. Total Synthesis of Strychnine (1) Woodward, R. B.; Cava, M. P.; Oliis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc.1954, 76, 4749. (Tetrahedron1963, 19, 247) (2) Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc.1993, 115, 8116-8129. (3) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, N. J. Am. Chem. Soc.1992, 114, 4403-4405. (4) Kuehne, M. E.; Xu, F. Journal of Organic Chemistry1998, 63, 9427-9433. (5) Kuehne, M. E.; Xu, F. Journal of Organic Chemistry1993, 58, 7490-7497. (6) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.1993, 115, 9293-9294. (7) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.1995, 117, 5776-5788. (8) Rawal, V. H.; Iwasa, S. J. Org. Chem.1994, 59, 2685-2686. (9) D. Sole, J. Bonjoch, S. Garcia-Rubio, E. Peidro, J. Bosch, Chemistry-a European Journal 2000, 6, 655. (10) D. Sole, J. Bonjoch, S. Garcia-Rubio, E. Peidro, J. Bosch, Angew. Chem. Int. Ed. 1999, 38, 395. (11) J. Bonjoch, D. Sole, S. GarciaRubio, J. Bosch, J. Am. Chem. Soc. 1997, 119, 7230. (12) M. J. Eichberg, R. L. Dorta, K. Lamottke, K. P. C. Vollhardt, Org. Lett. 2000, 2, 2479. (13) M. J. Eichberg, R. L. Dorta, D. B. Grotjahn, K. Lamottke, M. Schmidt, K. P. C. Vollhardt,J. Am. Chem. Soc. 2001, 123, 9324. (14) M. Ito, C. W. Clark, M. Mortimore, J. B. Goh, S. F. Martin, J. Am. Chem. Soc. 2001, 123, 8003. (15) G. J. Bodwell, J. Li, Angew. Chem. Int. Ed. 2002, 41, 3261. (16) M. Mori, M. Nakanishi, D. Kajishima, Y. Sato, J. Am. Chem. Soc. 2003, 125, 9801. (17) M. Nakanishi, M. Mori, Angew. Chem. Int. Ed. 2002, 41, 1934. (18) Ohshima, T.; Xu, J. Y.; Takita, R.; Shimizu, S.; Zhong, D. F.; Shibasaki, M.J. Am. Chem. Soc.2002, 124, 14546-14547. (19) Ohshima, T.; Xu, Y. J.; Takita, R.; Shibasaki, M.Tetrahedron2004, 60, 9569-9588. (20) Y. Kaburagi, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2004, 126, 10246.

3. Facts about Strychnine Strychnine (pronounced /strɪkniːn/ (British) or /strɪknaɪn/ (U.S.)) is a very toxic (LD50 = 1 mg/kg), colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as rodents. Strychnine causes muscular convulsions and eventually asphyxia or sheer exhaustion. The most common source is from the seeds of the Strychnos nux vomica tree. Strychnine is one of the most bitter substances in the world. Its taste is detectable in concentrations as low as 1 ppm. Strychnine acts as a blocker or antagonist at the inhibitory or strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in the spinal cord and the brain. Strychnine poisoning in humans Strychnine poisoning can be fatal to humans, and can be introduced to the body by inhalation, swallowing or absorption through eyes or mouth. It produces some of the best-known, most dramatic, terrifying, and painful symptoms imaginable. For this reason, strychnine poisoning is often used in literature and film. Ten to twenty minutes after exposure, the body's muscles begin to spasm, starting with the head and neck. The spasms then spread to every muscle in the body, with nearly continuous convulsions, and get worse at the slightest stimulus. They progress, increasing in intensity and frequency until the backbone arches continually. Death comes from asphyxiation caused by paralysis of the brain's breathing apparatus, or by exhaustion from the convulsions. At that time, the body "freezes," even in the middle of a convulsion. Rigor mortis sets in immediately, with the eyes left wide open. Treatment involves giving depressants, such as intravenous diazepam, to control the convulsions, and giving an activated charcoal infusion to drink, which serves to absorb any poison remaining within the digestive system. If the patient lives 24 hours, recovery is probable. Small doses of strychnine were sometimes used in over-the-counter medications as a laxative and as a treatment for other stomach ailments; this practice was eventually abandoned with the proliferation of safer alternatives.

4. Facts about Strychnine Strychnine poisoning in animals Strychnine poisoning in animals occurs usually from ingestion of baits designed for use against rodents (especially gophers and moles) and coyotes. Rodents baits are commonly available over-the-counter, but coyote baits are illegal in the United States. However, since 1990 in the United States most baits containing strychnine have been replaced with zinc phosphide baits.[1] The most common domestic animal to be affected is the dog, either through accidental ingestion or intentional poisoning. An approximate lethal dose for a dog is 0.75 mg per kg body weight.[2] For a 0.3% strychnine bait, five grams could be enough to kill a twenty kilogram dog. The onset of symptoms is 10 to 120 minutes after ingestion.[2] Symptoms include seizures, a "sawhorse" stance, and opisthotonus (rigid extension of all four limbs). Death is usually secondary to respiratory paralysis. Treatment is by detoxification using activated charcoal, pentobarbital for the symptoms, and artificial respiration for apnea. Trivia • In the 1904 Olympics, Thomas Hicks(USA) won the marathon at St. Louis and collapsed. It took hours to revive him; he had taken brandy mixed with strychnine to help him win his gold medal. • “Strychnine” is the title of a song by 60sAmericangarage rock band The Sonics (later covered by The Cramps), which includes the lines: Some folks like the water Some folks like the wine I like the taste Of straight strychnine • In the movie Office Space, when Milton is at the resort before the credits roll, he is brushed off by a waiter. After muttering a few threats, he says, “I could put strychnine in the guacamole…” • It was also used by Norman Bates (Psycho) to kill his mother and her lover (as exposed in Psycho IV: The Beginning) • A tonic laced with arsenic and strychnine that was religiously given to legendary racehorse Phar Lap may have caused his death. • Strychnine was used in several of the murders committed by serial killer Thomas Neill Cream, who poisoned prostitutes on the streets of London. • Strychnine dart is used to kill Bartholomew Sholto in Conan Doyle's The Sign of Four detective story, featuring Sherlock Holmes.

5. Isolation of Strychnine Strychnine tree Binomial name Strychnos nux-vomica Linnaeus The Strychnine tree (Strychnos nux-vomica) also known as Nux vomica, is an evergreentree native to southeast Asia, a member of familyLoganiaceae. It grows in open habitats, usually attaining a size about 25 meters tall. It is a major source of the highly poisonous alkaloidstrychnine, derived from the seeds inside the tree's round, green to orange fruit. However, the tree's bark also contains poisonous compounds, including brucine. In homeopathy, Nux-v. — as it is commonly abbreviated — is one of the most commonly prescribed remedies.

6. Crystal Structure of Strychnine Nature165, 690 - 691 (29 April 1950); doi:10.1038/165690a0 Crystal Structure of Strychnine Hydrobromide J. H. ROBERTSON & C. A. BEEVERS Dewar Crystallographic Laboratory, University of Edinburgh. Dec. 12. ALTHOUGH the structure of the strychnine molecule has now been fairly definitely established on chemical grounds the evidence of X-ray crystallography is of interest, especially as regards stereochemical details. The formula favoured by Robinson and Woodward1 was first confirmed by Bijvoet, Schoone and Bokhoven2, who examined the sulphate and selenate. We have completed a full analysis of strychnine hydrobromide, in which both three-dimensional Patterson and Fourier syntheses were employed. The chemical structure has been reliably verified, and moderately accurate representation of the molecule has been obtained. 1. Robinson , et al., J. Chem. Soc., 903 (1946). Nature, 160, 18 (1947). Woodward , Brehm and Nelson , J. Amer. Chem. Soc., 69, 2250 (1947). 2. Bijvoet , Schoone and Bokhoven , Kon. Ned. Akad. Wet., 50, No 8, 51, No. 8, 52, No. 2 (1947–49).

7. Some Reactions of Strychnine

8. Woodward’s Retrosynthetic Analysis veratryl protecting group

9. 1954 - Woodward Synthesis

10. 1954 - Woodward Synthesis

11. 1954 - Woodward Synthesis

12. 1954 - Woodward Synthesis

13. 1992: Magnus Retrosynthesis

14. 1992: Magnus Synthesis

15. 1992: Magnus Synthesis

16. 1992: Magnus Synthesis

17. 1992: Magnus Synthesis

18. 1992: Magnus Synthesis

19. 1993 - Kuehne’s Retrosynthesis

20. 1993 - Kuehne’s Synthesis

21. 1993 - Kuehne’s Synthesis

22. 1993 - Kuehne’s Synthesis

23. 1993 - Kuehne’s Synthesis

24. 1993 - Overman’s Retrosynthesis

25. 1993 - Overman’s Synthesis

26. 1993 - Overman’s Synthesis

27. 1993 - Overman’s Synthesis

28. 1993 - Overman’s Synthesis

29. 1994 - Rawal’s Retrosynthesis

30. 1994 - Rawal’s Synthesis

31. 1994 - Rawal’s Synthesis

32. 1994 - Rawal’s Synthesis

33. Bosch’s Retrosynthesis

34. 1999 - Bosch’s Retrosynthesis

35. 1999 - Bosch’s Retrosynthesis

36. 2000 - Vollhardt’s Retrosynthesis

37. 2000 - Vollhardt’s Synthesis

38. 2000 - Vollhardt’s Synthesis

39. 2001 - Martin’s Retrosynthesis

40. 2001 - Martin’s Synthesis

41. 2001 - Martin’s Synthesis

42. 2002 - Bodwell’s Retrosynthesis

43. 2002 - Bodwell’s Synthesis

44. 2002 - Mori’s Retrosynthesis

45. 2002 - Mori’s Synthesis

46. 2002 - Mori’s Synthesis

47. 2002 - Shibasaki’s Retrosynthesis Is it really worth it?

48. 2002 - Shibasaki’s Retrosynthesis

49. 2002 - Shibasaki’s Synthesis

50. 2002 - Shibasaki’s Synthesis