1. Synthesis of Gelsemine Alexander J. L. Clemens Burke Group October 26, 2006

2. 2 Genus Gelsemium G. rankini and G. sempervirens (Carolina Jasmine) native to southeastern U.S. G. elegans native to southeast Asia G sempervirens produces gelsemine (0.07% by weight) Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350. Picture: http://www.e-referencedesk.com/resources/state-flower/south-carolina.html

3. 3 Medicine and Homeopathy G. elegans traditional medicine in China and Japan G. elegans extract used as a clinical treatment for cancer G. sempervirens extracts sold as homeopathic treatment Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350. Picture: http://www.naturallythinking.com/product/asp/ProdID/100091/CtgID/237/af/page.htm

4. 4 Gelsemium Alkaloid Activity Around 20 alkaloids isolated from Gelsemium plants Many Gelsemium alkaloids have antitumor, analgesic, anti-inflammatory, immunomodulating, and/or antiarrhythmic effects a. Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. J. Nat. Prod. 2006, 69, 715-718. b. Xu, Y.-K.; Yang, S.-P.; Liao, S.-G.; Zhang, H.; Lin, L.-P.; Ding, J.; Yue, J.-M. J. Nat. Prod. 2006, 69, 1347-1350. c. Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. J. Am. Chem. Soc. 1990, 112, 5220- 5230.

5. 5 A Synthetic Challenge Hexacycle with seven contiguous stereocenters on five rings Very little functionality Four distinct synthetic challenges: [3.2.1] bicyclic system, spirooxindole, pyrrolidine ring, and tetrahydropyran ring

6. 6 Synthesis of Gelsemine Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 4, 1-5.

7. 7 Gelsemine Construction [3.2.1] bicyclic core Pyrrolidine ring Spirooxindole Tetrahydropyran ring

8. 8 [3.2.1] Construction Strategy

9. 9 [3.2.1] by Speckamp a. Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882-3884. b. Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768.

10. 10 Johnson’s Ring Closure Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, P. A. J. Chem. Soc., Chem. Commun. 1994, 763-764.

11. 11 Overman’s Opening Earley, W. G.; Jacobsem, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29(31), 3781-3784.

12. 12 Overman’s Aza-Cope Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 2934- 2936.

13. 13 Overman’s Ring Closure Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 2934- 2936.

14. 14 Hart’s Radical Cyclization I Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.

15. 15 Fukuyama’s Beginning Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.

16. 16 Divinylcyclopropane (1996) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.

17. 17 Divinylcyclopropane (2000) Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.

18. 18 [3.2.1] and Spirooxindole a. Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427. b. Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.

19. 19 Danishefsky’s [3.2.1] Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.

20. 20 [3.2.1] Bicyclic Synthesis Speckamp, Hart, Johnson, and Overman - create pyrrolidine ring at same time Fukuyama - simultaneous synthesis of a single isomer of spirooxindole Danishefsky - most limited; leaves olefins for further functionalization

21. 21 Pyrrolidine Ring Installation

22. 22 Fukuyama (1996) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426-7427.

23. 23 Fukuyama (2000) Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39 (22), 4073-4075.

24. 24  -Aminonitriles to Amides Yokoshima, S.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Chem. Lett. 2002, 122-123. R = alkyl, aromatic R’ = alkyl R” = alkyl, aromatic Yields typically above 70%, often above 80%

25. 25 Danishefsky’s Pyrrolidine Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.

26. 26 Oxetane Opening Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J Tetrahedron Lett. 2002, 545-548.

27. 27 The Spirooxindole Moiety

28. 28 Hart’s Radical Cyclization II Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.

29. 29 Johnson’s Triazole Radical Dutton, K. J.; Steel, R. W.; Tasker, A. S.; Popsavin, V.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 765-766.

30. 30 Speckamp’s Heck Reaction Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768. Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33 (34), 4859-4862. Overman’s protocol gives 9:1 selectivity Less selectivity due to more steric bulk on concave face

31. 31 Overman’s Trials Madin, A.; O’Donnell, C. J.; Oh, T.; Old. D, W.; Overman, L. E.; Sharp, M. J. J.Am. Chem. Soc. 2005, 127, 18054- 18065.

32. 32 Modified Heck Reaction Madin, A.; O’Donnell, C. J.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38 (19), 2934-2936.

33. 33 Heck Selectivity Rationale Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054- 18065. Substituted enol ether changes system - tetrasubstituted and electron-rich Vinyl group coordinates to Pd Overman et al. unable to optimize for natural isomer - requires correction

34. 34 Aziridine Intermediate Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38 (19), 2934-2936.

35. 35 Spirooxindole Correction Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 2934- 2936.

36. 36 Danishefsky’s Original [2,3] Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.

37. 37 Danishefsky’s Second [2,3] Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.

38. 38 Danishefsky’s Tribulations Ng, F. W.; Lin, H.; Chiu, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812-9824.

39. 39 [3,3] Rearrangement Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.

40. 40 Ring Contraction Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron, Lett. 2002, 549-551.

41. 41 Spirooxindole Synthesis

42. 42 Tetrahydropyran Synthesis

43. 43 Speckamp’s Oxymercuration a. Hiemstra, H.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882-3884. b. Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767-768. Fukuyama and Danishefsky used same oxymercuration/reduction conditions with similar yield

44. 44 Johnson’s Alkene Activation Sheikh, Z.; Steel, R.; Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 763-764.

45. 45 Hart’s Hemiacetal Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S. Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943-6944.

46. 46 Overman’s Nitrile Trap Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38(19), 2934- 2936.

47. 47 Synthetic Breakdown Most syntheses attacked more than one part at a time Danishefsky strategy: each section is made individually Overman’s biggest problem is Heck reaction selectivity Fukuyama’s 2000 synthesis only enantioselective route Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054-18065.

48. 48 Synthetic Benefits Development and exploration of new reactions: –Stereoselective, quaternary Heck reaction (Overman) –Amides from  -amino nitriles (Fukuyama) Despite similarities, syntheses demonstrate variety of strategies and reactions –Several distinct disconnection strategies –Many different types of reactions –Demonstrate power of sigmatropic rearrangements

49. 49 Acknowledgements Prof. Steven D. Burke Burke Group Practice Talk Attendees –Becca Splain– Katherine Traynor –Lauren Boyle– Maren Buck –Richard Grant– Chris Shaffer –Matt Windsor– Margie Mattmann Claire Poppe