--- Dead Ends and Detours

1. The Journey of Azadirachtin --- Dead Ends and Detours Supervisors: Prof. Zhen Yang & Jiahua Chen Reporter: Weiwu Ren 2008-01-11

2. Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

3. Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

4. Guanacastepene IMDA Tandem Cyclization Heck RCM/Robinson TandemRCM Stille/[2+2]

5. Dead Ends and Detours Planning Starting Materials Target Molecule Dead Ends Detours

6. Our Attitudes Reality Several Steps Condition B Starting Materials Condition A Product Condition C OR

7. Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

8. Brevetoxin B Brevetoxin B A marine neurotoxin First reported by Nakanishi in 1981 23 stereocenters All trans-contiguous ether rings Lin, Y.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.

9. First-generation Retrosynthetic Analysis Nicolaou, K. C.; Hwang, C. -K.. J. Am. Chem. Soc. 1986, 108, 6800.

10. Work with Model Nicolaou, K. C.; Hwang, C. -K. J. Am. Chem. Soc.1990, 112,3040.

11. But… Nightmare!!!

12. Is the Strategy Useless? Unfortunately, however, all attempts to achieve the bis(thionation) of the macrodilactone precursor failed… The lactone carbonyl flanked by the methyl group, defiantly resists the action of Lawesson’s reagent, presumably due to its hindered nature… ------ K. C. Nicolaou Significance: 1. Investigation of the chemistry of the molecule Brevetoxin B and the basis of the following total synthesis; 2. Developing a full body of methodology to build fused seven-membered rings;

13. Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

14. Azadirachtin 16 Contiguous Stereogenic Centers 7 Tetrasubstituted Carbons 4 Different Ester Groups 2 Hydroxy Groups 1 Acid and Base-Sensitive Hemiketal 1 Strained and Sterically-hindered Epoxide 2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH – C20OH)

15. 1986 1968 1986 1996 1996 2006 2006 2007 2007 Story Line Beginning Isolation and Structure Determination of Azadirachtin

16. 1985-1986 The correct structure was submitted and was confirmed by X-ray analysis 1975 The first complete structure was reported but not correct 1968 First report of the isolation of Azadirachtin by Morgan group Hop Skip and Jump

17. First Isolation Isolated from the seeds of Azadirachta indica A. Juss in India ( 印度苦楝树 ) Named Azadirachtin ( Azadirachta indica ) High activity against the desert locust（沙漠蝗虫） Molecular formula：C29H38O16(642.222) Butterworth, J. H.;Morgan,E. D. J. Chem. Soc., Chem. Commun. 1968, 23.

18. Right Molecular Formula & Partial Structure Butterworth, J. H.;Morgan,E. D. J. Chem. Soc., Chem. Commun. 1968, 23. Molecular Formula : C35H44O16 （Triterpenoid） Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Perkin Trans. I 1972, 2445.

19. The First Complete Structure Nakanishi’s Azadirachtin Correct Structure Based on: PRFT/CWD 13C NMR Hypothetical Relationship with Known Terpenoids Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc.1975, 97,1975.

20. Ley’s Modification Ley’s Modification Correct Structure Based on: 1D NOE & 2D NOESY Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986.

21. Azadirachtin Finally, the Correct Structure W. Kraus.; M. Bokel.; A. Klenk.; H. P. Khnl. Tetrahedron Lett. 1985, 26, 6435. Broughton, H. B.; Ley, S. V. J. Chem. Soc. Chem. Commun. 1986, 46.

22. First isolated by Morgan(1968) Partial structure(1972) Confirmed by X-ray analysis(1986) Azadirachtin The first complete structure (1975) Ley’s modification (1985) 22

23. 1986 1996 2006 2007 Story Line 1968 1986 1996 Ley’s Monodrama（独角戏） 2006 2007

24. Ley’s Idea We recognise this coupling involves the formation of a difficult bond, but therein lies the challenge. ---- S. V. Ley Ley, S. V. Pure Appl. Chem.1994, 66, 2099.

25. 1stSynthesis Ⅰ. Develop a flexible approach for the total synthesis Ⅱ. Study the functional groups responsible for activity (potential active center) Ley, S. V.; Santafianosa, D.Tetrahedron Lett. 1987, 28(2), 221.

26. Construction of This Fragment Ley, S. V.; Santafianosa, D.Tetrahedron Lett. 1987, 28(2), 221.

27. Absolute Configuration Method: Modified Mosher methodology using high field FT NMR techniques Ley, S. V.; Lovell, H.J. Chem. Soc., Chem. Commun. 1992, 1304.

28. Ley’s Other Work Azadirachtin

29. 1986 1996 2006 2007 Story Line 1968 1986 1996 Ley Cambridge Nicolaou Scripps 2006 2007 Watanabe Tokyo Murai Hokkaido

30. Ley’s Attempts on the Direct Coupling Complex ‘Right’ to Simple ‘Left’ Complex ‘Left’ to Simple ‘Right’ Ley, S. V. Pure Appl. Chem. 2005, 77, 1115.

31. Ways to Go Dead Ends Detour Connect the two parts through other functional groups and then close the desired bondintramolecularly! Introduce this bond in an earlier step of the synthesis! Prof. Ley & Prof. Nicolaou & Prof. Murai Prof. Watanabe

32. First Participant — Watanabe 1) Watanabe, H.; Watanabe, T.; Mori, K. Tetrahedron 1996, 52, 13939. 2) Watanabe, H.; Watanabe, T.; Mori, K.;Kitahara, T. Tetrahedron Lett. 1997, 38, 4429. 3) Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512.

33. Watanabe’s Model Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.

34. Tandem Radical Cyclization Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T.Tetrahedron Lett.1997, 38, 4429.

35. Murai’s Model Study Ireland – Claisen Rearrangement 1) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, 1907. 2) Yamamoto, Y.;Ishihara,J.; Kanoh,N.; Murai, A. Synthesis2000, 1894. 3) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

36. Ireland-Claisen Rearrangement Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

37. Diastereoselectivity Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

38. K. C. Nicolaou’s Model Study 2002 Radical 2002 Organometallic 2005 2003

39. From Radical Chemistry Nicolaou, K. C.;Follmann,M.; Roecker, A. J. Angew. Chem. Int. Ed. 2002, 41, 2103.

40. From Organometallic Chemistry Nicolaou, K. C.;Roecker, A.; J Follmann,M. Angew. Chem. Int. Ed. 2002, 41, 2107.

41. Greatest Challenge: C8-C14 Bond Azadirachtin Nicolaou Ley Murai Watanabe Brief Summary

42. 1986 1968 1986 1996 1996 2006 2006 2007 2007 Story Line Total Synthesis

43. Relay Study Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.

44. Back to ‘Azadirachtin’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.

45. Retrosynthetic Analysis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

46. Left ‘Shoulder’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

47. Right ‘Arm’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

48. Total Synthesis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

49. Total Synthesis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

50. Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents