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

2. OPSS 2008-01-11 Weiwu Ren 2 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

3. OPSS 2008-01-11 Weiwu Ren 3 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

4. OPSS 2008-01-11 Weiwu Ren 4 Guanacastepene Tandem Cyclization IMDA HeckRCM/Robinson TandemRCM Tandem RCMStille/[2+2]

5. OPSS 2008-01-11 Weiwu Ren 5 Dead Ends Detours Dead Ends and Detours Planning TargetMoleculeStartingMaterials

6. OPSS 2008-01-11 Weiwu Ren 6 Our Attitudes Starting StartingMaterials Product Condition B Condition A Condition C Several Steps OR Reality

7. OPSS 2008-01-11 Weiwu Ren 7 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

8. OPSS 2008-01-11 Weiwu Ren 8 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. OPSS 2008-01-11 Weiwu Ren 9 First-generation Retrosynthetic Analysis Nicolaou, K. C.; Hwang, C. -K.. J. Am. Chem. Soc. 1986, 108, 6800.

10. OPSS 2008-01-11 Weiwu Ren 10 Work with Model Nicolaou, K. C.; Hwang, C. -K. J. Am. Chem. Soc. 1990, 112, 3040.

11. OPSS 2008-01-11 Weiwu Ren 11 But… Nightmare!!!

12. OPSS 2008-01-11 Weiwu Ren 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… 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 Brevetoxin B and the basis of the following total synthesis; synthesis; 2. Developing a full body of methodology to build fused seven-membered rings; fused seven-membered rings;

13. OPSS 2008-01-11 Weiwu Ren 13 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

14. OPSS 2008-01-11 Weiwu Ren 14 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) Azadirachtin

15. OPSS 2008-01-11 Weiwu Ren 15 1968 2007 2006 1996 1986 1986 2006 1996 2007 Beginning Isolation and Structure Determination of Azadirachtin Story Line

16. OPSS 2008-01-11 Weiwu Ren 16 1975 1985-1986 1968 First report of the isolation of Azadirachtin by Morgan group The first complete structure was reported but not correct The correct structure was submitted and was confirmed by X-ray analysis Hop Skip and Jump

17. OPSS 2008-01-11 Weiwu Ren 17 Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23. 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 ： C 29 H 38 O 16 (642.222) First Isolation

18. OPSS 2008-01-11 Weiwu Ren 18 Molecular Formula : C 35 H 44 O 16 （ Triterpenoid ） Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Perkin Trans. I 1972, 2445. Right Molecular Formula & Partial Structure Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.

19. OPSS 2008-01-11 Weiwu Ren 19 Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 1975. Nakanishi’s Azadirachtin Based on: PRFT/CWD 13 C NMR Hypothetical Relationship with Known Terpenoids Hypothetical Relationship with Known Terpenoids Correct Structure The First Complete Structure

20. OPSS 2008-01-11 Weiwu Ren 20 Ley’s Modification Correct Structure Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986. Based on: 1D NOE & 2D NOESY Ley’s Modification

21. OPSS 2008-01-11 Weiwu Ren 21 Azadirachtin Azadirachtin W. Kraus.; M. Bokel.; A. Klenk.; H. P. Khnl. Tetrahedron Lett. 1985, 26, 6435. Finally, the Correct Structure Broughton, H. B.; Ley, S. V. J. Chem. Soc. Chem. Commun. 1986, 46.

22. OPSS 2008-01-11 Weiwu Ren 22 Azadirachtin First isolated by Morgan(1968) Partial structure(1972) The first complete structure (1975) Ley’s modification (1985) Confirmed by X-ray analysis(1986) 22

23. OPSS 2008-01-11 Weiwu Ren 23 1968 2007 2006 1996 1986 1986 2006 1996 2007 Ley’s Monodrama （独角戏） Story Line

24. OPSS 2008-01-11 Weiwu Ren 24 Ley’s Idea We recognise this coupling involves the formation of a difficult bond, but therein lies the challenge. ---- S. V. Ley ---- S. V. Ley Ley, S. V. Pure Appl. Chem. 1994, 66, 2099.

25. OPSS 2008-01-11 Weiwu Ren 25 1 st Synthesis Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221. Ⅰ. Develop a flexible approach for the total synthesis for the total synthesis Ⅱ. Study the functional groups responsible for activity responsible for activity (potential active center) (potential active center)

26. OPSS 2008-01-11 Weiwu Ren 26 Construction of This Fragment Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.

27. OPSS 2008-01-11 Weiwu Ren 27 Absolute Configuration Modified Mosher methodology using high field FT NMR techniques Method: Ley, S. V.; Lovell, H. J. Chem. Soc., Chem. Commun. 1992, 1304.

28. OPSS 2008-01-11 Weiwu Ren 28 Ley’s Other Work Azadirachtin

29. OPSS 2008-01-11 Weiwu Ren 29 1968 2007 2006 1996 1986 1986 2006 1996 2007 LeyCambridgeNicolaouScripps Murai Hokkaido WatanabeTokyo Story Line

30. OPSS 2008-01-11 Weiwu Ren 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. OPSS 2008-01-11 Weiwu Ren 31 Ways to Go Dead Ends Detour Introduce this bond in an earlier step of the synthesis! Introduce this bond in an earlier step of the synthesis! Prof. Watanabe Connect the two parts through other functional groups and then close the desired bond intramolecularly! Prof. Ley & Prof. Nicolaou & Prof. Murai

32. OPSS 2008-01-11 Weiwu Ren 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. OPSS 2008-01-11 Weiwu Ren 33 Watanabe’s Model Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.

34. OPSS 2008-01-11 Weiwu Ren 34 Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429. Tandem Radical Cyclization

35. OPSS 2008-01-11 Weiwu Ren 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. Synthesis 2000, 1894. 3) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

36. OPSS 2008-01-11 Weiwu Ren 36 Ireland-Claisen Rearrangement Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

37. OPSS 2008-01-11 Weiwu Ren 37 Diastereoselectivity Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

38. OPSS 2008-01-11 Weiwu Ren 38 K. C. Nicolaou’s Model Study 2002 2002Radical 2005 2003 Organometallic

39. OPSS 2008-01-11 Weiwu Ren 39 From Radical Chemistry Nicolaou, K. C.; Follmann, M.; Roecker, A. J. Angew. Chem. Int. Ed. 2002, 41, 2103.

40. OPSS 2008-01-11 Weiwu Ren 40 From Organometallic Chemistry Nicolaou, K. C.; Roecker, A.; J Follmann, M. Angew. Chem. Int. Ed. 2002, 41, 2107.

41. OPSS 2008-01-11 Weiwu Ren 41 Greatest Challenge: C 8 -C 14 Bond Azadirachtin Azadirachtin Ley Nicolaou Watanabe Murai Brief Summary

42. OPSS 2008-01-11 Weiwu Ren 42 1968 2007 2006 1996 1986 1986 2006 1996 2007 Total Synthesis Story Line

43. OPSS 2008-01-11 Weiwu Ren 43 Relay Study Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.

44. OPSS 2008-01-11 Weiwu Ren 44 Back to ‘Azadirachtin’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.

45. OPSS 2008-01-11 Weiwu Ren 45 Retrosynthetic Analysis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

46. OPSS 2008-01-11 Weiwu Ren 46 Left ‘Shoulder’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

47. OPSS 2008-01-11 Weiwu Ren 47 Right ‘Arm’ Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

48. OPSS 2008-01-11 Weiwu Ren 48 Total Synthesis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

49. OPSS 2008-01-11 Weiwu Ren 49 Total Synthesis Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.

50. OPSS 2008-01-11 Weiwu Ren 50 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

51. OPSS 2008-01-11 Weiwu Ren 51 Summary Ley and More Than 35 Co-workers Isolation and Structure Determination (18 years) Total Synthesis (22 years) Total Yield: 0.00015% 71 Steps (longest linear sequence 48 steps)

52. OPSS 2008-01-11 Weiwu Ren 52 Summary Logic! Convergence! Accuracy! Dead Ends ? Detours ? Beginning !

53. OPSS 2008-01-11 Weiwu Ren 53 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

54. OPSS 2008-01-11 Weiwu Ren 54 Prof. Yang & Prof. Chen Prof. Shi & Prof. Yu All the Members of Our Lab All theAudience All the Audience Acknowledgement

55. No Dead Ends Less Detours More success!!!

56. OPSS 2008-01-11 Weiwu Ren 56 Thank You ！！！