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

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

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

OPSS Weiwu Ren 4 Guanacastepene Tandem Cyclization IMDA HeckRCM/Robinson TandemRCM Tandem RCMStille/[2+2]

OPSS Weiwu Ren 5 Dead Ends Detours Dead Ends and Detours Planning TargetMoleculeStartingMaterials

OPSS Weiwu Ren 6 Our Attitudes Starting StartingMaterials Product Condition B Condition A Condition C Several Steps OR Reality

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

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

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

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

OPSS Weiwu Ren 11 But… Nightmare!!!

OPSS 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;

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

OPSS Weiwu Ren 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

OPSS Weiwu Ren Beginning Isolation and Structure Determination of Azadirachtin Story Line

OPSS Weiwu Ren 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

OPSS 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 ( ) First Isolation

OPSS 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, Right Molecular Formula & Partial Structure Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.

OPSS Weiwu Ren 19 Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 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

OPSS 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

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

OPSS 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

OPSS Weiwu Ren Ley’s Monodrama （独角戏） Story Line

OPSS 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.

OPSS 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)

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

OPSS 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.

OPSS Weiwu Ren 28 Ley’s Other Work Azadirachtin

OPSS Weiwu Ren LeyCambridgeNicolaouScripps Murai Hokkaido WatanabeTokyo Story Line

OPSS 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.

OPSS 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

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

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

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

OPSS Weiwu Ren 35 Murai’s Model Study Ireland – Claisen Rearrangement 1) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, ) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Synthesis 2000, ) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.

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

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

OPSS Weiwu Ren 38 K. C. Nicolaou’s Model Study Radical Organometallic

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

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

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

OPSS Weiwu Ren Total Synthesis Story Line

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

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

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

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

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

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

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

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

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

OPSS Weiwu Ren 52 Summary Logic! Convergence! Accuracy! Dead Ends ? Detours ? Beginning !

OPSS Weiwu Ren 53 Introduction Dead Ends and Detours – An Example Total Synthesis of Azadirachtin Summary Acknowledgement Contents

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

No Dead Ends Less Detours More success!!!

OPSS Weiwu Ren 56 Thank You ！！！