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- Dead Ends and Detours,Supervisors: Prof. Zhen Yang & Jiahua Chen,Reporter: Weiwu Ren2008-01-11,The Journey of Azadirachtin,2,Contents,3,Contents,4,Guanacastepene,Tandem Cyclization,IMDA,Heck,RCM/Robinson,Tandem RCM,Stille/2+2,5,Dead Ends,Detours,Dead Ends and Detours,Planning,Target Molecule,Starting Materials,6,Our Attitudes,Starting Materials,Product,Condition B,Condition A,Condition C,Several Steps,OR,Reality,7,Contents,8,Brevetoxin B,Brevetoxin B,A marine neurotoxinFirst reported by Nakanishi in 198123 stereocentersAll 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 Lawessons 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,Contents,14,16 Contiguous Stereogenic Centers7 Tetrasubstituted Carbons4 Different Ester Groups2 Hydroxy Groups1 Acid and Base-Sensitive Hemiketal1 Strained and Sterically-hindered Epoxide 2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH C20OH),Azadirachtin,15,BeginningIsolation and Structure Determination of Azadirachtin,Story Line,16,Hop Skip and Jump,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：C29H38O16(642.222),First Isolation,18,Molecular Formula : C35H44O16 （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,Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 1975.,Nakanishis Azadirachtin,Based on: PRFT/CWD 13C NMR Hypothetical Relationship with Known Terpenoids,Correct Structure,The First Complete Structure,20,Leys 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,Leys Modification,21,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,Azadirachtin,First isolated by Morgan(1968),Partial structure(1972),The first complete structure(1975),Leys modification(1985),Confirmed by X-ray analysis(1986),22,23,1968,1986,2006,1996,2007,Leys Monodrama（独角戏）,Story Line,24,Leys 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.,25,1st Synthesis,Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.,. Develop a flexible approach for the total synthesis. Study the functional groups responsible for activity (potential active center),26,Construction of This Fragment,Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.,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,Leys Other Work,Azadirachtin,29,1968,1986,2006,1996,2007,LeyCambridge,NicolaouScripps,MuraiHokkaido,WatanabeTokyo,Story Line,30,Leys 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,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,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,Watanabes Model,Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.,34,Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.,Tandem Radical Cyclization,35,Murais 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,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. Nicolaous Model Study,2002Radical,2005,2003,2002Organometallic,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,Brief Summary,42,Total Synthesis,Story Line,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