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Total Synthesis of BE-43472B. PhD Work with Prof. André B. Charette.

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Presentation on theme: "Total Synthesis of BE-43472B. PhD Work with Prof. André B. Charette."— Presentation transcript:

1 Total Synthesis of BE-43472B

2 PhD Work with Prof. André B. Charette

3 The Scripps Research Institute La Jolla, California

4 The Scripps Research Institute World's largest, private non-profit biomedical research facility Founded in 1961 by Frank Dixon, M.D. 289 Faculty members 815 Postdoctoral fellows 235 Graduate students 1,500 technical and administrative support personnel

5 The Scripps Research Institute K. C. Nicolaou - Chairman of chemistry dept. Barry K. Sharpless - Nobel laureate Phil S. Baran Dale Boger Carlos F. Barbas III Jin-Quan Yu Albert Eschenmoser Kim D. Jenda Richard Lerner Peter Schultz Julius Rebek Jr. Director, Skaggs Institute for Chemical Biology

6 BE-43472B Organism inhibited IC 50,  M MRSA, ATCC 43300 Methicilin-resistant Straphylococcus aureus 0.15 VRE, ATCC 51299 Vancomycin resistant Enterococcus faecalis 2.0 HCT-116 Human cancer cells 3.3 New structural class among known antimicrobial agents Isolated from marine streptomycete collected in Puerto Rico Chrysophanol dimer linked in tetrahydrofuran rings with an incorporated acetaldehyde molecule Socha, A. M.; Rowley D. C. et al. J. Nat. Prod. 2006, 69, 1070.

7 BE-43472B Retrosynthesis

8 Model Studies

9

10 Chrysophanol Derivative Synthesis

11 Hauser annulation

12 Chiral Diene Synthesis and Diels-Alder Reaction

13 E-Reduction of Propargylic Alcohol 1 st report by Corey in 1967 (LiAlH 4 + 2 MeOH) Red-Al introduced 15 years later by Denmark

14 Chiral Diene Synthesis and Diels-Alder Reaction

15 Ether 1,4-Elimination

16 Chiral Diene Synthesis and Diels-Alder Reaction

17 Quinone Acceptor Synthesis – Initial Hopes

18

19

20 Quinone Michael Acceptor Synthesis

21

22 hydrolysis happened in purification

23 Quinone Michael Acceptor Synthesis hydrolysis happened in purification

24 Quinone Michael Acceptor Synthesis hydrolysis happened in purification

25 Quinone Michael Acceptor Synthesis

26 Fragments Coupling and Aromatization

27 Fragments Coupling Attempts From model studies Real system

28 Fragments Coupling and Aromatization

29

30 1,4-Addition Attempts caused by in situ reducing metal?

31 1,4-Addition Attempts

32 Friedel-Crafts Fragments Coupling Attempts

33 New Strategy

34 Reversal of the Diene Electronics

35 Diene Synthesis

36 Diels-Alder with New Diene

37

38 Completion of the Synthesis

39 Photochemical Epoxide Rearrangement Nicolaou, K. C.; Lim, Y.-H.; Becker, J.; Lemire, A.; Neubauer, T.; Montero, A. J. Am. Chem. Soc. 2009, 131, 14812.

40 Acknowledgments Prof. K. C. Nicolaou Research group members Yee-Hwee Lim Jochen Becker

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