Total Synthesis of BE-43472B

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Total Synthesis of BE-43472B
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PhD Work with Prof. André B. Charette
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The Scripps Research InstituteLa Jolla,
California
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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
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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
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BE-43472B
Isolated from marine streptomycete collected in
Puerto Rico Chrysophanol dimer linked in
tetrahydrofuran rings with an incorporated
acetaldehyde molecule
New structural class among known antimicrobial
agents
Organism inhibited IC50, ?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
Socha, A. M. Rowley D. C. et al. J. Nat. Prod.
2006, 69, 1070.
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BE-43472B Retrosynthesis
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Model Studies
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Model Studies
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Chrysophanol Derivative Synthesis
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Chrysophanol Derivative Synthesis
Hauser annulation
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Chiral Diene Synthesis and Diels-Alder Reaction
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E-Reduction of Propargylic Alcohol
1st report by Corey in 1967 (LiAlH4 2
MeOH) Red-Al introduced 15 years later by Denmark
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Chiral Diene Synthesis and Diels-Alder Reaction
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Ether 1,4-Elimination
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Chiral Diene Synthesis and Diels-Alder Reaction
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Quinone Acceptor Synthesis Initial Hopes
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Quinone Acceptor Synthesis Initial Hopes
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Quinone Acceptor Synthesis Initial Hopes
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Quinone Michael Acceptor Synthesis
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Quinone Michael Acceptor Synthesis
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Quinone Michael Acceptor Synthesis
hydrolysis happened in purification
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Quinone Michael Acceptor Synthesis
hydrolysis happened in purification
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Quinone Michael Acceptor Synthesis
hydrolysis happened in purification
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Quinone Michael Acceptor Synthesis
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Fragments Coupling and Aromatization
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Fragments Coupling Attempts
Real system
From model studies
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Fragments Coupling and Aromatization
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Fragments Coupling and Aromatization
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1,4-Addition Attempts
caused by in situ reducing metal?
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1,4-Addition Attempts
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Friedel-Crafts Fragments Coupling Attempts
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New Strategy
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Reversal of the Diene Electronics
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Diene Synthesis
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Diels-Alder with New Diene
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Diels-Alder with New Diene
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Completion of the Synthesis
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Photochemical Epoxide Rearrangement
Nicolaou, K. C. Lim, Y.-H. Becker, J. Lemire,
A. Neubauer, T. Montero, A. J. Am. Chem. Soc.
2009, 131, 14812.
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Acknowledgments
Prof. K. C. Nicolaou Research group members
Yee-Hwee Lim Jochen Becker