Enantioselective Synthesis of
9’-Desmethylgarugamblin I
Andrew Willeford
Dr. Christopher M. Beaudry
Department of Chemistry
HHMI 2009
Natural Products
Opium Poppy
Penicillum Fungi
Morphine
Penicillin
Chromodoris macfarlandi
Macfarlandin E
Diaryl Ether Heptanoids
• Exhibit useful biological activities
1) Anti-inflammatory
2) Anticancer
3) Antibacterial
• General structure
1) Seven carbon chain tethered
together by a diaryl ether
linkage
2) Cyclophanes
Optical Activity
• 17 diaryl ether heptanoids do not possess stereocenters
1) Six of these 17 compounds are chiral by virtue of their
tethered-ring structure and have been isolated as
optically active compounds.
• Planar chirality
1) Mobius Strip
This work is licensed under a Creative Commons Attribution-Share Alike 3.0 Unported License.
Question
• These compounds are almost identical to each other
1) Minimal difference in substituents
2) Why such a difference in optical rotation?
Isolation
• All 17 compounds were isolated from plant sources
1) 9’-desmethylgarugamblin I is a bark extract of Garuga
pinnata
a)
b)
c)
A frankencense
Found in Asia
Used in folk medicine
• Typical isolation
1) Includes extraction in a Soxhlet
apparatus at high temperatures
Hypothesis
• Isolation of these compounds have led to racemization
1) Enantioselective synthesis of 9’-desmethylgarugamblin I
would allow verification of our hypothesis
2) Will offer proof of concept to enantioselectively
synthesize the compounds with non-reported optical
rotations
Enantioselectivity
• Selective synthesis of one enantiomer
• Pathway
1) Cu catalyst on non-racemic, chiral ligands promotes the
enantioselective synthesis of 9’-desmethylgarugamblin I
Chiral Catalysts
• A catalyst with enantiomeric forms
1) Holds substrate in specific conformation
2) Lowers energy barrier for formation of one enantiomer
• Examples
1)
2)
3)
4)
Walphos
Naud
Josiphos
Enzymes
Mechanistic Considerations
Progress
Future Research
• Enantioselective synthesis of other aryl ethers
Acknowledgements
• Howard Hughes Medical Institute
• Undergraduate Research, Innovation, Scholarship, &
Creativity (URISC) Program
• Dr. Christopher M. Beaudry
• Dr. Kevin Ahern