A Cycloaddition Cascade
Approach to the Total Synthesis
of (-)-FR182877
David A. Evans and JeremyT.Starr
Presented by Vijayarajan Devannah
2/19/2013
About Prof. David A.Evans
Education and Professional:
• 1941- Born in Washington D.C
• 1963- A.B degree, Oberlin College
• 1967- Ph.D at Cal.Tech under Robert E. Ireland
• 1973-1983 Professor at Caltech.
• 1983-present- Professor at Harvard University
Notable Awards:
• 1999 - The prelog medal, ETH, Zurich switzerland
• 2000- Arthur C.Cope Award, ACS
• 2007- Herbert C. Brown Award for creative research in synthetic methods, ACS
• 2008-Elected to fellow of Royal Society of Chemistry,UK
• 2010-ACS Award for creativity in Molecular Design and synthesis
• 2013-ACS Roger Adams Award
• >330 publications
Research Focus:
Target Oriented Synthesis and New reaction development
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About (-)FR182877
• In 1998, Sato and co-workers reported cytotoxic
natural product (WS9885B), isolated from
Streptomyces.
• WS9885B renamed as FR182877
• It is a potent microtubule-stabilizing agent and it
exhibits potent antitumor activity
• Its performance is similar to TAXOL in the
untreated Baby Hamster Kidney (BHK) cells, and it
holds forth promise as a new lead structure for
the development of antitumor therapeutics.
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Challenges posed by FR182877
• Hexacyclic architecture containing 12 stereogenic centers.
• It contains strained anti-Bredt bridgehead olefin
• Vinylogous carbonate embedded in a fused 6-6-7 ring
system
• The epoxide did not inhibit tumor cell growth and thus the
strained C2-C20 double bond may be necessary for the
observed antitumor activity.
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Retrosynthesis
C11-C20
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Aldol B
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Forward Synthesis
Scheme 2:
Scheme 3:
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Scheme 4:
7
Scheme 5:
Highly optimized suzuki coupling condition
The coupling was sensitive to the choice of base
• Strong bases (hydroxides or oxides) or less halophilic cations resulted
in slower reaction rate and competitive decomposition of SM via protodeborylation,
Oxidation, elimination etc.
• Silver bases completely decomposes products
• Carbonates had the good selectivity and Tl2CO3 gives good reaction at rt.
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Scheme 6:
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NMR analysis shows 2H pyran
equilibirium
Studying the inherent stereoselectivity of the TADA cascade
Scheme 7:
60oC, CDCl3
3hr
Model IMDA study shows good endo selectivity and poor
diastereoselectivity
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Scheme 8:
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Conclusion
•
1H
•
13C
NMR and Mass spectral characteristics were identical to those published
for the natural product 1.
NMR spectral data agreed within 2% margin of error.
• Synthetic 1 exhibited an optical rotation of [αD23]= -5o as compared to [αD23]=
-3.5o reported for the natural sample, and it lead to conclude that synthetic 1
was of the same absolute stereochemistry as natural (-)-FR182877.
• Semiempirical calculations of the transannular Diels-Alder cycloaddition
cascade were carried out to determine the origins of asymmetric induction.
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Thank You
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