A Cycloaddition Cascade Approach to the Total Synthesis

of (-)-FR182877David A. Evans and JeremyT.Starr

Presented by Vijayarajan Devannah2/19/2013

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About Prof. David A.EvansEducation 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 UniversityNotable 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 publicationsResearch 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

5C11-C20

Aldol B

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Forward SynthesisScheme 2:

Scheme 3:

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Scheme 4:

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Scheme 5:

Highly optimized suzuki coupling conditionThe 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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Studying the inherent stereoselectivity of the TADA cascade Scheme 7:

60oC, CDCl3

3hr

Model IMDA study shows good endo selectivity and poor diastereoselectivity

NMR analysis shows 2H pyran equilibirium

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Scheme 8:

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Conclusion

• 1H NMR and Mass spectral characteristics were identical to those published for the natural product 1.

• 13C NMR spectral data agreed within 2% margin of error.

• Synthetic 1 exhibited an optical rotation of [αD23]= -5o as compared to [αD

23]= -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