1. A Cycloaddition Cascade Approach to the Total Synthesis of (-)-FR182877 David A. Evans and JeremyT.Starr Presented by Vijayarajan Devannah 2/19/2013

2. 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 2

3. 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. 3

4. 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. 4

5. Retrosynthesis 5 C11-C20 Aldol B 5

6. Forward Synthesis Scheme 2: Scheme 3: 6

7. Scheme 4: 7

8. 8 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 Tl 2 CO 3 gives good reaction at rt.

9. Scheme 6: 9

10. Studying the inherent stereoselectivity of the TADA cascade Scheme 7: 10 60 o C, CDCl 3 3hr Model IMDA study shows good endo selectivity and poor diastereoselectivity NMR analysis shows 2H pyran equilibirium

11. Scheme 8: 11

12. 12 Conclusion 1 H NMR and Mass spectral characteristics were identical to those published for the natural product 1. 13 C NMR spectral data agreed within 2% margin of error. Synthetic 1 exhibited an optical rotation of [α D 23 ]= -5 o as compared to [α D 23 ]= -3.5 o 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.

13. Thank You 13