1. d, I- and meso-Isochrysohermidin: Total Synthesis and Interstrand DNA Cross-Linking Dale L. Boger and Carmen M. Baldino JACS (1993) 115, 11418-11425 1 Presented by Bryan Klebon March 20, 2012

2. Dale Boger Born 1952, Kansas B.S. University of Kansas, 1975 Ph.D. Harvard University, 1980 – E.J. Corey Assistant/Associate Professor of Medicinal Chemistry, University of Kansas, 1979-85 Associate Professor/Professor of Chemistry, Purdue University, 1985-91 Professor, The Scripps Research Institute, 1991-present 2

3. Isochrysohermadin Autoxidation product of hermidin, a chromogen in Mercurialis perennis Occurs naturally as a mixture of d,l- and meso stererisomers Effective interstrand DNA crosslinking agent 3

4. Retrosynthetic analysis 4 5 Tandem Endoperoxide fragmentation Double Diels-Alder Reaction 1O21O2 12 N-methylation, Selective ester hydrolysis 9

5. Retrosynthetic Analysis II 5 9 Double Reductive Ring Contraction 8 Double Azadiene Diels-Alder 6 7 +

6. Inverse Electron Demand Diels-Alder 6

7. 7 6 7 + 1) C 6 H 6, 80C, 72 h 2) C 6 H 6, HOAc, 80 C, 60 h Inverse electron Demand Diels- Alder Reaction Retro-Diels- Alder Reaction Inverse electron Demand Diels- Alder Reaction 7 Retro-Diels- Alder Reaction Aromatization 56% -2 MeOH 8 -N 2

8. Optimization of inverse-electron- demand Diels Alder 8

9. Double Reductive Ring Contraction 9 8 Zn, HOAc 22 C, 24 h Dearomatization Reductive Cleavage Enamine-Imine Condensation 68% 9

10. Differentiation of carbonyl groups 10 9 MeI, NaH 10 98% LiOH 100% TFAA 11 CH 2 N 2 H2OH2O 242512 83% From 11

11. Singlet Oxygen addition 11 12 O2, rose bengal, hv Collidine, H2O, i-PrOH 2:6:1 22 C, 1h Double Diels –Alder Reaction -CO 2 Endoperoxide Fragmentation ~70% (40%d,l 30% meso) 5

12. Conclusions Shows the utility of inverse-electron-demand Diels-Alder reactions in synthesis of complex heterocyclic systems Synthesis of isochrysohermadin in only 8 steps, including two different hetero-Diels- Alder reactions 12

13. Questions? 13

14. Additional Info Alternative method of differentiating carbonyls 14

15. Additional Info Optimization of singlet Oxygen reaction 15