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d, I- and meso- Isochrysohermidin : Total Synthesis and Interstrand DNA Cross-Linking

d, I- and meso- Isochrysohermidin : Total Synthesis and Interstrand DNA Cross-Linking. Dale L. Boger and Carmen M. Baldino JACS (1993) 115 , 11418-11425. Presented by Bryan Klebon March 20, 2012. Dale Boger. Born 1952, Kansas B.S. University of Kansas, 1975

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d, I- and meso- Isochrysohermidin : Total Synthesis and Interstrand DNA Cross-Linking

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  1. d, I- andmeso-Isochrysohermidin: Total Synthesis andInterstrand DNA Cross-Linking Dale L. Boger and Carmen M. Baldino JACS (1993) 115, 11418-11425 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

  3. Isochrysohermadin • Autoxidation product of hermidin, a chromogen in Mercurialisperennis • Occurs naturally as a mixture of d,l- and mesostererisomers • Effective interstrand DNA crosslinking agent

  4. Retrosynthetic analysis Tandem Endoperoxide fragmentation 5 Double Diels-Alder Reaction 1O2 N-methylation, Selective ester hydrolysis 9 12

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

  6. Inverse Electron Demand Diels-Alder

  7. 1) C6H6, 80C, 72 h 2) C6H6, HOAc, 80 C, 60 h + Inverse electron Demand Diels- Alder Reaction 7 6 -N2 7 Retro-Diels- Alder Reaction Inverse electron Demand Diels- Alder Reaction -N2 -2 MeOH Aromatization 56% Retro-Diels- Alder Reaction 8

  8. Optimization of inverse-electron-demand Diels Alder

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

  10. Differentiation of carbonyl groups MeI, NaH LiOH 98% 100% 9 11 10 TFAA CH2N2 H2O 83% From 11 24 25 12

  11. Singlet Oxygen addition O2, rose bengal, hv Collidine, H2O, i-PrOH 2:6:1 22 C, 1h Double Diels –Alder Reaction 12 -CO2 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

  13. Questions?

  14. Additional Info • Alternative method of differentiating carbonyls

  15. Additional Info • Optimization of singlet Oxygen reaction

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