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.

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Presentation transcript:

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

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, Associate Professor/Professor of Chemistry, Purdue University, Professor, The Scripps Research Institute, 1991-present 2

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

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

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

Inverse Electron Demand Diels-Alder 6

) 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

Optimization of inverse-electron- demand Diels Alder 8

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

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

Singlet Oxygen addition 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

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

Questions? 13

Additional Info Alternative method of differentiating carbonyls 14

Additional Info Optimization of singlet Oxygen reaction 15