and meso Isochrysohermidin Total Synthesis and Interstrand DNA CrossLinking Dale L Boger and Carmen M Baldino JACS 1993 115 1141811425 1 Presented by Bryan Klebon March 20 2012 ID: 205807
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d, I- and meso-Isochrysohermidin: Total Synthesis andInterstrand DNA Cross-Linking
Dale L. Boger and Carmen M. BaldinoJACS (1993) 115, 11418-11425
1
Presented by Bryan
Klebon
March 20, 2012Slide2
Dale BogerBorn 1952, KansasB.S. University of Kansas, 1975Ph.D. Harvard University, 1980
E.J. CoreyAssistant/Associate Professor of Medicinal Chemistry, University of Kansas, 1979-85Associate Professor/Professor of Chemistry, Purdue University, 1985-91Professor, The Scripps Research Institute, 1991-present2Slide3
IsochrysohermadinAutoxidation product of hermidin, a chromogen
in Mercurialis perennisOccurs naturally as a mixture of d,l- and meso stererisomers
Effective interstrand DNA crosslinking
agent
3Slide4
Retrosynthetic analysis4
5
Tandem
Endoperoxide
fragmentation
Double Diels-Alder
Reaction
1
O
2
12
N-methylation,Selective esterhydrolysis9Slide5
Retrosynthetic Analysis II5
9
Double
Reductive
Ring Contraction
8
Double
Azadiene
Diels-Alder
6
7
+Slide6
Inverse Electron Demand Diels-Alder6Slide7
7
6
7
+
1) C
6
H
6
, 80C,
72 h
2) C
6H6, HOAc, 80 C, 60 hInverse electronDemand Diels-Alder ReactionRetro-Diels-Alder Reaction
Inverse electronDemand Diels-Alder Reaction7Retro-Diels-Alder ReactionAromatization56%-2 MeOH8
-N2-N2Slide8
Optimization of inverse-electron-demand Diels Alder8Slide9
Double Reductive Ring Contraction9
8
Zn,
HOAc
22 C, 24 h
Dearomatization
Reductive Cleavage
Enamine-Imine
Condensation
68%
9Slide10
Differentiation of carbonyl groups10
9
MeI
,
NaH
10
98%
LiOH
100%
TFAA
11
CH2N
2H2O24251283%From 11Slide11
Singlet Oxygen addition11
12
O2, rose
bengal
,
hv
Collidine
, H2O,
i-PrOH
2:6:1
22 C, 1h
Double Diels –AlderReaction-CO2EndoperoxideFragmentation~70%(40%d,l30% meso)5Slide12
ConclusionsShows the utility of inverse-electron-demand Diels-Alder reactions in synthesis of complex heterocyclic systemsSynthesis of isochrysohermadin in only 8 steps, including two different hetero-Diels-Alder reactions
12Slide13
Questions?13Slide14
Additional InfoAlternative method of differentiating carbonyls
14Slide15
Additional InfoOptimization of singlet Oxygen reaction15