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d, I- and meso-Isochrysohermidin: Total Synthesis and
Interstrand DNA Cross-Linking
Dale L. Boger and Carmen M. BaldinoJACS (1993) 115, 11418-11425
Presented by Bryan KlebonMarch 20, 2012
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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
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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
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Retrosynthetic analysis
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NMeO
MeO2C OH
Me
O
N
MeO
MeO2C
HO
Me
O
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TandemEndoperoxidefragmentation
O
O
O
O
MeN
MeN
MeO2C
CO2Me
CO2H
OMe
MeO
O
OH
H
Double Diels-AlderReaction
1O2
NMe
NMe
MeO
MeO
CO2Me
CO2H
MeO2C CO2H
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N-methylation,Selective esterhydrolysis
NH
NH
MeO
MeO
CO2Me
CO2Me
MeO2C CO2Me
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Retrosynthetic Analysis II
NH
NH
MeO
MeO
CO2Me
CO2Me
MeO2C CO2Me
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DoubleReductiveRing Contraction
N N
MeO
MeO2C CO2Me
N
NMeO
MeO2C
CO2Me
8
DoubleAzadieneDiels-Alder
MeO OMe
MeO OMe
N
NN
N
CO2Me
CO2Me
6 7
+
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Inverse Electron Demand Diels-Alder
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N
N
N
N
MeO2C
CO2Me
OMeMeO
OMe
OMeMeO OMe
MeO OMe
N
NN
N
CO2Me
CO2Me
N N
MeO
MeO2C CO2Me
MeO
N
N
N
NCO2Me
MeO2C
OMe
MeO
N N
MeO
MeO
MeO2C CO2Me
MeO
OMe
N N
MeO
MeO2C CO2Me
MeO
N
NMeO
MeO2C
CO2Me
MeO
N N
MeO
MeO2C CO2Me
N
NMeO
MeO2C
CO2Me
6 7
+
1) C6H6, 80C, 72 h2) C6H6, HOAc, 80 C, 60 h
Inverse electronDemand Diels-Alder Reaction
Retro-Diels-Alder Reaction Inverse electron
Demand Diels-Alder Reaction
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Retro-Diels-Alder Reaction
Aromatization56%
-2 MeOH
8
-N2
-N2
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Optimization of inverse-electron-demand Diels Alder
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Double Reductive Ring Contraction
N N
MeO
MeO2C CO2Me
N
NMeO
MeO2C
CO2Me
8 HN N
MeO
MeO2C CO2Me
NH
NMeO
MeO2C
CO2Me
NH2 HN
MeO
MeO2C CO2Me
NH2
NHMeO
MeO2C
CO2Me
NH
NH
MeO
MeO
CO2Me
CO2Me
MeO2C CO2Me
Zn, HOAc22 C, 24 h
Dearomatization
Reductive Cleavage Enamine-ImineCondensation
68%
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Differentiation of carbonyl groups
NH
NH
MeO
MeO
CO2Me
CO2Me
MeO2C CO2Me
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NMe
NMe
MeO
MeO
CO2Me
CO2Me
MeO2C CO2MeNMe
NMe
MeO
MeO
CO2H
CO2H
HO2C CO2H
MeI, NaH
10
98%
LiOH
100%
TFAA
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NMe
NMe
MeO
MeO
CO2H
HO2C
O
O
O
NMe
NMe
MeO
MeO
CO2Me
MeO2C
O
O
O NMe
NMe
MeO
MeO
CO2Me
CO2H
MeO2C CO2H
CH2N2 H2O
24 25 12
83%From 11
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Singlet Oxygen addition
NMe
NMe
MeO
MeO
CO2Me
CO2H
MeO2C CO2H
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O2, rose bengal, hvCollidine, H2O, i-PrOH
2:6:122 C, 1h
Double Diels –AlderReaction
O
O
O
O
MeN
MeN
MeO2C
CO2Me
CO2H
OMe
MeO
O
OH
H
NMeO
MeO2C OH
Me
O
N
MeO
MeO2C
HO
Me
O
-CO2
EndoperoxideFragmentation
~70%(40%d,l
30% meso)
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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
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Questions?
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Additional Info• Alternative method of differentiating carbonyls
NMe
NMe
MeO
MeO
CO2Me
CO2Me
MeO2C CO2Me
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Additional Info• Optimization of singlet Oxygen reaction