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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

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

9

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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

+

6

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

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-N2

-N2

8

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%

9

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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