d i and meso isochrysohermidin total synthesis and interstrand dna cross linking n.
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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

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

dale boger
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
isochrysohermadin
Isochrysohermadin
  • Autoxidation product of hermidin, a chromogen in Mercurialisperennis
  • Occurs naturally as a mixture of d,l- and mesostererisomers
  • Effective interstrand DNA crosslinking agent
retrosynthetic analysis
Retrosynthetic analysis

Tandem

Endoperoxide

fragmentation

5

Double Diels-Alder

Reaction

1O2

N-methylation,

Selective ester

hydrolysis

9

12

retrosynthetic analysis ii
Retrosynthetic Analysis II

Double

Reductive

Ring Contraction

8

9

Double

Azadiene

Diels-Alder

+

7

6

slide7

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

double reductive ring contraction
Double Reductive Ring Contraction

Zn, HOAc

22 C, 24 h

Dearomatization

8

Enamine-Imine

Condensation

68%

Reductive Cleavage

9

differentiation of carbonyl groups
Differentiation of carbonyl groups

MeI, NaH

LiOH

98%

100%

9

11

10

TFAA

CH2N2

H2O

83%

From 11

24

25

12

singlet oxygen addition
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

conclusions
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
additional info
Additional Info
  • Alternative method of differentiating carbonyls
additional info1
Additional Info
  • Optimization of singlet Oxygen reaction