Bergman Cyclization of Sterically Hindered Substrates and Observation of Phenyl-Shifted Products

1. M1 Colloquium in Division Frontier Materials Science in 2005 Bergman Cyclization of Sterically Hindered Substrates and Observation of Phenyl-Shifted Products Kevin D. Lewis, and Adam J. Matzger* J. Am. Chem. Soc. 2005, 127, 9968. Tobe Laboratory Hiroyuki Kuge sterically hindered: 立体的に込み合った substrate: 基質

2. Contents 1. Introduction 2. Experiment 3. Results and Discussion 4. Summary

3. What is the “Bergman Cyclization” ? Enediyne have a C-C double bond and two C-C triple bonds 2 1 In 1972, Bergman and co-workers founded that deuteration compound 1 interconverts only 2 and the process that leads to the formation of aromatic 1,4-diradical system as intermediate The intermediate produces benzene in presence of hydrogen radical donor intermediate: 中間体

4. Mechanism of DNA Cleavage by Calicheamicin Bergman cyclization has been very available Isomerization that has found applications in areas ranging from drug design to materials synthesis Calicheamicin is an very potent antitumor agent. It has an endiyne moiety and readily cyclize, forming a highly reactive 1,4-benzenediradical intermediate. This radical can oxidatively cleave DNA. antitumor agent: 抗がん剤

5. Expected Cyclization of 1,2-bis(phenylethynyl)benzene

6. Products of Thermal Reaction of 1,2-Bis(phenylethynyl)benzene in benzene

7. Plausible Mechanism of Radical Species F B C E D

8. Products of Bergman Cyclization in hidered system

9. Possibility of transform from 2,3-diphenylnaphthalene to 1,3- and 1,4-diphenylnaphthalene

10. The Barrier to Formation of the Transition State in the case of phenyl shift onto the sp3 radical 14.5 kcal/mol in the case of phenyl shift onto the sp2radical 42.9 kcal/mol

11. Bird’s-eye view Side view Front view Modeled by MM2 calc. The view of 2,3-diphenylnaphthalene

12. Stability of Benzene Diradical Isomers

13. Stability of Naphthalene Diradical Isomers

14. Stability of Disubstitued Naphthalene Diradical Isomers ?

15. Proposed Mechanism of Cyclization of 1,2-Bis(phenylethynl)benzene

16. Proposed Mechanism of Cyclization of 1-phenylethynl-2-ethynylbenzene

17. The Mechanism of “Phenyl Walking” studies on a derivative of 2,3-diphenylehynylbenzenein which the phenyl rings were perdeuterated confirmed that no deuterium transfer to the naphthalene ring occurred thus ruling out this phenyl shifting mechanism

18. Summary The study of particularly hindered Bergman cyclizations revealed that phenyl shifts can dominate the products formed under certain conditions. Relief of steric hindrance and formation of more energetically favorable benzenediradicals will lead to a lowering of the barrier.