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

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

1 2 What is the “Bergman Cyclization” ? 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 Enediyne have a C-C double bond and two C-C triple bonds The intermediate produces benzene in presence of hydrogen radical donor intermediate: 中間体

Mechanism of DNA Cleavage by Calicheamicin 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. Bergman cyclization has been very available Isomerization that has found applications in areas ranging from drug design to materials synthesis antitumor agent: 抗がん剤

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

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

Plausible Mechanism of Radical Species B C F D E

Products of Bergman Cyclization in hidered system

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

14.5 kcal/mol 42.9 kcal/mol The Barrier to Formation of the Transition State in the case of phenyl shift onto the sp 3 radical in the case of phenyl shift onto the sp 2 radical

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

Stability of Benzene Diradical Isomers

Stability of Naphthalene Diradical Isomers

Stability of Disubstitued Naphthalene Diradical Isomers ?

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

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

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

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.