Bergman cyclization of acyclic amino acid derived enediynes leads to the formation of 2,3-dihydrobenzo[f]isoindoles.
Enediyne-peptide conjugates are recently recognized as useful tools in targeting various proteins, while the mechanism underlying the observed activity remains somewhat unclear. Addressing these issues, we have prepared acyclic amino acid derived enediynes and disclosed a novel thermally induced cyclization-elimination pathway. Initial formation of 1,4-benzene diradical and H-atom abstraction from an external donor is followed by S(N)2 substitution leading to 2,3-dihydrobenzo[f]isoindoles. The proposed mechanism is supported by experimental and computational data. Additionally, we showed that amino acid side chains, although placed three bonds away from acetylene terminuses, have an appreciable influence on the reactivity of studied enediynes. These results demonstrate that amino acid or peptide parts of enediyne-peptide conjugates cannot be considered as recognition elements exclusively but may also participate in various reactions through amine functionality.
Gredicak
Matija
M
Division of Organic Chemistry and Biochemistry, Ruder Bosković Institute, Zagreb, 10000-HR Croatia.
Matanović
Ivana
I
Zimmermann
Boris
B
Jerić
Ivanka
I
D000596:Amino Acids / Q000737:chemistry*; D003500:Cyclization; D053281:Enediynes / Q000737:chemistry*; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013237:Stereoisomerism
C554864:2,3-dihydrobenzo(f)isoindole; D000596:Amino Acids; D053281:Enediynes; D054833:Isoindoles