title: Efficient and accurate characterization of the Bergman cyclization for several enediynes including an expanded substructure of esperamicin A1.
abstract: Incorporation of enediynes into anticancer drugs remains an intriguing yet elusive strategy for the design of therapeutically active agents. Density functional theory was used to locate reactants, products, and transition states along the Bergman cyclization pathways connecting enediynes to reactive para-biradicals. Sum method correction to low-level calculations confirmed B3LYP/6-31G(d,p) as the method of choice in investigating enediynes. Herein described as MI:Sum, calculated reaction enthalpies differed from experiment by an average of 2.1 kcal x mol(-1) (mean unsigned error). A combination of strain energy released across the reaction coordinate and the critical intramolecular distance between reacting diynes explains reactivity differences. Where experimental and calculated barrier heights are in disagreement, higher level multireference treatment of the enediynes confirms lower level estimates. Previous work concerning the chemically reactive fragment of esperamcin, MTC, is expanded to our model system MTC2.
authors.affiliation: Department of Chemistry, Center for Molecular Design, Hamilton College, Clinton, New York 13323, USA. edward_sherer@merck.com
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.forename: Karl N
authors.initials: KN
authors.lastname: Kirschner
authors.forename: Frank C
authors.initials: FC
authors.lastname: Pickard
authors.forename: Chantelle
authors.initials: C
authors.lastname: Rein
authors.forename: Steven
authors.initials: S
authors.lastname: Feldgus
authors.forename: George C
authors.initials: GC
authors.lastname: Shields
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D003500:Cyclization; D053281:Enediynes / Q000737:chemistry*; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D000617:Aminoglycosides; D053281:Enediynes; C047543:esperamicin A1