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. 2008 Dec 25;112(51):16917-34.
doi: 10.1021/jp807341t.

Efficient and accurate characterization of the Bergman cyclization for several enediynes including an expanded substructure of esperamicin A1

Edward C Sherer  1 , Karl N Kirschner, Frank C Pickard 4th, Chantelle Rein, Steven Feldgus, George C Shields
Affiliations

Efficient and accurate characterization of the Bergman cyclization for several enediynes including an expanded substructure of esperamicin A1

Edward C Sherer et al. J Phys Chem B. .

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.

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Figures

Figure 1
Figure 1
The structure of the un-triggered calicheamicin and esperamicin A1 molecules.
Figure 2
Figure 2
Schematic of the Bergman Cyclization and hydrogen abstraction, note indication of forming bond Rcd.
Figure 3
Figure 3
Structures of compounds discussed including the MTC2 model system 15 where hydroxyl groups have replaced the carbohydrates and the carbamate tail has been removed. Compounds 12–14 have a silyl group present experimentally, which has been truncated to methyl for calculation. Compound 20 is calicheamicin. Structures 12b and 12c are boat and chair conformations respectively.
Figure 4
Figure 4
Additional structures calculated.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
See this image and copyright information in PMC

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