Enediyne computational study

PraU, M. Wittkopp, A. Schreiner, P. R. Can fulvenes form from enediynes A systematic high-level computational study on parent and benzannelated enediyne and enyne—allene cyclizations, 7. Phys. Chem. A 2001,105, 9265-9274. 

Schreiner, P.R., Navarro-Vazques, A. and Prall, M. (2005) Computational studies on the cyclizations of enediynes, enyne-allenes, and related polyunsaturated systems. Accounts of Chemical Research, 38(1), 19-i7. 

Quantum chemical studies of cyclizations of enediynes and enyneallenes have been reviewed.180 The intermediates are computationally tractable as a result of the unrestricted broken spin symmetry (UBS) approach using GGA functionals for the description of open-shell biradicals. The intermediacy of biradicals in Cope-type rearrangements, to which the Bergman and Myers-Saito reactions belong, are shown to be predictable using a very simple rule biradicals are likely to be intermediates if they are stabilized either by allyl resonance or by aromaticity. 

A theoretical study of the biological activity of dynamicin A (52) dealt in part with the question of the cd distance. Tuttle et al. examined the Bergman cycliza-tion of 52 to 53 and compared it to cyclization of activated dynamicin A (54) to its diradical product (55). Given the size of these molecules, they optimized the structures at the relatively small B3LYP/3-21G level, but it is important to note that this level predicts the barrier for the cyclization of the 10-member ring enediyne (44) with an error of less than 1 kcal mol —clearly a situation of fortuitous cancellation of errors. Energies were then computed at B3LYP/6-31G(d). The activation enthalpy for the cyclization of 52 is 52.3 kcal mol while the barrier for cyclization of 54 is dramatically reduced to 17.9 kcal mol It is even much lower than the barrier for the cyclization of 44 (28 kcal mol ). 

However, as there is no free DNA in the cell, and the real target for DNA-inter-active agents is the chromatin, it is not clear whether in vitro studies can contribute to understanding of cellular DNA sequence selectivity. Various synthetic approaches and mechanistic studies assisted by computer aided molecular design (CAMD) have been described aiming at an optimization of the pharmacological properties of the enediyne antibiotics [80]. It remains to be seen whether enediynes, either natural or designed, will become a useful supplement to the arsenal for the treatment of cancer. 

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