Can Fulvenes Form from Enediynes? A Systematic High-Level Computational Study on Parent and Benzannelated Enediyne and Enyne-Allene Cyclizations Matthias Prall, † Alexander Wittkopp, †,‡ and Peter R. Schreiner* ,†,‡ Institut fu ¨ r Organische Chemie der Georg-August-UniVersita ¨ t, Tammannstr. 2, 37077 Go ¨ ttingen, Germany, and Computational Center for Molecular Structure and Design, Department of Chemistry, UniVersity of Georgia, Athens, Georgia 30602-2556 ReceiVed: August 2, 2000; In Final Form: July 26, 2001 Apart from the well-known Bergman, Myers-Saito, and Schmittel ring closure reactions of parent enediyne (4) and enyne-allene (3), novel cyclization modes were identified using density functional (DFT) and coupled- cluster methods. The geometries obtained with several DFT functionals are quite similar; for consistency’s sake, we employed BLYP/6-31G* geometries; Brueckner double energy single points [BCCD(T)/cc-pVDZ] on these geometries were used to determine the relative energies. The C 1 -C 5 cyclization of 4 leading to fulvene biradical 8 is 40 kcal mol -1 endothermic, and the product lies 31 kcal mol -1 above 1,4-didehydro- benzene 7 because of the lack of aromatic stabilization. The heat of formation (Δ f H°) of 8 is predicted to be 172.0 ( 1.0 kcal mol -1 . Yet another ring closure of 4 leading to dimethylenecyclobutene biradical 12 is 69 kcal mol -1 endothermic and is hardly of preparative interest. A new cyclization of 3 should lead to the seven- membered ring biradical 13, which is located 33 kcal mol -1 above 3 and 24 kcal mol -1 above the Schmittel product 6. As the transition structure for both cyclizations differ by 11 kcal mol -1 , 13 may form under suitable conditions. All other possible modes of cyclization of 4 did not lead to stable products. Benzannelation has a significant effect on the endothermicities of the Bergman and Myers-Saito cyclizations, which are 8-9 kcal mol -1 above the parent reactions due to reduced aromatization energy in the naphthalene derivatives. The endothermicities of the other cyclization pathways are largely unaffected by benzannelation. Introduction The ring closure reactions of some polyunsaturated systems, such as enediynes or enyne-allenes, which are known as Bergman, 1-4 Myers-Saito, 5-9 and Schmittel cyclizations, 10-15 are of particular significance both for medicinal and organic materials chemistry. 16-22 Such or structurally related moieties lead to DNA-cleaving biradicals, i.e., they are potent antitumor drugs. 23-26 Naturally occurring examples are Calicheamicin γ I 1 (1) or Neocarzinostatin (2) (Scheme 1). 16,17,20,22 The parent reactions are now well understood both experimentally 13,26-39 and theoretically. 40-53 Although many modes of cyclization can be envisaged, only three principally different ones are known experimentally. However, as we wish to demonstrate in this paper, other entirely unexplored cyclization modes of enediyne and enyne-allene substrates are possible. In particular, this study includes details on a new and important five-membered ring closure of the enediyne parent system giving rise to fulvene derivatives. Background The exothermic (-15 ( 3 kcal mol -1 )C 2 -C 7 cycloaroma- tization of (Z)-1,2,4-heptatriene-6-yne (3, Myers-Saito cycliza- tion) leads to R,3-didehydrotoluene (5, Scheme 2), a σ,π- biradical which is stabilized by benzylic π-conjugation; 5-8 a similarly aromatic biradical stems from the C 1 -C 6 cyclization of (Z)-1,5-hexadiyne-3-ene (4, Bergman-cyclization). 1-4 In marked contrast to 5, 1,4-didehydrobenzene (7) is a nonconju- gated σ,σ-biradical (Scheme 2) which forms endothermically (8.5 ( 1.1 kcal mol -1 ), 54 i.e., only at rather high temperatures (cyclization temperature ca. 200 °C). In the presence of a suitable H-donor such as 1,4-cyclohexadiene or even DNA, the subsequent formation of two new C-H bonds is highly exothermic and renders the overall reaction irreversible. For both * Corresponding author. † Institut fu ¨r Organische Chemie der Georg-August-Universita ¨t. ‡ University of Georgia. SCHEME 1: Antitumor Antibiotics Calicheamicin γ I 1 1 and Neocarzinostatin 2 SCHEME 2: Cyclizations of Enyne-Allene 3 and Enediyne 4 9265 J. Phys. Chem. A 2001, 105, 9265-9274 10.1021/jp0028002 CCC: $20.00 © 2001 American Chemical Society Published on Web 09/18/2001