Tetrahydroxy 10-Membered Cyclic Enediynes Michael Klein, † Manfred Zabel, ‡ Gu ¨ nther Bernhardt, § and Burkhard Ko ¨nig* ,† Institut fu ¨ r Organische Chemie, Universita ¨ t Regensburg, D-93040 Regensburg, Germany burkhard.koenig@chemie.uni-regensburg.de Received August 27, 2003 The preparation of cyclic 10-membered tetrahydroxy enediynes is reported. The synthesis starts from tartaric acid and allows the control of the relative stereochemistry. Acetal protection of the 2,3-hydroxy groups stabilizes the enediyne during synthesis. Removal of the cyclic protecting group with EtSH/TFA transforms the stable compounds into reactive enediynes, and the rate constants of their cyclization were determined in benzene and water. The cytoxicity of the activated compounds was assayed against tumor cells in vitro, but the growth inhibitory effect was weak compared to cisplatin. Introduction The cytotoxic properties of natural products such as calicheamicin γ 1 I , dynemicin A, or neocarzinostatin 1 have their origin in strained cyclic enediyne or cumulene- eneyne structures. Their spontaneous thermal cyclization yields reactive aryl or benzyl diradicals, which abstract hydrogen atoms, leading to DNA strand cleavage and ultimately to cell death. 2 To fulfill their biological func- tion, the reactivity of the unsaturated macrocycles must be regulated. In the natural products this is achieved either by trigger mechanisms that unlock conformation- ally constrained precursors 3 or by proteins, which tightly bind and stabilize the enediyne or cumulene-eneynes chromophore. 4 To control the reactivity in synthetic enediyne model compounds, several strategies have been reported: release of a conformational constrain that prohibits spontaneous cyclization, 5 isomerization of ene- diynes to the more reactive cumulene-eneynes, 6 genera- tion of the enediyne system by retro-Diels-Alder, 7 S N 2′ reaction, 8 or alkyne deprotection 9 or the induction of the cyclization by catalytic antibodies, 10 metal cations, 11 oxidation, 12 or light. 13 Hydroxylated enediynes are well suited to reversibly lock their conformation and therefore modulate their reactivity by cyclic hydroxy protecting * Fax (int.): +49-941-943-1717. † Institut fu ¨ r Organische Chemie. ‡ Current address: Zentrale Analytik der NWF IV, Universita ¨t Regensburg, 93040 Regensburg, Germany. § Current address: Institut fu ¨ r Pharmazie, Universita ¨ t Regensburg, D-93040 Regensburg, Germany. 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