Oxaeunicellane skeleton

The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. 

In the total synthesis of Danishefsky et al. (Figure 3) the tricyclic skeleton is established before the arabinosyl unit is linked [10]. The key steps of this synthesis are the Nozaki-Kishi cydization to the furanophane, a sequence of rearrangements to the 4,7-oxaeunicellane framework [11], and the oxycarbaglycosidation of the tricyclic core structure. 

The reactivity of the strained, tricyclic skeleton of the 4,7-oxaeunicellanes was studied by Pietra in 1988 [4]. Treatment of sarcodictyin A (31) with methanolic potassium hydroxide led to the formation of the butenolide 32 (Scheme 4). The Michael acceptor property of the carbon atom C2 favors this rearrangement, leading to a relaxation of the strained ring system. After methanoly-sis of the A-methylurocanate, the newly formed hydroxyl group attacks at C2 and the fragmentation of the carbon-carbon bond between C3 and C4 immediately follows. 

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