Stereoselective Synthesis of Spiroacetal Domain Derivatives of the Plant Glycoside Ranuncoside and of Okadaic Acid and Dinophysistoxins-1 and 2 From Marine Algae

Abstract

Spiroacetals constitute the central structural core element of numerous natural products and are mostly represented as bicyclic or tricyclic domains. Typical natural products with tricyclic spiroacetals are (+)-ranuncoside 1, a glycoside isolated from plants of the Ranuncalaceae family, and the algal toxins (+)-okadaic acid 2 and the (+)-dinophysistoxins-1 and 2 (3 and 4). These substances possess a spiro furan-dioxane-pyran ring system 5 and a spiro furan-pyran-pyran scaffold 6, which are both essential for biological activity. Corresponding analogs with spiro furan-dioxane-cyclohexane framework 7 or ( ent)-7 have so far neither been found in living organisms nor been synthesized. To close this gap and to generate candidates for structure-activity relationship studies which could lead to the discovery of novel antibiotics and selective anticancer agents, we have developed an efficient and stereocontrolled synthetic route to analogous domains of the above natural products. Pyran-dioxane-cyclohexane tricycles 12, 17, and 25 were used as starting materials and, via ring contraction, yielded the 2 derivatives 16 and 29, with spiro ( R)- and spiro ( S)-configuration and tricyclic ring system 7 and ( ent)-7, respectively. The stereochemistry and conformation of all novel products were solved by nuclear magnetic resonance spectroscopy.