In 2004, Uemura and co-workers isolated the unique tricyclic iminium alkaloid (+)-symbioimine as part of a screen of marine natural products capable of inhibiting osteoclastogenesis. In addition to preventing the differentiation of pre-osteoclasts, (+)-symbioimine exhibited moderately selective COX-2 inhibitory activity. As part of our on-going efforts to synthesize structural variants, including diastereomers, of symbioimine for structure-activity relationship studies, we report herein the successful synthesis of desulfated (—)-2-epi-symbioimine via a remarkably diastereoselective intramolecular Diels-Alder cycloaddition (IMDA). Specifically, an unconstrained exocyclic chirality center and a removable trimethylsilyl group were combined to induce high p-facial selectivity and near-exclusive exo-selectivity in the IMDA cycloaddition of an appropriately functionalized dodeca-3,9,11-trien-5-one. This strategy provided direct access to polysubstituted trans-1-decalones related to symbioimine and its dimethylated congener neosymbioimine in good yield and acceptable diastereoselectivity.

Synthesis of desulfated 2-epi-symbioimine and related compounds via a highly stereoselective intramolecular Diels-Alder cycloaddition

253rd National Meeting (2017)

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