<jats:title>Abstract</jats:title><jats:p>Leucascandrolide A ((+)‐<jats:bold>1</jats:bold>), a doubly O‐bridged 18‐membered macrolide of a new type, <jats:italic>i.e.</jats:italic>, showing little C<jats:sub>1</jats:sub>‐branching <jats:italic>vs.</jats:italic> extensive 1,3‐dioxygenation and a peculiar side chain, was isolated from a calcareous sponge of a new genus, <jats:italic>Leucascandra caveolata</jats:italic> B<jats:sc>OROJEVIC</jats:sc> and K<jats:sc>LAUTAU</jats:sc> from the Coral Sea. Transesterification of (+)‐<jats:bold>1</jats:bold> gave the methyl ester <jats:bold>3</jats:bold>, derived from the side chain, and the 5‐hydroxy derivative (+)‐<jats:bold>2</jats:bold>, derived from the macrolide portion and with the natural configuration at C(5) (axial). <jats:italic>Mosher</jats:italic>'s MTPA esters <jats:bold>4</jats:bold> and <jats:bold>5</jats:bold> obtained from (+)‐<jats:bold>2</jats:bold> showed scattered Δδ = (δ(<jats:italic>S</jats:italic>) − δ(<jats:italic>R</jats:italic>)) data. However, inversion of the configuration at C(5) led, <jats:italic>via</jats:italic> ketone (+)‐<jats:bold>6</jats:bold>, to the less encumbered 5‐equatorial hydroxy derivative (+)‐<jats:bold>7</jats:bold>, whose MTPA esters <jats:bold>8</jats:bold> and <jats:bold>9</jats:bold> gave consistent Δδ data, allowing the assignment of the absolute configuration of (+)‐<jats:bold>7</jats:bold>, and hence of (+)‐<jats:bold>1</jats:bold>. The structural novelty of (+)‐<jats:bold>1</jats:bold> and its powerful antifungal and cytotoxic activities are likely to renew interest in calcareous sponges, previously limited to scarcely biologically active 2‐aminoimidazoles.