AbstractLeucascandrolide A ((+)‐1), a doubly O‐bridged 18‐membered macrolide of a new type,i.e., showing little C1‐branchingvs.extensive 1,3‐dioxygenation and a peculiar side chain, was isolated from a calcareous sponge of a new genus,Leucascandra caveolataBOROJEVICand KLAUTAUfrom the Coral Sea. Transesterification of (+)‐1gave the methyl ester3, derived from the side chain, and the 5‐hydroxy derivative (+)‐2, derived from the macrolide portion and with the natural configuration at C(5) (axial).Mosher's MTPA esters4and5obtained from (+)‐2showed scattered Δδ = (δ(S) − δ(R)) data. However, inversion of the configuration at C(5) led,viaketone (+)‐6, to the less encumbered 5‐equatorial hydroxy derivative (+)‐7, whose MTPA esters8and9gave consistent Δδ data, allowing the assignment of the absolute configuration of (+)‐7, and hence of (+)‐1. The structural novelty of (+)‐1and its powerful antifungal and cytotoxic activities are likely to renew interest in calcareous sponges, previously limited to scarcely