Leucascandrolide A, a new type of macrolide: The first powerfully bioactive metabolite of calcareous sponges (Leucascandra caveolata, a new genus from the coral sea)

Leucascandrolide A ((+)-1), a doubly O-bridged 18-membered macrolide of a new type, i.e., showing little CI-branching vs. extensive 1,3-dioxygenation and a peculiar side chain, was isolated from a calcareous sponge of a new genus, Leucascandra caveolata BOROJEVIC and KLAUTAU from the Coral Sea. Transesterification of (+)-1 gave the methyl ester 3, 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 esters 4 and 5 obtained from (+)-2 showed scattered Delta delta = (delta(S) - delta(R)) data. However, inversion of the configuration al C(5) led, via ketone (+)-6, to the less encumbered 5-equatorial hydroxy derivative (+)-7, whose MTPA esters 8 and 9 gave consistent Delta delta data, allowing the assignment of the absolute configuration of(+)-7, and hence of(+)-1. The structural novelty of(+)-1 and its powerful antifungal and cytotoxic activities are likely to renew interest in calcareous sponges, previously limited to scarcely biologically active 2-aminoimidazoles.