Absolute stereochemistry assignment of phosphoeleganin based on the synthesis of polyols analogues of its C8-C11 core fragment

Polyketides represent a large family of complex natural products built from simple carboxylic acid-derived residues. They are produced primarily by microorganisms and find wide ranging applications as pharmaceuticals.1,2 In the marine environment, they have been frequently isolated from invertebrate-associated bacteria and/or fungi.3−7 Most marine natural polyketides possess polyhydroxy and polyoxy substituents in their structures, but the phosphate group is a less recurring functionality. We can find it in the structures of the calyculins, a family of highly cytotoxic linear sponge-derived polyketides with potent protein phosphatase inhibitory activity.7 Calyculins likely represent the most extensively studied class of phosphorylated marine metabolites, due to their potential as tools for studying intracellular processes controlled by reversible phosphorylation. Chemical investigation of the Mediterranean ascidian Sidnyum elegans (Giard, 1872) has led to the isolation of phosphoeleganin, a phosphorylated polyketide with significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Its planar structure and the preliminary configuration analysis allowed us to two alternative configuration patterns 8S, 11S, 12R, 15S, 16R and 8S, 11R, 12S, 15S, 16R. Recently, we have completed the absolute configuration analysis of this metabolite through the synthesis of polyols analogues of its C8-C11 core fragment.The absolute configuration of C11 and C12 was determined by the combination of the method UDB (Universal NMR DataBase) and the CDA-resin method.8 The UDB NMR method (Universal Database NMR) is a recently introduced tool to deal with configurational analysis of natural compounds and, in particular, linear and flexible polyketide structures. This method is based on the comparison of the NMR chemical shift of the compounds with unknown configuration with model compounds libraries with known stereostructures.