STRUCTURE ELUCIDATION OF AUSTRALIFUNGIN, A POTENT INHIBITOR OF SPHINGANINE N-ACYLTRANSFERASE IN SPHINGOLIPID BIOSYNTHESIS FROM SPORORMIELLA-AUSTRALIS

The structure elucidation of the novel, potent sphinganine N-acyltransferase inhibitor, australifungin (1), from Sporormiella australis is described. Extensive exchange-broadening phenomena predominantly of the keto-enol type were observed on the NMR time scale which was resolved by derivatization to triacetate (2) and tetraacetate (3) derivatives. Residual exchange broadening in the acetates was attributed to hindered rotation about the C3-C11 single bond which was frozen out into two conformers at low temperature, The application of 2D NMR techniques to the structure elucidation of the acetate derivatives at ambient and low temperature therefore contributed considerably to the overall structure determination of 1. The conformation and complete relative stereochemistry followed from a consideration of the Karplus relationship for H-1-H-1 vicinal coupling constants and phase-sensitive NOE data. Temperature-dependent NMR experiments suggest an averaged conformational mixture of four to five forms in solution at ambient temperature whereas a predominant conformer 1 is indicated at low temperature with the enolized beta-keto aldehyde stabilized through internal H-bonding in the cis-orientation. The triacetate 2 and tetraacetate 3, by contrast, are enolized in the sterically favored trans configuration. The beta-keto alcohol derivative australifunginol (6) is also present.