Goniodomic\nAcid, a Transient Oxirane Intermediate\nin the Conversion of the Macrolide Algal Toxin Goniodomin A to Seco\nAcids

The algal macrolide goniodomin A (GDA) undergoes ring-cleavage\nunder unusually mild, alkaline conditions to form mixtures of stereoisomers\nof seco acids GDA-sa and iso-GDA-sa. In the primary fragmentation\npathway, opening of the macrolide ring occurs by displacement of the\ncarboxyl group by a base-catalyzed attack of the C32 hemiketal hydroxy\ngroup on C31, yielding an oxirane-carboxylic acid, named goniodomic\nacid. The oxirane ring is unstable, undergoing solvolytic opening\nto form mainly GDA-sa. Experimental support for this pathway obtained\nby carrying out the ring-opening reaction in H<sub>2</sub><sup>18</sup>O resulted in incorporation of the isotopic label at C32 of the seco\nacid. Collision-induced dissociation (CID) mass spectrometry of Na<sup>+</sup> and NH<sub>4</sub><sup>+</sup> ion adducts was employed to\nestablish that ring-opening of the macrolide ring occurred by alkyl-O\ncleavage. Fragmentation was dominated by Grob–Wharton decarboxylation\nand retro-Diels–Alder reactions of the labeled seco acids.\nDirect observation of goniodomic acid was achieved when the ring-opening\nreaction was carried out under anhydrous conditions. A minor alkyl-O\ncleavage pathway gives rise to iso-GDA-sa by allylic attack at C29\nof GDA or of the oxirane. In the formation of both GDA-sa and iso-GDA-sa,\nring-opening is likely to be catalyzed by Na<sup>+</sup> and NH<sub>4</sub><sup>+</sup>. Reversal of GDA-sa formation can occur in the\nmass spectrometer. CID fragmentation of the <sup>18</sup>O-labeled\nGDA-sa restores the oxirane ring but causes preferential loss of the <sup>18</sup>O label from C32.