Studies toward the total synthesis of the marine toxin, (-)-gymnodimine

Abstract

(-)-Gymnodimine is a member of a growing family of spirocylic imine containing marine natural products. The construction of the complete skeleton of (-)- gymnodimine has been accomplished in a convergent manner in 23 steps (the longest linear sequence). A highly diastereo- and enantioselective Diels-Alder reaction employing bis(oxazoline)·Cu(II) catalyst provided the spirolactam core structure of gymnodimine bearing a quaternary carbon stereogenic center. An improved procedure for hydrostannylation of the hindered internal triple bond in 96a was discovered by slow addition of tributyltin hydride to minimize formation of hydrogenated byproduct. Fragment coupling featured a Nozaki-Hiyama-Kishi reaction between a vinyl iodide derived from the spirolactam and a tetrahydrofuran moiety. The macrocyclization was realized through a rather unusual intramolecular opening of an activated Ntosyllactam by an alkyllithium species generated in situ. The butenolide was appended through a vinylogous Mukaiyama aldol addition of silyloxyfuran 155 to the ketone 163 under meticulously controlled conditions. The generality of this process was explored in some detail. Addition of silyloxyfurans to cyclohexanones proceeds with moderate to good diastereoselectivities. The potential application of this process to the synthesis of butenolide and g-lactone containing natural products was demonstrated by further transformations of the addition adducts. Finally, toward our goal of developing an enzyme-linked immunosorbent assay (ELISA) for gymnodimine monitoring a hapten derived from the tetrahydrofuran has been synthesized. Even though the raised antibodies failed to recognize the natural product itself, the results provided some information regarding the essential structural elements of an efficient hapten.