Studies on the Synthesis of (−)-Gymnodimine. Subunit Synthesis and Coupling

Two principal subunits of the marine algal toxin (−)-gymnodimine were synthesized. A trisubstituted
tetrahydrofuran representing C10−C18 of the toxin was prepared via a highly stereoselective iodine-mediated cyclization of an acyclic alkene bearing a bis-2,6-dichlorobenzyl (DCB) ether. The formation
of a cis-2,5-disubstituted tetrahydrofuran in this process conforms to a stereodirecting effect by the DCB
group proposed by Bartlett and Rychnovsky. A cyclohexene subunit corresponding to the C1−C8, C19−C24 portion of gymnodimine was synthesized via Diels−Alder cycloaddition of a 1,2,3-trisubstituted
diene to a symmetrical dienophile obtained from Meldrum's acid. Differentiation of carbonyl groups in
the cycloadduct was made by an intramolecular reaction with a neighboring alcohol to form a γ-lactone.
Linkage of the two subunits at C18−C19 was accomplished by using a B-alkyl Suzuki coupling in which
a borane prepared from the pendent alkenyl chain of the cyclohexene domain was reacted with the (E)-iodoalkene attached at C16 of the tetrahydrofuran sector. Subsequent transformations positioned functional
groups in the coupled product for a future macrocyclization event that would close the 15-membered
ring of gymnodimine.