A convergent intermolecular Diels-Alder approach to the spirocycles found in the marine neurotoxic agents, the gymnodimines

Abstract

Several approaches to the spirochetes found in the marine neurotoxic agents, the gymnodimines, were studied. The strategy involved intermolecular Dials-Alder reactions of α-exomethylene lactones and lactams. A convergent racemic synthesis of the spirocyclic core structure of the gymnodimines was achieved in 7 linear steps and 16.4% overall yield from diethyl malonate. The key step in the synthesis was a Lewis-acid promoted intermolecular Dials-Alder reaction of an N-tosyl α-methylene []-lactam and a dienyne. The large scale synthesis of the dienophile (>30 g quantities available) was achieved in 5 steps from diethyl malonate in 30% overall yield and the synthesis of the diene (>20 g available) was achieved in 4 steps from propane in 38% overall yield. Large scale synthesis of the Diets-Alder adduct (4.5 g) has been achieved in 67% yield from the dienophile and diene precursors. Single crystal x-ray analysis of the Diels-Alder adduct confirmed that the radiochemistry and diastereoselectivity required for the gymnodimines was obtained.