Chemistry and synthesis of the lignan (–)-cubebin

Abstract

Contrary to the established literature, ‘isocubebinic ether’, ‘cubebinic ether’, and ‘cubebinol’ are acid-catalysed cyclisation products, (IV), (VII; R = OAc), and (VII; R = H), respectively. Their formation from (–)-cubebin (I) is discussed.

The first synthesis of cubebin is described. (±)-α-(3,4-Methylenedioxybenzyl)-β-(3,4-methylenedioxybenzylidene)succinic acid (XIII) is prepared by a double Stobbe approach and resolved with quinine. Reduction to the diol (XXI) and oxidation with manganese dioxide gives (+)-, (–)-, and (±)-hibalactone (XXII)[the first synthesis of the natural (–)-form]; selective oxidation with this reagent gives dehydrocubebin (XXIII). (+)-, (–)-, and (±)-Isohinokinin (XXV) are obtained by hydrogenation of the corresponding hibalactones; epimerisation of (+)- and (–)-isohinokinin gives (–) and (+)-hinokinin (XXVI) respectively. By selective reduction with sodium aluminium hydride the lactone (–)-hinokinin is converted into the hemiacetal (–)-cubebin (I).