Structure-activity relations of polyfunctional diterpenes of the daphnane type. I. Revised structure for resiniferatoxin and structure-activity relations of resiniferonol and some of its esters

Abstract

Base catalyzed transesterifications of resiniferatoxin afforded the 9, 13, 14-orthophenylacetate (III), as well as (4-hydroxy-3-methyoxyphenyl) acetic acid methyl ester (II). Reesterification of III with homovanillic acid showed that the previously proposed structure for resiniferatoxin has to be revised to resiniferonol-9, 13, 14-orthophenylacetate-20-(4-hydroxy-3-methoxyphenyl) acetate (I). From III, different 20 esters (I, IV-IX) were prepared. The orthophenylacetate III was cleaved by Acidic hydrolysis to yield the 14-phenylacetate X. Subsequent alkaline transesterifications of X afforded the parent alcohol resiniferonol (XI), Starting from XI, the 14, 20-diesters XII and XV and the 9, 13, 20-diesters xii and XV and the 9, 13, 14-orthoesters XIII, XIV, XVI, XVII and XVIII were obtained. All esters were tested for irritant activity on the mouse ear. Some aspects of structure-activity relations of irritancy of resiniferonol esters are established and discussed.