New Types of Potentially Antimalarial Agents: Epidioxy‐substituted norditerpene and norsesterpenes from the marine sponge Diacarnus levii

Natural free carboxylic acids from the hadromerid sponge Diacarnus levii (Kelly‐Borges and Vacelet) were esterified to yield the new cyclic norditerpene peroxides ent ‐muqubilin benzyl ester (= (α R ,3 S ,6 R )‐α,6‐dimethyl‐6‐[( E )‐4‐methyl‐6‐(2,6,6‐trimethyl‐cyclohex‐1‐en‐1‐yl)hex‐3‐enyl]‐1,2‐dioxan‐3‐acetic acid benzyl ester; 6 , diacarnoate B methyl ester(= (α S ,3 R ,6 R )‐α,6‐dimethyl‐6‐{2‐(4a S ,8a S )‐3,4,4a,5,6,7,8,8a‐octahydro‐3‐oxo‐2,5,5,8a‐tetramethylnaphthalen‐1‐yl)ethyl}‐1,2‐dioxan‐3‐acetic acid methyl ester; 9 ), and deoxydiacarnoate B benzyl ester (= (α S ,3 R ,6 R )‐α,6‐dimethyl‐6‐{2‐[(4a S ,8a S )‐3,4,4a,5,6,7,8,8a‐octahydro‐2,5,5,8a‐tetramethyl‐1‐naphthalenyl]ethyl}‐1,2‐dioxan‐3‐acetic acid benzyl ester; 10 ), which were isolated following extensive chromatography. The relative configuration of the peroxide/α‐methylacetate moiety of 6 , 9 , and 10 , was directly determined from their NMR spectra. The absolute configurations of the peroxide/α‐methylacetate moiety was deduced from comparative 1 H‐NMR data of the ( S )‐ and ( R )‐phenylglycine methyl ester derivatives 7 and 8 as well as 11 / 13 and 12 / 14 , all obtained from a mixture of the precursors of 3 , 6 , and 10 . The absolute configuration at the carbobicyclic moiety of enone 9 and of 10 , is identical, as established by chemical interconversion, 9 and 10 belong to the normal labdane series according to empirical CD rules, applied either directly to 9 or to the parent (+)‐sclareolide‐derived enone 20 . In contrast, molar rotation additivity rules suggest the ent ‐labdane configuration for 9 and 10 . The epidioxides 1 – 3 , 6 , and 10 proved active in vitro against the malaria parasite Plasmodium falciparum ; especially the previously isolated methyl 3‐epinuapapuanoate ( 2 ) was active against a chloroquine‐resistant strain, and this with a good security index.