Modification of Natural Eudesmane Scaffolds via Mizoroki-Heck Reactions

Mohamed Zaki, Mohamed Akssira, Sabine Berteina-Raboin
2017 Molecules  
The Mizoroki-Heck reaction was applied to substrates derived from isocostic and ilicic acids, important sesquiterpene components of Dittrichia viscosa L. Greuter that were extracted directly from plant material collected in Morocco. After optimization of the metallo-catalysis conditions, various aryl-groups were successfully introduced on the exocyclic double bond with an exclusive E-configuration and without racemization. Molecules 2017, 22, 652 2 of 17 have already been submitted to various
more » ... mitted to various structural modifications, including the Mizoroki-Heck reaction [18] [19] [20] [21] [22] [23] . However, only a few modifications have been reported for analogues such as eudesmane-carboxylic acids, aldehydes or eudesmanols, and none included modifications of the exocyclic alkene part [24] [25] [26] . In view of the great biological potential of ilicic and isocostic acid derivatives [27] [28] [29] [30] , we decided to apply the Mizoroki-Heck cross-coupling reaction to these natural compounds to generate some novel eudesmane analogues. We report herein the behavior of these compounds extracted from plants in palladium-catalyzed reactions [31-34]. Results and Discussion Optimization of the Mizoroki-Heck Reaction on Ilicic Acid We first examined the behavior of ilicic acid methyl ester in a model Mizoroki-Heck reaction (Scheme 1). Unfortunately only starting material was recovered [20] . Protection of the alcohol was then considered and the methoxymethyl-ether (MOM) group was selected as the most efficient protecting group allowing the isolation of compound 3 in 60% yield. With 3 as starting material, compound 4b was then obtained in 30% yield in presence of Pd(OAc) 2 (0.1 equiv), p-tolyl iodide (1.1 equiv) and Et 3 N (3 equiv) in N,N-dimethylformamide (DMF) ( Table 1 , entry 1). The use of silver acetate as oxidizing agent and base offered no significant advantages (entry 2) [35, 36] . Next a bulky electron-rich phosphine, tri(o-tolyl)phosphine was used, enabling the isolation of 4b in 65% yield, and acetonitrile was used to replace DMF as solvent, but a reduced yield was noted (entry 5) [21, 22] . An increase in the catalytic system loading failed to improve this result (entry 6). The optimized conditions were as follows: 3 (1 equiv), aryl iodide (1.1 equiv), Et 3 N (3 equiv), Pd(OAc) 2 (0.1 equiv) and P(o-Tol) 3 (0.1 equiv) in DMF at 120 • C for 24 h. These conditions were extended to aryl bromides without any significant loss of reactivity (entry 8).
doi:10.3390/molecules22040652 pmid:28425951 fatcat:33jqfugljrb7rdwidyu4duuomy