Three Minor Diterpenoids with Three Carbon Skeletons from Euphorbia peplus

Abstract

Euphorbia peplus has been used in traditional medicine to treat asthma and psoriasis. Three highly modified diterpenoids, namely, pepluacetal (1) and pepluanol A-B (2-3), have been isolated and identified from this plant. Compounds 1-3 exhibit unprecedented 5/4/7/3, 5/6/7/3, and 5/5/8/3 ring systems, respectively. Their structures with absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and electronic circular dichroism calculations. Since Kv1.3 is a validated target for the treatment of autoimmune diseases, such as multiple sclerosis, type-1 diabetes, asthma, and psoriasis, Kv1.3 was studied in terms of its response to the new compounds. All three compounds inhibit Kv1.3, with compound 3 being the most effective with an IC50 value of 9.50 μM.

Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

“…Thes ubsequent regioselective oxidation of alcohol at C3 was achieved by TEMPO/NCS, [24] thus providing the ketone 19 in 95 %y ield. [6] In conclusion, we have developed an ovel titanium(III)catalyzed reductive annulation for the construction of diversely functionalized 1,5-diols in good to excellent yields. Synthetic 2 exhibited 1 Hand 13 CNMR spectra identical in all respects to those reported for the natural product.…”

“…Having rapidly assembled the [5,6,7] tricyclic skeleton, we turned to the late-stage synthesis of 2 (Scheme 4). Benefiting from the preferred boat transition state of 7,insitu generated dibromocarbene added exclusively to the less hindered convex face.U pon further reductive bismethylation, [23] the tetracycle 18 was formed in 44 %y ield.…”

“…Iodination of the readily available cycloheptenone 12, [17] by using Danishefskysm odified procedure, [18] afforded the a-iodoenone 13 in 88 %y ield. [20] Quenching the reaction at low temperature with 2 n hydrochloric acid provided the requisite cis- [6,7] bicyclic diketone 7,with generation of the quaternary carbon at C15, in 83 %y ield as as ingle diastereomer.S ubsequently,t he regioselective enol-triflation successfully took place on the ketone at C6, and was followed by installation of the methyl group through CuI-catalyzed cross-coupling [21] to deliver 15 in 72 %y ield over two steps.U pon exposure to NaOMe,t he inversion of the configuration at C13 proceeded smoothly with the concomitant removal of the benzoyl group.A fter afurther regioselective epoxidation at D 6,7 olefin by treatment with DMDO, 16 was formed in 58 %y ield over two steps. To our delight, after extensive optimization, the anticipated Diels-Alder cycloaddition between 10 and the Rawal diene 11 proceeded well at 40 8 8C.…”

Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

“…[5] Very recently,f urther investigation on extracts of the plant of E. peplus by Qiu and co-workers resulted in the discovery of three novel biogenetically related diterpenoids with effective inhibitory activity on the kv1.3 potassium channel, and they were subsequently named pepluacetal, penluanol A, and pepluanol B(1-3;F igure 1). [6] Structurally, 1-3 exhibit unprecedented [3,4,5,7], [ 3,5,6,7],a nd [3,5,5,8] tetracyclic ring systems,r espectively.T he unique polycyclic array with ahigh oxidation pattern, including the presence of six to eight stereogenic centers,m ake these molecules challenging synthetic prospects.I np articular, the commonly embedded pseudo-bicyclic 1,5-diol subunits prompted us to develop ag eneral and efficient approach for their rapid construction. Herein, we report our preliminary efforts culminating in aconcise and diastereoselective total synthesis of (AE)-pepluanol A( 2), and it also marks the first total synthesis of am ember of this family.…”

“…Different from the observation by Molander and co-workers, [7] ther eaction is not restricted to five-membered ring formation. Fore xample,t he cyclohexanol 5b was obtained in 88 %y ield as a1 .9:1 mixture of diastereomers.The double-bond geometry was found to have little influence on the cyclization,s ince both isomers of 4c were converted into 5c with as imilar yield and d.r.v alue.A series of diversely functionalized [5,6] and [6,6] bicyclic1 ,5diols (5d-g)w ere also constructed in excellent yields. Presumably,t he favored formation of the major diastereomers arises from the topographical bias of the conformationally fixed cyclic olefins.Furthermore,the 1,5-diols 5h-j,with differently sized bicyclicring systems,were produced as well, although the efficiencya nd diastereoselectivity gradually drops for longer tethers.…”