A Convergent Synthesis of the Triterpene Saponin Asiaticoside

Abstract

Asiaticoside (1), namely,2 a,3b,23-trihydroxy-urs-12-en-28-oic-O-a-l-rhamnopyranosyl-(1!4)-b-d-glucopyranosyl-(1!6)-b-d-glucopyranoside,t he major activeb iomarker of the traditional medicinal plant Centella asiatica,h as been synthesized for the first time. The strategy features alate-stage gold(I)-catalyzed glycosidic condensation of atriterpenoid acid and at risaccharide ortho-hexynylbenzoate. The overall preparation required at otal 31 steps with the longest linear sequence occurring over 14 steps in a6 % overall yield and startingf rom ursolic acid (3b-hydroxy-urs-12-en-28-oic acid). IntroductionCentella asiatica (L.) Urban, the synonym of which is Hydrocotyle asiatica L. and also knowna sg otu kola or Indianp ennywort, grows widely in tropical regions. It hasb een used since prehistoric times as ac ure-all, but most prominently it has been used fort he treatmento fd ermatoses and skin lesions such as excoriations, burns, and hypertrophic scars.[1] The major active biomarker of C. asiatica hasb een identified as an ursane-type triterpene glycoside, namely,a siaticoside (1). [2] Indeed, it has been reported that asiaticoside can stimulate collagen synthesis, [3] possibly through activation of the Smad pathway [3a] or the inhibition of glycogen phosphorylase.[4a] Asiaticoside( 1)i so ne of the earliestc haracterized saponins, [2a] and its structure was unambiguously established in 1987 by Xray diffraction as 2a,3b,23-trihydroxy-urs-12-en-28-[2b] Although analogues,m ostly derivatized from the aglycone,h ave been synthesized for structureactivity relationship studies, [4] the total synthesis of asiaticoside has not been realized.I nl ine with our prolonged interest in the chemical synthesis of saponins for biological studies, [5] we embarked on the preparation of asiaticoside( 1), and we herein reporti ts first total synthesis. Results and DiscussionAsiaticoside (1)c onsists of 2a,3b,23-trihydroxy-urs-12-en-28-oic acid (i.e.,a siatic acid) as an aglycone with ag lycan moiety attached at the ester linkage at C28. The convergent synthesis calls for the condensation of an asiatic acid derivativewith atrisaccharide donor, [5] such as the condensation between 3 and 2 ( Figure 1). Fortunately,t he linear trisaccharide allows for the installation of ap articipating group (i.e.,abenzoyl group) at C2 of the first glucose unit to ensure the required b-selective glycosylation.I nl ine with our current practice regarding gold(I)-catalyzed glycosylations with glycosyl ortho-alkynylbenzoates as donors, [6] perbenzoyl trisaccharide n-hexynylbenzoate 2 was envisioned asareliable donor.A siatic acid derivative 3 could be synthesized from commerciallya vailableu rsolic acid (4), throught he introduction of the 23-and 2a-hydroxy groups. [7] Given the robustness of the triterpenoid 28-ester linkage, we employed acetyl and benzoyl groups as permanent protecting groups,w hich couldb eg lobally removed without the hydrolysis of this typical triterpene glycosidic linkage. [5] We commencedt he synthesis by ...

Synthesis of the Diverse Glycosides in Traditional Chinese Medicine

“…[51] Recently, we reported the first synthesis of this triterpene glycoside (Scheme 5). [41] The structure of the aglycone, namely asiatic acid, is very close to ursolic acid (63), a naturally abundant triterpene. Thus, we prepared the required aglycone from the commercially available 63.…”

Facile Synthesis of Oleanane‐type Pentacyclic Triterpenoids Bearing Hydroxy Groups on D/E Rings

“…Further transformations are feasible to provide a large variety of the PTs, which are otherwise difficult to access. For example, oxidation of the primary C28−OH in 1 – 6 will provide the corresponding acids, [29,30] which can be subjected to glycosylation to provide various natural saponins [1,31–34] . The availability of these PT derivatives shall facilitate in‐depth studies on their biological activities.…”

“…For example, oxidation of the primary C28À OH in 1-6 will provide the corresponding acids, [29,30] which can be subjected to glycosylation to provide various natural saponins. [1,[31][32][33][34] The availability of these PT derivatives shall facilitate in-depth studies on their biological activities.…”

Advances in the Semi-Synthesis of Triterpenoids

“…Again, the glycosylation proceeded efficiently and stereoselectively under the assistance of neighboring group participation effect of C2-OBz of the reducing end glucosyl residue with Ph3PAuOTf as catalyst, and the desired trisaccharide saponin 140 was obtained in 85% yield, which was then exposed to global deprotection to provide asiaticoside 141 (70%). 61 Scheme 27 Synthesis of asiaticoside 141 Ginsenosides, the principle components of ginseng, the most magical and widely used Oriental herb, belong to dammaranetype saponins. The prominent synthetic challenge lies in the glycosidic bond construction of C20-OH, which is not only highly acid-sensitive but also resistant to glycosylation due to the severe steric hindrance.…”

“…saponin 140 was obtained in 85% yield, which was then exposed to global deprotection to provide asiaticoside (141) (70%). 61 Ginsenosides, the principal components of ginseng, the most magical and widely used Oriental herb, belong to dammarane-type saponins. The prominent synthetic challenge lies in construction of the glycosidic bond at C20-OH, which is not only highly acid-sensitive but is also resistant to glycosylation due to the severe steric hindrance.…”