Synthesis of 20S-protopanaxadiol 20-O-β-D-glucopyranoside, a metabolite of Panax ginseng glycosides, and compounds related to it

Abstract

Extract of Panax ginseng C. A. Meyer root, which is constantly attracting attention to itself owing to the breadth and variety of its biological activity, contains triterpene glycosides, which have been the subject of numerous investigations. Ginseng glycosides are transformed by intestinal microflora in the gastro-intestinal tract into compounds with new biological properties. In the last few years, the properties and mechanism of action of one of the main metabolites of ginseng glycosides, 20S-protopanaxadiol 20-O-β-D-glucopyranoside (1) (compound K), have been studied more frequently [1][2][3][4][5][6][7][8][9][10][11][12][13]. Glucoside 1 inhibits the growth of tumor cells and induces their apoptosis [3,9,10], decreases the toxicity of antitumor preparations [4], possesses antimetastatic and immunomodulating activity [2,11], and exhibits antiallergic [12] and anti-inflammatory [13] properties. In most of these investigations, 1 was prepared by treating ginseng extract or the enriched glycoside fraction with enzymes, bacteria, or intestinal microflora followed by chromatographic separation of the products of enzymatic hydrolysis.We previously prepared 1 as one of the condensation products of 20S-protopanaxadiol (dammar-24-en-3β,12β,20S-triol) (2) with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (α-acetobromoglucose) (3) under Koenig-Knorr reaction conditions [14,15]. Because all three hydroxyls of 3 were glycosylated, the main drawback was the lack of regioselectivity, which led to the formation of a complicated and difficultly separated mixture of mono-and diglucosides. Regioselective glycosylation of the 3,12-diacetate of 20S-protopanaxadiol (4) with one free hydroxyl on C-20 was unsuccessful [14], apparently because the 20-OH was sterically shielded by the 12β-OAc group.The present article is a continuation of investigations on the synthesis of glycosides based on tetracyclic dammarane triterpenoids. The goal was to develop a preparative semi-synthetic method for preparing 20S-protopanaxadiol 20-O-β-Dglucopyranoside (1).An attempt to synthesize 1 through regio-and stereoselective glycosylation of the tertiary hydroxyl on C-20 of 20S-hydroxydammar-24-en-3,12-dione (5) with subsequent reduction of both ketones on C-3 and C-12 into the glycosylation product (6) did not give the desired result. Reaction of 5 with 3 in the presence of Ag 2 O and 4Å molecular sieves in dichloroethane gave the tetraacetate of the diketone 20-O-β-D-glucopyranoside (6) (47% yield), reduction of which with NaBH 4 in isopropanol selectively reduced only one ketone on C-3 and formed the tetraacetate of 3β,20S-dihydroxydammar-24-en-12-one 20-O-β-D-glucopyranoside (7).

Highly Selective Bioconversion of Ginsenoside Rb1 to Compound K by the Mycelium of Cordyceps sinensis under Optimized Conditions

“…The HRMS data of 3 showed a similar [M + HCOOH − H] − m/z with CK and Rh2 of 667.4787, calculated for a molecular formula of C 36 H 62 O 8 (Figure 11). According to literature [42,43,44], the major structural difference between Rh2 and CK is the linking position of the glucosyl moiety, leading to obvious variations of chemical shifts at C-3, C-20 and glucosyl C-1″. As shown in Table 4 and Figure 12, metabolite 3 was proven to be CK due to the identical chemical shifts which distinguished it from Rh2 at C-3 (δ = 78.16), C-20 (δ = 83.55) and C-1″ (δ = 96.92).…”

Synthesis of 12‐epi‐Protopanaxadiol and Formal Synthesis of Ginsenoside Chikusetsusaponin‐LT8

“…sodium borohydride, or metallic sodium in toluene/2‐propanol or Birch conditions) did not afford protopanaxadiol 2 but regenerate 3β,12α‐diol 28 as the sole product. It is worth mentioning that diketone 29 has already been described by Atopkina and Denisenko for the semi‐synthetic preparation of ginsenoside glycosides and, in addition, our strategy allows the formal total synthesis, of chikusetsusaponin‐LT 8 30 , a bioactive ginsenoside isolated from Panax japonicus …”

“…Deprotection of the hydroxyl groups afforded 12‐ epi ‐protopaxadiol 28 after 19 steps with an overall 1.0 % yield. Diol 28 was further oxidized into diketone 29 , but attempts to reduce this ketone (e.g. sodium borohydride, or metallic sodium in toluene/2‐propanol or Birch conditions) did not afford protopanaxadiol 2 but regenerate 3β,12α‐diol 28 as the sole product.…”

Synthesis of Esters of Ginsenoside Metabolite M1 and Their Cytotoxicity on MGC80-3 Cells

“…Hasegawa proposed that the metabolized M1 was esterified with fatty acids in the liver, which resulted in longer permanence in the body and exhibits the antitumor activities, and concluded that ginsenoside is a pro-drug activated in the body by deglycosylation and esterification [ 2 , 11 ]. Compared to the fact that much attention has been devoted to the bioactivities, especially anticancer activity of M1 [ 15 , 16 , 17 ], there is scant synthetic work related to M1 in the literature [ 26 , 27 ]. Recently, we synthesized the monoesters of M1 via introduction of acyl groups onto the 6'-OH of the glucose moiety in M1 and found the esterified products exhibited cytotoxicity against several human cancer cell lines (breast cancer MCF-7, skin melanoma SK-MEL-2 and human ovarian carcinoma B16) [ 28 ].…”