L. N. Atopkina

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

A preparative semi-synthetic method was developed to prepare 20S-protopanaxadiol 20-O-β-Dglucopyranoside (1), a metabolite of Panax ginseng glycosides. The 20-O-•-D-glucopyranosides of 20S-hydroxydammar-24-en-3,12-dione, 3β,20S-dihydroxydammar-24-en-12-one, and 3β,12α, 20S-trihydroxydammar-24-ene were synthesized for the first time.

Synthesis of 3β,20S-dihydroxydammar-24-en-12-one 3,20-di-O-β-D-glucopyranoside (chikusetsusaponin-LT8), a glycoside from Panax japonicus

A method for preparative production of 3β,20S-dihydroxydammar-24-en-12-one 3,20-di-O-β-D-glucopyranoside (1), a glycoside from Panax japonicus, chikusetsusaponin-LT8 was developed. Chemical transformation of betulafolientriol, a component of Betula leaves extract, produced the 12-keto-20S-protopanaxadiol (3β,20S-dihydroxydammar-24-en-12-one) (2), exhaustive glycosylation of which by 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (3) under Koenigs—Knorr reaction conditions with subsequent removal of protecting groups formed 3β,20S-dihydroxydammar-24-en-12-one 3,20-di-O-β-D-glucopyranoside (1). The principal glycosylation product was 3β,20S-dihydroxydammar-24-en-12-one 3-O-β-D-glucopyranoside if equimolar amounts of (2) and (3) were used.

Synthesis of diglycosides of 3β,20S-dihydroxydammar-24-en-12-one

The 3-O-β-D-galactopyranosyl-20-O-β-D-glucopyranoside and 3-O-β-D-glucopyranosyl-20-O-β-Dgalactopyranoside of 3β,20S-dihydroxydammar-24-en-12-one, which are structural analogs of chikusetsusaponin-LT8 (1), a minor glycoside from Panax japonicus, were synthesized for the first time.

Glycosylation of panaxadiol

Glycosylation of 3β,12β-dihydroxy-20R,25-epoxydammarane (panaxadiol) (1) under Koenigs–Knorr, Helferich, and ortho-ester reaction conditions was studied. Condensation of panaxadiol and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (2) in the presence of silver oxide and 4-Å molecular sieves in dichloroethane gave a mixture of acetylated panaxadiol 3- and 12-O-β-D-glucopyranosides (3:1 ratio). Reaction of diol 1 and D-glucose tert-butylorthoacetate (3) in the presence of 2,4,6-collidinium perchlorate in chlorobenzene resulted in regioselective formation of panaxadiol 12-O-β-D-glucopyranoside tetraacetate. Reaction of equimolar amounts of 1 and glycosyl donor 2 in the presence of Hg(II) cyanide in nitromethane at 90°C was accompanied by opening of the tetrahydropyran ring and gave 3β,12β,25-trihydroxydammar20(22)E-ene 12-O-β-D-glucopyranoside tetraacetate. Panaxadiol 3- and 12-O-β-D-glucopyranosides and 3β,12β,25-trihydroxydammar-20(22)E-ene 12-O-β-D-glucopyranoside tetraacetate were synthesized for the first time.

Synthesis of panaxatriol glucosides

Glycosylation of 3β,6α,12β-trihydroxy-20R,25-epoxydammarane (panaxatriol) and its 3-, 6-, and 3,6-di-O-acetyl derivatives was studied under Koenigs—Knorr conditions. Panaxatriol 3-, 6-, and 12-O-β-Dglucopyranosides were synthesized for the first time.

Glycosylation of triterpenoids of the dammarane series. X. Regio- and stereoselective synthesis of 20(S)-protopanaxadiol 3-O-β-D-glucopyranoside (ginsenoside Rh2)

The regio- and stereoselective synthesis of ginsenoside Rh2, which possesses antitumoral activity, has been effected by the glycosylation of 12β-acetoxydammar-24-ene-3β,20(S)-diol. Condensation with α-acetobromoglucose was carried out in the presence of silver oxide in dichloroethane at room temperature, and the yield of the desired glycoside amounted to 50%. A method for the selective protection of the C-12-OH group of dammar-24-ene-3β,12β,20(S)-triol [20(S)-protopanaxadiol] has been proposed.

Glycosylation of panaxatriol under helferich reaction conditions

We first synthesized glucosides of panaxatriol (1) using Koenigs–Knorr reaction conditions [1]. Condensation of 1 with 2,3,4,6-tetra-O-acetyl-D-glucopyranosylbromide in the presence of silver oxide and 4 A° molecular sieves formed a mixture of glucosides in which panaxatriol 3-O-D-glucopyranoside dominated [1]. We carried out earlier regioand stereoselective glycosylation of the 12 -OH group in 20S,24R-epoxydammaran3,12 ,25-triols (72–73% yields) under Helferich reaction conditions [2]. Glycosylation of panaxadiol under these conditions was accompanied by opening of the tetrahydropyran ring and led to the formation of the tetraacetate of 3 ,12 ,25-trihydroxydammar-20(22)E-ene 12-O-D-glucopyranoside (3) [3]. The nucleophilicity of the 12 -OH O atom in panaxatriol (1), like in 20S,24R-epoxydammaran-3,12 ,25-triols, is elevated due to a strong intramolecular H-bond (IMHB) between the 12 -OH proton and the O atom of the tetrahydropyran ring. Under certain conditions, this can affect the regioselectivity of the glycosylation of the 12 -OH in triol 1. Therefore, we attempted to carry out the regioselective synthesis of panaxatriol 12-O-D-glucopyranoside 2 under modified Helferich conditions [2].

Synthesis of 20S-protopanaxadiol β-D-galactopyranosides

20S-Protopanaxadiol (3β,12β,20S-trihydroxydammar-24-ene) 3-, 12-, and 20-O-β-D-galactopyranosides were synthesized for the first time. Condensation of 12β-acetoxy-3β,20S-dihydroxydammar-24-ene (1) and 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosylbromide (α-acetobromogalactose) (2) under Koenigs–Knorr conditions with subsequent removal of the protecting groups resulted in regio- and stereoselective formation of 20S-protopanaxadiol 3-O-β-D-galactopyranoside, an analog of the natural ginsenoside Rh2. Glycosylation of 12β,20S-dihydroxydammar-24-en-3-one (5) by 2 with subsequent treatment of the reaction products with NaBH4 in isopropanol and deacetylation with NaOMe gave 20S-protopanaxadiol 12- and 20-O-β-Dgalactopyranosides.

Glycosylation of triterpenoids of the dammarane series. V. β-D-glucopyranosides of 12β-acetoxy-20(S),24(R)-epoxydammarane-3α,25-diol and of 3-epiocotillol

The synthesis of glucosides from the 12-O-acetyl derivatives of betulafolienetriol oxide and of 3-epiocotillol has been carried out under the conditions of the Koenigs-Knorr reaction and of Helferichs modification. It has been established that glycosylation in the presence of silver zeolite and mercury cyanide takes place nonregioselectively and gives a mixture of the corresponding 3-O- and 25-O-mono- and 3,25-di-O-β-D-glucopyranosides. The structures of all the newly obtained glucosides have been established on the basis of IR and13C NMR spectroscopy.

Synthesis of 12β-Acetoxy-3α,17α,25-Trihydroxy-20S,24R-epoxydammarane 3-O-β-D-Glucopyranoside, a Glycoside from Betula maximowicziana

12 -Acetoxy-3 ,17 ,25-trihydroxy-20S,24R-epoxydammarane 3-O-D-glucopyranoside (1) is a rarely encountered dammarane glycoside that was first isolated from the MeOH extract of fresh Betula maximowicziana leaves [1]. 3 ,12 ,17 ,25Tetrahydroxy-20S,24R-epoxydammarane (2) was observed earlier in the unsaponified part of the Et2O extract of air-dried Betula costata Trautv. leaves [2, 3]. Its structure was proved finally by an X-ray crystal structure analysis [4]. It was found that the additional OH group in tetraol 2 was located on C-17. The high content of 2 in B. costata leaves [2] enabled us to synthesize several glucosides from it [5]. The cytotoxicity in vitro of 2 and its semi-synthetic glucosides to human GLC4 carcinoma and COLO 320 tumor cells [6] and their hemolytic effects [7] were studied. The biological activity of glucoside 1 was not studied.