Synthesis of α-hederin, δ-hederin, and related triterpenoid saponins

FULL PAPER

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

[a]

´

Karen Ple,* Martin Chwalek, and Laurence Voutquenne-Nazabadioko

Keywords: Glycosylation / Natural products / Saponins / Total synthesis

The synthesis of α-hederin (3-O-[α-

(1Ǟ2)-α- -arabinopyranosyl]hederagenin, 1), δ-hederin (3-

O-(α- -arabinopyranosyl)hederagenin, 3), and three related

triterpenoid saponins is described as part of a study of the

structure−activity relationships between triterpenoid sapo-

L

-rhamnopyranosyl-

trichloroacetimidate (20) was performed in excellent yield to

give the desired disaccharides. Coupling of the trichloroace-

timidate derivatives of the disaccharides to allyl- or methyl-

hederagenin gave the protected saponosides in high yields.

The saponins and their corresponding methyl esters were

L

nins and hemolytic activity. 4-Methoxybenzyl α-L-arabinopy- then obtained in good to moderate yields after deprotection.

ranoside (11) was synthesized first and then used to prepare

the different arabinose acceptors. Glycosylation between the

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2004)

acceptors and 2,3,4-tri-O-benzoyl-α-

L-rhamnopyranosyl

Introduction

α-Hederin (3-O-[α--rhamnopyranosyl-(1Ǟ2)-α--arabi-

nopyranosyl]hederagenin, 1), also known as kalopanaxsa-

ponin A or sapindoside A, and δ-hederin (3-O-(α--arabi-

nopyranosyl)hederagenin, 3), also known as koelreuteria

saponin A, are natural products (Figure 1) belonging to the

family of triterpenoid saponins and are widely distributed

in nature.^[1]Both of these molecules possess molluscicidal^[2]

and cytotoxic^[3]activities. In addition, α-hederin has been

shown to possess antifungal and antileishmanial activi-

ties,^[4]as well as in vivo antitumor activity.^[5]More recently,

the antiinflammatory activity of α-hederin^[6]and α-hederin

methyl ester^[7](2) has also been reported.

One of the oldest known activities of α-hederin, δ-hed-

erin, and, in general, many saponins, is their ability to lyse

red blood cells.^[1,8]Our laboratory has long been interested

in saponin isolation and identification, and, more recently,

in the structureϪactivity relationships of hemolytic sap-

onins.^[9]Many saponins containing hederagenin have been

shown to possess strong hemolytic activity. For example, α-

hederin has a stronger activity (20 µg/mL for 100% hemo-

lysis) than the commercial saponin from Sigma^(75 µg/

mL), which is sold as a mixture of saponosides.^[9]Most of

the existing structureϪactivity relationships of hemolytic

saponins have focused on the aglycon or the number of su-

gar units involved.^[8Ϫ10]Using the activity of α-hederin as

a starting point, we wished to approach the problem in a

different way by restricting our study to saponins contain-

ing hederagenin, and by varying the type and position of

Figure 1. α-Hederin, δ-hederin and related saponins

the sugar units in relation to one another. A similar strategy

was used in the synthesis of the oleanolic acid saponins

Randianin and Arvensoside B.^[11,12]

Because saponin extraction from natural sources can be

long and tedious, and results in very small quantities of the

desired saponin being obtained, our goal was to synthesize

naturally occurring α-hederin (1), δ-hederin (3), as well as

the ‘‘non-natural’’ saponins 3-O-[α--rhamnopyranosyl-

(1Ǟ2)-β--arabinopyranosyl]hederagenin (5), 3-O-[α--

rhamnopyranosyl-(1Ǟ3)-α--arabinopyranosyl]hederagenin

[a]

´

Universite de Reims Champagne-Ardenne, CNRS UMR

6013, CPCBAI,

ˆ

Bat 18, Moulin de la Housse, BP 1039, 51687 Reims, France

E-mail: karen.ple@univ-reims.fr

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

DOI: 10.1002/ejoc.200300723

Eur. J. Org. Chem. 2004, 1588Ϫ1603

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

(7), and 3-O-[α--rhamnopyranosyl-(1Ǟ4)-α--arabinopyr- give access to all three compounds. Because the allyl group

anosyl]hederagenin (9), and their corresponding methyl es- is not compatible with the series of steps envisioned to pre-

ters (Figure 1).

pare the desired molecules, and the benzyl group proved

Interest in saponins is rapidly increasing because of their difficult to deprotect, we considered the 4-methoxybenzyl

diverse biological properties. Of the two types of saponins (MPM) group. Although the use of this protecting group is

present in nature, possessing either a steroid or triterpenoid widespread in oligosaccharide synthesis, protection in the

aglycon, the majority of synthetic studies have focused on anomeric position of sugars has, until now, been limited to

the former.^[13]Many syntheses of triterpenoid saponins ex- monosaccharides in the hexose family^[20]and a few disac-

ist in the literature,^[14]but those with aglycons other than charide derivatives.^[21]The new 4-methoxybenzyl α--arabi-

oleanolic acid are not widespread.^[10a,15]This situation is nopyranoside (11) was synthesized readily from -arabinose

due, perhaps, to the small quantities of aglycon obtained in four steps and 51% global yield without intermediate

from natural product extraction, which can be a limiting purification (Scheme 1).

factor in the synthesis of these types of molecules. For this

reason, and for ease of synthesis, all of the desired saponins

in our study were retrosynthetically disconnected into the

triterpenoid moiety and the mono- or disaccharide sugar

part.

Very little work has been published concerning the prep-

aration of rhamnoseϪarabinose disaccharides. The first

Scheme 1. Reagents and reaction conditions: (i) a) Ac₂O, pyridine;

b) 33% HBr/AcOH; c) p-methoxybenzyl alcohol, I₂, Ag₂CO₃; d)

synthesis of an α--rhamnopyranosyl-(1Ǟ2)-β--arabinop-

yranoside derivative was published in 1982 as part of a ¹³C

NMR spectroscopy study of methyl and benzyl β--arabi-

nose oligosaccharides.^[16]The desired disaccharide was syn-

thesized using a suitably protected benzyl-β-arabinose de-

rivative, having a free hydroxy group in position 2, and an

acetylated rhamnopyranosyl bromide in the presence of an

excess of mercury cyanide in 71% yield. Kamiya et al. also

reported the synthesis of α--rhamnopyranosyl-(1Ǟ2)--ar-

abinopyranoside in 1984,^[17]as part of a study to investigate

the substrate specificity of α--rhamnosidase induced in As-

pergillus niger. The protected disaccharide was synthesized

in only 38% yield, again using an acetylated rhamnopyr-

anosyl bromide as the donor. The same group then pub-

lished the synthesis of methyl α--rhamnopyranosyl-(1Ǟ4)-

β--arabinopyranoside in 1985.^[18]This compound was syn-

thesized from benzoylated rhamnopyranosyl bromide in 7%

yield after debenzoylation and peracetylation of the re-

sulting disaccharide. Finally, the synthesis of benzyl α--

rhamnopyranosyl-(1Ǟ3)-β--arabinopyranoside followed

in 1986;^[19]this derivative was synthesized via an acetylated

rhamnopyranosyl chloride in 70% yield.

Et₃N, MeOH, H₂O (51%, 4 steps)

This compound then served as the starting material for

monosaccharide elaboration. We began the synthesis of the

arabinose derivative 14 having a free hydroxy group in posi-

tion 2 by selective protection of the hydroxy groups in posi-

tion 3 and 4 of 11 with 2,2-dimethoxypropane, allylation

in position 2, and then removal of the acetonide to give

compound 12 in 73% yield over three steps. The free

hydroxy groups were then benzoylated to give 13, and the

allyl group was removed to give the desired compound 14

(Scheme 2).

We report here the first synthesis of the biologically ac-

tive saponins α-hederin and δ-hederin, related triterpenoid

saponins, and their methyl esters. We have developed a

highly improved method for the preparation of the

rhamnoseϪarabinose disaccharides and we have performed

the coupling of these disaccharides to methyl or allyl heder-

agenate in high yields. Total deprotection then affords the

desired saponins in good to moderate yields.

Scheme 2. Reagents and reaction conditions: (i) a) 2,2-dimeth-

oxypropane, TsOH, DMF; b) NaH, allyl bromide, DMF; c) 70%

AcOH, 70 °C (73%, 3 steps); (ii) benzoyl chloride, Et₃N, DMAP

(87%); (iii) PdCl₂/MeOH (68%)

Initially, we believed that the synthesis of the arabinose

derivative 15 having a free hydroxy group in position 4

would be possible by selective benzoylation of compound

11 at low temperature in pyridine.^[22]Previously, selective

benzoylation of allyl β--arabinopyranoside at Ϫ40 °C in

Results and Discussion

The starting point of our monosaccharide synthesis was our laboratory (unpublished results) gave the 2,3-di-O-ben-

the preparation of three suitably protected arabinose deriva- zoylated product preferentially. When this same reaction

tives ready for coupling in positions 2, 3, and 4. The pro- was applied to the α-MPM derivative 11, the reaction was

tecting group in the anomeric position of arabinose had to much less selective and give a range of all possible benzoyl-

be chosen carefully so that a unique starting material would ated products (Scheme 3).

Eur. J. Org. Chem. 2004, 1588Ϫ1603

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´

K. Ple, M. Chwalek, L. Voutquenne-Nazabadioko

FULL PAPER

To circumvent this problem, compound 18, which is ben-

zoylated in position 2, was prepared from 11 in good yield

(80% over three steps). It is interesting to note that the ar-

4

abinose derivative 18 is no longer in the common C₁con-

figuration: the six-membered ring ‘‘flips’’ to relieve steric

Scheme 3. Reagents and reaction conditions: (i) benzoyl chloride

(2.1 equiv.), pyridine, Ϫ40 °C

We believe that the outcome of the reaction is a direct

result of the MPM group being in the equatorial position

rather than the axial one. Based on the reaction products,

3-O-benzoylation occurred first; the mono-benzoylated

compound 17 was isolated in 17% yield. The resulting steric

interaction between a second benzoyl group in position 2

and the anomeric MPM group on one side and the 3-O-

benzoyl group on the other then influences the reaction’s

selectivity. Competition between ester formation in posi-

tions 2 or 4 is equal, and, in this case, the axial position

is favored as the 3,4-di-O-benzoylated compound 14 was

isolated as the major reaction product.

Scheme 5. Reagents and reaction conditions: (i) trichloroacetimid-

˚

ate 20, CH₂Cl₂, TMSOTF (0.05 equiv.), 4-A molecular sieves,

Ϫ20 °C

Scheme 4. Reagents and reaction conditions: (i) a) 2,2-dimeth-

oxypropane, TsOH, DMF; b) benzoyl chloride, Et₃N, DMAP; c)

70% AcOH, 70 °C (80%, 3 steps); (ii) benzoyl chloride (1.1 equiv.),

pyridine, Ϫ35 °C; (iii) a) PhC(OCH₃)₃, TsOH; b) 90% AcOH

Scheme 6. Reagents and reaction conditions: (i) a) TFA, H₂O; b)

CCl₃CN, DBU

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Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

hindrance. Selective benzoylation at Ϫ35 °C gave 74% of

FULL PAPER

The anomeric MPM group was then hydrolyzed with tri-

the desired product 15 as well as very small amounts of the fluoromethanesulfonic acid (TFA) and the resulting hemia-

2,4-di-O-benzoylated (4%) and tribenzoylated (3%) arabi- cetal was then treated with trichloroacetonitrile and cata-

nose derivatives (19 and 16, respectively; Scheme 4).

lytic 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form the

Compound 18 also served as a common intermediate in trichloroacetimidates 24, 25, and 26 in 81, 79, and 69%

the synthesis of the arabinose derivative having a free yields, respectively (Scheme 6).

hydroxy group in position 3. Treatment with trimethyl or-

thobenzoate, followed by acid-catalyzed opening of the or-

thoester, gave the desired product 19 in 72% yield, as well as

26% of the 2,3-di-O-benzoylated derivative 15 (Scheme 4).

Lewis acid-catalyzed assembly of the acceptors 14, 15,

and 19 and the donor 2,3,4-tri-O-benzoyl-α--rhamnopyr-

anosyl trichloroacetimidate (20)^[23]by trimethylsilyl trifluor-

omethanesulfonate (TMSOTf)^[24]was straightforward and

high yielding to give the disaccharides 21, 22, and 23

(Scheme 5). The choice of a benzoylated rhamnose deriva-

tive was essential for avoiding orthoester formation and in-

creasing reaction yields.

Scheme 7. Reagents and reaction conditions: (i) a) benzoyl chlo-

ride, pyridine; b) 33% HBr/AcOH; c) NaI/H₂O; d) CCl₃CN, DBU,

Scheme 8. Reagents and reaction conditions: i) benzoyl chloride,

pyridine, room temp. (71%)

4 h, 25 °C (77%, 4 steps)

˚

Scheme 9. Reagents and reaction conditions: (i) alcohol 29, TMSOTf (0.05 equiv.), 4-A molecular sieves, CH₂Cl₂, Ϫ20 °C

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FULL PAPER

The use of 2,3,4-tri-O-benzoyl-β--arabinose trichlo- substantial protecting group manipulation. To prepare the

roacetimidate (27) was also necessary for the δ-hederin syn- protected α-hederin derivative 31 in good yield, the coup-

thesis; it was readily prepared from -arabinose. Perben- ling reaction was carried out in propionitrile, which is

zoylation, bromination in the anomeric position with HBr/ known to promote equatorial bond formation in glycoside

AcOH, hydrolysis of the bromide by sodium iodide in the synthesis when neighboring group participation is nonexist-

presence of H₂O, and then reaction with trichloroacetonitr- ent.^[25]Glycosylation at Ϫ78 °C with 0.3 equiv. of TMSOTf

ile gave the desired product in 77% yield over 4 steps gave 72% of the desired saponin 31 along with 21% of the

(Scheme 7).

β anomer 30 (Scheme 10).

It is interesting to note that a short reaction time for

Total deprotection of the saponins proceeded in two

trichloroacetimidate formation leads to a mixture of α and steps. First, removal of the benzoate esters with 3% potass-

1

4

β products in the C₄and C₁configurations, respectively. ium hydroxide in CH₃OH gave the saponin methyl esters in

Leaving the reaction overnight favors the thermo- good to excellent yields. Deprotection of the methyl ester

dynamically more stable β anomer and facilitates purifi- proved difficult. Traditional saponification methods (5%

cation.

KOH/CH₃OH, 65 °C, several days; barium hydroxide/

With the various trichloroacetimidates in hand, the last CH₃OH/H₂O, reflux) failed. Halogenolysis with lithium

step was the preparation of the suitably protected triter- iodide in DMF^[26]gave the saponins in poor yields

penoid derivative. To have access to both the saponin (Scheme 11) because of the drastic reaction conditions and

methyl ester and the saponin, we chose methyl hederagenate the difficulties encountered during product purification (as

28 to be the starting material. Selective protection of the an aqueous workup was not possible).

primary alcohol was accomplished by treatment with 1.4

equivalents of benzoyl chloride at room temperature to give

the mono-protected derivative 29 in 71% yield (Scheme 8).

Saponin synthesis proceeded smoothly by reacting the

prepared trichloroacetimidates 25, 26, and 27 and the ac-

ceptor 29 at Ϫ20 °C in the presence of catalytic amounts of

TMSOTf. As expected, the α anomers were formed exclus-

ively in good to excellent yields. Glycosylation of donor 24

with acceptor 29 gave, because of the presence of rhamnose

in position 2, 81% of the β anomer (30) along with 8% of

the α anomer (31). This result was expected, because we

wished to synthesize, and later test, the ‘‘non-natural’’ sap-

onin that has the opposite anomeric configuration of α-hed-

erin between the disaccharide and the aglycon (Scheme 9).

Glycosylation that results in the formation of an equa-

torial bond between an aglycon and a disaccharide lacking

a participating ester group in position 2 is not a trivial mat-

ter. Many literature examples of saponin synthesis involve

stepwise construction of the disaccharide, i.e., glycosylation

of the aglycon with a monosaccharide protected in position

2 by an ester function, deprotection of the ester, and then

coupling of a second sugar unit. We chose not to apply this

strategy to the synthesis of α-hederin in an effort to avoid

Scheme 11. Reagents and reaction conditions: (i) 3% KOH/

CH₃OH; (ii) LiI, DMF, reflux, 5 d

This problem was eliminated by using an allyl ester pro-

tecting group. Glycosylation using allyl hederagenate 35

gave the protected saponins in yields identical to those ob-

tained with the methyl esters.^[27]Total deprotection (deben-

zoylation and palladium-catalyzed ester removal) was then

performed without intermediate purification to give the

corresponding saponins. For example, compound 37, the

protected α-hederin derivative, was synthesized in 56% yield

Scheme 10. Reagents and reaction conditions: (i) TMSOTf (0.3

˚

equiv.), 4-A molecular sieves, propionitrile, Ϫ78 °C

using the same reaction conditions as shown in Scheme 10.

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Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

Two-step deprotection, without purification of the inter- which are not abundant or readily isolated from natural

mediate, gave α-hederin (1) in 91% yield, which is a net sources.

improvement over the yield obtained in the case of the

methyl ester (36%) (Scheme 12).

The use of 4-methoxybenzyl α--arabinopyranoside (11)

gave ready access to the desired arabinose derivatives with

minimal protecting group manipulation. This synthesis of

the rhamnoseϪarabinose disaccharides is a great improve-

ment over previous methods, and the coupling to the agly-

con was achieved in excellent yields. Work is currently un-

derway to test the hemolytic activity of these molecules and

the preparation of other hederagenin containing saponins

is also in progress.

Experimental Section

General Remarks: All chemicals were reagent grade and used as

supplied unless otherwise noted. Dichloromethane (CH₂Cl₂) and

triethylamine were heated under reflux over calcium hydride and

distilled prior to use. All reactions were performed under Ar unless

otherwise indicated. Analytical thin-layer chromatography (TLC)

was performed on E. Merck Silica Gel 60 F₂₅₄plates. Compounds

were visualized by dipping in a solution of anisaldehyde in ethanol

and then heating. Column chromatography was performed using

E. Merck Geduran Silica Gel Si 60 (40Ϫ60 µM). Optical rotations

were recorded at 21 °C using a PerkinϪElmer 241 polarimeter.

ESI-MS were recorded using a Thermofinnigan quadripolar mass

spectrometer with positive ion data collected automatically. NMR

spectra were obtained using a Bruker Avance DRX 500 spec-

trometer (500 MHz for ¹H and 125 MHz for ¹³C). Elemental analy-

ses were performed with a PerkinϪElmer CHN 2400. Methyl hed-

eragenate (28)^[28]was obtained from an ivy plant extract^[29](Hedera

taurica, Araliaceae), which was enriched in hederasaponin C, by

acidic hydrolysis and treatment with diazomethane. The HPLC sys-

tem (Shimadzu) consisted of a solvent delivery system equipped

with dual pumps (LC-8A) and a UV spectrophotometric detector

(SPD-6A). Preparative HPLC was performed using a Merck Hibar

column [250 mm ϫ 25 mm; Lichrospher RP 18 (7µm)]. Protected

saponins were detected at 230 nm.

Scheme 12. Reagents and reaction conditions: (i) allyl bromide,

K₂CO₃, DMF, 50 °C (61%); (ii) benzoyl chloride, pyridine, room

temp. (63%); (iii) trichloroacetimidate 24, TMSOTf (0.3 equiv.), 4-

˚

A molecular sieves, propionitrile, Ϫ78 °C; (iv) 3% KOH/MeOH; (v)

[Pd(PPh₃)₄], pyrrolidine, THF (91%, 2 steps)

Using the allyl ester 35 resulted in a significant yield in-

crease for all of the saponins. Table 1 summarizes the yields

obtained for the last three synthetic steps: glycosylation, de-

benzoylation, and ester deprotection for the two aglycons

used.

4-Methoxybenzyl α-L-Arabinopyranoside (11): Acetic anhydride

(Ac₂O; 44 mL, 466 mmol, 5 equiv.) was slowly added to a solution

of -arabinose (14.0 g, 93 mmol) and pyridine (75.4 mL, 933 mmol,

10 equiv.) at 0 °C. After 48 h, toluene was added (3 ϫ) and the

solvent evaporated under reduced pressure until an oil was ob-

tained (35 g). A solution of 33% HBr in AcOH (50 mL) was then

added. After 2 h at room temperature, the reaction mixture was

diluted with CH₂Cl₂(200 mL) and poured into ice water (200 mL).

The aqueous layer was extracted with CH₂Cl₂(2 ϫ 150 mL). The

combined organic layers were then washed with H₂O (2 ϫ 250 mL),

satd. NaHCO₃(250 mL), and satd. NaCl (250 mL). The dried solu-

tion (Na₂SO₄) was evaporated under reduced pressure until forma-

tion of a white solid just began. Diethyl ether (50 mL) was added

and the product was left to precipitate for 30 min. The solid was

filtered and dried to give the bromide (21.7 g, 68%).

Table 1. Comparative overall yields for saponin glycosylation and

deprotection

Methyl

hederagenate

Allyl

hederagenate

α--Rha-(1Ǟ2)-α--Ara (1)

α--Rha-(1Ǟ2)-β--Ara (5)

α--Rha-(1Ǟ3)-α--Ara (7)

α--Rha-(1Ǟ4)-α--Ara (9)

α--Ara (3)

26%

34%

25%

41%

14%

51%

64%

79%

76%

74%

The bromide (19.9 g, 59 mmol) was then mixed with toluene

˚

(250 mL) and 4-A molecular sieves (44 g) for 40 min before adding

4-methoxybenzyl alcohol (37 mL, 294 mmol, 5 equiv.), I₂(22.3 g,

88.1 mmol, 1.5 equiv.), and Ag₂CO₃(32.4 g, 117 mmol, 2 equiv.).

After stirring overnight, the reaction mixture was filtered through

celite and the pad was washed with toluene. The organic layer was

then washed with 20% Na₂S₂O₃(500 mL), H₂O (500 mL), and

satd. NaCl (500 mL). The dried solution (Na₂SO₄) was then evapo-

In conclusion, we have synthesized the naturally occur-

ring saponins α-hederin (1) and δ-hederin (3), as well as the

‘‘non-natural’’ saponins 5, 7, and 9, in a clear and straight-

forward manner in yields ranging from 54 to 86% for the

saponin methyl esters, and 51Ϫ79% for the saponins. The

saponin syntheses developed here give access to products rated under reduced pressure to give an oil (49.8 g) that was stirred

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FULL PAPER

overnight in a mixture of MeOH/Et₃N/H₂O (8:1:1, 600 mL). The

reaction mixture was evaporated under reduced pressure and the

crude residue (45.9 g) was purified by column chromatography

(EtOAc then EtOAc/MeOH, 9:1) to give 11 as a white solid (11.9 g,

75%; 51% global yield from -arabinose). R_fϭ 0.34 (EtOAc/

4-Methoxybenzyl 2-O-Allyl-3,4-di-O-benzoyl-α- -arabinopyranoside

L

(13): Benzoyl chloride (3.0 mL, 25.5 mmol, 2.2 equiv.) was slowly

added to a mixture of compound 12 (3.6 g, 11.6 mmol), triethyl-

amine (8.1 mL, 58 mmol, 5.0 equiv.), and dimethylaminopyridine

(DMAP; 0.142 g, 1.2 mmol, 0.1 equiv.) in anhydrous CH₂Cl₂

MeOH, 9:1). M.p. 107Ϫ109 °C. [α]_Dϭ Ϫ26.1 (c ϭ 1, CH₃OH). ¹H (134 mL) at 0 °C. The reaction mixture was stirred for 24 h at room

NMR (CD₃OD): δ ϭ 3.53 (dd, J_2,3ϭ 8.9, J_3,4ϭ 3.4 Hz, 1 H, H-

temperature and quenched by the addition of MeOH. The reaction

3), 3.56 (dd, J_5a,5bϭ 12.5, J_4,5aϭ 1.6 Hz, 1 H, H-5a), 3.61 (dd, mixture was diluted with CH₂Cl₂(300 mL) and washed with 1 

J_2,3ϭ 8.8, J_1,2ϭ 7.0 Hz, 1 H, H-2), 3.80 (s, 3 H, OCH₃), 3.82 (m, HCl (300 mL), satd. NaHCO₃(300 mL), and satd. NaCl (300 mL).

1 H, H-4), 3.93 (dd, J_5a,5bϭ 12.5, J_4,5bϭ 3.1 Hz, 1 H, H-5b), 4.29 The dried solution (Na₂SO₄) was then evaporated under reduced

(d, J_1,2ϭ 7.0 Hz, 1 H, H-1), 4.56 (d, J ϭ 11.3 Hz, 1 H, CH₂MPM),

4.80 (d, J ϭ 11.3 Hz, 1 H, CH₂MPM), 6.90 (d, J ϭ 8.8 Hz, 2 H,

Ar-H), 7.34 (d, J ϭ 8.7 Hz, 2 H, Ar-H) ppm. ¹³C NMR (CD₃OD):

pressure to give an orange oil that was recrystallized from MeOH

(70 mL) to give compound 13 as white crystals (4.5 g, 74%). The

rest of the crude product was purified by column chromatography

δ ϭ 54.2 (OCH₃), 65.3 (C-5), 68.1 (C-4), 69.8 (CH₂MPM), 70.9 (C- (cyclohexane/EtOAc, 95:5) to give an additional amount of 13

2), 72.8 (C-3), 102.0 (C-1), 113.2 (CH), 129.4 (CH), 129.5 (C), 159.4 (0.767 g, 13%). Total yield: 87%. R_fϭ 0.58 (cyclohexane/EtOAc,

(C) ppm. ESI-MS: m/z ϭ 293 [M ϩ Na]^ϩ. C₁₃H₁₈O₆(270.28):

calcd. C 57.77, H 6.71; found C 57.62, H 6.91.

6:4). M.p. 72 °C. [α]_Dϭ ϩ81.8 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃):

δ ϭ 3.86 (dd, J_5a,5bϭ 12.4, J_4,5aϭ 2.2 Hz, 1 H, H-5a), 3.87 (s, 3

H, OCH₃), 3.92 (dd, J_2,3ϭ 8.2, J_1,2ϭ 5.9 Hz, 1 H, H-2), 4.25 (ddt,

J ϭ 12.6, 6.0, 1.4 Hz, 1 H, CH₂CHϭCH₂), 4.30 (dd, J_5a,5bϭ 12.6,

J_4,5bϭ 4.4 Hz, 1 H, H-5b), 4.37 (ddt, J ϭ 12.7, 5.5, 1.4 Hz, 1 H,

CH₂CHϭCH₂), 4.66 (d, J ϭ 11.3 Hz, 1 H, CH₂MPM), 4.72 (d,

J_1,2ϭ 5.9 Hz, 1 H, H-1), 4.93 (d, J ϭ 11.3 Hz, 1 H, CH₂MPM),

5.16 (ddd, J ϭ 10.3, 2.8, 1.1 Hz, 1 H, CH₂CHϭCH₂), 5.28 (ddd,

J ϭ 17.2, 3.2, 1.7 Hz, 1 H, CH₂CHϭCH₂), 5.48 (dd, J_2,3ϭ 8.2,

4-Methoxybenzyl 2-O-Allyl-α-L-arabinopyranoside (12): A solution

of 11 (11 g, 40.7 mmol), 2,2-dimethoxypropane (10 mL, 81.4 mmol,

2 equiv.), and p-toluenesulfonic acid (0.387 g, 2.0 mmol, 0.05

equiv.) in DMF (80 mL) was stirred for 2 h at room temperature.

The reaction was stopped by the addition of triethylamine (2.2 mL)

and then the mixture was diluted with diethyl ether (300 mL) and

washed with H₂O (250 mL). The aqueous layer was extracted with

diethyl ether (4 ϫ 250 mL). The combined organic layers were

washed with satd. NaHCO₃(800 mL) and satd. NaCl (800 mL).

The dried solution (Na₂SO₄) was then evaporated under reduced

pressure to give p-methoxybenzyl 3,4-O-isopropylidene-α--arabin-

opyranoside (12.3 g), which was used without purification in the

following step.

A mixture of this isopropylidene (5.3 g, 17.1 mmol) and allyl bro-

mide (1.8 mL, 20.5 mmol, 1.2 equiv.) in DMF (53 mL) was added

to a solution of NaH (80%; 1.076 g, 35.9 mmol, 2.1 equiv.) in DMF

(27 mL) at 0 °C. The reaction mixture was stirred for 1 h, quenched

by the addition of MeOH, diluted in diethyl ether (250 mL), and

washed with H₂O (400 mL). The aqueous layer was extracted with

diethyl ether (3 ϫ 250 mL). The combined organic layers were

washed with satd. NaHCO₃(600 mL) and satd. NaCl (600 mL).

The dried solution (Na₂SO₄) was evaporated under reduced press-

ure to give an orange oil (6.4 g), which was then mixed with 70%

AcOH (71.5 mL) and heated to 70 °C for 1 h. The reaction mixture

was cooled and the solvent evaporated under reduced pressure in

the presence of toluene (3 ϫ), MeOH (2 ϫ), and CH₂Cl₂(2 ϫ) to

give a yellow amorphous solid that was purified by column chro-

matography (cyclohexane/EtOAc, 4:6 to 2:8) to give 12 as a white

solid (3.9 g, 73%). R_fϭ 0.20 (cyclohexane/EtOAc, 6:4). M.p. 74 °C.

[α]_Dϭ Ϫ40.1 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 3.57 (dd,

J_3,4ϭ 3.5 Hz, 1 H, H-3), 5.63 (td, J_3,4ϭ J_4,5aϭ 4.2, J_4,5eϭ 2.3 Hz,

1 H, H-4), 5.85 (m, 1 H, CH₂CHϭCH₂), 6.92 (d, J ϭ 8.7 Hz, 2 H,

Ar-H), 7.36 (t, J ϭ 9.2 Hz, 4 H, Ar-H), 7.45 (t, J ϭ 8.0 Hz, 2 H,

Ar-H), 7.54 (t, J ϭ 7.5 Hz, 2 H, Ar-H), 7.59 (t, J ϭ 8.6 Hz, 2 H,

Ar-H), 7.96 (d, J ϭ 8.4 Hz, 2 H, Ar-H), 8.04 (d, J ϭ 8.4 Hz, 2 H,

Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 55.2 (OCH₃), 62.1 (C-5), 68.5

(C-4), 70.6 (CH₂MPM), 71.2 (C-3), 73.2 (CH₂CHϭCH₂), 76.2 (C-

2), 101.3 (C-1), 113.8 (CH), 117.3 (CH₂CHϭCH₂), 128.3 (CH),

128.4 (CH), 129.2 (C), 129.6 (CH), 129.7 (CH), 129.8 (CH), 133.0

(CH), 133.2 (CH), 134.5 (CH₂CHϭCH₂), 159.3 (C), 165.6 (CO),

165.6 (CO) ppm. ESI-MS: m/z ϭ 541 [M ϩ Na]^ϩ. C₃₀H₃₀O₈

(518.56): calcd. C 69.49, H 5.83; found C 69.69, H 5.74.

4-Methoxybenzyl 3,4-Di-O-benzoyl-α-L-arabinopyranoside (14): Pal-

ladium chloride (0.53 g, 0.3 mmol, 0.3 equiv.) was added to a solu-

tion of compound 13 (5.1 g, 9.9 mmol) in MeOH (52 mL) and the

reaction mixture was stirred for 48 h at room temperature. The mix-

ture was then filtered through Celite, the solvent was evaporated

under reduced pressure, and the residue purified by column chro-

matography (cyclohexane/EtOAc, 8:2) to give 14 as a white solid

(3.2 g, 68%). R_fϭ 0.42 (cyclohexane/EtOAc, 6:4). M.p. 134 °C.

1

[α]_Dϭ ϩ82.7 (c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 3.84 (s, 3

H, OCH₃), 3.85 (dd, J_5a,5bϭ 13.2, J_4,5aϭ 1.2 Hz, 1 H, H-5a), 4.19

(dd, J_2,3ϭ 9.5, J_1,2ϭ 7.3 Hz, 1 H, H-2), 4.30 (dd, J_5a,5bϭ 13.2,

J_4,5bϭ 2.7 Hz, 1 H, H-5b), 4.54 (d, J_1,2ϭ 7.1 Hz, 1 H, H-1), 4.66

(d, J ϭ 11.2 Hz, 1 H, CH₂MPM), 4.95 (d, J ϭ 11.2 Hz, 1 H,

CH₂MPM), 5.38 (dd, J_2,3ϭ 9.6, J_3,4ϭ 3.6 Hz, 1 H, H-3), 5.63 (m,

1 H, H-4), 6.93 (d, J ϭ 8.6 Hz, 2 H, Ar-H), 7.35 (m, 4 H, Ar-H),

7.47 (t, J ϭ 7.6 Hz, 2 H, Ar-H), 7.52 (t, J ϭ 7.4 Hz, 1 H, Ar-H),

7.60 (t, J ϭ 7.4 Hz, 1 H, Ar-H), 7.94 (d, J ϭ 8.4 Hz, 2 H, Ar-H),

8.08 (d, J ϭ 8.4 Hz, 2 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 55.3

(OCH₃), 64.0 (C-5), 69.0 (C-4), 69.9 (C-2), 70.9 (CH₂MPM), 72.6

(C-3), 101.9 (C-1), 114.0 (CH), 128.3 (CH), 128.4 (CH), 128.7 (C),

129.4 (C), 129.6 (C), 129.8 (CH), 129.8 (CH), 129.9 (CH), 133.1

(CH), 133.3 (CH), 159.5 (C), 165.7 (CO), 165.9 (CO) ppm. ESI-

MS: m/z ϭ 479 [M ϩ H]^ϩ. C₂₇H₂₆O₈(478.50): calcd. C 67.77, H

5.48; found C 67.66, H 5.53.

J

_2,3ϭ 6.1, J_1,2ϭ 4.5 Hz, 1 H, H-2), 3.63 (dd, J_5a,5bϭ 12.0, J_4,5aϭ

3.7 Hz, 1 H, H-5a), 3.81 (dd, J_5a,5bϭ 12.2, J_4,5bϭ 6.7 Hz, 1 H, H-

5b), 3.81 (m, 1 H, H-3), 3.83 (s, 3 H, OCH₃), 3.97 (td, J_3,4ϭ J_4,5aϭ

6.9, J_4,5eϭ 3.5 Hz, 1 H, H-4), 4.12 (dd, J ϭ 12.7, J ϭ 5.8 Hz, 1

H, CH₂CHϭCH₂), 4.24 (dd, J ϭ 12.7, J ϭ 5.8 Hz, 1 H, CH₂CHϭ

CH₂), 4.52 (d, J ϭ 11.4 Hz, 1 H, CH₂MPM), 4.61 (d, J_1,2ϭ 4.3 Hz,

1 H, H-1), 4.79 (d, J ϭ 11.4 Hz, 1 H, CH₂MPM), 5.21 (d, J ϭ

10.3 Hz, 1 H, CH₂CHϭCH₂), 5.28 (dd, J ϭ 17.2, J ϭ 1.5 Hz, 1 H,

CH₂CHϭCH₂), 5.90 (m, 1 H, CH₂CHϭCH₂), 6.91 (d, J ϭ 8.6 Hz,

2 H, Ar-H), 7.29 (m, J ϭ 8.6 Hz, 2 H, Ar-H) ppm. ¹³C NMR

(CDCl₃):

δ ϭ 55.2 (OCH₃), 62.1 (C-5), 65.8 (C-4), 69.8

(CH₂MPM), 70.4 (C-3), 72.4 (CH₂CHϭCH₂), 76.9 (C-2), 99.1 (C-

1), 113.9 (CH), 117.7 (CH₂CHϭCH₂), 128.7 (C), 129.7 (CH), 134.3

(CH₂CHϭCH₂), 159.4 (C) ppm. ESI-MS: m/z ϭ 333 [M ϩ Na]^ϩ.

4-Methoxybenzyl 2-O-Benzoyl-α-L-arabinopyranoside (18): This

C₁₆H₂₂O₆(310.35): calcd. C 61.92, H 7.15; found C 62.23, H 6.95. compound was synthesized using p-methoxybenzyl 3,4-O-isopro-

1594  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org

Eur. J. Org. Chem. 2004, 1588Ϫ1603

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

pylidene-α--arabinopyranoside, which was previously described in

the preparation of compound 12. Benzoyl chloride (2.8 mL,

(C), 129.6 (CH), 129.8 (CH), 129.9 (CH), 133.2 (CH), 133.3 (CH),

159.3 (C), 165.1 (CO), 166.0 (CO) ppm. ESI-MS: m/z ϭ 497 [M ϩ

23.8 mmol, 1.1 equiv.) was slowly added to a mixture of the isopro- H₂O ϩ H]^ϩ. C₂₇H₂₆O₈(478.50): calcd. C 67.77, H 5.48; found C

pylidene arabinose (6.7 g, 21.6 mmol), triethylamine (7.5 mL,

54.0 mmol, 2.5 equiv.), and DMAP (0.132 g, 1.1 mmol, 0.05 equiv.)

in anhydrous CH₂Cl₂(200 mL) at 0 °C. The reaction mixture was

stirred for 24 h at room temperature and then quenched by the

addition of MeOH. The reaction mixture was diluted with CH₂Cl₂

(500 mL) and washed with 1  HCl (400 mL), satd. NaHCO₃

(400 mL), and satd. NaCl (400 mL). The dried solution (Na₂SO₄)

was then evaporated under reduced pressure to give an orange solid

(9.2 g). The crude compound was then treated with 70% AcOH

(145 mL) and heated to 70 °C for 1 h. The reaction mixture was

cooled and then the solvent was evaporated under reduced pressure

in the presence of toluene (3 ϫ), MeOH (2 ϫ), and CH₂Cl₂(2 ϫ)

to give a yellow solid (8.1 g). A first recrystallization from MeOH

(80 mL) gave pure 18 (4.7 g, 59%). A second batch of crystals was

obtained (1.2 g, 14%), and the rest of the crude residue was purified

by column chromatography (cyclohexane/EtOAc, 1:1) to give an

additional amount of 18 (0.590 g, 7%). Total yield: 80%. R_fϭ 0.21

(cyclohexane/EtOAc, 6:4). M.p. 143Ϫ145 °C. [α]_Dϭ Ϫ49.7 (c ϭ 1,

67.75, H 5.71.

Compound 16: R_fϭ 0.51 (cyclohexane/EtOAc, 6:4). [α]_Dϭ ϩ115.8

(c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 3.81 (s, 3 H, OCH₃), 3.90

(dd, J_5a,5bϭ 12.6, J_4,5aϭ 2.0 Hz, 1 H, H-5a), 4.37 (dd, J_5a,5b

1

ϭ

12.6, J_4,5bϭ 4.5 Hz, 1 H, H-5b), 4.64 (d, J ϭ 11.8 Hz, 1 H,

CH₂MPM), 4.81 (d, J_1,2ϭ 6.0 Hz, 1 H, H-1), 4.88 (d, J ϭ 11.8 Hz,

1 H, CH₂MPM), 5.59 (dd, J_2,3ϭ 8.3, J_3,4ϭ 3.3 Hz, 1 H, H-3),

5.70 (m, 1 H, H-4), 5.76 (dd, J_2,3ϭ 8.2, J_1,2ϭ 6.2 Hz, 1 H, H-2),

6.79 (d, J ϭ 8.5 Hz, 2 H, Ar-H), 7.22 (d, J ϭ 8.5 Hz, 2 H, Ar-H),

7.30 (m, 2 H, Ar-H), 7.45 (m, 5 H, Ar-H), 7.59 (m, 2 H, Ar-H),

7.90 (d, J ϭ 7.2 Hz, 2 H, Ar-H), 8.00 (d, J ϭ 7.2 Hz, 2 H, Ar-H),

8.06 (d, J ϭ 7.2 Hz, 2 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 55.2

(OCH₃), 62.1 (C-5), 68.2 (C-4), 69.9 (C-2), 70.0 (CH₂MPM), 70.2

(C-3), 99.6 (C-1), 113.7 (CH), 128.3 (CH), 128.3 (CH), 128.4 (CH),

128.8 (C), 129.0 (C), 129.3 (C), 129.7 (CH), 129.8 (CH), 133.2

(CH), 133.3 (CH), 165.1 (CO), 165.5 (CO), 165.7 (CO) ppm. ESI-

MS: m/z ϭ 601 [M ϩ H₂O ϩ H]^ϩ.

1

CHCl₃). H NMR (CDCl₃): δ ϭ 2.56 (d, J ϭ 8.7 Hz, 1 H, OH-4),

4-Methoxybenzyl 2,4-Di-O-benzoyl-α-L-arabinopyranoside (19): Tri-

3.48 (d, J ϭ 9.0 Hz, 1 H, OH-3), 3.74 (dd, J_5a,5bϭ 11.9, J_4,5a

ϭ

methyl orthobenzoate (3.0 mL, 17.1 mmol, 2.0 equiv.) and p-tolu-

enesulfonic acid (0.325 g, 1.7 mmol, 0.2 equiv.) were added to a

stirred solution of compound 18 (3.2 g, 8.5 mmol) in CH₂Cl₂

(70 mL). After 2 h, the solvent was evaporated under reduced

pressure and 80% AcOH (25 mL) was added. The reaction mixture

was stirred for 10 min then diluted in CH₂Cl₂(500 mL). The or-

ganic layer was washed with H₂O (400 mL), satd. NaHCO₃(2 ϫ

400 mL), and satd. NaCl (400 mL). The dried solution (Na₂SO₄)

was then evaporated under reduced pressure to give a crude residue

(6.4 g), which was purified by column chromatography (cyclohex-

ane/EtOAc, 6:1 to 2.3:1) to give the desired 2,4 di-O-benzoylated

compound 19 (3.0 g, 72%) as well as the 2,3 di-O-benzoylated com-

pound 15 (1.1 g, 26%). 19: R_fϭ 0.41 (cyclohexane/EtOAc, 6:4).

4.2 Hz, 1 H, H-5a), 3.83 (s, 3 H, OCH₃), 3.86 (dd, J_5a,5bϭ 11.9,

J_4,5bϭ 8.2 Hz, 1 H, H-5b), 3.99 (m, 1 H, H-3), 4.04 (m, 1 H, H-

4), 4.57 (d, J ϭ 11.6 Hz, 1 H, CH₂MPM), 4.78 (d, J ϭ 11.6 Hz, 1

H, CH₂MPM), 4.83 (d, J_1,2ϭ 3.4 Hz, 1 H, H-1), 5.26 (dd, J_2,3

ϭ

5.1, J_1,2ϭ 3.7 Hz, 1 H, H-2), 6.89 (d, J ϭ 8.5 Hz, 2 H, Ar-H), 7.28

(d, J ϭ 7.8 Hz, 2 H, Ar-H), 7.48 (t, J ϭ 7.8 Hz, 2 H, Ar-H), 7.62

(t, J ϭ 7.5 Hz, 1 H, Ar-H), 8.03 (d, J ϭ 8.1 Hz, 2 H, Ar-H) ppm.

¹³C NMR (CDCl₃): δ ϭ 55.2 (OCH₃), 60.9 (C-5), 65.3 (C-4), 69.6

(CH₂MPM), 69.7 (C-3), 71.4 (C-2), 96.5 (C-1), 113.9 (CH), 128.2

(C), 128.4 (CH), 129.1 (C), 129.8 (CH), 129.9 (CH), 133.5 (CH),

159.6 (C), 165.7 (CO) ppm. ESI-MS: m/z ϭ 393 [M ϩ H₂OϩH]^ϩ.

C₂₀H₂₂O₇(374.39): calcd. C 64.16, H 5.92; found C 63.84, H 6.06.

1

[α]_Dϭ ϩ25.2 (c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 3.82 (s, 3

4-Methoxybenzyl 2,3-Di-O-benzoyl-α-L-arabinopyranoside (15):

H, OCH₃), 3.83 (dd, J_5a,5bϭ 12.3, J_4,5aϭ 2.6 Hz, 1 H, H-5a), 4.19

(dd, J_2,3ϭ 6.9, J_3,4ϭ 3.3 Hz, 1 H, H-3), 4.24 (dd, J_5a,5bϭ 12.3,

J_4,5bϭ 6.4 Hz, 1 H, H-5b), 4.62 (d, J ϭ 11.8 Hz, 1 H, CH₂MPM),

4.82 (d, J_1,2ϭ 5.0 Hz, 1 H, H-1), 4.83 (d, J ϭ 12.2 Hz, 1 H,

CH₂MPM), 5.40 (dd, J_2,3ϭ 6.9, J_1,2ϭ 4.8 Hz, 1 H, H-2), 5.46 (m,

1 H, H-4), 6.86 (d, J ϭ 8.6 Hz, 2 H, Ar-H), 7.27 (d, J ϭ 8.6 Hz, 2

H, Ar-H), 7.48 (m, 4 H, Ar-H), 7.62 (m, 2 H, Ar-H), 8.06 (d, J ϭ

8.4 Hz, 2 H, Ar-H), 8.13 (d, J ϭ 8.6 Hz, 2 H, Ar-H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 55.2 (OCH₃), 60.0 (C-5), 69.3 (C-3), 69.5 (C-

4), 69.9 (CH₂MPM), 72.1 (C-2), 97.6 (C-1), 113.9 (CH), 128.4

(CH), 129.2 (C), 129.4 (C), 129.8 (CH), 129.9 (CH), 133.4 (CH),

133.5 (CH), 159.5 (C), 165.9 (CO), 166.0 (CO) ppm. ESI-MS:

m/z ϭ 501 [M ϩ Na]^ϩ. C₂₇H₂₆O₈(478.50): calcd. C 67.77, H 5.48;

found C 67.56, H 5.57.

Benzoyl chloride (1.1 mL, 9.6 mmol, 1.1 equiv.) was added to a

solution of compound 18 (3.2 g, 8.7 mmol) in pyridine (70 mL) at

Ϫ35 °C. After stirring for 4 h at this temperature, the reaction was

quenched by the addition of MeOH. The mixture was taken up in

EtOAc (400 mL) and washed with 3  H₂SO₄(300 mL), satd.

NaHCO₃(300 mL), and H₂O (300 mL). The dried solution

(Na₂SO₄) was then evaporated under reduced pressure to give a

crude solid, which was purified by column chromatography (cyclo-

hexane/EtOAc, 6:1 to 1.5:1) to give the 2,3 di-O-benzoylated com-

pound 15 (3.1 g, 74%), as well as recovered starting material 18

(0.619 g, 19%). Two other compounds were identified: the 2,4 di-

O-benzoylated compound 19 (0.157 g, 4%) and the 2,3,4 tri-O-ben-

zoylated compound 16 (0.131 g, 3%).

Compound 15: R_fϭ 0.30 (cyclohexane/EtOAc, 6:4). [α]_Dϭ ϩ47.3

4-Methoxybenzyl (2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl)-(1Ǟ2)-

(c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 3.76 (dd, J_5a,5bϭ 12.2, 3,4-di-O-benzoyl-α-

L-arabinopyranoside (21): Alcohol 14 (1.0 g,

J_4,5aϭ 2.5 Hz, 1 H, H-5a), 3.81 (s, 3 H, OCH₃), 4.16 (dd, J_5a,5b

ϭ

2.1 mmol), trichloroacetimidate 20^[23](1.9 g, 3.1 mmol, 1.5 equiv.),

˚

12.2, J_4,5bϭ 5.2 Hz, 1 H, H-5b), 4.35 (m, 1 H, H-4), 4.60 (d, J ϭ and 4-A powdered molecular sieves (3 g) were stirred for 1 h at

11.7 Hz, 1 H, CH₂MPM), 4.75 (d, J_1,2ϭ 5.5 Hz, 1 H, H-1), 4.84 (d, room temperature in CH₂Cl₂(51 mL). The mixture was cooled to

J ϭ 11.7 Hz, 1 H, CH₂MPM), 5.37 (dd, J_2,3ϭ 7.7, J_3,4ϭ 3.2 Hz, 1 Ϫ20 °C for 30 minutes followed by the dropwise addition of a 0.1

H, H-3), 5.64 (dd, J_2,3ϭ 7.7, J_1,2ϭ 5.5 Hz, 1 H, H-2), 6.79 (dd,  solution of TMSOTf in CH₂Cl₂(1.05 mL, 0.1 mmol, 0.05 equiv.).

J ϭ 6.8, 1.8 Hz, 2 H, Ar-H), 7.22 (d, J ϭ 8.6 Hz, 2 H, Ar-H), 7.36

(t, J ϭ 7.9 Hz, 2 H, Ar-H), 7.44 (t, J ϭ 7.9 Hz, 2 H, Ar-H), 7.54

(t, J ϭ 7.5 Hz, 1 H, Ar-H), 7.58 (t, J ϭ 7.5 Hz, 1 H, Ar-H), 7.99

After stirring for 2 h at this temperature, the reaction mixture was

quenched with triethylamine and filtered through Celite, and then

the solvents were evaporated. The crude residue was purified by

(m, 4 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 55.2 (OCH₃), 63.6 column chromatography (toluene/EtOAc, 99:1 to 32:1) to give di-

(C-5), 66.2 (C-4), 69.7 (C-2), 69.7 (CH₂MPM), 72.5 (C-3), 98.2 (C-

saccharide 21 (1.9 g, 95%) as an amorphous solid. R_fϭ 0.35 (tolu-

1), 113.7 (CH), 128.3 (CH), 128.4 (CH), 128.9 (C), 129.1 (C), 129.3 ene/EtOAc, 9:1). [α]_Dϭ ϩ139.0 (c ϭ 1, CHCl₃). ¹H NMR

Eur. J. Org. Chem. 2004, 1588Ϫ1603

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1595

´

K. Ple, M. Chwalek, L. Voutquenne-Nazabadioko

FULL PAPER

(CDCl₃): δ ϭ 1.08 (d, J_5Ј,6Јϭ 6.2 Hz, 3 H, H-6Ј), 3.61 (s, 3 H, 2.8 Hz, 1 H, H-5a), 3.84 (s, 3 H, OCH₃), 4.35 (m, 1 H, H-5Ј), 4.38

OCH₃), 3.94 (dd, J_5a,5bϭ 13.1, J_4,5aϭ 1.0 Hz, 1 H, H-5a), 4.34 (dd, J_5a,5bϭ 11.8, J_4,5bϭ 6.5 Hz, 1 H, H-5b), 4.44 (m, 1 H, H-4),

(dd, J_5a,5bϭ 13.1, J_4,5bϭ 2.6 Hz, 1 H, H-5b), 4.37 (dd, J_2,3ϭ 9.4,

_1,2ϭ 7.1 Hz, 1 H, H-2), 4.56 (m, 1 H, H-5Ј), 4.66 (d, J ϭ 10.9 Hz,

4.63 (d, J ϭ 11.4 Hz, 1 H, CH₂MPM), 4.89 (m, 1 H, H-1), 4.90 (d,

J ϭ 11.6 Hz, 1 H, CH₂MPM), 5.28 (s, 1 H, H-1Ј), 5.64 (m, 2 H,

J

1 H, CH₂MPM), 4.79 (d, J_1,2ϭ 7.0 Hz, 1 H, H-1), 5.01 (d, J ϭ H-2, H-3), 5.68 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 10.0 Hz, 1 H, H-4Ј), 5.70 (m, 1

10.9 Hz, 1 H, CH₂MPM), 5.31 (d, J_1Ј,2Јϭ 1.2 Hz, 1 H, H-1Ј), 5.51 H, H-2Ј), 5.84 (dd, J_3Ј,4Јϭ 10.1, J_2Ј,3Јϭ 3.3 Hz, 1 H, H-3Ј), 6.86

(dd, J_2Ј,3Јϭ 3.4, J_1Ј,2Јϭ 1.5 Hz, 1 H, H-2Ј), 5.55 (dd, J_2,3ϭ 9.4, (dd, J ϭ 6.8, J ϭ 1.8 Hz, 2 H, Ar-H), 7.24Ϫ7.63 (m, 17 H, Ar-H),

J_3,4ϭ 3.5 Hz, 1 H, H-3), 5.58 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 10.1 Hz, 1 H, H-

7.82 (m, 2 H, Ar-H), 7.98Ϫ8.09 (m, 8 H, Ar-H) ppm. ¹³C NMR

4Ј), 5.69 (m, 1 H, H-4), 5.83 (dd, J_3Ј,4Јϭ 10.1, J_2Ј,3Јϭ 3.5 Hz, 1 H, (CDCl₃): δ ϭ 17.6 (C-6Ј), 55.2 (OCH₃), 61.3 (C-5), 67.4 (C-5Ј),

H-3Ј), 6.80 (d, J ϭ 8.6 Hz, 2 H, Ar-H), 7.25 (m, 4 H, Ar-H), 7.44 69.0 (C-3), 69.6 (C-3Ј), 69.9 (CH₂MPM), 70.0 (C-2), 70.4 (C-2Ј),

(m, 10 H, Ar-H), 7.59 (m, 3 H, Ar-H), 7.78 (d, J ϭ 7.7 Hz, 2 H, 71.6 (C-4), 71.7 (C-4Ј), 97.5 (C-1Ј), 97.9 (C-1), 113.8 (CH), 128.1

Ar-H), 7.82 (d, J ϭ 7.6 Hz, 2 H, Ar-H), 7.91 (d, J ϭ 7.2 Hz, 2 H,

(CH), 128.3 (CH), 128.5 (CH), 129.1 (C), 129.2 (C), 129.3 (C),

Ar-H), 7.98 (d, J ϭ 7.6 Hz, 2 H, Ar-H), 8.06 (d, J ϭ 7.6 Hz, 2 H, 129.4 (C), 129.6 (CH), 129.8 (CH), 129.9 (CH), 130.0 (CH), 132.0

Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 17.0 (C-6Ј), 55.0 (OCH₃), (CH), 133.1 (CH), 133.3 (CH), 159.3 (C), 164.9 (CO), 165.0 (CO),

63.8 (C-5), 67.1 (C-5Ј), 69.2 (C-4), 69.5 (C-3Ј), 70.4 (C-2Ј), 71.0 165.1 (CO), 165.7 (CO), 165.8 (CO) ppm. ESI-MS: m/z ϭ 959 [M

(CH₂MPM), 71.7 (C-4Ј), 73.6 (C-3), 74.2 (C-2), 98.3 (C-1Ј), 100.5 ϩ Na]^ϩ. C₅₄H₄₈O₁₅(936.97): calcd. C 69.22, H 5.16; found C

(C-1), 113.8 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 128.6 (C), 68.98, H 5.00.

129.0 (C), 129.0 (C), 129.3 (C), 129.4 (C), 129.6 (CH), 129.7 (CH),

(2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl)-(1Ǟ2)-3,4-di-O-ben-

129.8 (CH), 130.3 (CH), 133.0 (CH), 133.1 (CH), 133.3 (CH), 159.5

(C), 164.7 (CO), 165.4 (CO), 165.5 (CO), 165.7 (CO), 165.7 (CO)

ppm. ESI-MS: m/z ϭ 959 [M ϩ Na]^ϩ. C₅₄H₄₈O₁₅(936.97): calcd.

C 69.22, H 5.16; found C 69.17, H 5.54.

zoyl-β- -arabinopyranosyl Trichloroacetimidate (24): Trifluoroacetic

L

acid (5.82 mL, 76.1 mmol, 20 equiv.) and H₂O (0.8 mL, 45.7 mmol,

12 equiv.) were added to a solution of the disaccharide 21 (3.57 g,

3.8 mmol) in CH₂Cl₂(130 mL). The reaction mixture was vigor-

ously stirred overnight before being washed with H₂O, satd.

NaHCO₃, and satd. NaCl. The dried solution (Na₂SO₄) was then

4-Methoxybenzyl (2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl)-(1Ǟ3)-

2,4-di-O-benzoyl-α- -arabinopyranoside (22): This compound was

L

prepared from alcohol 19 (0.5 g, 1 mmol), trichloroacetimidate 20 evaporated under reduced pressure and the residue taken up in

(0.954 g, 1.6 mmol, 1.5 equiv.), and a 0.1  solution of TMSOTf CH₂Cl₂(19 mL). Trichloroacetonitrile (2.7 mL, 26.6 mmol,

7

in CH₂Cl₂(0.520 mL, 0.05 mmol, 0.05 equiv.) in the same manner

as that described for 21. The product was purified by column chro-

equiv.) was added, followed by DBU (0.058 mL, 0.38 mmol, 0.1

equiv.), and then the reaction mixture was stirred overnight. The

matography (toluene/EtOAc, 199:1 to 19:1) to give the disaccharide solvent was then evaporated and the crude residue was purified by

22 (0.950 g, 97%) as an amorphous solid. R_fϭ 0.38 (toluene/ column chromatography (cyclohexane/EtOAc, 9:1) to give 24

EtOAc, 9:1). [α]_Dϭ ϩ103.2 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): (2.96 g, 81%) as a white amorphous solid. R_fϭ 0.60 (cyclohexane/

δ ϭ 1.10 (d, J_5Ј,6Јϭ 6.3 Hz, 3 H, H-6Ј), 3.71 (s, 3 H, OCH₃), 3.82

EtOAc, 6:4). [α]_Dϭ ϩ169.1 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃):

(dd, J_5a,5bϭ 15.3, J_4,5aϭ 3.2 Hz, 1 H, H-5a), 4.20 (m, 1 H, H-5Ј), δ ϭ 1.40 (d, J_5Ј,6Јϭ 6.2 Hz, 3 H, H-6Ј), 4.16 (dd, J_5a,5bϭ 13.3,

4.37 (dd, J_2,3ϭ 6.7, J_3,4ϭ 3.3 Hz, 1 H, H-3), 4.47 (dd, J_5a,5bJ_4,5aϭ 1.9 Hz, 1 H, H-5a), 4.26 (m, 1 H, H-5Ј), 4.40 (br. d, J ϭ

12.2, J_4,5bϭ 6.2 Hz, 1 H, H-5b), 4.63 (d, J ϭ 12.0 Hz, 1 H, 12.8 Hz, 1 H, H-5b), 4.68 (dd, J_2,3ϭ 10.5, J_1,2ϭ 3.7 Hz, 1 H, H-

CH₂MPM), 4.80 (d, J_1,2ϭ 4.8 Hz, 1 H, H-1), 4.89 (d, J ϭ 12.0 Hz, 2), 5.41 (d, J_1Ј,2Јϭ 1.5 Hz, 1 H, H-1Ј), 5.51 (dd, J_2Ј,3Јϭ 3.3, J_1Ј,2Ј

1 H, CH₂MPM), 5.32 (d, J_1Ј,2Јϭ 1.4 Hz, 1 H, H-1Ј), 5.54 (m, 1 H, 1.7 Hz, 1 H, H-2Ј), 5.68 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 9.9 Hz, 1 H, H-4Ј), 5.80

H-2Ј), 5.56 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 10.0 Hz, 1 H, H-4Ј), 5.60 (dt, J_4,5aϭ (dd, J_2,3ϭ 10.5, J_3,4ϭ 3.4 Hz, 1 H, H-3), 5.85 (dd, J_3Ј,4Јϭ 10.1,

6.2, J_3,4ϭ J_4,5eϭ 3.1 Hz, 1 H, H-4), 5.65 (dd, J_2,3ϭ 6.6, J_1,2J_2Ј,3Јϭ 3.4 Hz, 1 H, H-3Ј), 5.98 (m, 1 H, H-4), 6.73 (d, J_1,2

5.2 Hz, 1 H, H-2), 5.78 (dd, J_3Ј,4Јϭ 10.1, J_2Ј,3Јϭ 3.4 Hz, 1 H, H- 3.7 Hz, 1 H, H-1), 7.24 (t, J ϭ 7.7 Hz, 2 H, Ar-H), 7.42 (m, 5 H,

3Ј), 6.80 (d, J ϭ 8.4 Hz, 2 H, Ar-H), 7.15Ϫ7.64 (m, 17 H, Ar-H), Ar-H), 7.50 (m, 6 H, Ar-H), 7.63 (m, 2 H, Ar-H), 7.77 (dd, J ϭ

7.80 (m, 4 H, Ar-H), 8.02 (m, 2 H, Ar-H), 8.10 (m, 2 H, Ar-H), 8.1, 1.1 Hz, 2 H, Ar-H), 7.94 (dd, J ϭ 8.0, 1.0 Hz, 2 H, Ar-H), 8.05

8.24 (m, 2 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 17.2 (C-6Ј), (m, 6 H, Ar-H), 8.86 (s, 1 H, NH) ppm. ¹³C NMR (CDCl₃): δ ϭ

55.1 (OCH₃), 60.7 (C-5), 67.3 (C-5Ј), 69.0 (C-4), 69.4 (C-3Ј), 69.7 17.6 (C-6Ј), 62.9 (C-5), 67.6 (C-5Ј), 68.9 (C-3Ј), 69.5 (C-4), 69.9 (C-

(CH₂MPM), 69.9 (C-2), 70.6 (C-2Ј), 71.5 (C-4Ј), 74.4 (C-3), 97.4 3), 70.8 (C-2Ј), 71.6 (C-4Ј), 74.3 (C-2), 95.7 (C-1), 99.8 (C-1Ј), 128.2

(C-1Ј), 97.9 (C-1), 113.8 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH), (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 129.1 (C), 129.4 (C),

ϭ

128.6 (CH), 129.0 (C), 129.1 (C), 129.2 (C), 129.3 (C), 129.4 (C),

129.5 (CH), 129.6 (CH), 129.7 (CH), 129.8 (CH), 129.9 (CH), 132.9

129.6 (C), 129.7 (CH), 129.8 (CH), 129.9 (CH), 133.0 (CH), 133.2

(CH), 133.4 (CH), 133.5 (CH), 161.6 (CϭNH), 165.0 (CO), 165.1

(CH), 133.2 (CH), 133.3 (CH), 133.4 (CH), 159.2 (C), 164.9 (CO), (CO), 165.5 (CO), 165.6 (CO), 165.8 (CO) ppm. ESI-MS: m/z ϭ

165.1 (CO), 165.2 (CO), 165.5 (CO), 166.0 (CO) ppm. ESI-MS:

1007 [M ϩ 2Na]^ϩ. C₄₈H₄₀Cl₃NO₁₄(961.20): calcd. C 59.98, H 4.19,

m/z ϭ 959 [M ϩ Na]^ϩ. C₅₄H₄₈O₁₅(936.97): calcd. C 69.22, H 5.16; N 1.46; found C 60.36, H 4.40, N 1.41.

found C 68.83, H 5.08.

(2,3,4-Tri-O-benzoyl-α-

zoyl-β- -arabinopyranosyl Trichloroacetimidate (25): This com-

-arabinopyranoside (23): This compound was pound was prepared from disaccharide 22 (0.950 g, 1 mmol) in the

L-rhamnopyranosyl)-(1Ǟ3)-2,4-di-O-ben-

4-Methoxybenzyl (2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl)-(1Ǟ4)-

L

2,3-di-O-benzoyl-α-

L

prepared from alcohol 15 (0.5 g, 1 mmol), trichloroacetimidate 20

(0.763 g, 1.3 mmol, 1.2 equiv.), and a 0.1  solution of TMSOTf

in CH₂Cl₂(0.520 mL, 0.05 mmol, 0.05 equiv.) in the same manner

as that described for 21. The product was purified by column chro-

matography (toluene/EtOAc, 99:1 to 19:1) to give the disaccharide

23 (0.960 g, 98%) as an amorphous solid. R_fϭ 0.37 (toluene/

same manner as that described for compound 24. Purification by

column chromatography (cyclohexane/EtOAc, 9:1 to 6:1) gave 25

(0.769 g, 79%) as an amorphous white solid. R_fϭ 0.58 (cyclohex-

ane/EtOAc, 3:2). [α]_Dϭ ϩ154.7 (c ϭ 1, CHCl₃). ¹H NMR

(CDCl₃): δ ϭ 1.29 (d, J_5Ј,6Јϭ 5.9 Hz, 3 H, H-6Ј), 4.23 (dd, J_5a,5bϭ

13.4, J_4,5aϭ 1.8 Hz, 1 H, H-5a), 4.24 (m, 1 H, H-5Ј), 4.33 (br. d,

EtOAc, 9:1). [α]_Dϭ ϩ90.3 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ J ϭ 12.8 Hz, 1 H, H-5b), 4.69 (dd, J_2,3ϭ 10.3, J_3,4ϭ 3.5 Hz, 1 H,

1.41 (d, J_5Ј,6Јϭ 6.2 Hz, 3 H, H-6Ј), 3.82 (dd, J_5a,5bϭ 11.8, J_4,5aH-3), 5.41 (d, J_1Ј,2Јϭ 1.5 Hz, 1 H, H-1Ј), 5.50 (dd, J_2Ј,3Јϭ 3.1,

ϭ

1596

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1588Ϫ1603

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

J_1Ј,2Јϭ 1.7 Hz, 1 H, H-2Ј), 5.59 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 9.9 Hz, 1 H, H- to give a crude residue (2 g), which was dissolved in CH₂Cl₂

4Ј), 5.65 (dd, J_3Ј,4Јϭ 10.0, J_2Ј,3Јϭ 3.2 Hz, 1 H, H-3Ј), 5.73 (m, 1 (40 mL). Trichloroacetonitrile (1.6 mL, 16.0 mmol, 5 equiv.) and

H, H-4), 5.84 (dd, J_2,3ϭ 10.3, J_1,2ϭ 3.5 Hz, 1 H, H-2), 6.88 (d, DBU (4 drops) were added. After 4 h, the solvent was evaporated,

J_1,2ϭ 3.5 Hz, 1 H, H-1), 7.23Ϫ7.77 (m, 19 H, Ar-H), 8.00 (d, J ϭ

8.1 Hz, 2 H, Ar-H), 8.12 (d, J ϭ 8.2 Hz, 2 H, Ar-H), 8.30 (d, J ϭ hexane/EtOAc, 19:1 to 6:1) to give the β-trichloroacetimidate

8.2 Hz, 2 H, Ar-H), 8.65 (s, 1 H, NH) ppm. ¹³C NMR (CDCl₃):

(0.5 g, 24%), and the α anomer (1.1 g, 53%). Leaving the reaction

δ ϭ 17.5 (C-6Ј), 63.0 (C-5), 67.6 (C-5Ј), 69.3 (C-3Ј), 69.8 (C-2), 70.4 overnight gave exclusively the thermodynamically more stable β-

and the crude residue purified by column chromatography (cyclo-

(C-2Ј), 71.2 (C-4), 71.4 (C-4Ј), 73.9 (C-3), 94.3 (C-1), 99.6 (C-1Ј),

128.1 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 128.9

(C), 129.0 (C), 129.1 (C), 129.4 (C), 129.5 (CH), 129.6 (CH), 129.8

(CH), 129.9 (CH), 130.0 (CH), 132.9 (CH), 133.2 (CH), 133.4

(CH), 133.6 (CH), 160.6 (CϭNH), 164.8 (CO), 165.1 (CO), 165.5

(CO), 165.8 (CO), 166.3 (CO) ppm. ESI-MS: m/z ϭ 984 [M ϩ

Na]^ϩ. C₄₈H₄₀Cl₃NO₁₄(961.20): calcd. C 59.98, H 4.19, N 1.46;

found C 60.34, H 4.29, N 1.24.

trichloroacetimidate.

2,3,4-Tri-O-benzoyl-β-L

-arabinopyranosyl Trichloroacetimidate-⁴C₁:

R_fϭ 0.65 (cyclohexane/EtOAc, 6:4). [α]_Dϭ ϩ183.0 (c ϭ 1,

CHCl₃). ¹H NMR (CDCl₃): δ ϭ 4.22 (dd, J_5a,5bϭ 13.3, J_5a,4

ϭ

1.9 Hz, 1 H, H-5a), 4.46 (br. d, J_5a,5bϭ 13.3 Hz, 1 H, H-5b), 5.92

(m, 1 H, H-4), 6.04 (dd, J_2,3ϭ 10.7, J_2,1ϭ 3.2 Hz, 1 H, H-2), 6.07

(dd, J_3,2ϭ 10.7, J_3,4ϭ 3.1 Hz, 1 H, H-3), 6.86 (d, J_1,2ϭ 3.0 Hz, 1

H, H-1), 7.32 (m, 3 H, Ar-H), 7.41 (m, 2 H, Ar-H), 7.54 (m, 3 H,

Ar-H), 7.67 (m, 1 H, Ar-H), 7.89 (d, J ϭ 8.1 Hz, 2 H, Ar-H), 8.00

(d, J ϭ 8.1 Hz, 2 H, Ar-H), 8.13 (d, J ϭ 8.0 Hz, 2 H, Ar-H), 8.68

(s, 1 H, NH) ppm. ¹³C NMR (CDCl₃): δ ϭ 63.1 (C-5), 67.9 (C-2),

67.9 (C-3), 69.4 (C-4), 94.3 (C-1), 128.3 (CH), 128.4 (CH), 128.6

(CH), 128.7 (C), 128.9 (C), 129.3 (C), 129.7 (CH), 129.8 (CH),

129.9 (CH), 133.3 (CH), 133.5 (CH), 133.5 (CH), 160.7 (CϭNH),

165.5 (CO), 165.6 (CO) ppm. C₂₈H₂₂Cl₃NO₈(606.84): calcd. C

55.42, H 3.65, N 2.31; found C 55.41, H 3.65, N 2.31.

(2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl)-(1Ǟ4)-2,3-di-O-ben-

zoyl-β- -arabinopyranosyl Trichloroacetimidate (26): This com-

L

pound was prepared from disaccharide 23 (0.979 g, 1.05 mmol) in

the same manner as that described for compound 24. Purification

by column chromatography (cyclohexane/EtOAc, 9:1 to 6:1) gave

26 (0.694 g, 69%) as an amorphous white solid. R_fϭ 0.60 (cyclo-

hexane/EtOAc, 6:4). [α]_Dϭ ϩ176.1 (c ϭ 1, CHCl₃). ¹H NMR

(CDCl₃): δ ϭ 1.40 (d, J_5Ј,6Јϭ 6.2 Hz, 3 H, H-6Ј), 4.22 (dd, J_5a,5bϭ

13.0, J_4,5aϭ 1.8 Hz, 1 H, H-5a), 4. 34 (d, J_5a,5bϭ 12.8 Hz, 1 H,

2,3,4-Tri-O-benzoyl-α-L

-arabinopyranosyl Trichloroacetimidate-¹C₄:

H-5b), 4.48 (m, 1 H, H-5Ј), 4.52 (m, 1 H, H-4), 5.30 (d, J_1Ј,2Ј

1.5 Hz, 1 H, H-1Ј), 5.75 (t, J_3Ј,4Јϭ J_4Ј,5Јϭ 10.0 Hz, 1 H, H-4Ј),

5.85 (dd, J_2Ј,3Јϭ 3.2, J_1Ј,2Јϭ 1.7 Hz, 1 H, H-2Ј), 5.97 (dd, J_2,3

ϭ

R_fϭ 0.59 (cyclohexane/EtOAc, 6:4). [α]_Dϭ ϩ74.1 (c ϭ 1, CHCl₃).

¹H NMR (CDCl₃): δ ϭ 4.14 (dd, J_5a,5bϭ 11.9, J_4,5aϭ 3.7 Hz, 1

H, H-5a) 4.50 (dd, J_5a,5bϭ 12.0, J_4,5bϭ 7.6 Hz, 1 H, H-5b), 5.80

(m, 1 H, H-4), 5.84 (m, 2 H, H-2, H-3), 6.36 (s, 1 H, H-1), 7.47

(m, 6 H, Ar-H), 7.59 (m, 3 H, Ar-H), 8.00 (m, 2 H, Ar-H), 8.13

(m, 4 H, Ar-H), 8.82 (s, 1 H, NH) ppm. ¹³C NMR (CDCl₃): δ ϭ

60.8 (C-5), 66.5 (C-4), 68.5 (C-3), 68.9 (C-2), 94.7 (C-1), 128.4

(CH), 128.4 (CH), 128.5 (CH), 128.7 (C), 129.0 (C), 129.1 (C),

129.9 (CH), 130.1 (CH), 133.5 (CH), 133.7 (CH), 160.8 (CϭNH),

164.8 (CO), 165.4 (CO).

ϭ

10.5, J_1,2ϭ 3.2 Hz, 1 H, H-2), 5.99 (dd, J_3Ј,4Јϭ 9.8, J_2Ј,3Јϭ 3.1 Hz,

1 H, H-3Ј), 6.01 (dd, J_3,2ϭ 10.6, J_3,4ϭ 3.0 Hz, 1 H, H-3), 6.92 (d,

J_1,2ϭ 3.2 Hz, 1 H, H-1), 7.29Ϫ7.66 (m, 15 H, Ar-H), 7.90 (m, 2

H, Ar-H), 8.03Ϫ8.17 (m, 8 H, Ar-H), 8.66 (s, 1 H, NH) ppm. ¹³C

NMR (CDCl₃): δ ϭ 17.6 (C-6Ј), 64.1 (C-5), 67.6 (C-5Ј), 68.3 (C-

2), 68.7 (C-3), 69.8 (C-3Ј), 70.6 (C-2Ј), 71.5 (C-4Ј), 76.0 (C-4), 94.3

(C-1), 99.7 (C-1Ј), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH),

128.9 (C), 129.1 (C), 129.2 (C), 129.7 (CH), 129.8 (CH), 129.9

(CH), 130.0 (CH), 133.0 (CH), 133.4 (CH), 133.5 (CH), 160.9 (Cϭ

NH), 165.2 (CO), 165.3 (CO), 165.5 (CO), 165.9 (CO) ppm. ESI-

MS: m/z ϭ 1007 [M ϩ 2Na]^ϩ. C₄₈H₄₀Cl₃NO₁₄(961.20): calcd. C

59.98, H 4.19, N 1.46; found C 60.18, H 3.93, N 1.77.

Methyl 23-O-Benzoylhederagenate (29): Benzoyl chloride (0.79 mL,

6.8 mmol, 1.4 equiv.) was slowly added to a mixture of methyl hed-

eragenate 28 (2.38 g, 4.9 mmol) in pyridine (50 mL, 618 mmol, 127

equiv.) and CH₂Cl₂(80 mL) at room temperature. After stirring for

1 h the reaction mixture was quenched by the addition of methanol.

Further CH₂Cl₂(120 mL) was added and the organic layer was

washed with 1  HCl (150 mL), satd. NaHCO₃(150 mL), and satd.

NaCl (150 mL). The dried solution (Na₂SO₄) was then evaporated

2,3,4-Tri-O-benzoyl-L-arabinopyranosyl Trichloroacetimidate (27):

Benzoyl chloride (7.5 mL, 64.6 mmol, 6.5 equiv.) was added to a

solution of -arabinose (1.5 g, 10 mmol) in pyridine (23 mL) at 0

°C. The reaction mixture was left to stir at room temp. overnight under reduced pressure and the crude residue purified by column

and was then quenched by addition of MeOH. Toluene was added

and the solvent evaporated under reduced pressure (3 ϫ). The

crude residue was taken up in EtOAc (100 mL) and washed with 1

chromatography (cyclohexane/EtOAc, 99:1 to 7:1) to give 29 (2.1 g,

71%) as a white solid. R_fϭ 0.58 (cyclohexane/EtOAc, 6:4). M.p.

99 °C. [α]_Dϭ ϩ18.5 (c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 0.76

1

 HCl (30 mL), satd. NaHCO₃(30 mL), and H₂O (30 mL). The (s, 3 H, H-26), 0.87 (s, 3 H, H-24), 0.91 (s, 3 H, H-29), 0.94 (s, 3

dried solution (Na₂SO₄) was then evaporated under reduced press- H, H-30), 0.99 (s, 3 H, H-25), 1.00Ϫ2.05 (m, 22 H), 1.12 (s, 3 H,

ure to give a crude solid, which was used without purification in H-27), 2.88 (dd, J ϭ 13.8, 4.0 Hz, 1 H, H-18), 3.51 (dd, J ϭ 11.2,

the next step. A solution of 33% HBr in AcOH (5 mL) was added

to the perbenzoylated arabinose derivative (1.8 g, 3.18 mmol) in

CH₂Cl₂(4.8 mL) at room temp. After stirring overnight, the mix-

5.6 Hz, 1 H, H-3), 3.65 (s, 3 H, OCH₃) 4.02 (d, J ϭ 11.5 Hz, 1 H,

H-23a), 4.54 (d, J ϭ 11.5 Hz, 1 H, H-23b), 5.31 (m, 1 H, H-12),

7.47 (t, J ϭ 7.9 Hz, 2 H, Ar-H), 7.60 (t, J ϭ 7.4 Hz, 1 H, Ar-H),

ture was diluted with CH₂Cl₂(150 mL) and then poured into H₂O 8.06 (dd, J ϭ 8.3, 1.2 Hz, 2 H, Ar-H) ppm. ¹³C NMR (CDCl₃):

(100 mL). The organic layer was washed with H₂O (100 mL), satd.

NaHCO₃(100 mL), and satd. NaCl (100 mL). The dried solution

(Na₂SO₄) was then evaporated under reduced pressure, and the

crude residue obtained was taken up in acetone (29 mL) and H₂O

(3.7 mL). Sodium iodide was added (0.05 g, 0.3 mmol), and the re-

action mixture was stirred for 24 h. The reaction mixture was di-

luted with EtOAc and the organic layer was washed with H₂O

δ ϭ 12.0 (C-24), 15.8 (C-25), 16.8 (C-26), 18.2 (C-6), 23.0 (C-16),

23.3 (C-11), 23.6 (C-30), 25.6 (C-27), 26.1 (C-2), 27.6 (C-15), 30.6

(C-20), 32.3 (C-22), 32.4 (C-7), 33.1 (C-29), 33.8 (C-21), 36.8 (C-

10), 38.4 (C-1), 39.2 (C-8), 41.3 (C-18), 41.5 (C-14), 42.5 (C-4), 45.8

(C-19), 46.7 (C-17), 48.0 (C-9), 48.2 (C-5), 51.5 (OCH₃), 66.7 (C-

23), 72.3 (C-3), 122.2 (C-12), 128.5 (CH), 129.5 (CH), 130.1 (C),

133.1 (CH), 143.7 (C-13), 166.8 (CO), 178.2 (C-28) ppm.

(100 mL), 10% Na₂S₂O₃(100 mL), satd. NaHCO₃(100 mL), and C₃₈H₅₄O₅·0.5H₂O (599.85): calcd. C 76.09, H 9.24; found C 76.00,

H₂O (100 mL). The dried solution (Na₂SO₄) was then evaporated H 9.13.

Eur. J. Org. Chem. 2004, 1588Ϫ1603

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1597

´

K. Ple, M. Chwalek, L. Voutquenne-Nazabadioko

FULL PAPER

Methyl 3-O-[2,3,4-Tri-O-benzoyl-α-

3,4-di-O-benzoyl-β-L-arabinopyranosyl]-23-O-benzoylhederagenate

(30): Acceptor 29 (0.070 g, 0.12 mmol), trichloroacetimidate 24

(0.17 g, 0.18 mmol, 1.5 equiv.), and powdered 4 A molecular sieves

L

-rhamnopyranosyl-(1Ǟ2)-

3ЈЈ), 70.6 (C-2ЈЈ, C-3Ј), 71.8 (C-4ЈЈ), 75.1 (C-2Ј), 82.2 (C-3), 98.5

(C-1ЈЈ), 102.4 (C-1Ј), 122.2 (C-12), 128.0 (CH), 128.2 (CH), 128.3

(CH), 128.4 (CH), 128.5 (CH), 129.1 (C), 129.2 (C), 129.4 (C),

129.4 (CH), 129.5 (C), 129.6 (CH), 129.8 (CH), 129.9 (CH), 130.3

˚

(0.650 g) were stirred for 1 h at room temperature in CH₂Cl₂(C), 132.8 (CH), 132.9 (CH), 133.0 (CH), 133.2 (CH), 133.3 (CH),

(3 mL). The mixture was cooled to Ϫ20 °C for 30 min followed by

the dropwise addition of a 0.1  solution of TMSOTf in CH₂Cl₂

(0.060 mL, 0.006 mmol, 0.05 equiv.). After 1 h the reaction mixture

143.7 (C-13), 164.8 (CO), 165.3 (CO), 165.4 (CO), 165.5 (CO),

165.8 (CO), 165.9 (CO), 178.2 (C-28) ppm. ESI-MS: m/z ϭ 1411

[M ϩ Na]^ϩ. C₈₄H₉₂O₁₈(1388.63): calcd. C 72.60, H 6.67; found C

was quenched with triethylamine, filtered through Celite, and the 72.51, H 6.96.

solvents were evaporated. Purification by column chromatography

Methyl 3-O-[2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl-(1Ǟ2)-

(toluene/EtOAc, 99:1 to 32:1) gave a mixture of α and β anomers,

which were then separated by HPLC (100% acetonitrile) to give the

β anomer 30 (0.134 g, 81%) and the α anomer 31 (0.013 g, 8%).

3,4-di-O-benzoyl-α- -arabinopyranosyl]-23-O-benzoylhederagenate

(31): Acceptor 29 (0.1 g, 0.17 mmol), trichloroacetimidate 24

(0.33 g, 0.34 mmol, 2.0 equiv.), and powdered 4-A molecular sieves

L

˚

(0.7 g) were stirred for 1 h at room temperature in dry propionitrile

(2.4 mL). The mixture was cooled to Ϫ78 °C for 30 min followed

by the rapid addition of a 0.1  solution of TMSOTf in propionitr-

ile (0.510 mL, 0.05 mmol, 0.3 equiv.). The reaction mixture was

stirred at this temperature until TLC indicated the disappearance of

the acceptor. Triethylamine was added and the mixture was filtered

through Celite and the solvents evaporated. The crude residue was

purified by column chromatography (toluene/EtOAc, 99:1 to 39:1)

to give a mixture of anomeric products, which were then separated

by HPLC (100% acetonitrile) to give the desired saponoside 31

(0.17 g, 72%), as a white foam, and the β anomer 30 (0.05 g, 21%),

which were previously described above.

Compound 30 (β anomer): R_fϭ 0.46 (toluene/EtOAc, 9:1). [α]_D

ϭ

1

ϩ151.3 (c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 0.81 (s, 3 H, H-

26), 0.93 (s, 3 H, H-29), 0.96 (s, 3 H, H-30), 1.00Ϫ2.10 (m, 22 H),

1.08 (s, 3 H, H-27), 1.10 (s, 3 H, H-25), 1.17 (s, 3 H, H-24), 1.38

(d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 2.91 (dd, J ϭ 13.7, 3.8 Hz, 1 H,

H-18), 3.68 (s, 3 H, OCH₃), 3.87 (d, J_5Јa,5Јbϭ 11.7 Hz, 1 H, H-5Јa),

3.97 (dd, J ϭ 11.2, 3.8 Hz, 1 H, H-3), 4.21 (d, J_5Јa,5Јbϭ 11.8 Hz, 1

H, H-5Јb), 4.36 (m, 1 H, H-5ЈЈ), 4.48 (s, 2 H, H-23), 4.53 (dd,

J_2Ј,3Јϭ 10.4, J_1Ј,2Јϭ 3.6 Hz, 1 H, H-2Ј), 5.34 (m, 1 H, H-12), 5.39

(s, 1 H, H-1ЈЈ), 5.41 (d, J_1Ј,2Јϭ 3.7 Hz, 1 H, H-1Ј), 5.53 (dd,

J_2ЈЈ,3ЈЈϭ 3.1, J_1ЈЈ,2ЈЈϭ 1.9 Hz, 1 H, H-2ЈЈ), 5.67 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈ

ϭ

9.9 Hz, 1 H, H-4ЈЈ), 5.74 (dd, J_2Ј,3Јϭ 10.4, J_3Ј,4Јϭ 3.3 Hz, 1 H, H-

3Ј), 5.83 (m, 1 H, H-4Ј), 5.90 (dd, J_3ЈЈ,4ЈЈϭ 10.0, J_2ЈЈ,3ЈЈϭ 3.3 Hz,

1 H, H-3ЈЈ), 7.20Ϫ8.10 (m, 30 H, Ar-H) ppm. ¹³C NMR (CDCl₃):

δ ϭ 13.2 (C-24), 15.7 (C-25), 16.9 (C-26), 17.7 (C-6ЈЈ), 18.1 (C-6),

21.4 (C-2), 23.0 (C-16), 23.5 (C-11), 23.6 (C-30), 25.4 (C-27), 27.6

(C-15), 30.7 (C-20), 32.3 (C-22), 32.4 (C-7), 33.1 (C-29), 33.8 (C-

21), 36.8 (C-10), 38.1 (C-1), 39.3 (C-8), 41.4 (C-18), 41.6 (C-14),

42.3 (C-4), 45.8 (C-19), 46.7 (C-17), 48.1 (C-9), 48.3 (C-5), 51.5

(OCH₃), 60.9 (C-5Ј), 65.7 (C-23), 67.3 (C-5ЈЈ), 69.0 (C-3ЈЈ), 70.2

(C-3Ј), 70.3 (C-4Ј), 70.7 (C-2ЈЈ), 71.9 (C-4ЈЈ), 73.9 (C-2Ј), 76.4 (C-

3), 94.6 (C-1Ј), 98.8 (C-1ЈЈ), 122.1 (C-12), 128.1 (CH), 128.2 (CH),

128.4 (CH), 128.5 (CH), 129.1 (C), 129.2 (C), 129.4 (C), 129.4

(CH), 129.6 (CH), 129.7 (CH), 129.8 (CH), 129.9 (CH), 130.3 (C),

132.9 (CH), 133.0 (CH), 133.2 (CH), 133.4 (CH), 143.9 (C-13),

164.9 (CO), 165.0 (CO), 165.6 (CO), 165.7 (CO), 166.0 (CO), 178.2

(C-28) ppm. ESI-MS: m/z ϭ 1411 [M ϩ Na]^ϩ. C₈₄H₉₂O₁₈

(1388.63): calcd. C 72.60, H 6.67; found C 72.43, H 6.75.

Methyl 3-O-[2,3,4-Tri-O-benzoyl-α-

L-rhamnopyranosyl-(1Ǟ3)-

2,4-di-O-benzoyl-α- -arabinopyranosyl]-23-O-benzoylhederagenate

L

(32): This compound was prepared from acceptor 29 (0.08 g,

0.14 mmol) and trichloroacetimidate 25 (0.20 g, 0.21 mmol, 1.5

equiv.) in the same manner as that described for 30. Purification

by column chromatography (toluene/EtOAc, 99:1 to 32:1) gave the

protected saponoside 32 (0.178 g, 94%) as a white foam. R_fϭ 0.50

(toluene/EtOAc, 9:1). [α]_Dϭ ϩ100.0 (c ϭ 1, CHCl₃). ¹H NMR

(CDCl₃): δ ϭ 0.73 (s, 3 H, H-26), 0.81 (s, 3 H, H-24), 0.92 (s, 3 H,

H-29), 0.94 (s, 3 H, H-30), 1.00Ϫ2.10 (m, 22 H), 1.02 (s, 3 H, H-

25), 1.04 (s, 3 H, H-27), 1.08 (d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 2.87

(dd, J ϭ 13.8, 3.9 Hz, 1 H, H-18), 3.64 (s, 3 H, OCH₃), 3.66 (dd,

J ϭ 11.5, 4.9 Hz, 1 H, H-3), 3.77 (dd, J_5Јa,5Јbϭ 12.3, J_4Ј,5Јa

ϭ

2.3 Hz, 1 H, H-5Јa), 4.06 (d, J ϭ 11.6 Hz, 1 H, H-23a), 4.19 (d,

J ϭ 11.6 Hz, 1 H, H-23b), 4.21 (m, 1 H, H-5ЈЈ), 4.37 (m, 1 H, H-

3Ј), 4.45 (dd, J_5Јa,5Јbϭ 12.2, J_4Ј,5Јbϭ 5.2 Hz, 1 H, H-5Јb), 4.82 (d,

J_1Ј,2Јϭ 4.8 Hz, 1 H, H-1Ј), 5.31 (m, 2 H, H-1ЈЈ, H-12), 5.55 (m, 3

H, H-2ЈЈ, H-4ЈЈ, H-4Ј), 5.65 (t, J_1Ј,2Јϭ J_2Ј,3Јϭ 4.2 Hz, 1 H, H-2Ј),

5.75 (dd, J_3ЈЈ,4ЈЈϭ 10.0, J_2ЈЈ,3ЈЈϭ 2.7 Hz, 1 H, H-3ЈЈ), 7.26Ϫ8.24

(m, 30 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 12.8 (C-24), 15.4

(C-25), 16.8 (C-26), 17.2 (C-6ЈЈ), 18.0 (C-6), 22.9 (C-16), 23.4 (C-

11), 23.6 (C-30), 25.3 (C-2), 25.4 (C-27), 27.5 (C-15), 30.6 (C-20),

32.3 (C-7, C-22), 33.1 (C-29), 33.8 (C-21), 36.5 (C-10), 38.4 (C-1),

39.2 (C-8), 41.3 (C-18), 41.5 (C-14), 42.2 (C-4), 45.8 (C-19), 46.7

(C-17), 48.0 (C-9), 48.1 (C-5), 51.5 (OCH₃), 61.2 (C-5Ј), 65.5 (C-

23), 67.3 (C-5ЈЈ), 69.6 (C-3ЈЈ, C-2ЈЈ), 70.5 (C-2Ј, C-4Ј), 71.4 (C-4ЈЈ),

75.2 (C-3Ј), 82.4 (C-3), 98.0 (C-1ЈЈ), 102.2 (C-1Ј), 122.3 (C-12),

128.2 (CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 129.1 (C), 129.2

(C), 129.3 (C), 129.4 (CH), 129.5 (C), 129.6 (CH), 129.8 (CH),

129.9 (CH), 130.0 (CH), 130.4 (C), 132.8 (CH), 132.9 (CH), 133.2

(CH), 133.3 (CH), 133.4 (CH), 143.7 (C-13), 165.0 (CO), 165.2

(CO), 165.5 (CO), 165.8 (CO), 166.1 (CO), 178.2 (C-28) ppm. ESI-

MS: m/z ϭ 1411 [M ϩ Na]^ϩ. C₈₄H₉₂O₁₈(1388.63): calcd. C 72.60,

H 6.67; found C 72.53, H 6.70.

Compound 31 (α anomer): R_fϭ 0.58 (toluene/EtOAc, 9:1). [α]_D

ϭ

ϩ90.6 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 0.76 (s, 3 H, H-26),

0.81 (s, 3 H, H-24), 0.90Ϫ2.10 (m, 22 H), 0.93 (s, 3 H, H-29), 0.96

(s, 3 H, H-30), 1.00 (s, 3 H, H-25), 1.09 (s, 3 H, H-27), 1.28 (d,

J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 2.89 (dd, J ϭ 13.7, 3.7 Hz, 1 H, H-

18), 3.65 (s, 3 H, OCH₃), 3.70 (dd, J ϭ 11.6, 4.4 Hz, 1 H, H-3),

3.86 (dd, J_5Јa,5Јbϭ 11.8, J_4Ј,5Јaϭ 2.7 Hz, 1 H, H-5Јa), 4.15 (d, J ϭ

11.4 Hz, 1 H, H-23a), 4.30 (dd, J_5Јa,5Јbϭ 11.8, J_4Ј,5Јbϭ 6.3 Hz, 1

H, H-5Јb), 4.37 (dd, J_2Ј,3Јϭ 6.3, J_1Ј,2Јϭ 4.5 Hz, 1 H, H-2Ј), 4.42

(d, J ϭ 11.7 Hz, 1 H, H-23b), 4.47 (m, 1 H, H-5ЈЈ), 4.90 (d, J_1Ј,2Ј

4.1 Hz, 1 H, H-1Ј), 5.33 (m, 1 H, H-12), 5.41 (s, 1 H, H-1ЈЈ), 5.59

(dd, J_2Ј,3Јϭ 6.6, J_3Ј,4Јϭ 3.2 Hz, 1 H, H-3Ј), 5.64 (t, J_4ЈЈ,5ЈЈ

J_3ЈЈ,4ЈЈϭ 10.0 Hz, 1 H, H-4ЈЈ), 5.66 (m, 1 H, H-4Ј), 5.75 (m, 1 H,

H-2ЈЈ), 5.87 (dd, J_3ЈЈ,4ЈЈϭ 10.2, J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-3ЈЈ),

7.15Ϫ7.71 (m, 18 H, Ar-H), 7.90Ϫ8.15 (m, 12 H, Ar-H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 12.8 (C-24), 15.7 (C-25), 16.8 (C-26), 17.5 (C-

6ЈЈ), 18.0 (C-6), 22.9 (C-16), 23.4 (C-11), 23.6 (C-30), 25.4 (C-27),

25.5 (C-2), 27.5 (C-15), 30.6 (C-20), 32.3 (C-22, C-7), 33.1 (C-29),

ϭ

33.8 (C-21), 36.5 (C-10), 38.5 (C-1), 39.2 (C-8), 41.3 (C-18), 41.5 Methyl 3-O-[2,3,4-Tri-O-benzoyl-α-

(C-14), 42.4 (C-4), 45.7 (C-19), 46.7 (C-17), 48.0 (C-9), 48.1 (C-5), 2,3-di-O-benzoyl-α- -arabinopyranosyl]-23-O-benzoylhederagenate

51.5 (OCH₃), 60.4 (C-5Ј), 65.4 (C-23), 67.7 (C-4Ј, C-5ЈЈ), 69.1 (C- (33): This compound was prepared from acceptor 29 (0.080 g,

L-rhamnopyranosyl-(1Ǟ4)-

L

1598

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1588Ϫ1603

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

0.14 mmol) and trichloroacetimidate 26 (0.20 g, 0.21 mmol, 1.5

equiv.) in the same manner as that described for 30. Purification

by column chromatography (toluene/EtOAc, 99:1 to 32:1) gave the

protected saponoside 33 (0.170 g, 90%) as a white foam. R_fϭ 0.50

(toluene/EtOAc, 9:1). [α]_Dϭ ϩ113.1 (c ϭ 1, CHCl₃). ¹H NMR

Methyl 3-O-(α-

L

-Arabinopyranosyl)hederagenate (4): Saponoside 34

(0.291 g, 0.28 mmol) was treated with a solution of 3% KOH in

MeOH (29 mL). The reaction mixture was stirred for 48 h before

being neutralized with Amberlite IR 120 (H^ϩform) and filtered,

and then the solvents were evaporated. The crude residue was puri-

(CDCl₃): δ ϭ 0.73 (s, 3 H, H-26), 0.75 (s, 3 H, H-24), 0.83Ϫ2.05 fied by column chromatography (CH₂Cl₂/MeOH, 39:1) to give the

(m, 22 H), 0.92 (s, 3 H, H-29), 0.94 (s, 3 H, H-30), 1.00 (s, 3 H, H- deprotected saponoside 4 (0.162 g, 93%) as an amorphous solid.

1

25), 1.03 (s, 3 H, H-27), 1.38 (d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 2.87 [α]_Dϭ ϩ42.6 (c ϭ 1, CH₃OH). H NMR (CD₃OD): δ ϭ 0.73 (s,

(dd, J ϭ 13.7, 3.9 Hz, 1 H, H-18), 3.64 (s, 3 H, OCH₃), 3.68 (dd,

J ϭ 11.3, 4.9 Hz, 1 H, H-3), 3.74 (br. d, J_5Јa,5Јbϭ 11.2 Hz, 1 H, H- H-29), 0.96 (s, 3 H, H-30), 1.00 (s, 3 H, H-25), 1.20 (s, 3 H, H-27),

5Јa), 4.03 (d, J ϭ 11.5 Hz, 1 H, H-23a), 4.10 (d, J ϭ 11.5 Hz, 1 H, 2.89 (dd, J ϭ 13.8, 4.1 Hz, 1 H, H-18), 3.31 (d, J ϭ 11.8 Hz, 1 H,

3 H, H-24), 0.77 (s, 3 H, H-26), 0.80Ϫ2.30 (m, 22 H), 0.93 (s, 3 H,

H-23b), 4.32 (dd, J_5Јa,5Јbϭ 12.5, J_4Ј,5Јbϭ 4.5 Hz, 1 H, H-5Јb), 4.38 H-23a), 3.51 (dd, J_2Ј,3Јϭ 9.0, J_3Ј,4Јϭ 3.3 Hz, 1 H, H-3Ј), 3.55 (dd,

(m, 1 H, H-4Ј), 4.41 (m, 1 H, H-5ЈЈ), 4.82 (d, J_1Ј,2Јϭ 5.9 Hz, 1 H, J_2Ј,3Јϭ 8.9, J_1Ј,2Јϭ 6.8 Hz, 1 H, H-2Ј), 3.56 (dd, J_5Јa,5Јbϭ 12.2,

H-1Ј), 5.19 (s, 1 H, H-1ЈЈ), 5.31 (m, 1 H, H-12), 5.54 (dd, J_2Ј,3Ј

8.3, J_3Ј,4Јϭ 3.2 Hz, 1 H, H-3Ј), 5.67 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 10.0 Hz,

ϭ

J_4Ј,5Јaϭ 1.3 Hz, 1 H, H-5Јa), 3.62 (d, J ϭ 11.8 Hz, 1 H, H-23b),

3.63 (dd, J ϭ 11.8, 5.5 Hz, 1 H, H-3), 3.64 (s, 3 H, OCH₃), 3.82

1 H, H-4ЈЈ), 5.74 (m, 2 H, H-2ЈЈ, H-2Ј), 5.92 (dd, J_3ЈЈ,4ЈЈϭ 10.1, (m, 1 H, H-4Ј), 3.86 (dd, J_5Јa,5Јbϭ 12.5, J_4Ј,5Јbϭ 2.9 Hz, 1 H, H-

J_2ЈЈ,3ЈЈϭ 3.4 Hz, 1 H, H-3ЈЈ), 7.20Ϫ8.15 (m, 30 H, Ar-H) ppm. ¹³

5Јb), 4.33 (d, J_1Ј,2Јϭ 6.6 Hz, 1 H, H-1Ј), 5.27 (m, 1 H, H-12) ppm.

NMR (CDCl₃): δ ϭ 12.7 (C-24), 15.6 (C-25), 16.8 (C-26), 17.6 (C- ¹³C NMR (CD₃OD): δ ϭ 12.0 (C-24), 14.9 (C-25), 16.2 (C-26),

6ЈЈ), 18.0 (C-6), 22.9 (C-16), 23.4 (C-11), 23.6 (C-30), 25.4 (C-2, C- 17.4 (C-6), 22.5 (C-30), 22.6 (C-16), 23.1 (C-11), 24.9 (C-2), 25.1

27), 27.5 (C-15), 30.6 (C-20), 32.3 (C-7, C-22), 33.1 (C-29), 33.8 (C-27), 27.3 (C-15), 30.1 (C-20), 31.9 (C-7), 32.1 (C-29, C-22), 33.3

(C-21), 36.5 (C-10), 38.3 (C-1), 39.2 (C-8), 41.3 (C-18), 41.5 (C-14), (C-21), 36.2 (C-10), 38.0 (C-1), 39.1 (C-8), 41.3 (C-18), 41.4 (C-14),

C

42.2 (C-4), 45.8 (C-19), 46.7 (C-17), 48.0 (C-9), 48.1 (C-5), 51.5 42.4 (C-4), 45.6 (C-19), 46.6 (C-5, C-17), 47.5 (C-9), 50.8 (OCH₃),

(OCH₃), 63.2 (C-5Ј), 65.4 (C-23), 67.4 (C-5ЈЈ), 69.7 (C-3ЈЈ), 70.4 63.3 (C-23), 65.4 (C-5Ј), 68.3 (C-4Ј), 71.5 (C-2Ј), 73.0 (C-3Ј), 81.8

(C-2Ј), 70.7 (C-2ЈЈ), 71.0 (C-3Ј), 71.7 (C-4ЈЈ), 73.2 (C-4Ј), 82.4 (C- (C-3), 104.9 (C-1Ј), 122.3 (C-12), 143.6 (C-13), 178.6 (C-28) ppm.

3), 98.2 (C-1ЈЈ), 102.3 (C-1Ј), 122.2 (C-12), 128.2 (CH), 128.3 (CH), ESI-MS: m/z ϭ 620 [M ϩ 2H]^ϩ. C₃₆H₅₈O₈·1.1H₂O (638.67): calcd.

128.4 (CH), 129.0 (C), 129.2 (C), 129.3 (C), 129.4 (CH), 129.6 C 67.70, H 9.50; found C 67.67, H 9.56.

(CH), 129.8 (CH), 130.1 (CH), 130.4 (C), 132.8 (CH), 132.9 (CH),

Methyl 3-O-[α-L-Rhamnopyranosyl-(1Ǟ2)-α-L-arabinopyranosyl]-

133.1 (CH), 133.3 (CH), 143.7 (C-13), 164.9 (CO), 165.1 (CO),

165.7 (CO), 165.8 (CO), 178.2 (C-28) ppm. ESI-MS: m/z ϭ 1411

[M ϩ Na]^ϩ. C₈₄H₉₂O₁₈·0.4CH₃OH (1402.46): calcd. C 72.28, H

6.73; found C 72.09, H 6.54.

hederagenate (2): This compound was prepared from saponoside

31 (0.475 g, 0.34 mmol) in the same manner as that described for

4. Purification by column chromatography (CH₂Cl₂/MeOH, 49:1

to 19:1) gave the α-hederin methyl ester 2 (0.196 g, 75%) as an

1

Methyl 3-O-(2,3,4-Tri-O-benzoyl-α-L-arabinopyranosyl)-23-O-ben-

amorphous white solid. [α]_Dϭ ϩ13.7 (c ϭ 1, CH₃OH). H NMR

zoylhederagenate (34): This compound was prepared from acceptor

29 (0.3 g, 0.51 mmol) and trichloroacetimidate 27 (0.46 g,

0.76 mmol, 1.5 equiv.) in the same manner as that described for 30.

The crude residue was purified by column chromatography (tolu-

ene/EtOAc, 99:1 to 24:1) to give saponoside 34 (0.391 g, 74%) as a

white foam. R_fϭ 0.55 (toluene/EtOAc, 9:1). [α]_Dϭ ϩ129.7 (c ϭ

(CD₃OD): δ ϭ 0.72 (s, 3 H, H-24), 0.77 (s, 3 H, H-26), 0.93 (s, 3

H, H-29), 0.96 (s, 3 H, H-30), 1.00 (s, 3 H, H-25), 1.00Ϫ2.10 (m,

22 H), 1.20 (s, 3 H, H-27), 1.26 (d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ),

2.89 (dd, J ϭ 13.2, 3.7 Hz, 1 H, H-18), 3.37 (d, J ϭ 11.2 Hz, 1 H,

H-23a), 3.40 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.5 Hz, 1 H, H-4ЈЈ), 3.51 (d, J ϭ

11.2 Hz, 1 H, H-23b), 3.52 (dd, J_5Јa,5Јbϭ 12.0, J_4Ј,5Јaϭ 2.4 Hz, 1

H, H-5Јa), 3.64 (m, 1 H, H-3), 3.64 (s, 3 H, OCH₃), 3.73 (m, 2 H,

H-2Ј, H-3Ј), 3.74 (m, 1 H, H-3ЈЈ), 3.79 (m, 1 H, H-4Ј), 3.86 (dd,

J_5Јa,5Јbϭ 12.0, J_4Ј,5Јbϭ 4.5 Hz, 1 H, H-5Јb), 3.87 (m, 1 H, H-5ЈЈ),

1

1, CHCl₃). H NMR (CDCl₃): δ ϭ 0.69 (s, 3 H, H-24), 0.72 (s, 3

H, H-26), 0.91 (s, 3 H, H-29), 0.94 (s, 3 H, H-30), 0.96 (s, 3 H, H-

25), 1.00Ϫ2.00 (m, 22 H), 1.03 (s, 3 H, H-27), 2.86 (dd, J ϭ 13.6,

3.8 Hz, 1 H, H-18), 3.63 (s, 3 H, OCH₃), 3.67 (dd, J ϭ 11.3, 4.4 Hz,

1 H, H-3), 3.85 (br. d, J ϭ 12.4 Hz, 1 H, H-5Јa), 3.94 (d, J ϭ

11.5 Hz, 1 H, H-23a), 4.10 (d, J ϭ 11.5 Hz, 1 H, H-23b), 4.31 (dd,

3.93 (dd, J_2ЈЈ,3ЈЈϭ 3.1, J_1ЈЈ,2ЈЈϭ 1.5 Hz, 1 H, H-2ЈЈ), 4.57 (d, J_1Ј,2Ј

ϭ

5.2 Hz, 1 H, H-1Ј), 5.18 (s, 1 H, H-1ЈЈ), 5.27 (m, 1 H, H-12) ppm.

¹³C NMR (CD₃OD): δ ϭ 12.3 (C-24), 14.9 (C-25), 16.2 (C-26),

16.5 (C-6ЈЈ), 17.3 (C-6), 22.5 (C-30), 22.6 (C-16), 23.0 (C-11), 25.0

(C-27), 25.1 (C-2), 27.3 (C-15), 30.1 (C-20), 31.8 (C-7), 32.0 (C-29),

32.1 (C-22), 33.3 (C-21), 36.1 (C-10), 38.2 (C-1), 39.0 (C-8), 41.3

(C-18), 41.4 (C-14), 42.5 (C-4), 45.6 (C-19), 46.6 (C-5, C-17), 47.5

(C-9), 50.7 (OCH₃), 63.1 (C-23), 63.4 (C-5Ј), 67.7 (C-4Ј), 68.7 (C-

5ЈЈ), 70.5 (C-2ЈЈ), 70.7 (C-3ЈЈ), 72.2 (C-3Ј), 72.5 (C-4ЈЈ), 75.2 (C-2Ј),

80.7 (C-3), 100.4 (C-1ЈЈ), 102.9 (C-1Ј), 122.3 (C-12), 143.6 (C-13),

J_5Јa,5Јbϭ 13.3, J_4Ј,5Јbϭ 2.9 Hz, 1 H, H-5Јb), 4.81 (d, J_1Ј,2Јϭ 7.0 Hz,

1 H, H-1Ј), 5.30 (m, 1 H, H-12), 5.56 (dd, J_2Ј,3Јϭ 9.5, J_3Ј,4Ј

ϭ

3.5 Hz, 1 H, H-3Ј), 5.68 (m, 1 H, H-4Ј), 5.84 (dd, J_2Ј,3Јϭ 9.4,

J_1Ј,2Јϭ 7.2 Hz, 1 H, H-2Ј), 7.33 (m, 4 H, Ar-H), 7.48 (m, 6 H, Ar-

H), 7.61 (m, 2 H, Ar-H), 7.91 (d, J ϭ 7.4 Hz, 2 H, Ar-H), 8.04 (d,

J ϭ 8.6 Hz, 2 H, Ar-H), 8.06 (d, J ϭ 8.9 Hz, 2 H, Ar-H), 8.10 (d,

J ϭ 7.4 Hz, 2 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 12.6 (C-24),

15.5 (C-25), 16.8 (C-26), 17.9 (C-6), 22.9 (C-16), 23.4 (C-11), 23.6

(C-30), 25.4 (C-2, C-27), 27.5 (C-15), 30.6 (C-20), 32.3 (C-7, C-22),

33.1 (C-29), 33.8 (C-21), 36.4 (C-10), 38.3 (C-1), 39.2 (C-8), 41.3

(C-18), 41.5 (C-14), 42.1 (C-4), 45.7 (C-19), 46.6 (C-17), 47.9 (C-

178.6 (C-28) ppm. ESI-MS: m/z

ϭ

766 [M

ϩ

2H]^ϩ.

C₄₂H₆₈O₁₂·3.3H₂O (824.45): calcd. C 61.19, H 9.12; found C 61.15,

H 8.97.

9), 48.0 (C-5), 51.5 (OCH₃), 63.3 (C-5Ј), 65.2 (C-23), 68.8 (C-4Ј), Methyl 3-O-[α-

70.0 (C-2Ј), 71.1 (C-3Ј), 82.8 (C-3), 102.9 (C-1Ј), 122.2 (C-12), 128.2 hederagenate (6): This compound was prepared from saponoside

(CH), 128.3 (CH), 128.4 (CH), 128.9 (C), 129.0 (C), 129.4 (C), 30 (0.135 g, 0.10 mmol) in the same manner as that described for

L-Rhamnopyranosyl-(1Ǟ2)-β-L-arabinopyranosyl]-

129.4 (CH), 129.8 (CH), 129.9 (CH), 130.3 (C), 132.9 (CH), 133.2 4. Purification by column chromatography (CH₂Cl₂/MeOH, 49:1

(CH), 133.3 (CH), 143.7 (C-13), 165.3 (CO), 165.5 (CO), 165.7 to 19:1) gave the deprotected saponoside 6 (0.067 g, 90%) as an

1

(CO), 165.8 (CO), 178.2 (C-28) ppm. ESI-MS: m/z ϭ 1057 [M ϩ amorphous white solid. [α]_Dϭ ϩ76.4 (c ϭ 1, pyridine). H NMR

Na]^ϩ. C₆₄H₇₄O₁₂·0.1CH₃OH (1038.49): calcd. C 74.14, H 7.22; (CD₃OD): δ ϭ 0.72 (s, 3 H, H-24), 0.77 (s, 3 H, H-26), 0.93 (s, 3

found C 73.82, H 7.44.

H, H-29), 0.96 (s, 3 H, H-30), 1.01 (s, 3 H, H-25), 1.02Ϫ2.1 (m, 22

Eur. J. Org. Chem. 2004, 1588Ϫ1603

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1599

´

K. Ple, M. Chwalek, L. Voutquenne-Nazabadioko

FULL PAPER

H), 1.20 (s, 3 H, H-27), 1.27 (d, J_5ЈЈ,6ЈЈϭ 6.3 Hz, 3 H, H-6ЈЈ), 2.89 11.2 Hz, 1 H, H-5Јa), 3.58 (dd, J_2Ј,3Јϭ 9.4, J_3Ј,4Јϭ 3.4 Hz, 1 H,

(dd, J ϭ 13.6, 3.6 Hz, 1 H, H-18), 3.35 (m, 1 H, H-23a), 3.42 (t, H-3Ј), 3.62 (dd, J ϭ 11.7, 4.7 Hz, 1 H, H-3), 3.63 (m, 1 H, H-23b),

J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.5 Hz, 1 H, H-4ЈЈ), 3.50 (d, J ϭ 11.0 Hz, 1 H, 3.64 (s, OCH₃), 3.75 (dd, J_3ЈЈ,4ЈЈϭ 9.5, J_2ЈЈ,3ЈЈϭ 3.4 Hz, 1 H, H-

H-23b), 3.59 (dd, J_5Јa,5Јbϭ 12.4, J_4Ј,5Јaϭ 2.2 Hz, 1 H, H-5Јa), 3.64

(s, 3 H, OCH₃), 3.67 (dd, J_3ЈЈ,4ЈЈϭ 9.5, J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-

3ЈЈ), 3.81 (m, 1 H, H-5ЈЈ), 3.85 (m, 1 H, H-4Ј), 3.98 (m, 1 H, H-

5Јb), 4.00 (dd, J_2ЈЈ,3ЈЈϭ 3.3, J_1ЈЈ,2ЈЈϭ 1.3 Hz, 1 H, H-2ЈЈ), 4.31 (d,

3ЈЈ), 3.72 (dd, J ϭ 11.8, 4.2 Hz, 1 H, H-3), 3.78 (m, 1 H, H-5ЈЈ), J_1Ј,2Јϭ 7.1 Hz, 1 H, H-1Ј), 4.96 (d, J_1ЈЈ,2ЈЈϭ 1.3 Hz, 1 H, H-1ЈЈ),

3.85 (dd, J_2Ј,3Јϭ 9.5, J_1Ј,2Јϭ 3.2 Hz, 1 H, H-2Ј), 3.90 (m, 1 H, H-

4Ј), 3.93 (dd, J_2Ј,3Јϭ 9.5, J_3Ј,4Јϭ 3.3 Hz, 1 H, H-3Ј), 3.95 (m, 1 H,

5.27 (m, 1 H, H-12) ppm. ¹³C NMR (CD₃OD): δ ϭ 12.0 (C-24),

15.0 (C-25), 16.2 (C-26), 16.5 (C-6ЈЈ), 17.4 (C-6), 22.5 (C-30), 22.6

H-5Јb), 3.97 (m, 1 H, H-2ЈЈ), 4.95 (d, J_1ЈЈ,2ЈЈϭ 1.4 Hz, 1 H, H-1ЈЈ), (C-16), 23.1 (C-11), 24.9 (C-2), 25.1 (C-27), 27.3 (C-15), 30.1 (C-

5.09 (d, J_1Ј,2Јϭ 3.3 Hz, 1 H, H-1Ј), 5.28 (m, 1 H, H-12) ppm. ¹³C

20), 31.9 (C-7), 32.1 (C-29, C-22), 33.3 (C-21), 36.2 (C-10), 38.0

NMR (CD₃OD): δ ϭ 12.5 (C-24), 14.9 (C-25), 16.2 (C-26), 16.6 (C-1), 39.1 (C-8), 41.3 (C-18), 41.4 (C-14), 42.4 (C-4), 45.6 (C-19),

(C-6ЈЈ), 17.3 (C-6), 20.6 (C-2), 22.5 (C-30), 22.6 (C-16), 23.1 (C-

11), 25.0 (C-27), 27.3 (C-15), 30.1 (C-20), 31.8 (C-7), 32.0 (C-29),

46.6 (C-17), 46.7 (C-5), 47.5 (C-9), 50.7 (OCH₃), 63.3 (C-23), 64.6

(C-5Ј), 68.7 (C-5ЈЈ), 70.7 (C-2ЈЈ), 70.8 (C-3ЈЈ), 71.8 (C-2Ј), 72.6 (C-

32.1 (C-22), 33.3 (C-21), 36.4 (C-10), 37.6 (C-1), 39.1 (C-8), 41.3 4ЈЈ), 72.9 (C-3Ј), 76.2 (C-4Ј), 82.1 (C-3), 102.1 (C-1ЈЈ), 105.1 (C-1Ј),

(C-18), 41.4 (C-14), 42.1 (C-4), 45.6 (C-19), 46.4 (C-5), 46.6 (C-17), 122.3 (C-12), 143.6 (C-13), 178.6 (C-28) ppm. ESI-MS: m/z ϭ 766

47.4 (C-9), 50.7 (OCH₃), 63.2 (C-5Ј, C-23), 68.6 (C-3Ј), 68.7 (C-

[M ϩ 2H]^ϩ. C₄₂H₆₈O₁₂·4.4 CH₃OH (905.98): calcd. C 61.52, H

5ЈЈ), 69.6 (C-4Ј), 70.6 (C-2ЈЈ), 71.0 (C-3ЈЈ), 72.3 (C-4ЈЈ), 74.0 (C-3), 9.52; found C 61.51, H 9.65.

76.0 (C-2Ј), 94.2 (C-1Ј), 102.2 (C-1ЈЈ), 122.3 (C-12), 143.6 (C-13),

2H]^ϩ.

3-O-(α-L-Arabinopyranosyl)hederagenin (δ-Hederin) (3): Lithium

178.6 (C-28) ppm. ESI-MS: m/z

ϭ

766 [M

ϩ

iodide (0.89 g, 6.6 mmol, 50 equiv.) was added to a solution of com-

pound 4 (0.082 g, 0.13 mmol) in DMF (8.8 mL) and then the reac-

tion mixture was heated under reflux for 5 days. The solvent was

evaporated under reduced pressure and the crude residue passed

through a column of hydrophobic resin (Mitsubishi HP20SS), elut-

ing sequentially with H₂O, 20% Na₂S₂O₃, H₂O, and CH₃OH. The

solvent was evaporated and the residue was purified by column

C₄₂H₆₈O₁₂·1.4H₂O (790.22): calcd. C 63.84, H 9.03; found C 63.83,

H 9.28.

Methyl 3-O-[α-L-Rhamnopyranosyl-(1Ǟ3)-α-L-arabinopyranosyl]-

hederagenate (8): This compound was prepared from saponoside

32 (0.136 g, 0.10 mmol) in the same manner as that described for

4. Purification by column chromatography (CH₂Cl₂/MeOH, 19:1

to 12:1) gave the deprotected saponoside 8 (0.065 g, 87%) as an

chromatography (CH₂Cl₂/MeOH, 19:1) to give δ-hederin

3

1

amorphous white solid. [α]_Dϭ ϩ22.6 (c ϭ 1, CH₃OH). H NMR

(0.016 g, 20%) as an amorphous white solid. Spectral identification,

performed in CD₃OD, was in accordance with published data.^[30]

(CD₃OD): δ ϭ 0.73 (s, 3 H, H-24), 0.77 (s, 3 H, H-26), 0.93 (s, 3

H, H-29), 0.96 (s, 3 H, H-30), 1.00 (s, 3 H, H-25), 1.05Ϫ2.10 (m,

22 H), 1.19 (s, 3 H, H-27), 1.27 (d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ),

2.89 (dd, J ϭ 13.7, 3.7 Hz, 1 H, H-18), 3.31 (d, J ϭ 11.3 Hz, 1 H,

3-O-[α-L-Rhamnopyranosyl-(1Ǟ2)-α-L-arabinopyranosyl]hederage-

nin (α-Hederin) (1): This compound was prepared from saponoside

2 (0.196 g, 0.26 mmol) in the same manner as that described for 3.

Final purification by column chromatography (CH₂Cl₂/MeOH,

19:1) gave α-hederin 1 (0.092 g, 48%) as an amorphous white solid

that was identical to an authentic sample of α-hederin (TLC). Spec-

tral identification was performed in [D₅]pyridine and was in ac-

cordance with published data.^[31]

H-23a), 3.41 (t, J_3ЈЈ,

ϭ J_4ЈЈ,5ЈЈϭ 9.5 Hz, 1 H, H-4ЈЈ), 3.58 (d,

4ЈЈ

J

_5Јa,5Јbϭ 12.4 Hz, 1 H, H-5Јa), 3.59 (dd, J_2Ј,3Јϭ 9.3, J_3Ј,4Јϭ 3.3 Hz,

1 H, H-3Ј), 3.63 (m, 2 H, H-23b, H-3), 3.64 (s, 3 H, OCH₃), 3.68

(dd, J_2Ј,3Јϭ 9.2, J_1Ј,2Јϭ 7.5 Hz, 1 H, H-2Ј), 3.81 (dd, J_3ЈЈ,4ЈЈϭ 9.5,

J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-3ЈЈ), 3.82 (m, 1 H, H-5ЈЈ), 3.85 (dd,

J_5Јa,5Јbϭ 12.6, J_4Ј,5Јbϭ 2.5 Hz, 1 H, H-5Јb), 3.90 (m, 1 H, H-4Ј),

3.99 (dd, J_2ЈЈ,3ЈЈϭ 3.3, J_1ЈЈ,2ЈЈϭ 1.6 Hz, 1 H, H-2ЈЈ), 4.35 (d, J_1Ј,2Ј

ϭ

3-O-[α-L-Rhamnopyranosyl-(1Ǟ2)-β-L-arabinopyranosyl]hederage-

7.3 Hz, 1 H, H-1Ј), 5.05 (d, J_1ЈЈ,2ЈЈϭ 1.3 Hz, 1 H, H-1ЈЈ), 5.27 (m,

1 H, H-12) ppm. ¹³C NMR (CD₃OD): δ ϭ 12.0 (C-24), 15.0 (C-

25), 16.2 (C-26), 16.5 (C-6ЈЈ), 17.4 (C-6), 22.6 (C-30, C-16), 23.1

(C-11), 24.9 (C-2), 25.0 (C-27), 27.3 (C-15), 30.1 (C-20), 31.9 (C-

7), 32.1 (C-29), 32.2 (C-22), 33.3 (C-21), 36.2 (C-10), 38.0 (C-1),

39.1 (C-8), 41.3 (C-18), 41.4 (C-14), 42.4 (C-4), 45.6 (C-19), 46.7

(C-17, C-5), 47.5 (C-9), 50.8 (OCH₃), 63.3 (C-23), 65.7 (C-5Ј), 68.4

(C-4Ј), 68.6 (C-5ЈЈ), 70.6 (C-2ЈЈ, C-3ЈЈ), 70.8 (C-2Ј), 72.6 (C-4ЈЈ),

79.6 (C-3Ј), 81.8 (C-3), 102.2 (C-1ЈЈ), 105.1 (C-1Ј), 122.3 (C-12),

143.6 (C-13), 178.6 (C-28) ppm. ESI-MS: m/z ϭ 766 [M ϩ 2H]^ϩ.

C₄₂H₆₈O₁₂·2.1 CH₃OH (832.28): calcd. C 63.64, H 9.25; found C

63.84, H 9.59.

nin (5): This compound was prepared from saponoside 6 (0.055 g,

0.07 mmol) in the same manner as that described for 3. Final puri-

fication by column chromatography (CH₂Cl₂/MeOH, 19:1) gave sa-

ponoside 5 (0.025 g, 46%) as an amorphous white solid. [α]_D

ϭ

ϩ72.5 (c ϭ 1, pyridine). ¹H NMR ([D₅]pyridine): δ ϭ 0.92 (s, 6 H,

H-25, H-29), 0.94 (s, 3 H, H-24), 0.95Ϫ2.23 (m, 22 H), 0.99 (s, 3

H, H-30), 1.01 (s, 3 H, H-26), 1.24 (s, 3 H, H-27), 1.64 (d, J_5ЈЈ,6ЈЈ

ϭ

6.1 Hz, 3 H, H-6ЈЈ), 3.28 (dd, J ϭ 13.5, 3.5 Hz, 1 H, H-18), 3.67

(d, J ϭ 10.5 Hz, 1 H, H-23a), 3.97 (d, J ϭ 10.8 Hz, 1 H, H-23b),

4.13 (dd, J_5Јa,5Јbϭ 11.9, J_4Ј,5Јaϭ 1.7 Hz, 1 H, H-5Јa), 4.31 (m, 1

H, H-3), 4.33 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.3 Hz, 1 H, H-4ЈЈ), 4.38 (m, 1

H, H-4Ј), 4.50 (m, 2 H, H-5ЈЈ, H-5Јb), 4.60 (dd, J_3ЈЈ,4ЈЈϭ 9.3,

J_2ЈЈ,3ЈЈϭ 3.2 Hz, 1 H, H-3ЈЈ), 4.66 (dd, J_2Ј,3Јϭ 9.5, J_3Ј,4Јϭ 3.2 Hz,

1 H, H-3Ј), 4.77 (m, 1 H, H-2Ј), 4.78 (m, 1 H, H-2ЈЈ), 5.49 (m, 1

H, H-12), 5.73 (d, J_1Ј,2Јϭ 3.0 Hz, 1 H, H-1Ј), 5.86 (s, 1 H, H-1ЈЈ)

ppm. ¹³C NMR ([D₅]pyridine): δ ϭ 13.7 (C-24), 15.6 (C-25), 17.1

(C-26), 17.8 (C-6), 18.2 (C-6ЈЈ), 21.3 (C-2), 23.3 (C-16), 23.4 (C-

Methyl 3-O-[α-L-Rhamnopyranosyl-(1Ǟ4)-α-L-arabinopyranosyl]-

hederagenate (10): This compound was prepared from saponoside

33 (0.150 g, 0.11 mmol) in the same manner as that described for

4. Purification by column chromatography (CH₂Cl₂/MeOH, 9:1)

gave the deprotected saponoside 10 (0.080 g, 96%) as an amorph-

ous white solid. [α]_Dϭ ϩ27.5 (c ϭ 1, pyridine). ¹H NMR 30), 23.6 (C-11), 25.8 (C-27), 27.9 (C-15), 30.6 (C-20), 32.4 (C-7),

(CD₃OD): δ ϭ 0.74 (s, 3 H, H-24), 0.77 (s, 3 H, H-26), 0.93 (s, 3

H, H-29), 0.96 (s, 3 H, H-30), 0.98Ϫ2.10 (m, 22 H), 1.00 (s, 3 H,

32.8 (C-22), 32.9 (C-29), 33.8 (C-21), 36.7 (C-10), 37.9 (C-1), 39.4

(C-8), 41.6 (C-18), 41.8 (C-14), 42.7 (C-4), 46.1 (C-19), 46.3 (C-17),

H-25), 1.19 (s, 3 H, H-27), 1.27 (d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 47.0 (C-5), 47.7 (C-9), 63.8 (C-23), 64.3 (C-5Ј), 69.4 (C-3Ј), 69.6

2.89 (dd, J ϭ 13.7, 4.0 Hz, 1 H, H-18), 3.31 (d, J ϭ 11.4 Hz, 1 H, (C-5ЈЈ), 70.2 (C-4Ј), 71.8 (C-2ЈЈ), 72.2 (C-3ЈЈ), 73.4 (C-4ЈЈ), 74.7 (C-

H-23a), 3.39 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.5 Hz, 1 H, H-4ЈЈ), 3.52 (dd,

J_2Ј,3Јϭ 9.4, J_1Ј,2Јϭ 7.2 Hz, 1 H, H-2Ј), 3.54 (br. d, J_5Јa,5Јb

3), 76.5 (C-2Ј), 95.4 (C-1Ј), 103.2 (C-1ЈЈ), 122.2 (C-12), 144.5 (C-

ϭ

13), 180.1 (C-28) ppm. ESI-MS: m/z ϭ 774 [M ϩ Na ϩ H]^ϩ.

1600

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 1588Ϫ1603

Synthesis of α-Hederin, δ-Hederin, and Related Triterpenoid Saponins

FULL PAPER

C₄₁H₆₆O₁₂·1.6H₂O (779.79): calcd. C 63.15, H 8.95; found C 63.02,

H 9.17.

50 °C for 5 h. After cooling, EtOAc was added and the organic

layer was washed with 1  HCl. The aqueous layer was then ex-

tracted with EtOAc (3ϫ), and the combined organic layers washed

with satd. NaHCO₃(sat) and NaCl (sat). The dried solution

(Na₂SO₄) was then evaporated under reduced pressure to give the

crude product, which was purified by column chromatography

(cyclohexane/EtOAc, 4:1 to 2:1) to give 35 (2.58 g, 61%) as a white

foam. R_fϭ 0.25 (cyclohexane/EtOAc, 6:4). [α]_Dϭ ϩ60.1 (c ϭ 1,

CHCl₃). ¹H NMR (CDCl₃): δ ϭ 0.78 (s, 3 H, H-26), 0.85Ϫ2.07

(m, 22 H), 0.94 (s, 3 H, H-24), 0.95 (s, 3 H, H-29), 0.98 (s, 3 H, H-

30), 1.00 (s, 3 H, H-25), 1.18 (s, 3 H, H-27), 2.93 (dd, J ϭ 13.7,

4.0 Hz, 1 H, H-18), 3.48 (d, J ϭ 10.3 Hz, 1 H, H-23a), 3.69 (dd,

J ϭ 8.5, 7.3 Hz, 1 H, H-3), 3.78 (d, J ϭ 10.3 Hz, 1 H, H-23b), 4.58

(m, 2 H, CH₂CHϭCH₂), 5.26 (dd, J ϭ 10.4, 0.9 Hz, 1 H, CH₂CHϭ

CH₂), 5.35 (m, 2 H, H-12, CH₂CHϭCH₂), 5.94 (m, 1 H, CH₂CHϭ

CH₂) ppm. ¹³C NMR (CDCl₃): δ ϭ 11.3 (C-24), 15.7 (C-25), 17.0

(C-26), 18.5 (C-6), 23.0 (C-16), 23.3 (C-11), 23.6 (C-30), 25.9 (C-

27), 26.7 (C-2), 27.6 (C-15), 30.7 (C-20), 32.4 (C-22), 32.5 (C-7),

33.1 (C-29), 33.8 (C-21), 36.9 (C-10), 38.1 (C-1), 39.3 (C-8), 41.3

(C-18), 41.7 (C-14), 41.8 (C-4), 45.8 (C-19), 46.7 (C-17), 47.6 (C-

9), 49.8 (C-5), 64.8 (CH₂CHϭCH₂), 72.2 (C-23), 76.9 (C-3), 117.7

(CH₂CHϭCH₂), 122.3 (C-12), 132.5 (CH₂CHϭCH₂), 143.6 (C-13),

177.4 (C-28) ppm. C₃₃H₅₂O₄(512.77): calcd. C 77.30, H 10.22;

found C 77.11, H 10.49.

3-O-[α-L-Rhamnopyranosyl-(1Ǟ3)-α-L-arabinopyranosyl]hederage-

nin (7): This compound was prepared from saponoside 8 (0.068 g,

0.09 mmol) in the same manner as that described for 3. Final puri-

fication by column chromatography (CH₂Cl₂/MeOH, 19:1) gave sa-

ponoside 7 (0.021 g, 31%) as an amorphous white solid. [α]_D

ϭ

ϩ30.6 (c ϭ 1, pyridine). ¹H NMR ([D₅]pyridine): δ ϭ 0.90 (s, 3 H,

H-24), 0.92 (s, 3 H, H-25), 0.93 (s, 3 H, H-29), 0.99 (s, 3 H, H-30),

1.01 (s, 3 H, H-26), 1.04Ϫ2.23 (m, 22 H), 1.26 (s, 3 H, H-27), 1.67

(d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 3.28 (dd, J ϭ 13.7, 3.3 Hz, 1 H,

H-18), 3.70 (m, 2 H, H-23a, H-5Јa), 4.16 (dd, J_2Ј,3Јϭ 9.3, J_3Ј,4Ј

ϭ

3.0 Hz, 1 H, H-3Ј), 4.26 (dd, J_5Јa,5Јbϭ 12.2, J_4Ј,5Јbϭ 1.9 Hz, 1 H,

H-5Јb), 4.27 (m, 1 H, H-3), 4.30 (d, J ϭ 11.1 Hz, 1 H, H-23b), 4.34

(t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.4 Hz, 1 H, H-4ЈЈ), 4.40 (m, 1 H, H-4Ј), 4.55

(dd, J_2Ј,3Јϭ 9.2, J_1Ј,2Јϭ 7.5 Hz, 1 H, H-2Ј), 4.64 (m, 1 H, H-5ЈЈ),

4.65 (dd, J_3ЈЈ,4ЈЈϭ 9.2, J_2ЈЈ,3ЈЈϭ 2.9 Hz, 1 H, H-3ЈЈ), 4.77 (dd,

J_2ЈЈ,3ЈЈϭ 3.1, J_1ЈЈ,2ЈЈϭ 1.3 Hz, 1 H, H-2ЈЈ), 4.99 (d, J_1Ј,2Јϭ 7.4 Hz,

1 H, H-1Ј), 5.48 (m, 1 H, H-12), 6.00 (s, 1 H, H-1ЈЈ) ppm. ¹³C

NMR ([D₅]pyridine): δ ϭ 13.4 (C-24), 15.8 (C-25), 17.2 (C-26),

17.8 (C-6), 18.3 (C-6ЈЈ), 23.3 (C-16), 23.5 (C-30), 23.6 (C-11), 25.9

(C-27), 25.9 (C-2), 28.0 (C-15), 30.6 (C-20), 32.5 (C-7), 32.9 (C-22),

33.0 (C-29), 33.8 (C-21), 36.6 (C-10), 38.4 (C-1), 39.4 (C-8), 41.6

(C-18), 41.8 (C-14), 43.2 (C-4), 46.1 (C-19), 46.4 (C-17), 47.1 (C-

5), 47.8 (C-9), 63.7 (C-23), 66.9 (C-5Ј), 69.0 (C-4Ј), 69.7 (C-5ЈЈ), Allyl 23-O-Benzoylhederagenate (36): Allyl hederagenate 35 (2.3 g,

71.5 (C-2Ј), 71.8 (C-2ЈЈ), 72.1 (C-3ЈЈ), 73.7 (C-4ЈЈ), 80.4 (C-3Ј), 81.7 4.5 mmol) was treated with benzoyl chloride in the same manner

(C-3), 103.5 (C-1ЈЈ), 106.5 (C-1Ј), 122.3 (C-12), 144.5 (C-13), 180.1 as that described for methyl 23-O-benzoylhederagenate (29). Purifi-

(C-28) ppm. ESI-MS: m/z

ϭ 774 [M ϩ Na ϩ

H]^ϩ. cation by column chromatography (cyclohexane/EtOAc, 9:1) gave

C₄₁H₆₆O₁₂·2.7H₂O (799.61): calcd. C 61.59, H 9.00; found C 61.50,

H 8.68.

the desired product 36 (1.74 g, 63%). R_fϭ 0.60 (cyclohexane/

EtOAc, 6:4) [α]_Dϭ ϩ17.3 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ

0.80 (s, 3 H, H-26), 0.85Ϫ2.07 (m, 22 H), 0.90 (s, 3 H, H-24), 0.95

(s, 3 H, H-29), 0.98 (s, 3 H, H-30), 1.02 (s, 3 H, H-25), 1.16 (s, 3

H, H-27), 2.94 (dd, J ϭ 13.8, 4.0 Hz, 1 H, H-18), 3.55 (dd, J ϭ

11.4, 5.5 Hz, 1 H, H-3), 4.05 (d, J ϭ 11.4 Hz, 1 H, H-23a), 4.57

(m, 3 H, H-23b, CH₂CHϭCH₂), 5.26 (dd, J ϭ 10.5, 1.3 Hz, 1 H,

CH₂CHϭCH₂), 5.35 (m, 1 H, H-12), 5.37 (m, 1 H, CH₂CHϭCH₂),

5.96 (m, 1 H, CH₂CHϭCH₂), 7.51 (t, J ϭ 8.0 Hz, 2 H, Ar-H), 7.63

(t, J ϭ 7.4 Hz, 1 H, Ar-H), 8.10 (dd, J ϭ 8.4, 1.3 Hz, 2 H, Ar-H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 12.0 (C-24), 15.8 (C-25), 17.0 (C-

26), 18.2 (C-6), 23.0 (C-16), 23.4 (C-11), 23.6 (C-30), 25.5 (C-27),

26.1 (C-2), 27.6 (C-15), 30.7 (C-20), 32.4 (C-22), 32.5 (C-7), 33.1

(C-29), 33.9 (C-21), 36.8 (C-10), 38.4 (C-1), 39.3 (C-8), 41.4 (C-18),

41.6 (C-14), 42.5 (C-4), 45.8 (C-19), 46.7 (C-17), 48.0 (C-9), 48.3

(C-5), 64.8 (CH₂CHϭCH₂), 66.7 (C-23), 72.4 (C-3), 117.7

(CH₂CHϭCH₂), 122.3 (C-12), 128.5 (CH), 129.5 (CH), 130.1 (C),

132.5 (CH₂CHϭCH₂), 133.1 (CH), 143.6 (C-13), 166.8 (CO), 177.3

(C-28) ppm. C₄₀H₅₆O₅(616.88): calcd. C 77.88, H 9.15; found C

77.59, H 9.34.

3-O-[α-L-Rhamnopyranosyl-(1Ǟ4)-α-L-arabinopyranosyl]hederage-

nin (9): This compound was prepared from saponoside 10 (0.043 g,

0.056 mmol) in the same manner as that described for 3. Final puri-

fication by column chromatography (CH₂Cl₂/MeOH, 12:1) gave sa-

ponoside 9 (0.020 g, 47%) as an amorphous white solid. [α]_D

ϭ

ϩ26.6 (c ϭ 1, pyridine). ¹H NMR ([D₅]pyridine): δ ϭ 0.90 (s, 3 H,

H-25), 0.91 (s, 3 H, H-24), 0.92 (s, 3 H, H-29), 0.99 (s, 3 H, H-30),

1.00 (s, 3 H, H-26), 1.01Ϫ2.27 (m, 22 H), 1.24 (s, 3 H, H-27), 1.64

(d, J_5ЈЈ,6ЈЈϭ 6.2 Hz, 3 H, H-6ЈЈ), 3.27 (dd, J ϭ 13.5, 3.4 Hz, 1 H, H-

18), 3.70 (d, J ϭ 10.9 Hz, 1 H, H-23a), 3.76 (d, J_5Јa,5Јbϭ 11.6 Hz, 1

H, H-5Јa), 4.18 (dd, J_2Ј,3Јϭ 9.2, J_3Ј,4Јϭ 3.1 Hz, 1 H, H-3Ј), 4.25

(dd, J ϭ 11.9, 4.3 Hz, 1 H, H-3), 4.29 (d, J ϭ 11.0 Hz, 1 H, H-

23b), 4.30 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.2 Hz, 1 H, H-4ЈЈ), 4.36 (m, 2 H,

H-4Ј, H-5Јb), 4.40 (dd, J_2Ј,3Јϭ 8.9, J_1Ј,2Јϭ 7.5 Hz, 1 H, H-2Ј), 4.47

(m, 1 H, H-5ЈЈ), 4.57 (dd, J_3ЈЈ,4ЈЈϭ 9.4, J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-

3ЈЈ), 4.73 (dd, J_2ЈЈ,3ЈЈϭ 3.2, J_1ЈЈ,2ЈЈϭ 1.4 Hz, 1 H, H-2ЈЈ), 4.99 (d,

J_1Ј,2Јϭ 7.2 Hz, 1 H, H-1Ј), 5.48 (m, 1 H, H-12), 5.92 (s, 1 H, H-

1ЈЈ) ppm. ¹³C NMR ([D₅]pyridine): δ ϭ 13.3 (C-24), 15.7 (C-25),

17.1 (C-26), 17.8 (C-6), 18.2 (C-6ЈЈ), 23.3 (C-16), 23.4 (C-30), 23.5

Allyl

3-O-[2,3,4-Tri-O-benzoyl-α-

-arabinopyranosyl]-23-O-benzoylhederagenate

(37): This compound was prepared in the same manner as that

39.4 (C-8), 41.6 (C-18), 41.8 (C-14), 43.1 (C-4), 46.0 (C-19), 46.3 described for 31 using allyl hederagenate 36 (0.150 g, 0.24 mmol)

(C-17), 47.1 (C-5), 47.8 (C-9), 63.8 (C-23), 65.6 (C-5Ј), 69.8 (C-5ЈЈ), and the trichloroacetimidate 24 (0.468 g, 0.48 mmol, 2 equiv.) in

L-rhamnopyranosyl-(1Ǟ2)-3,4-

(C-11), 25.8 (C-2), 25.8 (C-27), 27.9 (C-15), 30.6 (C-20), 32.4 (C- di-O-benzoyl-α-

7), 32.8 (C-22), 32.9 (C-29), 33.8 (C-21), 36.5 (C-10), 38.3 (C-1),

L

71.6 (C-2ЈЈ), 72.0 (C-3ЈЈ), 72.6 (C-2Ј), 73.7 (C-4ЈЈ), 73.8 (C-3Ј), 75.6 propionitrile at Ϫ78 °C. The crude residue was purified by column

(C-4Ј), 82.0 (C-3), 103.0 (C-1ЈЈ), 106.4 (C-1Ј), 122.2 (C-12), 144.5 chromatography (toluene/EtOAc, 99:1 to 39:1) to give a mixture of

(C-13), 180.0 (C-28) ppm. ESI-MS: m/z ϭ 774 [M ϩ Na ϩ H]^ϩ. anomeric products that were separated by HPLC (100% aceto-

C₄₁H₆₆O₁₂·3.2H₂O (808.62): calcd. C 60.90, H 9.03; found C 60.91,

H 8.98.

nitrile) to give the desired saponoside 37 (0.192 g, 56%) as a white

foam and the β anomer 38 (0.075 g, 22%).

Allyl Hederagenate 35: Allyl bromide (1.43 mL, 16.5 mmol, 2

Compound 37 (α anomer): R_fϭ 0.50 (toluene/EtOAc, 9:1). [α]_Dϭ

equiv.) and potassium carbonate (2.48 g, 24.8 mmol, 3 equiv.) were ϩ90.2 (c ϭ 1, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 0.79 (s, 3 H, H-26),

added to a solution of hederagenin (see general remarks; 3.9 g,

8.3 mmol) in DMF (54 mL). The reaction mixture was heated to

0.83 (s, 3 H, H-24), 0.95 (s, 3 H, H-29), 0.98 (s, 3 H, H-30), 1.02

(s, 3 H, H-25), 1.05Ϫ2.10 (m, 22 H), 1.11 (s, 3 H, H-27), 1.33 (d,

Eur. J. Org. Chem. 2004, 1588Ϫ1603

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1601

´

K. Ple, M. Chwalek, L. Voutquenne-Nazabadioko

FULL PAPER

J_5ЈЈ,6ЈЈϭ 5.9 Hz, 3 H, H-6ЈЈ), 2.93 (dd, J ϭ 13.7, 3.6 Hz, 1 H, H- 37 (0.203 g, 0.14 mmol) by treatment with 3% KOH in methanol

18), 3.72 (dd, J ϭ 11.6, 4.3 Hz, 1 H, H-3), 3.88 (dd, J_5Јa,5Јbϭ 11.8, in the same manner as that described for 4. Neutralization of the

J_4Ј,5Јaϭ 2.4 Hz, 1 H, H-5Јa), 4.17 (d, J ϭ 11.4 Hz, 1 H, H-23a),

4.32 (dd, J_5Јa,5Јbϭ 11.9, J_4Ј,5Јbϭ 6.1 Hz, 1 H, H-5Јb), 4.39 (dd, evaporation gave the crude allyl ester, which was used without puri-

J_2Ј,3Јϭ 6.3, J_1Ј,2Јϭ 4.7 Hz, 1 H, H-2Ј), 4.45 (d, J ϭ 11.7 Hz, 1 H, fication in the next step. Tetrakis(triphenylphosphane)palladium(0)

H-23b), 4.49 (m, 1 H, H-5ЈЈ), 4.58 (m, 2 H, CH₂CHϭCH₂), 4.91 (0.050 g, 0.043 mmol, 0.3 equiv.) was added to a mixture of the

(d, J_1Ј,2Јϭ 4.0 Hz, 1 H, H-1Ј), 5.26 (d, J ϭ 10.5 Hz, 1 H, CH₂CHϭ crude allyl ester, triphenylphosphane (0.023 g, 0.086 mmol, 0.6

CH₂), 5.37 (m, 3 H, H-12, CH₂CHϭCH₂), 5.43 (s, 1 H, H-1ЈЈ), equiv.), and pyrrolidine (24 µL, 0.28 mmol, 2 equiv.) in THF

5.60 (dd, J_2Ј,3Јϭ 6.6, J_3Ј,4Јϭ 3.3 Hz, 1 H, H-3Ј), 5.64 (t, J_4ЈЈ,5ЈЈ(1 mL) at room temp. The reaction mixture was stirred overnight

reaction mixture with Amberlite IR 120 (H^ϩform), filtration, and

ϭ

J_3ЈЈ,4ЈЈϭ 10.1 Hz, 1 H, H-4ЈЈ), 5.68 (m, 1 H, H-4Ј), 5.78 (m, 1 H, or until TLC indicated the total disappearance of the starting mate-

H-2ЈЈ), 5.89 (dd, J_3ЈЈ,4ЈЈϭ 10.2, J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-3ЈЈ), 5.95 rial. Evaporation of the solvent and purification by column chro-

(m, 1 H, CH₂CHϭCH₂), 7.22Ϫ7.72 (m, 20 H, Ar-H), 7.99 (d, J ϭ matography (CH₂Cl₂/MeOH, 19:1) gave α-hederin 1 (0.096 g, 91%)

7.7 Hz, 2 H, Ar-H), 8.05 (d, J ϭ 7.7 Hz, 2 H, Ar-H), 8.1 (t, J ϭ as an amorphous white solid that was identical to an authentic

7.6 Hz, 6 H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 12.8 (C-24), 15.8 sample of α-hederin (TLC). Spectral identification was performed

(C-25), 17.0 (C-26), 17.5 (C-6ЈЈ), 18.0 (C-6), 23.0 (C-16), 23.4 (C-

11), 23.6 (C-30), 25.4 (C-27), 25.5 (C-2), 27.5 (C-15), 30.7 (C-20),

32.4 (C-22), 32.5 (C-7), 33.1 (C-29), 33.9 (C-21), 36.5 (C-10), 38.5

(C-1), 39.3 (C-8), 41.4 (C-18), 41.6 (C-14), 42.4 (C-4), 45.8 (C-19),

46.7 (C-17), 48.0 (C-9), 48.2 (C-5), 60.3 (C-5Ј), 64.8 (CH₂CHϭ

CH₂), 65.4 (C-23), 67.8 (C-4Ј, C-5ЈЈ), 69.1 (C-3ЈЈ), 70.7 (C-2ЈЈ, C-

3Ј), 71.8 (C-4ЈЈ), 75.1 (C-2Ј), 82.2 (C-3), 98.6 (C-1ЈЈ), 102.5 (C-1Ј),

117.7 (CH₂CHϭCH₂), 122.3 (C-12), 128.0 (CH), 128.2 (CH), 128.3

(CH), 128.4 (CH), 128.5 (CH), 129.1 (C), 129.2 (C), 129.4 (C),

129.5 (CH), 129.6 (C), 129.7 (CH), 129.8 (CH), 129.9 (CH), 130.3

(C), 132.5 (CH₂CHϭCH₂), 132.8 (CH), 133.0 (CH), 133.1 (CH),

133.2 (CH), 133.4 (CH), 143.7 (C-13), 164.8 (CO), 165.3 (CO),

165.4 (CO), 165.5 (CO), 165.8 (CO), 165.9 (CO), 177.3 (C-28) ppm.

C₈₆H₉₄O₁₈·0.2 EtOAc (1433.30): calcd. C 72.74, H 6.72; found C

72.41, H 6.92.

in [D₅]pyridine and was in accordance with published data.^[31]

[1]

K. Hostettmann, A. Marston, Saponins, Cambridge University

Press, Cambridge, UK, 1995.

[2]

K. Hostettmann, Helv. Chim. Acta 1980, 63, 606Ϫ609.

[3]

J. Quetin-Leclercq, R. Elias, G. Balansard, R. Bassler, L. Ang-

enot, Planta Med. 1992, 58, 279Ϫ281.

[4] [4a]

´

A. Favel, M. D. Steinmetz, E. Ollivier, R. Elias, P. Regli, G.

[4b]

Balansard, Planta Med. 1992, 58, 279Ϫ281.

adze, A. Favel, F. Delmas, R. Elias, R. Faure, G. Dekanosidze,

V. Mshvild-

E. Kemertelidze, G. Balansard, Pharmazie 2000, 55, 325Ϫ326.

[4c]

O. Ridoux, C. Di Giorgio, F. Delmas, R. Elias, V. Mshvild-

adze, G. Dekanosidze, E. Kemertelidze, G. Balansard, P. Ti-

mon-David, Phytother. Res. 2001, 15, 298Ϫ301.

[5]

^[5a]S. S. Muthu Kumara, B. T. Kwong Huat, Planta Med. 2001,

Compound 38 (β anomer): R_fϭ 0.46 (toluene/EtOAc, 9:1). [α]_D

ϭ

[5b]

67, 29Ϫ32.

H.-J. Park, S.-H. Kwon, J.-H. Lee, K.-H. Lee,

1

ϩ153.8 (c ϭ 1, CHCl₃). H NMR (CDCl₃): δ ϭ 0.84 (s, 3 H, H-

26), 0.95 (s, 3 H, H-29), 0.99 (s, 3 H, H-30), 1.05Ϫ2.20 (m, 22 H),

1.11 (s, 3 H, H-27), 1.13 (s, 3 H, H-25), 1.19 (s, 3 H, H-24), 1.41

(d, J_5ЈЈ,6ЈЈϭ 6.3 Hz, 3 H, H-6ЈЈ), 2.95 (dd, J ϭ 13.8, 3.8 Hz, 1 H,

H-18), 3.90 (dd, J_5Јa,5Јbϭ 13.0, J_4Ј,5Јaϭ 1.6 Hz, 1 H, H-5Јa), 4.00

(dd, J ϭ 11.3, 3.9 Hz, 1 H, H-3), 4.30 (d, J_5Јa,5Јbϭ 12.7 Hz, 1 H,

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H-5Јb), 4.38 (m, 1 H, H-5ЈЈ), 4.48 (s, 2 H, H-23), 4.55 (dd, J_2Ј,3Ј

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(dd, J ϭ 10.4, 1.2 Hz, 1 H, CH₂CHϭCH₂), 5.37 (m, 1 H, H-12),

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5.39 (m, 1 H, CH₂CHϭCH₂), 5.41 (s, 1 H, H-1ЈЈ), 5.43 (d, J_1Ј,2Ј

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3.7 Hz, 1 H, H-1Ј), 5.55 (dd, J_2ЈЈ,3ЈЈϭ 3.1, J_1ЈЈ,2ЈЈϭ 1.8 Hz, 1 H,

H-2ЈЈ), 5.70 (t, J_3ЈЈ,4ЈЈϭ J_4ЈЈ,5ЈЈϭ 9.9 Hz, 1 H, H-4ЈЈ), 5.76 (dd,

J_2Ј,3Јϭ 10.4, J_3Ј,4Јϭ 3.3 Hz, 1 H, H-3Ј), 5.85 (m, 1 H, H-4Ј), 5.93

(dd, J_3ЈЈ,4ЈЈϭ 10.0, J_2ЈЈ,3ЈЈϭ 3.3 Hz, 1 H, H-3ЈЈ), 5.98 (m, 1 H,

CH₂CHϭCH₂), 7.24Ϫ7.68 (m, 18 H, Ar-H), 7.82 (d, J ϭ 7.3 Hz,

2 H, Ar-H), 8.02 (m, 8 H, Ar-H), 8.12 (d, J ϭ 7.3 Hz, 2 H, Ar-H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 13.3 (C-24), 15.8 (C-25), 17.1 (C-

26), 17.7 (C-6ЈЈ), 18.1 (C-6), 21.4 (C-2), 23.0 (C-16), 23.5 (C-11),

23.6 (C-30), 25.4 (C-27), 27.6 (C-15), 30.7 (C-20), 32.3 (C-22), 32.5

(C-7), 33.1 (C-29), 33.8 (C-21), 36.8 (C-10), 38.1 (C-1), 39.4 (C-8),

41.4 (C-18), 41.7 (C-14), 42.3 (C-4), 45.8 (C-19), 46.7 (C-17), 48.1

(C-9), 48.3 (C-5), 60.9 (C-5Ј), 64.8 (CH₂CHϭCH₂), 65.8 (C-23),

67.3 (C-5ЈЈ), 69.0 (C-3ЈЈ), 70.2 (C-3Ј), 70.3 (C-4Ј), 70.7 (C-2ЈЈ), 71.9

(C-4ЈЈ), 73.9 (C-2Ј), 76.4 (C-3), 94.6 (C-1Ј), 98.8 (C-1ЈЈ), 117.8

(CH₂CHϭCH₂), 122.2 (C-12), 128.2 (CH), 128.3 (CH), 128.4

(CH), 128.5 (CH), 129.2 (C), 129.3 (C), 129.4 (C), 129.5 (CH),

129.6 (CH), 129.7 (CH), 130.4 (C), 132.5 (CH₂CHϭCH₂), 133.0

(CH), 133.2 (CH), 133.4 (CH), 133.5 (CH), 143.9 (C-13), 164.9

(CO), 165.0 (CO), 165.6 (CO), 165.7 (CO), 166.0 (CO), 177.3 (C-

28) ppm. ESI-MS: m/z ϭ 1438 [M ϩ Na]^ϩ.

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3-O-[α-

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1602

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1588Ϫ1603

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Received November 13, 2003

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www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1603

Article Doi

Synthesis of α-hederin, δ-hederin, and related triterpenoid saponins

DOI: 10.1002/ejoc.200300723

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