Synthesis of Δ20-Ginsenosides Rh4, (20E)-Rh3, Rg6, and Rk1: A General Approach to Access Dehydrated Ginsenosides

Article abstract of DOI:10.1021/acs.joc.7b02987

Four representative Δ²⁰-ginsenosides, namely, ginsenosides Rh₄ (1), (20E)-Rh₃ (2), Rg₆ (3), and Rk₁ (4) from Panax Ginseng, were chemically synthesized for the first time. Dehydration of the naturally occurring 20(S)-protopanaxatriol and 20(S)-protopanaxadiol provided all types of Δ²⁰-sapogenins, which were separated due to a judicious choice of protecting groups. The Δ²⁰-sapogenins were then directly glycosylated with glycosyl ortho-alkynylbenzoate donors under the catalysis of Ph₃PAuNTf₂ as key steps. The neutral conditions of the glycosylations were crucial to prevent the acid-labile Δ^20,21 double bond from isomerization.

Full text of DOI:10.1021/acs.joc.7b02987

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Article
Synthesis of #20-Ginsenosides Rh4, (20E)-Rh3, Rg6 and Rk1:
A General Approach to Access Dehydrated Ginsenosides
Renzeng Shen, Stephane Laval, Xin Cao, and Biao Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02987 • Publication Date (Web): 12 Feb 2018
Downloaded from http://pubs.acs.org on February 13, 2018
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Synthesis of ꢀ20ꢁGinsenosides Rh4, (20E)ꢁRh3, Rg6 and Rk1: A General Approach to Access Dehydrated
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Ginsenosides
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Renzeng Shen, Stephane Laval, Xin Cao,* and Biao Yu*
†
State Key Laboratory of Bioꢀorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
ABSTRACT: Four representative ꢁ20ꢀginsenosides, namely ginsenosides Rh4 (1), (20E)ꢀRh3 (2), Rg6 (3) and
Rk1 (4) from Panax Ginseng were chemically synthesized for the first time. Dehydration of the naturally
occurring 20(S)ꢀprotopanaxatriol and 20(S)ꢀprotopanaxadiol provided all type of ꢁ20ꢀsapogenins, which were
separated due to a judicious choice of protecting groups. The ꢁ20ꢀsapogenins were then directly glycosylated
with glycosyl orthoꢀalkynylbenzoate donors under the catalysis of Ph3PAuNTf2 as key steps. The neutral
conditions of the glycosylations were crucial to prevent the acidꢀlabileꢁ20,21 double bond from isomerization.
INTRODUCTION
Ginseng is a slowꢀgrowing perennial plant belonging to the genus Panax of the family Araliaceae which has
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been used as an herbal remedy in Asia for its tonic and restorative actions for thousands of years. Its
beneficial effects have been widely reported in the literature and are attributed to ginsenosides, triterpenoid
saponins present in all parts of the plant.1 While ginseng can be consumed in its raw form, preliminary
treatment is usually applied in order to extend its preservation, reduce or eliminate the toxicity and side
effects of the raw material and enhance its medical efficacy. The steamꢀheating and/or sunꢀdrying of the
ginseng’s roots are two traditional processes used to produce white and red ginsengs. Such processing
methods modify the content of ginsenosides and thus alter the medicinal effects of the plant.2 Indeed, such
operations mainly undergo cleavage of the glycosidic bond at the Cꢀ20 of dammaraneꢀtype ginsenosides,
dehydration of the resulting hydroxyl group at Cꢀ20 and epoxidation/hydroxylation of double bonds,
resulting in a wide range of dehydrated and polyoxygenated dammaraneꢀtype ginsenosides, which are either
entirely absent or present only in trace amounts in the raw material.3 ꢁ20ꢀginsenosides are dehydrated
saponins in which the side chain of the dammaraneꢀtype sapogenins, either 20(S)ꢀprotopanaxadiol (PPD) or
20(S)ꢀprotopanaxatriol (PPT), contains a carbonꢀcarbon double bond at the Cꢀ20. The double bond can be
located between the C20ꢀC21 or between the C20ꢀC22 with Eꢀ or Zꢀconfiguration, as exemplified by
ginsenosides Rh4 (1), (20E)ꢀRh3 (2), Rg6 (3) and Rk1 (4) (Fig. 1).3,4,5,6 Among them, Rh4, Rh3 and Rk1 have
shown potent antiꢀtumor activities in different cancer cell lines either by their cytotoxicity or by their
capacity to induce apoptosis.7,8,9 Moreover, Rh4 demonstrated hepatocytoprotective and nephroprotective
activities,10 as well as immunological adjuvant effect.11 (20E)ꢀRh3 exhibited potent inhibitory effect against
dermatitis induced by oxazolone,12 whereas Rk1 displayed strong antiꢀvascular permeability and antiꢀplatelet
aggregation activities,13 and a potential atopic dermatitis effect.14 Recently, Rk1 and other ꢁ20ꢀginsenosides
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have also been isolated from Centella asiatica (L.) Urban (Apiaceae family),15 and we believe that novel
structures will be reported in the future due to the improvement of analytical techniques.
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As plant extracts, ginsenosides are produced in heterogeneous mixtures and in low yields, which renders
their isolation difficult and hampers their biological studies. To overcome these difficulties, our group has
devoted a persistent effort on the chemical syntheses of all kind of ginsenosides with the aim of producing
homogeneous compounds in appreciable amounts and hence, accelerates their structureꢀactivity relationship
study.16, 17 More recently, we reported a convenient and effective synthesis of natural and synthetic
ocotillolꢀtype ginsenosides.18 As a part of our continuous effort, we report herein the first chemical syntheses
of ꢁ20ꢀginsenosides Rh4 (1), (20E)ꢀRh3 (2), Rg6 (3) and Rk1 (4), which, to the best of our knowledge, have
never been reported so far. The syntheses were conveniently achieved via a direct glycosylation between the
appropriate ꢁ20ꢀsapogenin acceptor and a glycosyl orthoꢀalkynylbenzoate donor under gold(I)ꢀcatalysis. The
neutral condition of this protocol, developed in our group, is essential to keep intact the acidꢀlabile C20ꢀC21
double bond.19
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Name
ꢀ
R1
R2
ginsenoside Rh4 (1)
isoginsenoside Rh3 (2)
ginsenoside Rg6 (3)
ginsenoside Rk1 (4)
20,22(E)
20,22(E)
20,21
20,21
H
OꢀGlc
Glc
H
H
OꢀGlc2ꢀ1Rha
Glc2ꢀ1Glc
H
Figure 1. Representative ꢁ20ꢀginsenosides (1ꢁ4). Glc = βꢀ
Dꢀglucopyranosyl; Rha = αꢀLꢀrhamnopyranosyl.
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RESULTS AND DISCUSSION
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The synthesis commenced with the preparation and separation of all type of ꢁ20ꢀsapogenins via dehydration
of the 20ꢀOH of the corresponding partially protected 20(S)ꢀPPT and 20(S)ꢀPPD. Previously, we reported the
reactivity sequence of the four hydroxyl groups of 20(S)ꢀPPT to be 12ꢀOH > 3ꢀOH > 6ꢀOH >> 20ꢀOH.17
Based on this result, the 3ꢀ, 6ꢀ and 12ꢀOHs of 20(S)ꢀPPT were selectively acetylated, providing the
corresponding 3,6,12ꢀtriꢀOAcꢀ20(S)ꢀol PPT in 88% yield, which was then subjected to dehydration (Scheme
1). We have already observed that under glycosylation conditions promoted by TMSOTf or
AgOTf/2,6ꢀlutidine,17b this alcohol undergoes dehydration with modest stereoselectivity, the three possible
ꢁ20ꢀisomers being isolated in mixture. Aiming to dehydrate in a stereoselective manner, other reaction
conditions, including TsOH.H2O,20 POCl3/pyridine,21 PPh3/I2,22 and Burgess’ reagent,23 were attempted.
However, depending on the conditions, modest stereoselectivity was observed and a mixture of
ꢁ20ꢀsapogenins 5/6(E)/6(Z) was isolated in a comparable ratio, 6(E) being the major isomer. The best yield
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1
was obtained using POCl3/pyridine (93%), with a 5/6(E)/6(Z) H NMR ratio of 2:6:1, respectively. At this
step, a careful column chromatography enabled us to separate and isolate 6(Z) in 11% yield for which the
position of the double bond between the C20ꢀC22 with a Zꢀconfiguration was confirmed by Xꢀray diffraction
analysis (CCDC1414226, Fig. 2. left). However, olefins 5 and 6(E) remained inseparable at this stage.
Consequently, a modification of the protecting group pattern was then carried out in order to separate these
two isomers. After full deacetylation under basic conditions (KOH, CH3OH), the 3ꢀ and 12ꢀOHs were
selectively protected as tertꢀbutyldimethylꢀsilyl ethers (TBSCl, imidazole, DMF) and the remaining 6ꢀOHs
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were acetylated (Ac2O, Py, DMAP). At this stage, the corresponding 3,12ꢀdiꢀOTBSꢀ6ꢀOAc olefins 7 and 8(E)
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could be separated and isolated as pure compounds in 21% and 55% yields, respectively, over 3 steps.
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Scheme 1. Synthesis of ꢁ20ꢀPPT sapogenins.
As depicted in Scheme 2, a similar approach was adopted for the synthesis of ꢁ20ꢀPPD sapogenins. The 3ꢀ
and 12ꢀOHs of 20(S)ꢀPPD were selectively protected as acetates in 82% yield. Then, dehydration using
POCl3/pyridine provided a mixture of the three isomers 9/10(E)/10(Z) in 85% yield and in a 1H NMR ratio of
2:6:1, respectively. As previously, the ꢁ20,22(Z)ꢀisomer 10(Z) could be separated from 9 and 10(E), inseparable
at this stage. In that case, full deacetylation enabled us to separate and isolate 11 and 12(E) in 28% and 65%
yields, respectively. A single crystal of 12(E) was subjected to Xꢀray diffraction analysis and confirmed the
position of the double bond between the C20ꢀC22 as well as the Eꢀconfiguration (CCDC1414221, Fig. 2.
right).
Scheme 2. Synthesis of ꢁ20ꢀPPD sapogenins.
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Figure 2. The ORTEP drawing of 6(Z) (left, CCDC1414226) and 12(E) (right, CCDC1414221) were represented with thermal
ellipsoids shown at 30% probability; the solvent of crystallization have been omitted for clarity.
The preparation and separation of all type of ꢁ20ꢀsapogenins paved the way for the synthesis of
ꢁ20ꢀginsenosides 1ꢀ4. As a key step, the sugar units were attached to the sapogenins by a gold(I)ꢀcatalyzed
glycosylation with glycosyl orthoꢀalkynylbenzoate donors. A benzoyl group was installed at the 2ꢀposition of
the donors in order to ensure the required 1,2ꢀtrans glycosidic linkage.
As illustrated in Scheme 3, the acetyl group at the 6 position of ꢁ20ꢀgenin 8(E) was removed under basic
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condition
(95%)
and
the
corresponding
6ꢀOH
acceptor
was
coupled
with
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7
2,3,4,6ꢀtetraꢀOꢀbenzoylꢀ
Dꢀglucopyranosyl orthoꢀcyclopropylethynylbenzoate donor 13 under the promotion
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of Ph3PAuNTf2 in CH2Cl2 at room temperature. Given the low reactivity of the 6ꢀOH, in order to increase the
glycosylation yield while reducing the orthoester byꢀproduct as discovered previously,17 higher loading of
promoter (0.5 eq.) was employed and the desired 6ꢀOꢀglucoside 14(E) was isolated in an excellent 95% yield.
It is worth mentioning that this glycosylation could also be performed at 40 ºC without affecting the yield and
the stable C20ꢀC22 double bond. Then, desilylation was achieved with a HF·pyridine complex in Py/THF at
room temperature. Under these conditions, even the stable 3ꢀOTBS was cleanly removed. Finally,
saponification of the benzoyl groups afforded ginsenoside Rh4 (1) in an excellent 94% yield over 2 steps.
Similarly, the 12ꢀOH of 12(E) was protected as silyl ether (54%) and the remaining 3ꢀOH was
glycosylated with 13 under the promotion of Ph3PAuNTf2 in CH2Cl2. The 3ꢀOH of PPDꢀsapogenins being
more reactive than the 6ꢀOH of PPTꢀsapogenins,17 the glycosylation proceeded smoothly with 0.2 eq. of
promoter at room temperature and provided the corresponding 3ꢀOꢀglucoside 15(E) in 79% yield. The TBS
group was then cleanly removed with a HF·pyridine complex and subsequent saponification of the benzoyl
groups furnished isoginsenoside Rh3 (2) in 83% over 2 steps.
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Scheme 3. Synthesis of 1 and 2
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TBSO
H
OH
H
H
H
12
12
1) KOH, THF/CH3OH, overnight, 95%;
1) HF.Py, Py/THF, 0 C-rt, 6h;
2) KOH, CH3OH, rt, overnight.
13
2) , Ph3PAuNTf2 (0.5 eq.)
5Å MS, CH2Cl2, rt, 2h, 95%
H
H
3
3
8(E)
6
6
TBSO
BzO
HO
HO
H
94% for 2 steps
H
14(E)
1
O
O
BzO
O
O
O
BzO
BzO
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O
BzO
BzO
HO
HO
BzO
OBz
OH
O
13
1) TBSCl, imidazole, DMF,
C-rt, 2h, 54%;
2) , Ph3PAuNTf2 (0.2 eq.)
5Å MS, CH2Cl2, rt, 2h, 79%
TBSO
OH
H
H
0
13
H
H
1) HF.Py, THF, 3h;
2) KOH, CH3OH, rt,
overnight
BzO
HO
12(E)
H
H
O
O
BzO
BzO
BzO
HO
HO
83% for 2 steps
O
15(E)
O
2
H
H
HO
For the synthesis of ginsenosides Rg6 (3) and Rk1 (4), a stepwise glycosylation strategy was adopted in
order to control the 1,2ꢀtrans configuration of the two glycosidic bonds. As depicted in Scheme 4, the acetyl
group of ꢁ20ꢀgenin 7 was firstly removed under basic conditions, yielding the corresponding
3,12ꢀdiꢀOTBSꢀ6ꢀol (95%). Due to our stepwise glycosylation strategy, the “super armed”
2ꢀOꢀbenzoylꢀ3,4,6ꢀtriꢀOꢀbenzylꢀDꢀglucopyranosyl orthoꢀcyclopropylethynylbenzoate 16 was used as a donor
in order to improve the nucleophilicity of the future 2’ꢀOH acceptor.17 The coupling between the
3,12ꢀdiꢀOTBSꢀ6ꢀol sapogenin and 16 proceeded smoothly with 0.5 eq. of Ph3PAuNTf2 at room temperature
and furnished the 6ꢀOꢀglucoside 17 in quantitative yield. It is worth mentioning that heating to 40 ºC resulted
in partial isomerization of the C20ꢀC21 double bond, thus decreasing the yield of the desired glycoside.
Removal of the benzoyl group under basic conditions (> 99%) afforded the corresponding 2’ꢀOH acceptor,
which
was
effectively
coupled
with
2,3,4ꢀtriꢀOꢀbenzoylꢀLꢀrhamnopyranosyl
orthoꢀcyclopropylethynylbenzoate donor 18. Under the promotion of 0.5 eq. of Ph3PAuNTf2, the desired
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fully protected ꢁ20ꢀginsenoside 19 was obtained in 84% yield. At this point, the deprotection sequence rose to
be crucial for preserving the C=C bond from isomerization and reduction. Indeed, the usual hydrogenolytic
conditions (H2/Pd cat.) employed to remove benzyl groups would also reduce the C=C bonds. 24
Consequently, other reducing systems such as Li/NH3 and Li/naphthalene were tested.25,26 In any order,
Li/NH3 removed the benzyl groups but also reduced the C=C bonds. The system Li/naphthalene did not
removed the benzyl groups cleanly if the TBS and benzoyl groups were previously removed. However, the
same system worked smoothly at ꢀ20ºC on the fully protected ꢁ20ꢀginsenoside 19. Indeed, the reduction of
the three benzyl groups occurred first, followed by the cleavage of the three benzoyl groups after a prolonged
reaction. Final desilylation with a HF·pyridine complex provided the desired ginsenoside Rg6 (3) in 82%
yield over 2 steps.
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Scheme 4. Synthesis of 3
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Following a similar approach, the 12ꢀOH of ꢁ20ꢀgenin 11 was firstly protected as silyl ether (57%, Scheme
5). The remaining 3ꢀOH was coupled with donor 16 under the promotion of Ph3PAuNTf2 (0.2 eq.) at room
temperature, affording the corresponding 3ꢀOꢀglucoside 20 in quantitative yield. Subsequent saponification
provided the corresponding 2’ꢀOH acceptor which was then glycosylated with donor 13 (0.5 eq. of
Ph3PAuNTf2), furnishing the fully protected ꢁ20ꢀginsenoside 21 in a good 81% yield (2 steps). Concerning
the deprotection sequence, similar results as the ones obtained with 19 were noted with 21. The three benzyl
and four benzoyl groups were smoothly removed with Li/naphthalene at ꢀ20 ºC without affecting the C=C
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bonds. The TBS group was finally cleaved with a HF·pyridine complex, leading to ginsenosides Rk1 (4) in
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6
7
68% yield over 2 steps.
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Scheme 5. Synthesis of 4
1) TBSCl, imidazole, DMF,
TBSO
0 °C-rt, 2h, 57%;
H
H
2) 16, Ph3PAuNTf2 (0.2 eq.)
5Å MS, CH2Cl2, rt, 2h, >99%
11
BnO
BzO
H
O
O
BnO
20
H
BnO
1) KOH, THF/CH3OH, rt,
overnight, >99%;
2) 13, Ph3PAuNTf2 (0.5 eq.)
5Å MS, CH2Cl2, rt, 2h, 81%
TBSO
H
H
H
BnO
BnO
O
O
H
BnO
21
O
O
BzO
BzO
BzO
OH
H
OBz
H
HO
H
H
O
1) Li/Naphthalene, THF, -20 C, overnight;
2) HF.Py, Py/THF, 0 C-rt, 3h
O
HO
HO
O
O
HO
4
68% for 2 steps
HO
HO
OH
CONCLUSION
In conclusion, we reported the first chemical syntheses of four representative ꢁ20ꢀginsenosides, namely
ginsenosides Rh4 (1), (20E)ꢀRh3 (2), Rg6 (3) and Rk1 (4). Our strategy relied on (1) the preparation and
separation of all type of ꢁ20ꢀsapogenins, (2) a gold(I)ꢀcatalyzed glycosylation between the ꢁ20ꢀsapogenins
and glycosyl orthoꢀalkynylbenzoate donors, (3) orthogonal deprotection which prevents the C=C bonds
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present on the ꢁ20ꢀsapogenins from isomerization and reduction. Following this rational, syntheses of
ꢁ20ꢀginsenosides 1ꢀ4 were conveniently and effectively achieved in longest 7ꢀ11 linear steps. We assume that
this strategy represents a general and valuable approach to access dehydrated ginsenosides.
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EXPERIMENTAL SECTION
General Information. All reactions were carried out under N2 or Ar with anhydrous solvents in flameꢀdried
glassware, unless otherwise noted. All glycosylation reactions were performed in the presence of 5Å
molecular sieves, which were flameꢀdried under high vacuum immediately before use in the reaction.
Glycosylation solvents were dried using a solvent purification system and used directly without further
drying. The chemicals used were reagent grade as supplied, except where noted. Analytical thinꢀlayer
chromatography was performed using silica gel 60 F254 glass plates. Compound spots were visualized by
UV light (254 nm) and by heating with a solution with 10% H
was performed on silica gel and RPꢀ18. NMR spectra were referenced using Me
(1H NMR δ = 7.26 ppm, 13C NMR δ = 77.23 ppm), or C5D5N (1H NMR δ = 7.22 ppm, 13C NMR δ = 123.87
2
SO
4
in ethanol. Flash column chromatography
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Si (0 ppm), residual CDCl3
ppm). Peak and coupling constant assignments are based on H NMR, Hꢀ1H COSY, and Hꢀ13C HSQC
1
1
1
experiments. Splitting patterns are indicated as s (singlet), d (doublet), t (triplet), q (quartet), and brs (broad
1
singlet) for H NMR data. Highꢀresolution mass spectra were recorded on ESIꢀTOF and MALDIꢀFT
spectrometers. Optical rotations were measured on a polarimeter using either CHCl3 or CH3OH as solvent.
Protopanaxadiol (20(S)ꢀPPD) and protopanaxatriol (20(S)ꢀPPT) were prepared readily from the crude
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extract of ginseng following the known procedure.17,27 Glucosyl donors 13, 16, and rhamnosyl donor 18
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were synthesized according to literature procedures.19,28
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General procedure for gold(I)ꢁcatalyzed glycosylation with orthoꢁalkynylbenzoate donors. To a flask
were added the glycosyl donor, the ꢁ20ꢀsapogenin acceptor and freshly activated 5Å molecular sieves (weight
equal to the combined weight of the donor and acceptor). The flask was evacuated and refilled with Ar and
this process was repeated for three times. Then, CH2Cl2 was added and the resulting mixture was stirred at
room temperature for 30 min. After 30 min, PPh3AuNTf2 was added and the mixture was stirred at room
temperature until control TLC showed complete consumption of the donor. The reaction mixture was filtered
through a pad of Celite® and the filtrate was evaporated under vacuum. The resulting residue was purified by
silica gel column chromatography to provide the coupled glycosides.
General saponification procedure. KOH was added to a solution of the esterified compound in CH3OH
(and/or THF) and the mixture was stirred at room temperature or reflux. When control TLC showed complete
consumption of the esterified compound, the reaction mixture was cooled to room temperature and the
solvents were evaporated under reduced pressure. The resulting residue was then purified by silica gel
column chromatography to provide the corresponding alcohol.
3β,6α,12βꢀTriꢀOꢀacetylꢀ5R, 9R, 13Rꢀdammaraneꢀ(Z)ꢀ20(22),24(25)ꢀdiene (6Z). Ac2O (3.0 mL) was added
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dropwise to a solution of 20(S)ꢀPPT (500 mg, 1.05 mmol) in pyridine (3.0 mL) at 0 C. After complete
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addition, the ice bath was removed and the resulting mixture was stirred at room temperature overnight. The
mixture was then diluted with EtOAc and successively washed with saturated aqueous NaHCO3, 1 aqueous
M
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HCl and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum
ether/EtOAc, 6:1) to provide the 3β,6α,12βꢀtriꢀOꢀacetylꢀ5R, 9R, 13Rꢀ20(S)ꢀprotopanaxatriol (557 mg, 88%)
as a white solid.
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3β,6α,12βꢀTriꢀOꢀacetylꢀ20(S)ꢀprotopanaxatriol (557 mg，0.92 mmol) was dissolved in pyridine (30 mL)
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and POCl3 (3.0 mL) was added dropwise at ꢀ20 C. The resulting mixture was allowed to warm to room
temperature and was stirred overnight. The mixture was then diluted with EtOAc and successively washed
with water, 1
M
aqueous HCl and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was
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concentrated under reduced pressure. At this stage, H NMR analysis showed that the crude residue is
composed of a mixture of 5/6(E)/6(Z) with a 1H NMR ratio of 2:6:1. The crude residue was purified by silica
gel column chromatography (petroleum ether/EtOAc, 15:1) to provide an inseparable mixture of 5/6(E) (444
mg, 82%) and 6(Z) (57 mg, 11%) as a white solid.
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6(Z): [α]25 = +12.2 (c 1.0, CHCl3); m.p. 175ꢀ178 C; H NMR (400 MHz, CDCl3) δ 5.40ꢀ5.31 (m, 1H),
D
5.08ꢀ4.97 (m, 2H), 4.91 (td, J = 11.5, 8.3 Hz, 1H), 4.47 (dd, J = 12.1, 4.4 Hz, 1H), 2.98 (dd, J = 16.2, 10.1 Hz,
1H), 2.67 (dd, J = 14.8, 7.4 Hz, 1H), 2.58 (dd, J = 14.9, 7.2 Hz, 1H), 2.05 (s, 6H), 1.87 (s, 3H), 1.67 (s, 3H),
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1.65 (s, 3H), 1.61 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.92 (s, 3H); C NMR (101
MHz, CDCl3) δ 170.8, 170.3, 170.2, 137.2, 131.0, 124.0, 123.6, 80.0, 77.2, 73.9, 70.3, 58.6, 50.9, 49.7, 46.5,
42.4, 40.9, 39.3, 38.3, 37.7, 32.0, 30.3, 28.0, 27.8, 26.4, 25.7, 23.1, 22.0, 21.2, 20.8, 17.6, 17.2, 16.84, 16.77,
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16.6; IR: ṽ = 3444, 2952, 2872, 1732, 1459, 1399, 1370, 1244, 1162, 1147, 1122, 1105, 1071, 1019, 975, 922,
900, 867, 807, 659, 606, 547, 512, 493 cm−1; HRMS (ESI) calcd for C36H57O6 [M+H]+ 585.4150, found
585.4151.
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3β,12βꢀDiꢀOꢀtertꢀbutyldimethylsilylꢀ6αꢀOꢀacetylꢀ5R, 9R, 13Rꢀdammaraneꢀ20(21),24(25)ꢀdiene (7) and
3β,12βꢀdiꢀOꢀtertꢀbutyldimethylsilylꢀ6αꢀOꢀacetylꢀ5R, 9R, 13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdiene (8E). The
inseparable mixture of 5/6(E) (1.012 g, 1.76 mmol) was subjected to the general saponification procedure
with KOH (146 mg, 2.6 mmol) in CH3OH (10 mL) at reflux for 5 hours. After workup, purification by silica
gel column chromatography (petroleum ether/EtOAc, 3:1) provided the corresponding of 3β,6α,12βꢀtriols
(724 mg, 90%) in mixture as a white solid.
The two 3β,6α,12βꢀtriols (724 mg, 1.58 mmol) and imidazole (516 mg, 7.9 mmol) were dissolved in DMF
o
(7.0 mL) and cooled to 0 C (ice bath). TBSCl (1.19 g, 7.9 mmol) was then added and the resulting mixture
was stirred at room temperature for 4 hours and TLC showed complete consumption of the 3β,6α,12βꢀtriols.
The mixture was then diluted with EtOAc and successively washed with 1
M aqueous HCl and brine. The
organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 20:1) to provide
the corresponding 3β,12βꢀdiꢀOTBSꢀ6αꢀols (922 mg, 85%) in mixture as a white solid.
Ac2O (2.0 mL) was added dropwise to a solution of the two 3β,12βꢀdiꢀOTBSꢀ6αꢀols (200 mg, 0.29 mmol)
o
and DMAP (17.7 mg, 0.15 mmol) in pyridine (5.0 mL) at 0 C. After complete addition, the ice bath was
removed and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with
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EtOAc and successively washed with saturated aqueous NaHCO3, 1
M aqueous HCl and brine. The organic
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layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 250:1) to afford 7 (60 mg,
28%) and 8(E) (155 mg, 72%) separately, as white solids.
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7: [α]25D = +28.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.33 (td, J = 10.3, 5.1 Hz, 1H), 5.16 (brs,
1H), 4.75 (s, 1H), 4.60 (s, 1H), 3.53 (td, J = 10.1, 4.6 Hz, 1H), 3.17 (dd, J = 10.9, 4.5 Hz, 1H), 2.50 (td, J =
10.7, 6.1 Hz, 1H), 2.04 (s, 3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.15 (s, 3H), 1.09 (s, 3H), 0.99 (s, 3H), 0.90 (s, 3H),
13
0.89 (s, 9H), 0.83 (s, 9H), 0.80 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), ꢀ0.00 (s, 3H), ꢀ0.04 (s, 3H); C NMR (126
MHz, CDCl3) δ 170.2, 152.5, 131.1, 124.8, 107.6, 78.9, 73.2, 70.9, 58.8, 50.9, 50.1, 49.2, 47.8, 42.8, 40.8,
39.4, 39.2, 38.6, 32.7, 32.5, 32.1, 30.7, 30.6, 27.4, 26.2, 26.0, 25.9, 25.7, 22.0, 18.13, 18.08, 17.7, 17.3, 16.93,
16.87, 16.1, ꢀ3.6, ꢀ4.3, ꢀ4.7, ꢀ5.0; IR: ṽ = 2957, 2933, 2855, 1724, 1637, 1472, 1463, 1387, 1362, 1248, 1191,
1101, 1061, 1023, 969, 937, 921, 896, 884, 836, 774, 670, 630, 614, 574, 512, 478 cm−1; HRMS (ESI) calcd
for C44H80O4Si2Na [M+Na]+ 751.5487, found 751.5481.
8(E): [α]25D = +29.3 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.34 (td, J = 10.5, 4.6 Hz, 1H), 5.11 (t,
J = 6.8 Hz, 1H), 5.03 (t, J = 6.6 Hz, 1H), 3.55 (td, J = 10.2, 4.8 Hz, 1H), 3.18 (dd, J = 11.2, 4.7 Hz, 1H),
2.75ꢀ2.65 (m, 1H), 2.64ꢀ2.56 (m, 1H), 2.44 (td, J = 10.7, 6.4 Hz, 1H), 2.04 (s, 3H), 1.69 (s, 3H), 1.62 (s, 3H),
1.56 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H), 0.90 (s, 12H), 0.84 (s, 9H), 0.81 (s, 3H), 0.06 (s,3H),
13
0.05 (s, 3H), 0.00 (s, 3H), ꢀ0.05 (s, 3H); C NMR (126 MHz, CDCl3) δ 170.2, 138.3, 130.8, 123.9, 122.3,
79.0, 73.1, 70.9, 58.8, 50.9, 50.1, 49.3, 49.0, 42.8, 40.8, 39.4, 39.2, 38.6, 32.7, 32.0, 30.7, 30.1, 27.4, 27.0,
26.0, 25.9, 25.7, 22.0, 18.13, 18.06, 17.7, 17.3, 17.02, 16.95, 16.1, 13.0, ꢀ3.6, ꢀ4.4, ꢀ4.6, ꢀ5.0; IR: ṽ = 2958,
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2934, 2855, 1723, 1471, 1462, 1386, 1364, 1248, 1192, 1100, 1070, 1023, 967, 936, 922, 896, 886, 849, 835,
815, 773, 669, 618, 567, 516, 437 cm−1; HRMS (ESI) calcd for C44H80O4Si2Na [M+Na]+ 751.5487, found
751.5482.
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3β,12βꢀDiꢀOꢀacetylꢀ5R, 9R, 13Rꢀdammaraneꢀ(Z)ꢀ20(22),24(25)ꢀdiene (10Z). Ac2O (7.5 mL) was added
dropwise to a solution of 20(S)ꢀPPD (1.0 g, 2.17 mmol) in pyridine (7.5 mL) at 0 oC. After complete addition,
the ice bath was removed and the resulting mixture was stirred at room temperature overnight. The mixture
was then diluted with EtOAc and successively washed with saturated aqueous NaHCO3, 1M aqueous HCl and
brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc,
7:1) to provide the 3β,12βꢀdiꢀOꢀacetylꢀ20(S)ꢀprotopanaxadiol (967 mg, 82%) as a white solid.
3β,12βꢀDiꢀOꢀacetylꢀ20(S)ꢀprotopanaxadiol (300 mg，0.55 mmol) was dissolved in pyridine (15 mL) and
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POCl3 (1.5 mL) was added dropwise at ꢀ20 C. The resulting mixture was allowed to warm to room
temperature and was stirred overnight. The mixture was then diluted with EtOAc and successively washed
with water, 1
M
aqueous HCl and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was
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concentrated under reduced pressure. At this stage, H NMR analysis showed that the crude residue is
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composed of a mixture of 9/10(E)/10(Z) with a H NMR ratio of 2:6:1. The crude residue was purified by
silica gel column chromatography (petroleum ether/EtOAc, 30:1) to furnish an inseparable mixture of 9/10(E)
(225mg, 77%) and 10(Z) (24 mg, 8%) as a white solid.
10(Z): [α]25D = ꢀ28.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.06ꢀ4.99 (m, 2H), 4.93 (td, J = 11.0,
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5.3 Hz, 1H), 4.49 (dd, J = 11.4, 4.4 Hz, 1H), 2.99 (dd, J = 17.5, 10.7 Hz, 1H), 2.69 (dt, J = 15.0, 7.3 Hz, 1H),
2.61ꢀ2.53 (m, 1H), 2.05 (s, 3H), 1.87 (s, 3H), 1.68 (s, 3H), 1.65 (s, 3H), 1.62 (s, 3H), 1.04 (s, 3H), 0.99 (s,
3H), 0.90 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 170.9, 170.3, 137.5, 130.9, 123.8,
123.7, 80.6, 74.4, 55.8, 51.1, 50.3, 47.0, 40.0, 38.7, 37.9, 37.2, 34.8, 32.1, 28.1, 28.0, 27.9, 26.4, 25.7, 23.6,
21.3, 20.8, 18.1, 17.6, 16.7, 16.5, 16.2, 15.6; IR: ṽ = 2962, 2852, 1731, 1653, 1463, 1392, 1362, 1246, 1199,
1144, 1106, 1022, 983, 955, 926, 900, 859, 803, 657, 609, 597, 554, 501 cm−1; HRMS (ESI) calcd for
C34H55O4 [M+H]+ 527.4095, found 527.4093.
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5R,
9R,
13RꢀDammaraneꢀ20(21),24(25)ꢀdieneꢀ3β,12βꢀdiol
(11)
and
5R,
9R,
13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdieneꢀ3β,12βꢀdiol (12E). The inseparable mixture of 9/10(E) (912 mg,
1.77 mmol) was subjected to the general saponification procedure with KOH (495 mg, 8.85 mmol) in
CH3OH (10 mL) at reflux for 4 hours. After workup, purification by silica gel column chromatography
(petroleum ether/EtOAc, 10:1) provided 11 (215mg, 28%) and 12(E) (500 mg, 65%) as white solids.
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11: [α]25 = +22.0 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 5.14 (t, J = 5.8 Hz, 1H), 5.03 (s, 1H),
D
4.79 (s, 1H), 3.70 (td, J = 10.5, 5.1 Hz, 1H), 3.20 (dd, J = 11.4, 4.8 Hz, 1H), 2.69ꢀ2.54 (m, 1H), 1.70 (s, 3H),
13
1.63 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.78 (s, 3H); C NMR (126 MHz, CDCl3)
δ 155.5, 131.9, 124.1, 109.2, 78.8, 73.3, 55.9, 50.81, 50.78, 50.4, 48.0, 40.1, 39.0, 38.9, 37.2, 35.0, 32.3, 30.9,
29.1, 28.0, 27.4, 26.8, 25.7, 18.3, 17.8, 16.7, 16.2, 15.7, 15.4; IR: ṽ = 3424, 3080, 2961, 2870, 2726, 1635,
1450, 1387, 1295, 1262, 1189, 1118, 1080, 1026, 958, 930, 872, 802, 647, 578, 503 cm−1; HRMS (ESI) calcd
for C30H50O2Na [M+ Na]+ 465.3703, found 465.3704.
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12(E): [α]25 = ꢀ9.3 (c 1.0, CHCl3); m.p. 112ꢀ114 C ; H NMR (500 MHz, CDCl3) δ 5.39 (t, J = 7.0 Hz,
D
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1H), 5.05 (t, J = 7.0 Hz, 1H), 3.72 (td, J = 10.4, 5.2 Hz, 1H), 3.19 (dd, J = 11.4, 4.7 Hz, 1H), 2.76ꢀ2.55 (m,
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3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.87 (s, 6H), 0.77 (s, 3H); C NMR
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(126 MHz, CDCl3) δ 140.3, 132.1, 124.7, 122.1, 78.8, 73.3, 55.9, 50.5, 50.3, 50.2, 50.1, 40.1, 39.0, 38.9, 37.2,
35.0, 32.4, 30.4, 28.0, 27.4, 27.3, 27.0, 25.6, 18.2, 17.7, 16.7, 16.2, 15.6, 15.3, 12.4; IR: ṽ = 3404, 3067, 2958,
1712, 1641, 1452, 1388, 1345, 1296, 1257, 1189, 1118, 1079, 1024, 957, 928, 876, 846, 824, 646, 579, 514
cm−1; HRMS (ESI) calcd for C30H50O2Na [M+ Na]+ 465.3703, found 465.3706.
3β,12βꢀDiꢀOꢀtertꢀbutyldimethylsilylꢀ6αꢀOꢀ(2’,3’,4’,6’ꢀtetraꢀOꢀbenzoylꢀβꢀ
D
ꢀglucopyranosyl)ꢀ5R,
9R,
13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdiene (14E). 8(E) (135 mg, 0.18 mmol) was subjected to the general
saponification procedure with KOH (31 mg, 0.56 mmol) in a solvent mixture of CH3OH (1.0 mL)/THF (1.0
mL) at room temperature overnight. After workup, purification by silica gel column chromatography
(petroleum ether/EtOAc, 20:1) yielded the corresponding 3β,12βꢀdiꢀOTBSꢀ6αꢀol (121 mg, 95%) as a white
solid.
The aforementioned 3β,12βꢀdiꢀOꢀTBSꢀ6αꢀol (86 mg, 0.12 mmol) was subjected to the general
glycosylation procedure with donor 13 (191 mg, 0.25 mmol), PPh3AuNTf2 (46 mg, 0.062 mmol) and CH2Cl2
(2.0 mL) at room temperature for 2 hours. After workꢀup, purification by silica gel column chromatography
(petroleum ether/EtOAc, 20:1) afforded 14(E) (150 mg, 95%) as a white solid.
14(E): [α]25D = +20.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 2H), 7.91 (t, J =
7.5 Hz, 4H), 7.79 (d, J = 7.6 Hz, 2H), 7.59ꢀ7.17 (m, 12H), 5.92 (t, J = 9.6 Hz, 1H), 5.68ꢀ5.58 (m, 2H),
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5.21ꢀ5.06 (m, 2H), 5.00 (t, J = 6.4 Hz, 1H), 4.66ꢀ4.55 (m, 1H), 4.52 (dd, J = 12.1, 5.4 Hz, 1H), 4.29ꢀ4.22 (m,
1H), 4.07ꢀ4.00 (m, 1H), 3.52ꢀ3.44 (m, 1H), 2.99 (dd, J = 11.3, 4.4 Hz, 1H), 2.76ꢀ2.65 (m, 1H), 2.64ꢀ2.56 (m,
1H), 2.44ꢀ2.29 (m, 1H), 2.06ꢀ2.00 (m, 1H), 1.70 (s, 3H), 1.63 (s, 3H), 1.49 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H),
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0.85 (s, 3H), 0.82 (s, 12H), 0.71 (s, 9H), 0.66 (s, 3H), ꢀ0.02 (s, 3H), ꢀ0.07 (s, 6H), ꢀ0.18 (s, 3H); C NMR
(126 MHz, CDCl3) δ 166.2, 165.8, 165.2, 165.1, 138.4, 133.4, 133.14, 133.11, 133.0, 130.7, 129.82, 129.79,
129.7, 129.6, 129.4, 128.84, 128.81, 128.4, 128.3, 128.2, 128.1, 123.9, 122.2, 102.6, 80.9, 79.6, 73.5, 73.2,
72.2, 69.7, 63.6, 60.2, 50.8, 50.0, 49.2, 49.0, 45.3, 41.0, 39.3, 39.2, 38.6, 32.7, 31.7, 30.4, 30.0, 27.14, 27.06,
26.0, 25.9, 25.7, 18.1, 18.0, 17.7, 17.4, 16.9, 16.0, 13.0, ꢀ3.7, ꢀ4.4, ꢀ4.6, ꢀ5.2; IR: ṽ = 3063, 2957, 2855, 1739,
1603, 1585, 1472, 1452, 1390, 1362, 1316, 1262, 1178, 1104, 1068, 1027, 1004, 972, 934, 898, 886, 851,
835, 804, 773, 708, 686 cm−1; HRMS (MALDI) calcd for C76H104O12Si2Na [M+Na]+ 1287.6959, found
1287.6982.
6αꢀOꢀβꢀDꢀGlucopyranosylꢀ5R, 9R, 13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdieneꢀ3β,12βꢀdiol (1). HF·Py (1.0 mL)
was added to a solution of 14(E) (50 mg, 0.040 mmol) in pyridine (1.0 mL) and THF (4.0 mL) at 0 oC. After
addition, the mixture was stirred at room temperature for 6 hours and TLC showed complete consumption of
14(E). Then saturated aqueous NaHCO3 was added to quench the reaction. The two layers were separated
and the aqueous one was extracted with EtOAc. The organic layers were combined and successively washed
with 1M aqueous HCl and brine, and dried over Na2SO4. The solvents were evaporated under vacuum and the
resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 2:1) to provide
the corresponding 3β,12βꢀdiol intermediate as a white solid.
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The aforementioned 3β,12βꢀdiol intermediate was subjected to the general saponification procedure with
KOH (8.8 mg, 0.16 mmol) in CH3OH (2.0 mL) at room temperature overnight . After workup, purification by
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RPꢀ18 column chromatography (CH3OH/H2O, 5:1) yielded 1 (23 mg, 94% over 2 steps) as a white solid.
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1: [α]25 = +21.0 (c 1.0, CH3OH); H NMR (500 MHz, pyridineꢀd5 + one drop D2O) δ 5.46 (t, J = 6.7 Hz,
D
1H), 5.19 (t, J = 6.5 Hz, 1H), 4.98 (d, J = 7.7 Hz, 1H), 4.48 (m, 1H), 4.40 (td, J = 10.4, 2.3 Hz, 1H), 4.32 (dd,
J = 11.5, 5.3 Hz, 1H), 4.26 (t, J = 8.9 Hz, 1H), 4.17 (t, J = 9.2 Hz, 1H), 4.05 (t, J = 8.3 Hz, 1H), 3.97ꢀ3.83 (m,
2H), 3.49 (dd, J = 11.3, 4.5 Hz, 1H), 2.77ꢀ2.67 (m, 2H), 2.52ꢀ2.46 (m, 1H), 2.02 (s, 3H), 1.80 (s, 3H), 1.60 (s,
13
3H), 1.57 (s, 3H), 1.54 (s, 3H), 1.21 (s, 3H), 0.99 (s, 3H), 0.82 (s, 3H); C NMR (126 MHz, pyridineꢀd5) δ
140.0, 131.2, 123.8, 123.4, 105.9, 80.0, 79.6, 78.5, 78.0, 75.4, 72.5, 71.7, 63.0, 61.4, 50.8, 50.6, 50.5, 50.3,
45.2, 41.2, 40.3, 39.7, 39.4, 32.4, 32.2, 31.6, 28.7, 27.8, 27.4, 25.6, 17.65, 17.63, 17.3, 16.7, 16.3, 13.0;
HRMS (MALDI) calcd for C36H60O8Na [M+Na]+ 643.4180, found 643.4151.
3βꢀOꢀ(2’,3’,4’,6’ꢀTetraꢀOꢀbenzoylꢀβꢀ
D
ꢀglucopyranosyl)ꢀ12βꢀdiꢀOꢀtertꢀbutyldimethylsilylꢀ5R,
9R,
13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdiene (15E). 12(E) (112 mg, 0.25 mmol) and imidazole (34 mg, 0.51
o
mmol) were dissolved in DMF (1.0 mL) and cooled to 0 C (ice bath). TBSCl (76 mg, 0.51 mmol) was then
added and the resulting mixture was stirred at room temperature for 2 hours and TLC showed complete
consumption of 12(E). The mixture was then diluted with EtOAc and successively washed with 1
M aqueous
HCl and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum
ether/EtOAc, 50:1 to 5:1) to provide the corresponding 12βꢀOTBSꢀ3βꢀol (77 mg, 54%) as a white solid.
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The aforementioned 12βꢀOTBSꢀ3βꢀol (85 mg, 0.15 mmol) was subjected to the general glycosylation
procedure with donor 13 (175 mg, 0.23 mmol), PPh3AuNTf2 (22 mg, 0.030 mmol) and CH2Cl2 (2.0 mL) at
room temperature for 2 hours. After workꢀup, purification by silica gel column chromatography (petroleum
ether/EtOAc, 20:1) yielded 15(E) (137 mg, 79%) as a white solid.
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15(E): [α]25D = +33.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.96 (d, J =
7.6 Hz, 2H), 7.93 (d, J = 7.7 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.57ꢀ7.48 (m, 3H), 7.45ꢀ7.37 (m, 6H),
7.33ꢀ7.24 (m, 3H), 5.93 (t, J = 9.7 Hz, 1H), 5.66ꢀ5.57 (m, 2H), 5.12 (t, J = 6.6 Hz, 1H), 5.04 (t, J = 6.6 Hz,
1H), 4.89 (d, J = 7.9 Hz, 1H), 4.65 (dd, J = 11.9, 2.8 Hz, 1H), 4.51 (dd, J = 11.9, 6.4 Hz, 1H), 4.19ꢀ4.12 (m,
1H), 3.56 (td, J = 9.9, 4.7 Hz, 1H), 3.15 (dd, J = 11.7, 4.3 Hz, 1H), 2.75ꢀ2.65 (m, 1H), 2.67ꢀ2.57 (m, 1H),
2.46 (td, J = 10.6, 6.5 Hz, 1H), 1.70 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 0.98 (s, 3H), 0.86 (s, 12H), 0.84 (s,
3H), 0.70 (s, 3H), 0.67 (s, 3H), 0.03 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 166.0, 165.9,
165.3, 165.0, 138.6, 133.4, 133.2, 133.10, 133.08, 130.7, 129.83, 129.75, 129.72, 129.70, 129.68, 129.4,
128.85, 128.81, 128.4, 128.33, 128.28, 124.0, 122.2, 103.2, 90.6, 73.3, 73.0, 72.2, 72.0, 70.2, 63.5, 56.1, 51.0,
50.5, 49.4, 39.8, 39.0, 38.8, 36.8, 34.9, 32.8, 32.0, 30.2, 27.6, 27.1, 26.0, 25.7, 18.1, 17.7, 17.0, 16.2, 16.0,
15.7, 13.1, ꢀ4.1, ꢀ4.5; IR: ṽ = 3063, 2960, 2856, 1735, 1602, 1585, 1452, 1389, 1368, 1315, 1263, 1177, 1093,
1068, 1027, 973, 935, 889, 858, 836, 800, 774, 709, 686, 639, 505 cm−1; HRMS (MALDI) calcd for
C70H90O11SiNa [M+Na]+ 1157.6145, found 1157.6153.
3βꢀOꢀβꢀ
D
ꢀGlucopyranosylꢀ5R, 9R, 13Rꢀdammaraneꢀ(E)ꢀ20(22),24(25)ꢀdieneꢀ12βꢀol (2). HF·Py (0.2 mL)
o
was added to a solution of 15(E) (91 mg, 0.080 mmol) in THF (2.0 mL) at 0 C. After addition, the mixture
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extracted with EtOAc. The organic layers were combined and successively washed with 1M aqueous HCl and
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brine, and dried over Na2SO4. The solvents were evaporated under vacuum and the resulting residue was
purified by silica gel column chromatography (petroleum ether/EtOAc, 7:1) to provide the corresponding
12βꢀol intermediate (81 mg, > 99%) as a white solid.
The aforementioned 12βꢀol intermediate (50 mg, 0.049 mmol) was subjected to the general saponification
procedure with KOH (27 mg, 0.49 mmol) in CH3OH (1.0 mL) at room temperature overnight. After workup,
purification by silica gel column chromatography (CH2Cl2/CH3OH, 15:1) yielded 2 (25 mg, 83%) as a white
solid.
1
2: [α]25D = +2.1 (c 1.0, CH3OH); H NMR (500 MHz, pyridineꢀd5) δ 5.51 (t, J = 6.8 Hz, 1H), 5.22 (t, J =
6.5 Hz, 1H), 4.95 (d, J = 7.7 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 4.40 (dd, J = 11.5, 5.3 Hz, 1H), 4.27ꢀ4.17 (m,
2H), 4.07ꢀ3.98 (m, 2H), 3.95ꢀ3.88 (m, 1H), 3.38 (dd, J = 11.5, 3.9 Hz, 1H), 2.85ꢀ2.75 (m, 2H), 2.25ꢀ2.15 (m,
1H), 1.82 (s, 3H), 1.62 (s, 3H), 1.58 (s, 3H), 1.32 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.81 (s, 3H);
13C NMR (126 MHz, pyridineꢀd5) δ 140.1, 131.2, 123.7, 123.4, 106.9, 88.7, 78.7, 78.4, 75.8, 72.5, 71.8, 63.0,
56.4, 51.0, 50.9, 50.7, 50.4, 40.2, 39.6, 39.2, 37.0, 35.3, 32.6, 32.2, 28.8, 28.1, 27.4, 26.7, 25.7, 18.4, 17.7,
17.0, 16.8, 16.4, 15.8, 13.1; HRMS (MALDI) calcd for C36H60O7Na [M+Na]+ 627.4231, found 627.4224.
3β,12βꢀDiꢀOꢀtertꢀbutyldimethylsilylꢀ6αꢀOꢀ(2’ꢀOꢀbenzoylꢀ3’,4’,6’ꢀtriꢀOꢀbenzylꢀβꢀDꢀglucopyranosyl)ꢀ5R, 9R,
13Rꢀdammaraneꢀ20(21),24(25)ꢀdiene (17). 7 (140 mg, 0.19 mmol) was subjected to the general
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saponification procedure with KOH (32 mg, 0.57 mmol) in a solvent mixture of CH3OH (1.0 mL)/THF (1.0
mL) at room temperature overnight. After workup, purification by silica gel column chromatography
(petroleum ether/EtOAc, 20:1) provided the corresponding 3β,12βꢀdiꢀOTBSꢀ6αꢀol intermediate (125 mg,
95%) as a white solid.
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The aforementioned 3β,12βꢀdiꢀOTBSꢀ6αꢀol intermediate (88 mg, 0.13 mmol) was subjected to the general
glycosylation procedure with donor 16 (185 mg, 0.26 mmol), PPh3AuNTf2 (47 mg, 0.064 mmol) in CH2Cl2
(1.0 mL) at room temperature for 2 hours. The reaction was quenched by addition of NEt3 and after workꢀup,
purification by silica gel column chromatography (petroleum ether/EtOAc, 25:1) afforded 17 (152 mg, >
99%) as a white solid.
17: [α]25D = +24.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.3
Hz, 1H), 7.42ꢀ7.19 (m, 12H), 7.17ꢀ7.03 (m, 5H), 5.36 (t, J = 8.1 Hz, 1H), 5.20 (brs, 1H), 4.82 (d, J = 11.0 Hz,
1H), 4.8ꢀ4.7 (m, 3H), 4.66ꢀ4.59 (m, 4H), 4.54 (d, J = 12.0 Hz, 1H), 3.95 (t, J = 9.3 Hz, 1H), 3.82 (t, J = 8.9
Hz, 1H), 3.80ꢀ3.73 (m, 2H), 3.69 (d, J = 10.2 Hz, 1H), 3.62ꢀ3.56 (m, 1H), 3.51 (td, J = 10.0, 4.7 Hz, 1H),
2.99 (dd, J = 11.3, 4.4 Hz, 1H), 2.50 (td, J = 10.7, 6.2 Hz, 1H), 1.73 (s, 3H), 1.65 (s, 3H), 1.05 (s, 3H), 0.92
(s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.84 (s, 9H), 0.72 (s, 9H), 0.64 (s, 3H), ꢀ0.01 (s, 3H), ꢀ0.04 (s, 3H), ꢀ0.06
(s, 3H), ꢀ0.17 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.2, 152.7, 138.1, 138.0, 137.7, 132.9, 131.0, 130.1,
129.9, 128.4, 128.3, 128.2, 128.15, 128.0, 127.8, 127.64, 127.60, 127.59, 124.9, 107.5, 103.0, 83.3, 80.6,
79.6, 78.2, 75.2, 75.0, 74.9, 73.9, 73.3, 69.4, 60.2, 51.0, 50.1, 49.3, 47.9, 45.3, 41.1, 39.3, 39.2, 38.6, 32.8,
32.4, 31.9, 30.6, 30.5, 27.2, 26.2, 26.0, 25.9, 25.8, 18.1, 18.0, 17.7, 17.4, 17.3, 16.8, 15.9, ꢀ3.7, ꢀ4.3, ꢀ4.6, ꢀ5.2;
HRMS (MALDI) calcd for C76H110O9Si2Na [M+Na]+ 1245.7581, found 1245.7642.
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3β,12βꢀDiꢀOꢀtertꢀbutyldimethylsilylꢀ6αꢀOꢀ[2’’,3’’,4’’ꢀtriꢀOꢀbenzoylꢀαꢀ
Lꢀrhamnopyranosylꢀ(1→2)ꢀ3’,4’,6’ꢀtriꢀ
7
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Oꢀbenzylꢀβꢀ ꢀglucopyranosyl)ꢀ5R, 9R, 13Rꢀdammaraneꢀ20(21),24(25)ꢀdiene (19). 17 (120 mg, 0.10 mmol)
D
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was subjected to the general saponification procedure with KOH (28 mg, 0.50 mmol) in a solvent mixture of
CH3OH (1.0 mL)/THF (1.0 mL) at room temperature overnight. After workup, purification by silica gel
column
chromatography
(petroleum
ether/EtOAc,
25:1)
furnished
the
corresponding
3β,12βꢀdiꢀOTBSꢀ6αꢀOGlcꢀ2’ꢀol intermediate (113 mg, > 99%) as a white solid.
The aforementioned 3β,12βꢀdiꢀOTBSꢀ6αꢀOGlcꢀ2’ꢀol intermediate (77 mg, 0.069 mmol) was subjected to the
general glycosylation procedure with donor 18 (88 mg, 0.14 mmol), PPh3AuNTf2 (25 mg, 0.034 mmol) in
CH2Cl2 (1.5 mL) at room temperature for 2 hours. The reaction was quenched by addition of NEt3 and after
workꢀup, purification by silica gel column chromatography (petroleum ether/EtOAc, 30:1) provided 19 (91
mg, 84%) as a white solid.
19: [α]25D = +29.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 7.5 Hz, 2H), 7.97 (d, J = 7.4
Hz, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H),
7.41 (t, J = 7.6 Hz, 3H), 7.39 ꢀ7.19 (m, 14H), 7.04 (t, J = 7.4 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 5.83ꢀ5.77 (m,
2H), 5.62 (t, J = 9.8 Hz, 1H), 5.52 (s, 1H), 5.20 (t, J = 6.6 Hz, 1H), 4.93 (d, J = 10.9 Hz, 1H), 4.88ꢀ4.80 (m,
4H), 4.76 (s, 1H), 4.67ꢀ4.57(m, 4H), 4.40 (td, J = 10.5, 3.4 Hz,1H), 3.90ꢀ3.84 (m, 2H), 3.84ꢀ3.74 (m, 3H),
3.60ꢀ3.55 (m, 1H), 3.51 (td, J = 10.2, 4.6 Hz, 1H), 3.23 (dd, J = 11.2, 4.7 Hz, 1H), 2.49 (td, J = 10.8, 6.0 Hz,
1H), 1.71 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.33 (d, J = 6.1 Hz, 3H), 1.07 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H),
13
0.89 (s, 9H), 0.85 (s, 9H), 0.82 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H), ꢀ0.03 (s, 3H), ꢀ0.07 (s, 3H); C NMR (126
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MHz, CDCl3) δ 165.8, 165.2, 165.1, 152.6, 138.2, 138.0, 137.9, 133.2, 133.1, 132.8, 131.1, 129.92, 129.86,
129.7, 129.65, 129.57, 129.5, 128.44, 128.39, 128.2, 128.1, 127.9, 127.8, 127.7, 127.67, 127.66, 127.6, 127.4,
124.9, 107.6, 99.8, 97.8, 85.8, 79.9, 78.6, 77.2, 76.2, 75.48, 75.46, 74.8, 74.0, 73.4, 72.6, 72.0, 70.5, 69.7,
69.3, 66.5, 60.7, 51.0, 49.9, 49.3, 47.8, 46.0, 40.8, 39.8, 39.2, 39.0, 32.8, 32.6, 32.2, 31.8, 30.7, 27.5, 26.2,
26.07, 26.05, 25.95, 25.8, 18.15, 18.12, 17.7, 17.4, 17.3, 17.2, 17.0, 16.8, ꢀ3.7, ꢀ4.3, ꢀ4.6, ꢀ5.0; IR: ṽ = 3064,
3031, 2958, 2855, 1733, 1640, 1603, 1585, 1497, 1471, 1452, 1391, 1361, 1315, 1262, 1206, 1177, 1105,
1068, 1027, 934, 898, 885, 836, 803, 773, 753, 709, 616, 516, 459 cm−1; HRMS (MALDI) calcd for
C96H128O15Si2Na [M+Na]+ 1599.8684, found 1599.8748.
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6αꢀOꢀ[αꢀ
L
ꢀRhamnopyranosylꢀ(1→2)ꢀβꢀ
D
ꢀglucopyranosyl]ꢀ5R,
9R,
13Rꢀdammaraneꢀ20(21),24(25)ꢀdieneꢀ3β,12βꢀdiol (3). A solution of 19 (50 mg, 0.032 mmol) in THF (1.0 mL)
was added dropwise to a solution of Li (11 mg, 1.6 mmol) and naphthalene (406 mg, 3.2 mmol) in THF (2.0
mL) at ꢀ20 oC. The resulting mixture was stirred at the same temperature overnight. Saturated aqueous NH4Cl
was then added to quench the reaction and the solvents were evaporated under vacuum. The resulting residue
was purified by silica gel column chromatography (CH2Cl2/CH3OH, 25:1) to lead to the corresponding
debenzylated and debenzoylated glycoside intermediate as a white solid.
HF·Py (0.5 mL) was added to a solution of the aforementioned glycoside intermediate in a solvent mixture
of pyridine (0.5 mL)/THF (2.0 mL) at 0 oC. After addition, the mixture was stirred at room temperature for 6
hours and TLC showed complete consumption of the glycoside intermediate. NEt3 was then added to quench
the reaction and the solvents were evaporated under vacuum. The resulting residue was purified by RPꢀ18
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column chromatography (CH3OH/H2O, 3:1) to yield 3 (20 mg, 82% over 2 steps) as a white solid.
3: [α]25D = ꢀ4.3 (c 1.0, CH3OH); 1H NMR (500 MHz, pyridineꢀd5) δ 6.56 (s, 1H), 5.37 (t, J = 6.8 Hz, 1H),
5.34 (d, J = 6.9 Hz, 1H), 5.18 (s, 1H), 5.03 (dt, J = 15.5, 6.1 Hz, 1H), 4.95 (s, 1H), 4.86 (d, J = 2.4 Hz, 1H),
4.78 (dd, J = 10.7, 3.3 Hz, 1H), 4.74 (dd, J = 9.3, 3.5 Hz, 1H), 4.60 (dd, J = 11.4, 2.4 Hz, 1H), 4.49ꢀ4.36 (m,
4H), 4.28 (t, J = 9.0 Hz, 1H), 4.07ꢀ4.01 (m, 1H), 3.97 (td, J = 10.3, 5.0 Hz, 1H), 3.55 (dd, J = 11.6, 4.8 Hz,
1H), 2.84 (td, J = 10.6, 6.0 Hz, 1H), 2.19 (s, 3H), 1.86 (d, J = 6.2 Hz, 3H), 1.74 (s, 3H), 1.66 (s, 3H), 1.43 (s,
10
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13
3H), 1.32 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H); C NMR (101 MHz, pyridineꢀd5) δ 155.5, 131.2, 125.4, 108.1,
102.0, 101.8, 79.5, 78. 6, 78.4, 78.3, 74.4, 74.2, 72.6, 72.5, 72.3, 69.5, 63.1, 60.9, 52.1, 51.2, 50.2, 48.3, 46.2,
41.4, 40.0, 39.7, 39.5, 33.7, 32.8, 32.6, 32.2, 30.7, 27.8, 27.1, 25.8, 18.8, 17.8, 17.6, 17.2, 16.9; HRMS
(MALDI) calcd for C42H70O12Na [M+Na]+ 789.4760, found 789.4724.
3βꢀOꢀ(2’ꢀOꢀBenzoylꢀ3’,4’,6’ꢀtriꢀOꢀbenzylꢀβꢀ
D
ꢀglucopyranosyl)ꢀ12βꢀOꢀtertꢀbutyldimethylsilylꢀ5R,
9R,
13Rꢀdammaraneꢀ20(21),24(25)ꢀdiene (20). 11 (170 mg, 0.39 mmol) and imidazole (52 mg, 0.77 mmol) were
o
dissolved in DMF (1.5 mL) and cooled to 0 C. TBSCl (116 mg, 0.77 mmol) was then added and the
resulting mixture was stirred at room temperature for 2 hours and TLC showed complete consumption of 11.
The mixture was then diluted with EtOAc and successively washed with 1
M aqueous HCl and brine. The
organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc, 50:1 to 5:1) to
provide the corresponding 12βꢀOTBSꢀ3βꢀol intermediate (123 mg, 57%) as a white solid.
The aforementioned 12βꢀOTBSꢀ3βꢀol intermediate (42 mg, 0.075 mmol) was subjected to the general
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glycosylation procedure with donor 16 (82 mg, 0.11 mmol), PPh3AuNTf2 (11 mg, 0.015 mmol) in CH2Cl2
(1.0 mL) at room temperature for 2 hours. The reaction was quenched by addition of NEt3 and after workꢀup,
purification by silica gel column chromatography (petroleum ether/EtOAc, 20:1 to 15:1) furnished 20 (82
mg, > 99%) as a white solid.
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20: [α]25D = +42.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.3
Hz, 1H), 7.44 (t J = 7.7 Hz, 2H), 7.42ꢀ7.25 (m, 10H), 7.19ꢀ7.13 (m, 5H), 5.37 (t, J = 8.7 Hz, 1H), 5.20 (brs,
1H), 4.88 (d, J = 10.9 Hz, 1H), 4.78 (d, J = 10.8 Hz, 2H), 4.71 (d, J = 11.2 Hz, 1H), 4.69ꢀ4.61 (m, 4H), 4.59
(d, J = 7.9 Hz, 1H), 3.90ꢀ3.79 (m, 2H), 3.79ꢀ3.69 (m, 2H), 3.65ꢀ3.50 (m, 2H), 3.09 (dd, J = 11.6, 4.1 Hz, 1H),
2.54 (td, J = 10.7, 6.1 Hz, 1H), 1.73 (s, 3H), 1.65 (s, 3H), 1.01 (s, 3H), 0.88 (s, 15H), 0.70 (s, 3H), 0.65 (s,
3H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.1, 152.8, 138.3, 138.0, 137.9, 132.9,
131.1, 130.1, 129.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.61, 127.57, 124.9, 107.5, 103.4,
89.7, 82.9, 78.3, 75.1, 75.04, 75.02, 74.2, 73.5, 73.4, 69.0, 56.2, 51.0, 50.6, 49.6, 47.9, 39.8, 39.0, 36.8, 35.0,
32.8, 32.6, 32.1, 30.7, 27.7, 26.22, 26.16, 26.0, 25.8, 25.4, 18.11, 18.07, 17.7, 16.9, 16.3, 16.0, 15.7, ꢀ4.2, ꢀ4.6;
HRMS (MALDI) calcd for C70H96O8SiNa [M+Na]+ 1115.6767, found 1115.6807.
3βꢀOꢀ[2’’,3’’,4’’,6’’ꢀTetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosylꢀ(1→2)ꢀ3’,4’,6’ꢀtriꢀOꢀbenzylꢀβꢀDꢀglucopyranosyl)ꢀ1
2βꢀOꢀtertꢀbutyldimethylsilylꢀ5R, 9R, 13Rꢀdammaraneꢀ20(21),24(25)ꢀdiene (21). 20 (100 mg, 0.091 mmol)
was subjected to the general saponification procedure with KOH (25 mg, 0.46 mmol) in a solvent mixture of
CH3OH (2.0 mL)/THF (1.0 mL) at room temperature overnight. After workup, purification by silica gel
column
chromatography
(petroleum
ether/EtOAc,
20:1)
provided
the
corresponding
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12βꢀOTBSꢀ3βꢀOGlcꢀ2’ꢀol intermediate (90 mg, > 99%) as a white solid.
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The aforementioned 12βꢀOꢀTBSꢀ3βꢀOꢀGlcꢀ2’ꢀol intermediate (64 mg, 0.065 mmol) was subjected to the
general glycosylation procedure with donor 13 (98 mg, 0.13 mmol), PPh3AuNTf2 (24 mg, 0.032 mmol) in
CH2Cl2 (1.0 mL) at room temperature for 2 hours. The reaction was quenched by addition of NEt3 and after
workꢀup, purification by silica gel column chromatography (petroleum ether/EtOAc, 10:1) afforded 21 (82
mg, 81%) as a white solid.
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21: [α]25D = +11.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 7.3 Hz, 2H), 7.90 (d, J = 7.4
Hz, 2H), 7.86 (d, J = 7.4 Hz, 2H), 7.82 (d, J = 7.4 Hz, 2H), 7.54ꢀ7.20 (m, 25H), 7.12 (dd, J = 6.4, 2.7 Hz, 2H),
5.86 (t, J = 9.7 Hz, 1H), 5.71 (t, J = 9.7 Hz, 1H), 5.57 (dd, J = 9.6, 8.2 Hz, 1H), 5.41 (d, J = 8.0 Hz, 1H), 5.21
(t, J = 6.7 Hz, 1H), 4.78 (s, 1H), 4.70ꢀ4.57 (m, 7H), 4.54 (t, J = 11.3 Hz, 1H), 4.45 (dd, J = 12.1, 4.8 Hz, 1H),
4.39 (d, J = 7.7 Hz, 1H), 4.11ꢀ4.02 (m, 1H), 3.94ꢀ3.92 (m, 1H), 3.72 (d, J = 9.5 Hz, 1H), 3.63 (dd, J = 10.8,
5.1 Hz, 1H), 3.60ꢀ3.48 (m, 3H), 3.44ꢀ3.37 (m, 1H), 3.10 (dd, J = 11.7, 4.5 Hz, 1H), 2.55 (td, J = 10.9, 5.9 Hz,
1H), 1.73 (s, 3H), 1.65 (s, 3H), 1.18 (s, 3H), 1.02 (s, 3H), 0.91 (s, 3H), 0.86 (s, 9H), 0.81 (s, 3H), 0.79 (s, 3H),
0.03 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 166.2, 165.8, 165.1, 165.0, 152.9, 138.25, 138.17,
137.8, 133.3, 133.13, 133.08, 132.9, 131.0, 129.9, 129.8, 129.7, 129.2, 128.9, 128.8, 128.6, 128.36, 128.35,
128.3, 128.24, 128.22, 127.82, 127.76, 127.59, 127.58, 127.5, 124.9, 107.4, 103.7, 100.6, 90.3, 85.6, 78.6,
78.0, 75.3, 74.8, 74.6, 73.5, 73.4, 73.2, 72.4, 72.0, 69.9, 69.0, 63.2, 56.3, 51.1, 50.6, 49.7, 47.9, 39.9, 39.4,
39.0, 36.8, 35.1, 32.9, 32.6, 32.1, 30.7, 27.7, 26.22, 26.16, 26.0, 25.7, 18.1, 18.0, 17.7, 16.9, 16.3, 16.2, 15.7,
ꢀ4.2, ꢀ4.6; IR: ṽ = 3448, 3064, 3032, 2927, 2855, 1964, 1738, 1638, 1602, 1585, 1496, 1452, 1388, 1360,
1315, 1264, 1214, 1178, 1093, 1068, 1026, 937, 889, 862, 836, 801, 773, 735, 709, 502 cm−1; HRMS
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