Synthetic access toward the diverse ginsenosides

Article abstract of DOI:10.1039/c3sc51479j

All the possible types of the protopanaxatriol and protopanaxadiol glycosides, the major active yet extremely heterogeneous principles of ginsengs, could be accessed by the present sequence of transformations, including global removal of the sugar residue

Full text of DOI:10.1039/c3sc51479j

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Synthetic Access Toward the Diverse Ginsenosides
Jun Yu, Jiansong Sun,* Yiming Niu, Rongyao Li, Jinxi Liao, Fuyi Zhang, Biao Yu†,*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
All the possible types of the protopanaxatriol and protopanaxadiol glycosides, the major active yet
extremely heterogeneous principles of ginsengs, could be accessed by the present sequence of
transformation, including global removal of the sugar residues from the crude ginseng extracts and
stepwise elaboration of the glycans onto the aglycone. In particular, an intramolecular hydrogenꢀbonding
and neutral condition have enabled glycosylation of the highly sterically hindered and acid labile
10 dammarane C20ꢀOH.
INTRODUCTION
R4O
H
R3O
12
Ginseng or the panax genus plants, literally ‘man root’ in Chinese
or ‘panacea’ in Greek, are one of the most magical and widely
used Oriental medicines.1 It has been claimed to be effective in
15 improving diabetes, cardiovascular disorders, immune functions,
vitality, sexual function, and cognitive and physical performance.
The major active principles in ginseng are recognized to be the
dammarane glycosides, which indeed have shown numerous
pharmacological activities, including immunostimulatory,
20
H
H
6
3
R1O
H
OR2
1 (Ginsenoside F3): R1 = R2 = R3 = H, R4
=
-
L
-Arap-(1-6)- -
α
β
D-Glc
β
-D-Glc
(Chikusetsusaponin L10): R1 = R2 = R4 = H, R3
=
2
3
(Ginsenoside Rh1): R1 = R3 = R4 = H, R2
=
=
-
-D
D
-Glc
-Glc
β
β
20 antiatherosclerotic,
antihypertensive,
antidiabetic,
4 (Ginsenoside Rg1): R1 = R3 = H, R2 = R4
anticarcinogenic, and CNS protective activities.2 These
ginsenosides occur in such a heterogeneous manner that over 200
ginsenosides, mainly the protopanaxadiol and protopanaxatriol
glycosides, have been identified from Panax genus.2c Biological
25 studies on homogeneous ginsenosides have been limited to only a
very few of the major components such as ginsenosides Re and
Rb1. Chemical glycosylation of dammaranes could provide
homogeneous ginsenosides, however, this is hampered by the
difficulty in glycosylation of the sterically hindered and acid
30 labile dammarane derivatives.3,4 Especially, glycosylation of the
protopanaxatriol derivatives to prepare protopanaxatriol
ginsenosides have never been reported.5
5 (Ginsenoside la): R2 = R3 = H, R1 = R4
β
= -D-Glc
HO
O
OH
L
-Arap
6 (Ginsenoside Rb2):
O
O
OH
HO
HO
O
HO
OH
D
-Glc
OH
HO
HO
HO
HO
HO
O
O
O
O
OH
The numerous protopanaxatriol ginsenosides can be
categorized into five types,2 i.e., the 20ꢀOꢀglycosides, 12ꢀOꢀ
35 glycosides, 6ꢀOꢀglycosides, 6,20ꢀOꢀbisglycosides, and 3,20ꢀOꢀ
bisglycosides, as examplified by ginsenoside F3 (1),
chikusetsusaponin L10 (2), ginsenoside Rh1 (3), ginsenoside Rg1
(4), and ginsenoside Ia (5), respectively (Fig. 1). Among them
ginsenosides 1, 3, and 4 show immunomodulatory activities,6
50 Fig. 1 Representative ginsenosides.
Results and Discussion
Acquisition of protopanaxatriol and –diol and differentiation
of the dammarane hydroxyl groups. The total saponin extract
of Panax ginseng, containing extremely heterogeneous
55 ginsenosides, is commercially available and very cheap (~0.3
$/g). Treatment of the plant extract (60 g) with air under basic
conditions (0.2 g/mL NaOEt, BuOH, air, 90 oC) led to full
cleavage of the glycosidic linkages, providing the homogeneous
protopanaxatriol (7, 8 g) and protopanaxadiol (2 g) conveniently
60 via silica gel column chromatography.3g,10 Differentiation of the
3,6,12,20ꢀhydroxyl groups on protopanaxatriol was then
examined (Scheme 1).
40 ginsenoside
5
shows
inhibitory
effect
against
hypoxia/reoxygenation induced protein tyrosine kinase
activation,7 and ginsenoside 3 induces apoptosis of human
leukemia cell lines.8 Herein, we report divergent syntheses of
these representative protopanaxatriol ginsenosides (1-5) as well
45 as ginsenoside Rb2 (6, which shows potent immunosuppressive
and antidiabetic activities)9 representing the most complex type
protopanaxadiol ginsenosides.
Treatment of tetraol 7 with Ac2O in pyridine at rt afforded
3,6,12ꢀtriacetate 8 in 87% yield, with the tertiary 20ꢀOH
65 remaining intact. The 12ꢀOꢀacetyl group on 8 was selectively
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removed under the effect of NaOMe in MeOH at rt, providing
12,20ꢀdiol 9 (98%). Treatment of 7 with PivCl and Et3N in
CH2Cl2 at rt led cleanly to the 12ꢀOꢀpivaloylated derivative 10
(89%). Subjection of triol 10 to silylation with TBSCl and
Thus, the perbenzoyl glucopyranosyl trifluoroacetimidate 17
was examined first to condense with protopanaxatriol 20ꢀol 8 and
13 in the presence of 0.1 equiv of TMSOTf (4Å MS, CH2Cl2,
rt).13 However, the major products were determined to be the
5
imidazole in DMF provided the 3ꢀOꢀtertꢀbutyldimethylsilyl 35 olefin derivatives 24a (91%) and 24b (74%), respectively, with
derivative 11 as the major product (68%), with ~30% of the
starting material (10) being recovered. At this junction, the
reactivity sequence of the four OHs on protopanaxatriol (7)
became apparent that 12ꢀOH > 3ꢀOH > 6ꢀOH >> 20ꢀOH. In fact,
no coupled glycosides being detected (Scheme 2, entries 1 and
2).14 We then examined the glycosylation of the acid labile 8 and
13 with glucosyl bromide 18 in the presence of AgOTf and 2,6ꢀ
lutidine.15 However, this again resulted in dehydration of the
10 the most reactive 12ꢀOH could be etherified selectively. Thus, 40 acceptors (entries 3 and 4). Glycosyl sulfoxides are reputed for
treatment of tetraol 7 with allyl bromide (1.2 equiv) and NaH in
dry DMF at rt provided 12ꢀOꢀallyl ether 12 in a good 80% yield.
Acetylation of 3,6,20ꢀtriol 12 gave 20ꢀol 13 (84%). Alternatively,
triol 12 was silylated selectively to provide the 3ꢀOꢀTBS
glycosylation of poorly reactive acceptors,16 therefore,
perbenzoyl glucosyl sulfoxide 19 was employed to glycosylate 8
and 13 with Tf2O/DTBMP (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylꢀpyridine)
as promoter. However, the major products isolated were
15 derivative 14 (93%). Subsequent acetylation of 14 (86%) 45 determined to be the tolylsulfides 25a (47%) and 25b (72%),
followed by desilylation (95%) afforded 3,20ꢀdiol 16 via
intermediate 15.
respectively,14 which were derived from the addition of the 20ꢀ
OH to the C24(25) double bond induced by the in situ generated
tolylsulfenic trifluoromethanesulfonic anhydride (entries 5 and
6).17
HO
PivO
HO
HO
50
Our final resort to glycosylate the protopanaxatriol 20ꢀol 8 and
13 was to use glycosyl orthoꢀalkynylbenzoates as donors and
gold(I) complex as promoter under neutral conditions.18,19
Nevertheless, the condensation of 8 with perbenzoyl glucosyl oꢀ
cyclopropylethynylbenzoate 20 in the presence of PPh3AuNTf2
RO
AcO
9
OH
11 R = TBS
10 R = H
OAc
AcO
TBSCl, imidazole,
DMF, rt, 68%
NaOMe, MeOH,
rt, 98%
55 (0.15 equiv) was unsuccessful, with 8 being fully recovered
(entry 7). Gratifyingly, under similar conditions, condensation of
13 (which has the 12ꢀOꢀacetyl group in 8 being replaced with
allyl group) with 20 afforded the desired 20ꢀOꢀβꢀglucoside 22 in
a satisfactory ~80% yield (entry 8). This reaction was easily
60 reproducible at gram scale syntheses. Glycosylation of 13 with 6ꢀ
Oꢀtertꢀbutyldiphenylsilylꢀglucosyl oꢀcyclopropylethynylbenzoate
21, a more reactive donor than its 6ꢀOꢀbenzoate counterpart 20,20
led to 20ꢀOꢀβꢀglucoside 23 in a better yield of 88% (entry 9).
PivCl, Et3N, CH2Cl2, rt, 89%
HO
HO
OH
20
12
Ac2O, pyridine,
rt, 87%
3
6
AcO
HO
8
7
OAc
AllO
OH
AllBr (1.2 eq), NaH, DMF, 0 oC-rt, 80%
HO
HO
AllO
OR
O
OBz
O
Ac2O, pyridine,
rt, 84%
BzO
BzO
BzO
BzO
O
X
OBz
O
OBz
AcO
12
13
HO
17 X = OC(NPh)CF3
18
20
21
R = Bz
OAc
AllO
OH
R = TBDPS
α
X = -Br
TBSCl, imidazole, DMF, rt, 93%
β
19 X = -S(O)Tol
8 or 13
HO
HO
AllO
promoter, CH2Cl2,
4Å MS, rt
17-21 (2.0 equiv)
CSA, MeOH,
CH2Cl2, rt, 95%
STol
O
BzO
AllO
21
O
OR
TBSO
HO
16
OR
O
24
22
20
OR
OAc
14 R = H
15
Ac2O, DMAP,
pyridine, rt, 86%
R = Ac
Scheme 1. Full differentiation of the four hydroxyl groups on
20 protopanaxatriol (7).
24a
R = Ac
24b R = All
25a R = Ac
25b R = All
22 23
&
entry donor
acceptor
promoter (equiv)
product
yieldb
Glycosylation of the tertiary dammarane 20-OH. With the
hydroxyl groups in protopanaxatriol being fully differentiated,
glycosylation of these hydroxyl groups was explored. It was
anticipated that the glycosylation of the 20ꢀOH would be the most
25 challenging task, due to the high hindrance evidenced by its
resistance to acetylation (i.e., 7→8, 12→13, and 14→15).11 In
addition, this tertiary OH is prone to dehydration, as implied by
the biosynthetic route of protopanaxatriol in which the 20ꢀOH is
derived from quenching of a stable dammarenyl Cꢀ20 cation with
30 water.12
17
17
18
18
19
19
8
13
8
24a
24b
24a
24b
25a
25b
1
TMSOTf (0.1)
91%
2
TMSOTf (0.1)
74%
63%
37%
47%
3
AgOTf (1.1)/2,6-lutidine (0.9)
AgOTf (1.1)/2,6-lutidine (0.9)
Tf2O (1.1)/DTBMP (1.2)
13
8
4
5a
6a
13
Tf2O (1.1)/DTBMP (1.2)
Ph3PAuNTf2 (0.15)
Ph3PAuNTf2 (0.15)
Ph3PAuNTf2 (0.15)
72%
--
80%
88%
20
20
21
8
13
13
7
8
9
--
22
23
65
aThe reaction was conducted at ꢀ78 oC to rt. bIsolated yield.
2
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Scheme 2. Attempts at glycosylation of the dammarane 20ꢀol
derivatives 8 and 13.
An intramolecular H-bonding of the dammarane 20-OH
enabled its glycosidation. It was found, surprisingly, that the 12ꢀ
Oꢀsubstituent on protopanaxatriol, that has an acetyl group on 8
and an allyl group on 13, played a decisive role on the
glycosylation of the 20ꢀOH (cf., entry 7 and 8 in Scheme 2). This
promoted us to examine carefully the structural difference
5
10 between 8 and 13. Thus, single crystals of 8 and 13 were
crystallized and subjected to Xꢀray diffraction analysis.14,21 As
shown in Figure 2, a Hꢀbond of 1.900 Å in length is formed
between the H of the 20ꢀOH and the oxygen atom of the 12ꢀOꢀ
allyl ether in compound 13. In contrast, a homologous Hꢀbond in
15 the 12ꢀOꢀacetyl ester 8 is not formed, in that the distance between
the 20ꢀO and the 12ꢀO is 2.774 Å. Similar Hꢀbonding situation
was found in another pair of the dammarane derivatives, i.e., 3ꢀOꢀ
tertꢀbutyldimethylsilylꢀ6ꢀOꢀchloroacetylꢀ12ꢀOꢀallylꢀ
8
protopanaxatriol (S1) and 3,12ꢀdiꢀOꢀacetylꢀprotopanaxadiol
20 (S2).14,21 The intramolecular Hꢀbond in compound 13 (and in S1
as well) was also observed in solution and demonstrated to be
strong. Thus, the 1H NMR signal of the 20ꢀOH appeared at a
downfield of 5.30 ppm in CDCl3, which was not deuterated by
D2O22 and remained unchanged under varied concentrations.23 In
25 contrast, the 1H NMR signal of the 20ꢀOH in compound 8 (and in
S2 as well), which is not Hꢀbonded, was readily deuterated and
thus shown in low intensity. That no Hꢀbonding occurs in 8/S2
(in comparison to 13/S1) is attributable to the lone pair of the
oxygen overlaps with the antibonding CꢀO* orbital of the
30 carbonyl to lead to reduction of electron density of the oxygen
lone pair.
13
Fig. 2 ORTEP drawing of the protopanaxatriol derivatives 8 and
50 13.
Syntheses of the representative protopanaxatriol
ginsenosides 1-5. The successful construction of the challenging
20ꢀOꢀglycosidic linkage paved the way for divergent synthesis of
55 protopanaxatriol glycosides (Schemes 3 and 4). Subjection of 20ꢀ
Oꢀglucoside 23 to selective removal of the 6’ꢀOꢀTBDPS group
(TBAF, AcOH, THF, rt) provided 26 (70%), which was ready for
glycan elongation. Nevertheless, glycosylation of 26 with
It is conceivable that the Hꢀbonding of the 20ꢀOH to the 12ꢀO
in allyl ether 13 (but not to the less electron rich 12ꢀO in acetate 8)
increases the electron density at the 20ꢀO, thus makes this oxygen
35 a better nucleophile than the 20ꢀO in 8. Remarkably, this gain of
nucleophilicity (in acceptor 13) from intramolecular Hꢀbonding
enabled the glycosidation which otherwise could not proceed.24
Noteworthy is that a relevant Hꢀbonding could also account for
the previous success in the glycosylation of 3βꢀacetoxyꢀ20Sꢀ
40 hdyroxydammarꢀ24ꢀenꢀ12ꢀone.3g In fact, we have prepared the
corresponding protopanaxatriol 12ꢀketone derivative from 3,6ꢀ
perbenzoyl
Lꢀarabinopyranosyl alkynylbenzoate 27 led to the
60 desired disaccharide 28 in only moderate yield (~40%). The
existing 20ꢀOꢀglycosidic linkage (in 26 and 28) was found to be
highly sensitive toward acid and underwent elimination readily to
give the olefin derivative 24b. Finally, via strict exclusion of
moisture and lowering the catalyst Ph3PAuNTf2 loading to 0.06
65 equiv, the desired disaccharide 28 was obtained in a good 75%
yield. Global deprotection of 28, i.e., cleavage of the 12ꢀOꢀallyl
group followed by removal of the acetyl and benzoyl groups,
1
diacetate 9 (CrO3, pyridine, rt, 71%); the H NMR signal of its
20ꢀOH (at 3.10 ppm) was found undeuteratable, thus proving the
formation of Hꢀbond with the proximal 12ꢀoxo group.
45 Glycosylation of this 12ꢀketoneꢀ20ꢀol derivative under the
gold(I)ꢀcatalyzed conditions led expectedly to the corresponding
20ꢀOꢀglycoside in high yield.
provided ginsenoside F3 (1) (59% for two steps).
OBz
OR
O
BzO
BzO
O
BzO
O
BzO
O
BzO
BzO
BzO
OAll
12
O
PPh3AuNTf2 (0.06 eq),
4Å MS, CH2Cl2, rt, 75%
20
O
BzO
OAll
OBz
3
6
OAc
O
O
AcO
BzO
OBz
O
AcO
27
TBAF, AcOH,
THF, rt, 70%
23 R = TBDPS
26 R = H
OAc
28
1
1) PdCl2, MeOH, CH2Cl2, rt, 79%;
2) 10% KOH, MeOH, rt, 75%
70 Scheme 3. Synthesis of ginsenoside F3 (1).
Glycosylation of the protopanaxatriol 12,20ꢀdiol
9 with
perbenzoyl glucosyl oꢀalkynylbenzoate 20 proceeded smoothly
under the promotion of 0.2 equiv of Ph3PAuNTf2, leading
75 regioselectively to the expected 12ꢀOꢀglucoside 29 in a high 82%
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OBz
O
yield; the 20ꢀOꢀglycosylated products were not detected at all
(Scheme 4). Removal of the acyl groups on 29 (10% KOH,
MeOH, rt, 85%) provided chikusetsusaponin L10 (2).
BzO
BzO
HO
O
BzO
20
20
9
2
12
Similar glycosylation of the protopanaxatriol 6,20ꢀdiol 11 with
its 12ꢀOH being protected by pivaloyl group with 20 proceeded
apparently slower, and formation of the corresponding orthoester
byproduct was detected. This testified again that the reactivity of
the protopanaxatriol 6ꢀOH was much lower than that of the 12ꢀ
OH. Nevertheless, upon raising the gold(I) catalyst to 0.5 equiv,
10 the desired 6ꢀOꢀglucoside 30 was obtained in 78% yield. The
bulky 12ꢀOꢀpivaloyl group in 11 further blocked the tertiary 20ꢀ
OH toward substitution, so that no 20ꢀOꢀglycosylation could take
place. Removal of the 3ꢀOꢀTBS group on 30 was achieved
cleanly under mild acid conditions (camphorsulfonic acid,
15 MeOH, CH2Cl2, rt, 91%) without affecting the 6ꢀOꢀglycosidic
linkage. Subsequent cleavage of the acyl groups with 10% KOH
in MeOH furnished ginsenoside Rh1 (3) in 80% yield.
Glycosylation of 6,20ꢀdiol 14 with its 12ꢀOH being blocked by
an allyl group would lead to the protopanaxatriol 6,20ꢀOꢀ
20 bisglycosides. Considering that glycosylation of the 20ꢀOH in 13
with 6ꢀOꢀTBDPSꢀglucosyl alkynylbenzoate 21 gave better yield
than with the perbenzoyl donor 20, 21 (3.0 equiv) was selected as
the donor to couple with 6,20ꢀdiol 14. Thus, under the catalysis of
0.25 equiv of Ph3PAuNTf2, the desired 6,20ꢀOꢀbisglucoside 31
25 was isolated in a respectable 55% yield. Sequential removal of
the 12ꢀOꢀallyl group, the 3ꢀOꢀTBS group, the 6’,6’’ꢀdiꢀOꢀTBDPS
group, and the remaining acetyl and benzoyl groups on 31
delivered ginsenoside Rg1 (4) in 45% yield over 4 steps.
10% KOH,
MeOH, rt, 85%
PPh3AuNTf2 (0.2 eq),
4Å MS, CH2Cl2, rt, 82%
5
3
6
AcO
29
OAc
HO
PivO
PPh3AuNTf2 (0.5 eq),
4Å MS, CH2Cl2, rt, 78%
1) CSA, MeOH,
CH2Cl2, rt, 91%
11
3
20
2) 10% KOH,
MeOH, rt, 80%
TBSO
BzO
OBz
OBz
OBz
O
30
O
OTBDPS
1) PdCl2, MeOH,
CH2Cl2, rt, 71%
2) CAS, MeOH,
CH2Cl2, rt, 72%
O
BzO
BzO
O
PPh3AuNTf2 (0.25 eq),
BzO OAll
4Å MS, CH2Cl2, rt, 55%
4
14
3) TBAF, CH3COOH,
THF, rt;
4) 10% KOH, MeOH,
rt, 88%
21
TBSO
BzO
O
OBz
OBz
OTBDPS
O
31
OTBDPS
O
BzO
BzO
O
PPh3AuNTf2 (0.3 eq),
4Å MS, CH2Cl2, rt, 57%
BzO
OR
16
5
21
1) TBAF, CH3COOH,
THF, rt;
2) 10% KOH, MeOH,
rt, 73%
OTBDPS
O
O
Applying a similar approach as that for the synthesis of 6,20ꢀ
BzO
BzO
OAc
OBz
30 Oꢀbisglycoside
4,
protopanaxatriol
3,20ꢀOꢀbisglucoside
32
33
R = OAll
R = H
PdCl2, MeOH, CH2Cl2, rt, 79%
ginsenoside Ia (5) could also be obtained successfully via
intermediate 3,20ꢀOꢀbisglucosides 32 and 33.
35 Scheme 4. Syntheses of chikusetsusaponin L10 (2), ginsenoside
Rh1 (3), ginsenoside Rg1 (4), and ginsenoside Ia (5).
Synthesis of the representative complex type protopanaxadiol
ginsenoside Rb2 (6). The complex ginsenoside Rb2 (6), which
contains two different disaccharides at C3 and C20, respectively,
40 was synthesized as shown in Schemes 5 and 6. 3ꢀOꢀChloroacetylꢀ
12ꢀOꢀallylꢀprotopanaxadiol
34,
easily
prepared
from
protopanaxadiol in 2 steps and 71% yield (cf., 7→13),14 was
subjected to glycosylation with glucosyl alkynylbenzoate 21
under the previously optimized conditions (cf., 21+13→23) to
45 provide the desired 20ꢀOꢀglucoside 35 in a good 75% yield. We
found that the stability of the dammarane 20ꢀOꢀglycosidic linkage
was highly dependent on the protecting group at the proximal 12ꢀ
OH. The 12ꢀOꢀallylꢀ20ꢀOꢀglycosides (i.e., the previous 26/28 and
the present 35) underwent elimination easily in the presence of a
50 trace amount of acid, which is generated in situ and could usually
be consumed via protonolysis of the vinyl gold(I) intermediate in
the gold(I)ꢀcatalyzed glycosylation reaction.18c In contrast, the
12ꢀOꢀacetyl counterparts (e.g., 36) stayed intact even upon
treatment with 0.5 equivalents of TMSOTf. A rationale is that the
55 electron density on the 12ꢀO atom determines the propensity of
formation of the protonated intermediate [C20ꢀO(H+)ꢀsugar] for
the elimination of the glycoside.25 Thus, the 12ꢀOꢀallyl group in
35 was replaced with an acetyl group to afford 36. Subsequent
removal of the 6’ꢀOꢀTBDPS group led to 37, which was coupled
60 with arabinose alkynylbenzoate 27 to provide disaccharide 38 in
nearly quantitative yield. Selective removal of the 3ꢀOꢀ
chloroacetyl group (CA) on 38 was achieved with DABCO in
4
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DOI: 10.1039/C3SC51479J
EtOH to afford 39 (80%).26 Gold(I)ꢀcatalyzed coupling of C3ꢀol
perbenzoyl glucosyl alkynylbenzoate 4614,31 under the standard
39 with glucosyl alkynylbenzoate 40, which was installed with a 30 gold(I)ꢀcatalyzed conditions led to the desired tetrasaccharide 47
neighboringꢀparticipating and selectively removable 2ꢀ
(azidomethyl)benzoyl (AZMB) group,27 afforded the desired
glycoside in a high 80% yield. Subsequent cleavage of the 2’’’ꢀ
OꢀAZMB group with nBu3P in aqueous THF led to 41 (76%).
Unexpectedly, attempts at installation of a glucopyranose unit
onto the 2’’’ꢀOH in 41 was found to be futile. With perbenzoyl
glucopyranosyl imidate 17 or alkynylbenzoate 20 as donor, 41
in a good 84% yield. Finally, global removal of the protecting
groups, including one allyl, one benzylidene acetal, one acetyl,
and ten benzoyl groups, furnished ginsenoside Rb2 (6) (63%
yield for 3 steps).
5
OBz
O
BzO
O
BzO
O
Ph
BzO
O
O
10 stayed intact even under forced conditions (5 equiv. of the donor
in the presence of 0.2 equiv of TMSOTf or 1 equiv of
O
O
BzO
AllO
AZMBO
43
O
BzO
O
OAc
nBu
Ph3PAuNTf2,
respectively).
Employing
glucopyranosyl
20
12
39
alkynylbenzoate 42 as donor,28 which was equipped with a
‘superꢀarmed’ pattern of protecting groups,29 the coupling
15 reaction still hardly proceeded, with the coupled glycoside being
obtained in less than 20% yield under the promotion of 0.5 equiv
of Ph3PAuNTf2.14
PPh3AuNTf2 (0.2 eq),
5Å MS, CH2Cl2, rt, 83%
Ph
O
O
3
O
AllO
O
RO
44 R = AZMB
45 R = H
nBu3P, THF, H2O, rt, 61%
OTBDPS
O
BzO
BzO
OBz
OBz
HO
O
AllO
12
BzO
O
BzO
BzO
O
O
BzO
20
O
BzO
OR
BzO
BzO
OBz
21, PPh3AuNTf2 (0.15 eq),
O
O
4Å MS, CH2Cl2, rt, 75%
46
nBu
O
BzO
3
OAc
PPh3AuNTf2 (0.2 eq),
5Å MS, CH2Cl2, rt, 84%
CAO
34
CAO
Ph
O
O
35 R = All
1) PdCl2, MeOH, rt, 86%
2) Ac2O, pyridine, 0 oC-rt, 75%
O
AllO
O
36
R = Ac
O
BzO
BzO
BzO
O
OH
BzO
BzO
47
1) PdCl2, MeOH, CH2Cl2, rt;
O
OBz
2) p-TsOH, MeOH, CH2Cl2, rt, 70%
O
BzO
3) KOH, MeOH, reflux, 90%
6
27
OAc
HF, pyridine, THF, rt, 80%
35
Scheme 6. Completion of the synthesis of ginsenoside Rb2 (6).
PPh3AuNTf2 (0.1 eq),
4Å MS, CH2Cl2, rt, 99%
37
CAO
Conclusion
OBz
OBz
Ginsenoside F3 (1), chikusetsusaponin L10 (2), ginsenoside Rh1
(3), ginsenoside Rg1 (4), ginsenoside Ia (5), and ginsenoside Rb2
O
BzO
O
BzO
BzO
O
O
BzO
BzO
BzO
40 (6) have been conveniently synthesized. Their analytical data are
in good agreement with those reported for the natural products.14
Compounds 1ꢀ5 represent all the possible protopanaxatriol
ginsenosides, which bear the sugar moieties at the 20ꢀOH, 12ꢀ
OH, 6ꢀOH, 6,20ꢀOHs, 3,20ꢀOHs, respectively; while compounds
45 6 is a representative congener of the most complex type of
ginsenosides. The syntheses are succeeded resorting especially to
the fully differentiation of the hydroxyl groups on
protopanaxatriol and ꢀdiol, the effective gold(I)ꢀcatalyzed
glycosylation (of the acid labile 20ꢀOH) under neutral conditions,
50 and the critical enhancing of the acceptor 20ꢀOH via
intramolecular Hꢀbonding. With the present approaches at hand,
access to the diverse ginsenosides and their analogs has become a
feasible task. The availability of these homogeneous ginsenosides
will greatly facilitate the studies on their biological and
55 pharmacological activities, so that the magic therapeutic effects
of ginseng could finally be deciphered.
O
AZMBO
O
O
BzO
40
OAc
1) PPh3AuNTf2 (0.2 eq),
5Å MS, CH2Cl2, rt, 80%
2) nBu3P, THF, H2O, rt, 76%
38
39
RO
R = CA
R = H
DABCO, EtOH, 50oC, 80%
OBz
OBn
O
BzO
O
O
BnO
BnO
O
BzO
BzO
O
BzO
BzO
O
42
O
BzO
nBu
OAc
17 20
42
,
, or
BzO
BzO
BzO
O
O
41
OH
Scheme 5. Towards the synthesis of ginsenoside Rb2 (6).
20
Alternatively, we turned to increase the reactivity of the 2’’’ꢀ
OH via modification of the protecting groups on the 3ꢀOꢀ glucose
unit in 41.30 A successful attempt is shown in Scheme 6. Thus,
C3ꢀol 39 was coupled with glucopyranosyl oꢀalkynylbenzoate 43
(under standard conditions) to provide 3ꢀOꢀglucopyranoside 44
Acknowledgements
This work was financially supported by the National Basic
60 Research Program of China (2010CB833202, 2010CB529706)
and the National Natural Science Foundation of China
(91213301, 20902097, and 20932009). The picture of ginseng in
25 (83%). Subsequent removal of the 2’’’ꢀOꢀAZMB group led to 45,
TOC
is
taken
from
4
in that the 2’’’ꢀOH is situated in a C1 glucopyranose fixed by
http://www.taopic.com/tuku/201109/97355.html.
4’’’,6’’’ꢀOꢀbenzylidene and neighbored by a electron donating 3ꢀ
Oꢀallyl group. Glycosylation of the 2’’’ꢀOH in 45 with
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DOI: 10.1039/C3SC51479J
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State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, China
Fax: (0086)-21-64166128
5
E-mail: byu@mail.sioc.ac.cn and jssun@mail.sioc.ac.cn
Dr. J. Liao
Department of Chemistry, University of Science and Technology of
10 China, 96 Jinzhai Road, Hefei, Anhui 230026, China.
Y. Niu, R. Li, and Prof. F. Zhang
Department of Chemistry, The Key Lab of Chemical Biology and Organic
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6
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