Synthetic Access Toward Cycloastragenol Glycosides

Article abstract of DOI:10.1021/acs.joc.7b00080

The first efficient synthetic approach toward four types of the cycloartane glycosides, the cycloastragenol 25-O; 3-O; 3,6-O-bis; and 3,25-O-bisglycoside, have been established, which featured the PPY-mediated, concentration-controlled acetylation and Au(I)-catalyzed Yu glycosylation. Through the synthetic investigation, the reactivity sequence of the four OHs in cycloastragenol was fixed for the first time and a detour strategy for the highly efficient removal of bulky pivaloyl protecting groups was discovered.

Full text of DOI:10.1021/acs.joc.7b00080

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Article
The Synthetic Access Toward Cycloastragenol Glycosides
Ting Liu, Jin-Xi Liao, Yang Hu, Yuan-Hong Tu, and Jian-Song Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00080 • Publication Date (Web): 27 Mar 2017
Downloaded from http://pubs.acs.org on March 29, 2017
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The Synthetic Access Toward Cycloastragenol Glycosides
Ting Liu, JinꢀXi Liao, Yang Hu, YuanꢀHong Tu and JianꢀSong Sun*
The National Research Centre for Carbohydrate Synthesis, Jiangxi Normal University
99 Ziyang Avenue, Nanchang 330022, China
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jssun@jxnu.edu.cn
Table of content:
Abstract:
The first efficient synthetic approach toward four types of the cycloartane glycosides,
the cycloastragenol 25ꢀO, 3ꢀO, 3,6ꢀOꢀbis, and 3,25ꢀOꢀbisglycoside, have been
established, which featured the PPYꢀmediated, concentrationꢀcontrolled acetylation
and Au(I)ꢀcatalyzed Yu glycosylation. Through the synthetic investigation, the
reactivity sequence of the four OHs in cycloastragenol was fixed for the first time and
a detour strategy for the highly efficient removal of bulky pivaloyl protecting groups
was discovered.
Introduction
Astragali Radix (Huangqi), the root of Astraglus membranaceus, has long been
used as one of the most important tonic herbs in traditional Chinese medicine. Studies
regarding its pharmacological and clinical use demonstrated that Astragali Radix has
many biological functions, including hepatoprotection,1 neuroprotection,2
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immunomodulating activity,3 antitumoral effects.4 The major active principles
responsible for the above mentioned activities are recognized to be the cycloartane
glycosides, which indeed have shown numerous pharmaceutical activities, including
immunostimulatory,5 cardioprotective,6 anticarcinogenic,7 neuroprotective,8 and
antiflammatory activities.9 Cycloartane glycosides occur in Astragali Radix in such a
heterogeneous manner that more than 30 members, mainly the cycloastragenol
glycosides, have been isolated and characterized. Therefore, to access ample amounts
of homogeneous cycloartane glycosides from natural resources for detailed
pharmaceutical investigation is a formidable task. As a result, all biological studies
regarding pure cycloartane glycoside have been limited to astragaloside IV, a
congener with the highest natural content. Chemical synthesis could provide
homogeneous cycloartane glycosides. However, due to the lack of methods for OHs
discrimination and glycosidic linkage construction, no synthetic investigation toward
these biologically important compounds has been reported.10a Especially, the
construction of Cꢀ25 tertiary OH glycosidic linkage poses considerable synthetic
challenge.10bꢀe
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Structurally, the main cycloartane glycosides isolated from Astraglus
membranaceus can be categorized into three types, i.e., the cycloastragenol
3ꢀOꢀglycoside, cycloastragenol 3,6ꢀOꢀbisglycoside, as well as the cycloastragenol
3,25ꢀOꢀbisglycoside, as exemplified by astramembrannin II (2),11 astragaloside IV
(3),12 and isoastragaloside IV (4),12 respectively (Figure 1). As an representative of
cycloastragenol 25ꢀOꢀglycoside, although (1) has not yet been isolated directly from
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the natural resources, as an enzymatic hydrolysis product of astragaloside V it has
already been characterized.13 Thus, there is no reason to doubt its existence in
Astraglus membranaceus, and the low natural content is responsible for the temporary
absence. In fact, as the richest ingredient, astragaloside IV only accounts for 1.17% of
the whole Astragali Radix weight, not to mention the minor components (0.42% and
0.017% for 2 and 4, respectively). To facilitate the following reactivity study of
astragaloside IV as well as the searching for new pharmaceutically important
cycloartane glycosides, a reliable chemical synthetic approach is urgently needed.
Leveraging on the judicious differentiation of the four inert hydroxyl groups of
cycloastragenol as well as the Yu glycosylation14,15 featuring the mild glycosylation
conditions and impressive glycosylation potential, the first and efficient approach
toward cycloartane glycosides have been discovered, through which the representative
members 1ꢀ4 have been successfully synthesized.
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Figure 1. Representative cycloastragenol glycosides.
Results and discussion
The first problem that should be solved en route to the establishment of an efficient
approach toward the four target molecules is the discrimination of the four OHs in
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cycloastragenol 5 (Scheme 1). The low reactivity of 6,16,25ꢀOHs makes the most
simple protecting group manipulation, the acetylation, become sluggish and difficult.
It has been reported that even under the harsh acetylation conditions, that is, large
excess of acetylating reagents (Ac2O/pyridine: v/v = 1 : 1.2), elevated temperature (60
oC), and prolonged reaction time (50 days), the peracetylated cycloastragenol product
was obtained only in 56% yield. Shortened reaction time or decreased reaction
temperature resulted in a complex mixture of monoꢀ and diacetate.16 These
precedented results indicate that the hydroxyl groups discrimination of
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cycloastragenol 5 is by no way a trivial problem.
Given the low reactivity of OHs in cycloastragenol, the acetylation was tried with
4ꢀ(1ꢀpyrrolidino)ꢀpyridine (PPY) as promoter, as it has been demonstrated to be the
most effective catalyst for the acylation of bulky and inert tertiary OHs.17a,b Pleasantly,
after extensive screening, it was found that under the combined effects of Ac2O (10.0
equiv), PPY (2.0 equiv), and N,Nꢀdiisopropylethylamine (DIPEA, 15.0 equiv),
cycloastragenol 5 was fluently acetylated in toluene at 105 oC, delivering the
triacetate 6 which is ready for the due 25ꢀOH sugar residue installation in a good 81%
yield. In sharp contrast to the previous reports,16 under the PPY mediated acetylation
conditions, the triacetylation proceeded so rapidly that only 2 hours were required for
the completion of the reaction. Thus, the first efficient method for acetylation of
cycloastragenol was established, laying firm foundation for the following thorough
differentiation of the four OHs of cycloastragenol. It also should be pointed out that
the Lewis acidꢀcatalyzed acylation conditions which have been proved to be powerful
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for the acylation of inert hydroxyl groups could not work well in our hand.17c
Encouraged by this promising result, the discrimination of 3ꢀOH from the other three
OHs was investigated subsequently. In order to secure satisfactory selectivity, the
bulky and easilyꢀcleavable TBS was selected. At the outset, in order to avoid the
overꢀsilylation side reaction, 5 was exposed to the conventional silylation conditions,
that is, 1.2 equivalents of TBSCl and 2.0 equivalents of imidazole in DMF at room
temperature. However, only 40% yield of 7 was isolated with the major starting
material being recovered. Further investigation proved that the reactivity disparity
between 3ꢀOH and the remaining 6,16,25ꢀOHs was so huge that only trace amount of
the overꢀsilylated product was detected even when 4.0 equivalents of TBSCl and 6.0
equivalents of imidazole were applied. The modified conditions brought about a
dramatic improvement in the chemical yield, and 77% yield of 7 was obtained. With 7
in hand, full acetylation of resting free OHs including the tertiary 25ꢀOH was required
so as to realize the final discrimination of the 3ꢀOH. Although the Ac2O/PPY/DIPEA
system has showcased impressive potential in the transformation of 5 to 6, the
conditions could only acetylate the secondary OHs with the tertiary 25ꢀOH left
untouched. To realize the acetylation of all free OHs of 7, further optimization of the
Ac2O/PPY/DIPEA conditions was required. Extensive investigation revealed that the
concentration of cycloastragenol derivatives had a profound effect on the acetylation
potential of the Ac2O/PPY/DIPEA system, and the full acetylation of 7 was efficiently
realized with Ac2O/PPY/DIPEA under a high concentration condition (above 50
mg/mL) to afford 8 in almost quantitative yield. To release the 3ꢀOH for the
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subsequent glucosyl residue incorporation, the selective cleavage of 3ꢀOTBS in 8 was
achieved with CAS in MeOH, furnishing 3ꢀOH free intermediate 9 (89%).
Interestingly, the conventional TBS cleavage conditions such as TBAF and
HF/pyridine could not effect the transformation. At this junction, the efficient
differentiation of 3ꢀ and 25ꢀOH of cycloastragenol was achieved, which was heavily
dependent on the PPY mediated and concentrationꢀcontrolled acetylation conditions.
Alternatively, in compound 7 the 25ꢀOH could also be discriminated with the
bulky pivaloyl group. Thus, treated with PivCl and pyridine, the two secondary OHs
in 7 were esterified to generate 15, an acceptor suitable for the synthesis of
3,6ꢀOꢀbisglycoside, efficiently (95%). Excess amounts of acylating reagent (10.0
equivalents of PivCl) as well as high reaction concentration are the prerequisites for
high pivaloylation yield. For the preparation of cycloastragenol 3,6ꢀOꢀbisglycosides,
the discrimination between 3ꢀ and 6ꢀOHs in 5 is entailed. To this end, the acetylation
of 5 under the conventional conditions (Ac2O, pyridine) was conducted as a model
reaction, and the diacetylated cycloastragenol 10 was isolated in an excellent yield
(96%).16 This result indicated that the four OHs could be divided into two groups by
esterification, which would facilitate following discrimination between 3ꢀ and 6ꢀOH
of cycloastragenol. Inspired by the result of the model reaction, attempt to direct
levulination of 3,6ꢀOHs of 5 under the effect of LevOH, DCC, and DMAP was made.
While 2.5 equivalents of DCC and LevOH afforded a mixture of mono and
dilevulinated cycloastragenols, increasing the amounts of DCC and LevOH to 10.0
equivalents resulted in the clean formation of 3,6ꢀdilevulinated cycloastragenol 11
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(98%), which was subsequently subjected to the PPY mediated full acetylation
conditions to yield 12 (84%). NH2NH2/HOAc mediated delevulination resulted in the
diol intermediate 13 smoothly (99%). With TBS as a temporary protecting group, the
differentiation of 3ꢀOH at the presence of 6ꢀOH was realized to afford 14 (87%),
which could act as a suitable acceptor for the synthesis of cycloastragenol
3,6ꢀOꢀbisglycoside. Thus far, with acetyl, tertꢀbutyldimethyl, pivaloyl, and levulinyl
as protecting groups, all four acceptors 6, 9, 14, and 15 needed for the synthesis of the
target molecules were obtained successfully. Meanwhile, the detailed protecting
group manipulations let to the determination of the reactivity sequence of the four
OHs in cycloastraginol 5 as 3ꢀOH > 6ꢀOH > 16ꢀOH > 25ꢀOH. Theoretically, applying
the devised hydroxyl group differentiation strategy, all cycloastrgenol acceptors with
different patterns of free OH could be obtained, thus paving the way for the highly
efficient synthesis of other types of cycloartane glycosides.
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OH
O
5
OPiv
6
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TBSO
TBSO
HO
OPiv
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PivCl, pyridine, 50 oC,
95%
OH
O
OAc
O
Ac2O (10.0 equiv), PPY (2.0 equiv),
DIPEA (15.0 equiv), toluene, 105 oC
OH
OAc
5 h, 99%
RO
OH
OAc
7
8 R = TBS
9 R = H
CAS, MeOH, rt, 89%
TBSCl, imidazole
DMF, rt, 77%
OH
OH
Ac2O (10.0 equiv), PPY (2.0 equiv),
O
O
OAc
OH
DIPEA (15.0 equiv), toluene, 105 oC
AcO
2 h, 81%
OAc
OH
cycloastragenol (5)
6
Ac2O, pyridine, or LevOH, DCC,
0 oC to rt, 96%
DMAP,DCM,
rt, 98%
OAc
OH
O
O
OAc
Ac2O (10.0 equiv), PPY (2.0 equiv),
DIPEA (15.0 equiv), toluene, 105 oC
OH
5 h, 84%
R1O
RO
OR2
OR
12 R1 = R2 = Lev
13 R1 = R2 = H
14 R1 = TBS, R2 = H
NH2NH2-HOAc, rt, 99%
TBSCl, imidazole, 87%
10 R = Ac
11 R = Lev
Scheme 1. Differentiation of the four hydroxyl groups on cycloastragenol (5)
With all acceptors equipped with appropriate protecting groups in hand, the
synthesis of Yu donors was conducted following the known procedures (Scheme 2).
Thus, treated with EDCI, DIPEA, and DMAP, the condensation between hemiacetals
16,10c 1715b and orthoꢀalkynylbenzoic acid proceeded efficiently to afford glycosyl
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donors 1810c and 19 (93% and 89% yield respectively). To secure the desired
1,2ꢀtransꢀglycosidic linkages, the donors were equipped with benzoyl groups whereby
the stereocontrol of the glycosidic linkages could be guaranteed through the reliable
neighboring group participation effect.
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Scheme 2. Synthesis of glycosyl orthoꢀalkynylbenzoate donors 18 and 19.
With both donors and acceptors in hand, now the stage was set for the critical
glycosidic linkages constructions and the completion of the syntheses of all target
molecules (Scheme 3). Thus, under the catalysis of Ph3PAuNTf2 (0.5 equiv),
glycosylation of the tertiary 25ꢀOH acceptor 6 with glucosyl donor 18 proceeded
fluently, and the desired monoglycoside 20 was isolated in 94% yield. Under the
identical conditions, the condensation between 3ꢀOH acceptor 9 with xylosyl donor
19 proceeded without any problem to afford cycloastragenol 3ꢀOꢀglycoside 21
efficiently (92%). Surprisingly, when the 6ꢀOH acceptor 14 was subjected to the same
glycosylation conditions, its condensation with donor 18 proceeded so sluggishly that
the conjugating product 22 was isolated in only moderate yield after stirring for 48 h
at room temperature (54%), although the 6ꢀOH of cycloastragenol was originally
determined to be the second most reactive OH in the differentiation investigations.
Replacing Ph3PAuNTf2 with more reactive Ph3PAuOTf (0.5 equiv) resulted in a
evident enhancement in the glycosylation yield and 80% yield of 22 was obtained.
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The abnormal reactivity could presumably be attributed to the double
5
6
7
8
stereodifferentiation effect.19 With the 6ꢀOꢀglucosyl residue settled, further
glycosylation of 3ꢀOH in 23, obtained by CAS mediated desilylation of 22, with
xylosyl donor 19 was proved to be even more difficult. Both Ph3PAuNTf2 (0.5 equiv)
and Ph3PAuOTf (0.5 equiv) delivered the cycloastragenol bisglycoside 24 with
moderate yields (around 58%). The extremely lowered reactivity of the 3ꢀOH of 23
was caused by the closely located and bulky 6ꢀOꢀglucosyl residue, which probably
blocked the attack of active donor species toward 3ꢀOH from the originally less
hindered αꢀface. Systematic screenings resulted in the establishment of the optimal
glycosylation conditions in which 2.5 equivalents of donor 19 and 1.0 equivalents of
Ph3PAuOTf were involved, through which 80% yield of 24 were recorded. To further
examine the potential of the Yu glycosylation in the synthesis of cycloartane
glycosides, the reaction between 15 and 18 under the catalysis of reduced amounts of
Ph3PAuNTf2 (0.2 equiv) was checked. Pleasantly, no evident drop in chemical yield
was observed, and 25 was obtained in a comparable 92% yield (vs 94.2% of 20).
Because the detrimental steric effect exerted by the 6ꢀOꢀglucosyl residue was
eliminated in monosaccharide acceptor 26, derived from 25 via selective 3ꢀOTBS
cleavage, even under the catalysis of 0.2 equivalents of Ph3PAuNTf2, the 3ꢀOH
glycosylation of 26 with donor 19 proceeded so efficiently that 83% yield of
cycloastragenol 3,25ꢀOꢀbisglycoside 27 was isolated. Benefited from the anchimeric
effect of benzoyl groups in donors 18 and 19, all glycosidic linkages were fashioned
in a stereoselective manner and only βꢀisomers were detected, as verified by 1H NMR
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spectra (for anomeric protons: 5.20 ppm, dd, J = 8.0 Hz for 20; 4.85 ppm, dd, J = 5.6
Hz for 21; 4.86 ppm, d, J = 7.6 Hz and 4.20 ppm, d, J = 6.4 Hz for 24; 5.30 ppm, d, J
= 7.6 Hz and 4.80 ppm, d, J = 6.4 Hz for 27). In addition, the evident upfield shift of
the xylosyl anomeric proton from 4.80 ppm to 4.20 ppm in 24 provided a convincing
evidence to verify the spatial proximity between 3ꢀOꢀxylosyl and the 6ꢀOꢀglucosyl
residues.
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With fully protected target molecules 20, 21, 24 and 27 in hand, the global
deprotection was then investigated. NaOMe mediated Zemplén saponification worked
quite well to transform 20, 21, and 24 to the corresponding target molecules 1,
astramembrannin II (2), and astragaloside IV (3) in 84%, 86%, and 76% yields,
respectively. However, when 27 carrying two Pivs was exposed to the identical
saponification conditions, the desired isoastraganoside IV (4) was not obtained as
expected, instead, the partially deprotected intermediate with the 6,16ꢀOPivs intact
was isolated. The bulky characteristics of pivaloyl group renders Piv to enjoy a quite
broad scope of regioselectivity in OH protections, however, in some cases, the same
property brings about problems for its removal.20 In order to cleave the two pivaloyl
protecting groups, different conditions including elevated temperature and various
bases such as LiOH, KOH, and hydrazine were tried. Unfortunately, all trials met
with failure uniformly, and no clean conversion was obtained. Finally, a detour
strategy was devised to fulfill the global deacylation goal, wherein the sequential
lithium aluminum hydride (LAH) mediated reductive acyl group cleavage,
reacetylation with Ac2O and pyridine (to facilitate the removal of aluminum salts),
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and NaOMe promoted Zemplén saponification were involved. Although an indirect
strategy was adopted, the whole deprotection efficiency was not compromised and 92%
yield of isoastraganoside IV (4) was isolated (3 steps). The spectroscopic data of all
synthetic compounds were in good accordance with those either reported in literature
or recorded with authentic sample,21 verifying the correctness of synthetic
compounds.18
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R O
O
2
O
OR2
OR2
O
OR1
Ph3PAuNTf2, 4A MS, CH2Cl2
rt, 94%
6
18
+
R2O
R1O
OR1
20 R1 = Ac, R2 = Bz
1 R1 = R2 = H
NaOMe, MeOH, 84%
OR2
O
OR2
Ph3PAuNTf2, 4A MS, CH2Cl2
9
19
+
rt, 92%
O
R1O
R1O
O
OR2
OR1
21 R1 = Bz, R2 = Ac
2 R1 = R2 = H
NaOMe, MeOH, 86%
OAc
O
OR2
O
OAc
OR2
19, Ph3PAuOTf, 4A MS, CH2Cl2
Ph3PAuOTf, 4A MS, CH2Cl2
rt, 80%
O
R1O
R1O
RO
14
18
O
+
rt, 80%
O
O
OR1
O
O
BzO
R1O
BzO
BzO
R1O
R1O
OBz
OR1
CAS, MeOH, 0 oC to rt,
84%
22 R = TBS
23 R = H
24 R1 = Bz, R2 = Ac
3 R1 = R2 = H
NaOMe, MeOH, 76%
BzO
OBz
OBz
O
O
O
OPiv
BzO
19, Ph3PAuNTf2, 4A MS, CH2Cl2
Ph3PAuNTf2, 4A MS, CH2Cl2
rt, 92%
15
18
+
rt, 83%
RO
OPiv
CAS, MeOH, 0 oC to rt,
83%
25 R = TBS
26 R = H
HO
O
OH
BzO
OBz
OBz
O
O
O
O
O
OH
OH
OPiv
HO
BzO
O
1) LiAlH4, THF, 0 oC to rt
HO
HO
O
BzO
BzO
O
O
2) Ac2O, pyridine, 0 oC to rt
OH
OH
OPiv
OBz
27
3) NaOMe, MeOH, 92%
(3 steps)
Isoastraganoside IV (4)
Scheme 3. Synthesis of the target molecules 1ꢀ4.
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Conclusion
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In summary, compounds 1–4 represent the four types of cycloastragenol glycosides
isolated from Astraglus membranaceus, which bear the sugar moieties at the 25ꢀOH,
3ꢀOH, 3,6ꢀOHs, and 3,25ꢀOHs, respectively. The synthetic approach features not only
the full differentiation of the hydroxyl groups on cycloastragenol but also the highly
efficient construction of glycosidic linkages via the Yu glycosylation protocol. With
the present approach in hand, access to the diverse cycloastragenol glycosides and
their analogs has become feasible. The availability of these homogeneous glycosides
will greatly facilitate studies of their biological and pharmacological activities, so that
their therapeutic effects can finally be deciphered.
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Experimental section
General Comments. All reactions were monitored by thinꢀlayer chromatography
over silicaꢀgelꢀcoated TLC plates (Yantai Chemical Industry Research Institute). The
spots on TLC were visualized by warming 5% H2SO4 (5% H2SO4 in ethanol) sprayed
plates on a hot plate. Column chromatography was performed using silica gel
(Qingdao Marine Chemical Inc., China), and Sephadex LHꢀ20 (GE Healthcare
BioꢀSciences AB, Sweden). NMR spectra were recorded on a Bruker AMꢀ400
spectrometer (400 MHz). Optical rotations were measured at 25 °C with a Rudolph
Autopol IV automatic polarimeter using a quartz cell with 2 mL capacity and a 1 dm
path length. Concentrations (c) are given in g/100 mL. High resolution mass spectra
were recorded on a Bruker micrOTOF II spectrometer using electrospray ionization
(ESI).
3,6,16ꢀTriꢀOꢀacetylꢀcycloastragenol (6). To a solution of cycloastragenol 522 (180
mg, 0.37 mmol), PPY (108 mg, 0.74 mmol), and DIPEA (0.91 mL, 5.6 mmol) in dry
o
toluene (10 mL) was added Ac2O (0.35 mL, 3.7 mmol) dropwise at 0 C under N2
atmosphere. After the addition was completed, the reaction mixture was heated to 105
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oC, and the stirring was continued at the same temperature for 2 h. After cooled to
room temperature, the reaction mixture was diluted with ethyl acetate. The resulting
mixture was washed successively with water, 1N HCl, aqueous saturated NaHCO3,
and brine, and then dried over anhydrous Na2SO4. Filtration was followed by
concentration under reduced pressure to give the crude product which was further
purified by silica gel chromatography (PE/EA = 5 : 1) to afford 6 (184 mg, 81%) as a
white solid: [α]D25 = 73.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.44ꢀ5.39 (m,
1 H), 4.75 (td, J = 4.4, 9.2 Hz, 1 H), 4.60 (dd, J = 4.4, 11.2 Hz, 1 H), 3.72 (dd, J = 6.8,
8.4 Hz, 1 H), 2.50 (d, J = 8.4 Hz, 1 H), 2.38 (td, J = 5.2, 11.6 Hz, 1 H), 2.17 (dd, J =
8.0, 13.6 Hz, 1 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H), 1.30 (s, 3 H), 1.29 (s, 3
H), 1.20 (s, 3 H), 1.09 (s, 3 H), 0.99 (s, 3 H), 0.98 (s, 3 H), 0.85 (s, 3 H), 0.61 (d, J =
3
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4.8 Hz, 1 H), 0.38 (d, J = 4.8 Hz, 1 H); C NMR (100 MHz, CDCl3) δ 170.8, 170.6,
170.4, 85.6, 81.9, 79.5, 75.6, 70.9, 70.2, 57.1, 49.7, 46.2, 46.1, 45.3, 45.0, 40.1, 36.5,
32.9, 32.5, 31.4, 29.7, 29.2, 28.4, 27.8, 27.7, 26.6, 26.0 (2 C), 24.5, 21.8, 21.6, 21.2,
20.7, 20.4, 20.0, 16.2; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C36H57O8 617.4048;
found 617.4049.
3ꢀOꢀtertꢀButyldimethylsilylꢀcycloastragenol (7). To a solution of cycloastragenol 5
(400 mg, 0.82 mmol) and imidazole (333 mg, 4.9 mmol) in dry DMF (0.6 mL) was
o
added TBSCl (489 mg, 3.3 mmol) at 0 C. Then the reaction mixture was warmed to
room temperature and stirring was continued at the same temperature for 8 h, at which
time TLC showed that all starting material disappeared. Ethyl acetate was added to
dilute the reaction and the resulting mixture was washed successively with water, 1N
HCl, aqueous saturated NaHCO3, and brine, and then was dried over anhydrous
Na2SO4. Filtration and concentration afforded the crude product which was further
purified by silica gel chromatography (petroleum ether/ethyl acetate = 1 : 1) to deliver
7 (376.5 mg, 77%) as a white solid: [α]D25 = 30.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 4.67 (dd, J = 7.6, 14.4 Hz, 1 H), 3.72 (dd, J = 6.0, 8.0 Hz, 1 H), 3.51 (td, J =
3.6, 9.6 Hz, 1 H), 3.25 (dd, J = 4.8, 10.0 Hz, 1 H), 2.59 (dd, J = 10.4, 21.6 Hz, 1 H),
2.31 (d, J = 8.0 Hz, 1 H), 2.00ꢀ1.92 (m, 4 H), 1.76 (dd, J = 4.0, 12.0 Hz, 1 H), 1.25 (s,
3 H), 1.21 (s, 3 H), 1.17 (s, 3 H), 1.13 (s, 3 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 0.91 (s, 3
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H), 0.89 (s, 3 H), 0.85 (s, 9 H), 0.47 (d, J = 4.0 Hz, 1 H), 0.31 (d, J = 4.4 Hz, 1 H),
0.00 (s, 3 H), ꢀ0.005 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 87.1, 81.4, 78.8, 73.4,
71.8, 68.9, 57.5, 53.7, 46.9, 46.5, 46.0, 45.0, 42.1, 37.7, 34.4, 33.0, 32.1, 31.4, 30.8,
29.4, 28.6, 27.9, 27.7, 26.4, 25.9 (2 C), 25.8, 21.4, 20.5, 20.0, 18.1, 15.8; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C36H65O5Si 605.4596; found 605.4599.
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3ꢀOꢀtertꢀButyldimethylsilylꢀ6,16,25ꢀtriꢀOꢀacetylꢀcycloastragenol (8). Except for the
concentration of 7, similar procedure as that used for the synthesis of 6 was applied to
afford 8 (139.7 mg, 99%) as a white solid: [α]D25 = 78.3 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 5.31 (m, 1 H), 4.70 (td, J = 4.8, 8.8 Hz, 1 H), 3.96 (t, J = 7.2 Hz, 1 H),
3.24 (m, 1 H), 2.40 (d, J = 8.0 Hz, 1 H), 2.14 (m, 1 H), 2.13 (dd, J = 8.0, 13.6 Hz, 1
H), 1.98 (s, 3 H), 1.95 (s, 3 H), 1.93 (s, 3 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.29 (s, 3 H),
0.92 (s, 3 H), 0.85 (s, 15 H), 0.84 (s, 3 H), 0.54 (d, J = 4.8 Hz, 1 H), 0.27 (d, J = 4.8
Hz, 1 H), 0.00 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 170.4 (2 C), 170.2, 85.6, 83.1,
81.3, 78.4, 75.8, 70.6, 57.5, 49.6, 46.5, 46.3, 45.4, 44.6, 41.8, 37.3, 32.8, 32.3, 31.6,
30.6, 28.8, 28.4, 27.0 (2 C), 26.2, 26.0, 25.9, 22.8, 22.5, 21.8, 21.6, 21.5, 20.5, 20.2,
19.9, 18.1, 15.5; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C42H71O8Si 731.4913;
found 731.4912.
6,16,25ꢀTriꢀOꢀacetylꢀcycloastragenol (9). To a solution of 8 (20 mg, 0.03 mmol) in
o
MeOH (2.0 mL) was added CAS (26 mg, 0.11 mmol) at 0 C. Then the reaction
mixture was warmed to room temperature, and the stirring was continued for another
3 h. Et3N was added to quench the reaction, then the volatile solvent was removed
under reduced pressure to yield the crude product which was further purified by silica
gel chromatography (petroleum ether/ethyl acetate = 4 : 1) to afford 9 (15 mg, 89%)
25
1
as a white solid: [α]D = 162.2 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
5.35ꢀ5.30 (m, 1 H), 4.76 (td, J = 4.4, 9.2 Hz, 1 H), 4.02 (t, J = 7.6 Hz, 1 H), 3.32 (dd,
J = 3.6, 10.8 Hz, 1 H), 2.43 (d, J = 8.0 Hz, 1 H), 2.18ꢀ2.12 (m, 2 H), 2.01 (s, 3 H),
2.00 (s, 3 H), 1.97 (s, 3 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 1.324 (s, 3 H), 1.319 (s, 3 H),
0.99 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 3 H), 0.59 (d, J = 4.8 Hz, 1 H), 0.36 (d, J = 4.4 Hz,
1 H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.2, 85.5, 83.1, 81.3, 77.8, 75.8, 70.7,
57.5, 49.7, 46.4, 46.3, 45.5, 45.1, 41.2, 37.3, 33.1, 32.3, 31.7, 30.2, 29.2, 28.6, 27.0,
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26.6, 26.2, 26.0, 22.8, 22.5, 21.8, 21.6, 21.5, 20.6, 20.3, 20.0, 15.1; HRMS (ESIꢀTOF)
m/z: [M+H]+ calcd for C36H57O8 617.4048; found 617.4048.
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3,6ꢀDiꢀOꢀacetylꢀcycloastragenol (10). To a solution of 5 (300 mg, 0.61 mmol) in dry
pyridine (2.0 mL) was added Ac2O (2.0 mL) dropwise via a syringe at 0 oC under N2
atmosphere. The iceꢀbath was then removed and the stirring was continued overnight.
Ethyl acetate was added to dilute the reaction, the resulting solution was washed with
water, 1N HCl, aqueous saturated NaHCO3, and brine, and then dried over anhydrous
Na2SO4. Filtration was followed by concentration in vacuo to give a residue which
was further purified by silica gel chromatography (petroleum ether/ethyl acetate = 3 :
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1) to deliver 1016 (337 mg, 96%) as a white solid. For comparison purpose, the H
1
NMR was recorded: H NMR (400 MHz, CDCl3) δ 4.78 (td, J = 4.0, 9.2 Hz, 1 H),
4.71ꢀ4.66 (m, 1 H), 4.59 (dd, J = 4.4, 10.8 Hz, 1 H), 3.78 (td, J = 2.4, 7.2 Hz, 1 H),
2.61 (q, J = 10.4 Hz, 1 H), 2.34 (d, J = 7.6 Hz, 1 H), 2.05 (s, 3 H), 1.99 (s, 3 H), 1.31
(s, 3 H), 1.24 (s, 6 H), 1.16 (s, 3 H), 1.00 (s, 3 H), 0.95 (s, 3 H), 0.85 (s, 3 H), 0.62 (d,
J = 4.8 Hz, 1 H), 0.36 (d, J = 4.8 Hz, 1 H).
3,6ꢀDiꢀOꢀlevulinylꢀcycloastragenol (11). To a solution of 5 (300 mg, 0.61 mmol),
DMAP (160 mg, 1.22 mmol), and levulinic acid (350 mg, 3.1 mmol) in dry CH2Cl2 (9
o
mL) was added DCC (630 mg, 3.1 mmol) under N2 atmosphere at 0 C. The reaction
mixture was then warmed to room temperature and the stirring was continued until
TLC showed that all the starting material disappeared. After diluted with CH2Cl2, the
resulting solution was washed with 1N HCl, saturated aqueous NaHCO3, and brine,
then was dried over anhydrous Na2SO4. Filtration and concentration afforded a
residue which was then subjected to purification by silica gel chromatography
(petroleum ether/ethyl acetate = 1 : 2) to deliver 11 (413 mg, 98%) as a white solid:
[α]D25 = 39.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.78 (td, J = 4.8, 9.2 Hz,
1 H), 4.71 (dd, J = 7.6, 14.4 Hz, 1 H), 4.60 (dd, J = 4.4, 10.8 Hz, 1 H), 3.77 (t, J = 7.2
Hz, 1 H), 3.52ꢀ3.45 (m, 1 H), 2.77ꢀ2.70 (m, 4 H), 2.59 (t, J = 6.4 Hz, 2 H), 2.51 (t, J =
6.8 Hz, 2 H), 2.34 (d, J = 7.6 Hz, 1 H), 2.19 (s, 3 H), 2.18 (s, 3 H), 2.01ꢀ1.88 (m, 6 H),
1.30 (s, 3 H), 1.24 (s, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), 0.99 (s, 3 H), 0.94 (s, 3 H),
0.87 (s, 3 H), 0.60 (d, J = 4.8 Hz, 1 H), 0.34 (d, J = 4.4 Hz, 1 H); 13C NMR (100 MHz,
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CDCl3) δ 206.6, 206.4, 172.4, 172.0, 87.0, 81.4, 79.9, 73.3, 71.7, 70.7, 57.3, 49.7,
49.2, 45.9, 45.8, 45.1, 44.7, 40.2, 38.1, 37.8, 34.4, 33.9, 33.0, 32.7, 31.4, 29.8, 28.8,
28.4, 28.2, 27.8, 27.7, 26.5 (2 C), 25.8, 25.6 (2 C), 24.9, 20.8, 20.7, 19.7, 16.3; HRMS
(ESIꢀTOF) m/z: [M+Na]+ calcd for C40H62O9Na 709.4286; found 709.4288.
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3,6ꢀDiꢀOꢀlevulinylꢀ16,25ꢀdiꢀOꢀacetylꢀcycloastragenol (12). Similar procedure as
that used for the synthesis of 8 was adopted to convert 11 to 12 (349 mg, 84%) as a
white solid: [α]D25 = 63.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.35ꢀ5.30 (m,
1 H), 4.74 (td, J = 4.4, 9.2 Hz, 1 H), 4.60 (dd, J = 4.8, 11.2 Hz, 1 H), 4.02 (t, J = 7.6
Hz, 1 H), 2.77ꢀ2.69 (m, 4 H), 2.59 (t, J = 6.4 Hz, 2 H), 2.50 (t, J = 6.8 Hz, 2 H), 2.43
(d, J = 8.0 Hz, 1 H), 2.19 (s, 3 H), 2.18 (s, 3 H), 2.01 (s, 3 H), 1.96 (s, 3 H), 1.43 (s, 3
H), 1.41 (s, 3 H), 1.323 (s, 3 H), 1.316 (s, 3 H), 0.98 (s, 3 H), 0.96 (s, 3 H), 0.88 (s, 3
H), 0.60 (d, J = 4.8 Hz, 1 H), 0.37 (d, J = 4.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 206.5, 206.3, 172.3, 172.1, 170.4, 170.2, 85.5, 83.0, 81.2, 79.8, 75.8, 70.7, 57.4,
49.8, 46.4, 46.2, 45.4, 45.1, 40.2, 38.0, 37.8, 37.3, 32.8, 32.2, 31.3, 29.8, 29.3, 28.7,
28.4, 28.3, 26.9, 26.6, 26.5, 26.1, 26.0, 22.8, 22.5, 21.6, 21.5, 20.7, 20.3, 20.0, 16.2;
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C44H66O11Na 793.4497; found 793.4496.
16,25ꢀDiꢀOꢀacetylꢀcycloastragenol (13). To a solution of 12 (530 mg, 0.69 mmol) in
a mixed solvent of pyridine and HOAc (7.5 mL, v/v = 1.5 : 1) was added the freshly
prepared NH2NH2/HOAc (0.9 mL, 18.6 mmol) at room temperature. The resulting
mixture was stirred at the same temperature for another 12 h. Ethyl acetate was added
to dilute the reaction, the resulting solution was washed with water, 1N HCl, aqueous
saturated NaHCO3, and brine and then was dried over anhydrous Na2SO4. Filtration
and concentration gave a residue which was further purified by silica gel
chromatography (petroleum ether/ethyl acetate = 2 : 1) to furnish 13 (355 mg, 99%)
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as a white solid: [α]D = 59.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
5.36ꢀ5.30 (m, 1 H), 4.02 (t, J = 7.2 Hz, 1 H), 3.56 (td, J = 3.2, 9.2 Hz, 1 H), 3.33 (dd,
J = 4.8, 11.2 Hz, 1 H), 2.43 (d, J = 8.0 Hz, 1 H), 2.26ꢀ2.13 (m, 2 H), 2.02 (s, 3 H),
1.97 (s, 3 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.34 (s, 3 H), 1.33 (s, 3 H), 1.25 (s, 3 H),
13
0.98 (s, 3 H), 0.96 (s, 3 H), 0.52 (d, J = 4.0 Hz, 1 H), 0.37 (d, J = 4.4 Hz, 1 H); C
NMR (100 MHz, CDCl3) δ 170.5, 170.3, 85.6, 83.1, 81.3, 78.3, 75.9, 68.8, 57.6, 53.6,
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46.6, 46.4, 46.3, 41.5, 37.6, 37.3, 32.3, 32.0, 30.8, 30.2, 29.4, 28.0, 27.0, 26.2, 26.0,
22.8, 22.5, 21.6, 20.8, 20.6, 20.2, 15.2; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C34H54O7Na 597.3762; found 597.3764.
9
3ꢀOꢀtertꢀButyldimethylsilylꢀ16,25ꢀdiꢀOꢀacetylꢀcycloastragenol
(14).
Similar
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procedure as that used for the synthesis of 7 was applied to convert 13 to 14 (271 mg,
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87%) as a white solid: [α]D = 81.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
5.36ꢀ5.31 (m, 1 H), 4.02 (t, J = 7.2 Hz, 1 H), 3.55 (td, J = 4.0, 9.2 Hz, 1 H), 3.28 (dd,
J = 4.8, 10.0 Hz, 1 H), 2.44 (dd, J = 7.6 Hz, 1 H), 2.58ꢀ2.15 (m, 2 H), 2.02 (s, 3 H),
1.97 (s, 3 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.33 (s, 6 H), 1.15 (s, 3 H), 0.98 (s, 3 H),
13
0.92 (s, 3 H), 0.89 (s, 9 H), 0.50 (d, J = 4.4 Hz, 1 H), 0.33 (d, J = 4.4 Hz, 1 H); C
NMR (100 MHz, CDCl3) δ 170.5, 170.2, 85.6, 83.1, 81.4, 78.8, 75.9, 68.6, 57.6, 53.7,
46.5, 46.3, 46.2, 45.6, 42.0, 37.4, 37.2, 32.3, 31.9, 30.8, 30.4, 29.7, 29.2, 28.4, 26.9,
26.1, 26.0, 25.9, 22.8, 22.5, 21.6, 20.7, 20.5, 20.1, 18.1, 15.7, ꢀ3.8, ꢀ4.9; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C40H69O7Si 689.4807; found 689.4808.
3ꢀOꢀtertꢀButyldimethylsilylꢀ6,16ꢀdiꢀOꢀpivaloylꢀcycloastragenol (15). To a solution
of 7 (300 mg, 0.5 mmol) in dry pyridine (1 mL) was added PivCl (50 µL, 4.96 mmol)
o
via a syringe at 0 C under N2 atmosphere. After the addition was finished, the
o
iceꢀbath was removed and the mixture was heated to 50 C. The stirring was
continued at the same temperature until TLC showed that all starting material
disappeared. Ethyl acetate was added to dilute the reaction, the resulting solution was
washed successively with water, 1N HCl, aqueous saturated NaHCO3, and brine, and
then was dried over Na2SO4. Filtration was followed by evaporation under reduced
pressure afforded the crude product which was further subjected to silica gel
chromatography (petroleum ether/ethyl acetate = 10 : 1) to give 15 (383.3 mg, 95%)
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1
as a white solid: [α]D = 72.9 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
5.31ꢀ5.26 (m, 1 H), 4.74ꢀ4.69 (m, 1 H), 3.74 (t, J = 7.2 Hz, 1 H), 3.24 (dd, J = 4.8,
10.0 Hz, 1 H), 2.37 (d, J = 8.0 Hz, 1 H), 2.08ꢀ2.00 (m, 2 H), 1.36 (s, 3 H), 1.31 (s, 3
H), 1.18 (s, 3 H), 1.16 (s, 9 H), 1.13 (s, 9 H), 1.07 (s, 3 H), 0.96 (s, 3 H), 0.85 (s, 12
H), 0.80 (s, 3 H), 0.54 (d, J = 4.8 Hz, 1 H), 0.21 (d, J = 4.8 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 178.2, 177.7, 85.5, 83.3, 78.5, 75.7, 71.2, 69.7, 57.5, 49.2, 46.7, 46.2,
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45.1, 43.0, 41.9, 38.6, 38.2, 32.5, 31.9, 31.4, 27.8, 27.4, 27.3, 27.2, 27.1 (2 C), 26.6,
26.2, 26.0, 25.9, 25.4, 24.5, 20.7, 19.8, 19.6, 18.1, 15.4; HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C46H81O7Si 773.5746; found 773.5743.
9
2,3,4,6ꢀTetraꢀOꢀbenzoylꢀ
D
ꢀglucopyranosyl
orthoꢀcyclopropylethynylbenzoate
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(18).
Compound 1610c (100 mg, 0.17 mmol) was dissolved in anhydrous CH2Cl2 (4 mL) at
room temperature. To which orthoꢀalkynylbenzoic acid (ABzOH) (37.4 mg, 0.2
mmol), DMAP (28.1 mg, 0.23 mmol), EDCI (43.9 mg, 0.23 mmol), and DIPEA (74
µL) was added. After being stirred overnight at room temperature, the mixture was
diluted with CH2Cl2, and washed with 1N HCl, saturated aqueous NaHCO3, and brine,
respectively. The organic phase was dried over anhydrous Na2SO4 and concentrated in
vacuo. The crude product was purified by silica gel chromatography (petroleum
ether/ethyl acetate, 5 : 1) to provide 1810c (121 mg, 93%) as a white foam. For
1
comparison purpose, an aliquot of pure α isomer was obtained and the H NMR was
1
1
acquired. H NMR (400 MHz, CDCl3) δ H NMR (400 MHz, CDCl3) δ 8.07 (d, J =
7.5 Hz, 2 H), 7.92ꢀ7.87 (m, 6 H), 7.44ꢀ7.28 (m, 17 H), 6.94 (d, J = 3.3 Hz, 1 H), 6.38
(dd, J = 9.6, 9.9 Hz, 1 H), 5.94 (dd, J = 9.9, 10.2 Hz, 1 H), 5.76 (dd, J = 3.3, 9.9 Hz, 1
H), 4.80ꢀ4.66 (m, 2 H), 4.54 (dd, J = 3.3, 6.0 Hz, 1 H), 1.56 (m, 1 H), 0.84 (d, J = 6.6
Hz, 4 H).
2,3,4ꢀTriꢀOꢀbenzoylꢀDꢀxylopyranosyl orthoꢀcyclopropylethynylbenzoate (19).
Similar procedure as that used for the synthesis of 18 was adopted to convert 1715b to
19 (612 mg, 89%) as a white foam. An aliquot of pure α isomer was obtained for
detailed characterization: [α]D25 = 0.02 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
8.04ꢀ7.98 (m, 6 H), 7.90 (dd, J = 1.2, 8.0 Hz, 1 H), 7.58ꢀ7.51 (m, 3 H), 7.49ꢀ7.42 (m,
2 H), 7.38ꢀ7.30 (m, 6 H), 7.21 (td, J = 1.6, 7.6 Hz, 1 H), 6.42 (d, J = 7.6 Hz, 1 H),
5.81 (t, J = 5.2 Hz, 1 H), 5.58 (dd, J = 4.0, 5.2 Hz, 1 H), 5.36ꢀ5.32 (m, 1 H), 4.63 (dd,
J = 3.6, 12.8 Hz, 1 H), 4.06 (dd, J = 4.8, 12.4 Hz, 1 H), 1.54ꢀ1.47 (m, 1 H), 0.90ꢀ0.84
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ 164.9, 164.4, 164.3, 163.3, 133.7, 132.8,
129.9, 129.7, 129.4, 129.3, 128.5, 128.3, 127.8 (2 C), 126.3, 124.7, 99.7, 91.4, 73.6,
67.8, 67.6, 67.2, 60.9, 8.2, ꢀ0.0; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C38H31O9
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631.1968; found 631.1966.
3,6,16ꢀTriꢀOꢀacetylꢀ25ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀ
D
ꢀglucopyranosyl)ꢀcycloastra
7
8
9
genol (20). To a solution of 6 (12 mg, 0.02 mmol) and 18 (31 mg, 0.05 mmol) in dry
CH2Cl2 (2.0 mL) was added 4Å MS under nitrogen atmosphere. The resulting mixture
was stirred at room temperature for 30 minutes and then Ph3PAuNTf2 (7.0 mg, 0.01
mmol) was added. The stirring was continued at room temperature for 3 h (until 6 was
consumed as monitored by TLC). The mixture was filtered, the filtrate was
concentrated under reduced pressure to yield a residue, which was further purified by
silica gel column chromatography (petroleum ether/ethyl acetate 5 : 1) to provide 20
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25
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(22 mg, 94%) in only βꢀisomer as a white solid: [α]D = 72.6 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ 8.00ꢀ7.95 (m, 4 H), 7.91 (dd, J = 1.2, 8.4 Hz, 2 H), 7.85
(dd, J = 1.2, 8.0 Hz, 2 H), 7.56ꢀ7.48 (m, 3 H), 7.44ꢀ7.33 (m, 7 H), 7.30ꢀ7.27 (m, 2 H),
5.92 (t, J = 9.6 Hz, 1 H), 5.58 (t, J = 10.0 Hz, 1 H), 5.50 (dd, J = 8.0, 10.0 Hz, 1 H),
5.29ꢀ5.26 (m, 1 H), 5.20 (d, J = 8.0 Hz, 1 H), 4.74 (td, J = 4.0, 9.2 Hz, 1 H), 4.60ꢀ4.56
(m, 2 H), 4.47 (dd, J = 6.8, 12.0 Hz, 1 H), 4.16ꢀ4.11 (m, 1 H), 3.70 (t, J = 7.2 Hz, 1 H),
2.41 (d, J = 8.0 Hz, 1 H), 2.18 (dd, J = 8.0, 14.0 Hz, 1 H), 2.05 (s, 3 H), 2.00 (s, 3 H),
1.97 (s, 3 H), 1.30 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 1.12 (s, 3 H), 0.98 (s, 3 H),
13
0.97 (s, 3 H), 0.86 (s, 3 H), 0.60 (d, J = 4.8 Hz, 1 H), 0.38 (d, J = 4.8 Hz, 1 H); C
NMR (100 MHz, CDCl3) δ 170.8, 170.4, 170.2, 166.0, 165.9, 165.3, 164.9, 133.4,
133.2, 133.1, 129.8 (2 C), 129.7 (2 C), 129.6, 128.9 (2 C), 128.4 (2 C), 128.3, 96.1,
85.8, 82.7, 80.0, 79.6, 76.0, 73.2, 72.1, 72.0, 70.5, 70.3, 63.8, 57.6, 49.8, 46.4, 46.3,
45.6, 45.4, 40.1, 37.4, 33.2, 32.2, 31.4, 29.8, 29.7, 28.6, 26.7, 26.6 (2 C), 25.9, 23.2,
22.2, 21.8, 21.5, 21.2, 20.6, 20.4, 20.1, 16.3; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd
for C70H82O17Na 1217.5444; found 1217.5447.
3ꢀOꢀ(2,3,4ꢀTriꢀOꢀbenzoylꢀβꢀDꢀxylopyranosyl)ꢀ6,16,25ꢀtriꢀOꢀacetylꢀcycloastragenol
(21). Similar procedure as that used for the synthesis of 20 was applied for the
glycosylation between 9 (12 mg, 0.02%) and 19 (25 mg, 0.04%), product 21 (22 mg,
92%) was isolated as a white solid: [α]D25 = 29.4 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.01ꢀ7.94 (m, 6 H), 7.56ꢀ7.47 (m, 3 H), 7.40ꢀ7.31 (m, 6 H), 5.78 (t, J = 7.6
Hz, 1 H), 5.45 (dd, J = 5.6, 7.6 Hz, 1 H), 5.34ꢀ5.28 (m, 2 H), 4.85 (d, J = 5.6 Hz, 1 H),
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4.64 (td, J = 4.4, 8.8 Hz, 1 H), 4.46 (dd, J = 4.4, 12.0 Hz, 1 H), 4.02 (t, J = 7.2 Hz, 1
H), 3.68 (dd, J = 7.6, 12.0 Hz, 1 H), 3.25 (dd, J = 4.4, 11.6 Hz, 1 H), 2.42 (d, J = 8.0
Hz, 1 H), 2.00 (s, 3 H), 1.96 (s, 3 H), 1.90 (s, 3 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 1.32 (s,
3 H), 1.30 (s, 3 H), 0.95 (s, 3 H), 0.80 (s, 3 H), 0.78 (s, 3 H), 0.55 (d, J = 4.4 Hz, 1 H),
0.34 (d, J = 4.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.3 (2 C), 165.6,
165.5, 165.2, 133.4, 133.3, 133.2, 129.9, 129.8, 129.4, 129.2, 129.1, 128.4 (2 C),
128.3, 102.5, 88.3, 85.6, 83.1, 81.2, 75.8, 70.8, 70.7, 70.3, 69.5, 61.5, 57.4, 49.7, 46.4,
46.3, 45.4, 44.6, 41.5, 37.2, 32.8, 32.3, 31.6, 29.7, 28.9, 28.8, 28.1, 27.1, 26.2, 26.0,
22.8, 22.6, 21.8, 21.6, 20.6, 20.2, 20.0, 15.8; HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd
for C62H80O15N 1078.5522; found 1078.5530.
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3ꢀOꢀtertꢀButyldimethylsilylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)ꢀ16,
25ꢀdiꢀOꢀacetylꢀcycloastragenol (22). Except for the catalyst and amounts
(Ph3PAuOTf, 0.5 equivalents), similar procedure as that used for the synthesis of 20
25
was adopted to synthesize 22 (11.7 mg, 80%) as a white solid: [α]D = 10.1 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 1.2, 8.0 Hz, 2 H), 8.28ꢀ8.25 (m,
4 H), 8.17 (dd, J = 1.2, 8.0 Hz, 2 H), 7.93ꢀ7.88 (m, 1 H), 7.86ꢀ7.81 (m, 2 H),
7.56ꢀ7.52 (m, 1 H), 7.50ꢀ7.45 (m, 2 H), 7.44ꢀ7.30 (m, 7 H), 7.27ꢀ7.23 (m, 2 H), 5.90 (t,
J = 9.2 Hz, 1 H), 5.61 (t, J = 9.6 Hz, 1 H), 5.57 (dd, J = 8.0, 9.6 Hz, 1 H), 5.39ꢀ5.34
(m, 1 H), 4.96 (d, J = 8.0 Hz, 1 H), 4.60 (dd, J = 3.2, 12.0 Hz, 1 H), 4.49 (dd, J = 7.2,
12.0 Hz, 1 H), 4.18ꢀ4.13 (m, 1 H), 3.98 (t, J = 7.2 Hz, 1 H), 3.55 (dd, J = 5.2, 12.4 Hz,
1 H), 3.02 (dd, J = 4.8, 9.6 Hz, 1 H), 2.41 (d, J = 8.0 Hz, 1 H), 2.32 (dd, J = 8.0, 13.2
Hz, 1 H), 1.98 (s, 3 H), 1.95 (s, 3 H), 1.44 (s, 3 H), 1.42 (s, 3 H), 1.29 (s, 3 H), 1.11 (s,
3 H), 0.98 (s, 3 H), 0.75 (s, 12 H), 0.61 (s, 3 H), 0.45 (d, J = 4.8 Hz, 1 H), 0.05 (d, J =
4.8 Hz, 1 H), ꢀ0.13 (s, 3 H), ꢀ0.36 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.5,
170.0, 165.8 (2 C), 165.2, 165.0, 133.4, 133.1 (2 C), 133.0, 129.9, 129.8, 129.7 (2 C),
129.6, 129.4, 129.0, 128.9, 128.4, 128.3, 128.2, 101.9, 85.8, 83.2, 81.8, 78.6, 78.4,
75.5, 73.4, 72.4, 72.2, 70.1, 63.9, 57.5, 50.4, 46.6, 46.1, 44.0, 42.4, 41.7, 37.8, 32.6,
31.9, 31.1, 30.4, 28.1, 27.7, 26.7, 26.1, 26.0, 25.9, 22.8, 22.6, 21.6, 21.5, 21.0, 19.2,
19.1, 18.0, 15.6, ꢀ4.0, ꢀ5.2; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C74H95O16Si
1267.6384; found 1267.6406.
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6ꢀOꢀ(2,3,4,6ꢀTetraꢀOꢀbenzoylꢀβꢀ
D
ꢀglucopyranosyl)ꢀ16,25ꢀdiꢀOꢀacetylꢀcycloastrage
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6
7
nol (23). Similar procedure as that used for the synthesis of 9 was used to convert 22
25
1
to 23 (7.6 mg, 84%) as a white solid: [α]D = 21.5 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 7.57ꢀ7.46 (m, 4 H), 7.43ꢀ7.32 (m, 7 H), 7.28 (m, 1 H), 5.90 (t, J = 9.6
Hz, 1 H), 5.62 (t, J = 10.0 Hz, 1 H), 5.54 (dd, J = 8.0, 9.6 Hz, 1 H), 5.36ꢀ5.31 (m, 1
H), 4.98 (d, J = 8.0 Hz, 1 H), 4.60 (dd, J = 2.8, 12.0 Hz, 1 H), 4.50 (dd, J = 6.8, 12.0
Hz, 1 H), 4.19ꢀ4.14 (m, 1 H), 3.99 (t, J = 7.2 Hz, 1 H), 3.56ꢀ3.51 (m, 1 H), 3.11 (dd, J
= 4.4, 10.4 Hz, 1 H), 2.38 (d, J = 8.0 Hz, 1 H), 2.26 (dd, J = 8.0, 13.6 Hz, 1 H), 1.98
(s, 3 H), 1.97 (s, 3 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.14 (s,
3 H), 0.92 (s, 3 H), 0.78 (s, 3 H), 0.76 (s, 3 H), 0.45 (d, J = 4.4 Hz, 1 H), 0.15 (d, J =
4.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.0, 165.8, 165.2, 165.0, 133.4,
133.1 (2 C), 129.9, 129.8, 129.7 (2 C), 129.4, 128.9, 128.4, 128.2, 101.3, 85.6, 83.2,
81.7, 78.8, 78.0, 75.5, 73.8, 72.5, 72.4, 70.0, 63.8, 57.5, 50.7, 46.5, 46.1, 44.5, 44.0,
41.2, 38.8, 32.8, 32.4, 31.3, 29.8, 29.7, 28.3, 27.4, 26.7, 26.9, 26.7, 26.0 (2 C), 22.9,
22.6, 21.6, 21.5, 21.0, 19.6, 19.5, 15.3; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C68H81O16 1153.5519; found 1153.5523.
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3ꢀOꢀ(2,3,4ꢀTriꢀOꢀbenzoylꢀβꢀDꢀxylopyranosyl)ꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgl
ucopyranosyl)ꢀ16,25ꢀdiꢀOꢀacetylꢀcycloastragenol (24). Except for the catalyst and
amounts (Ph3PAuOTf, 1.0 equivalents), similar procedure as that used for the
25
synthesis of 20 was adopted to synthesize 24 (10.0 mg, 80%) as a white solid: [α]D
=
ꢀ4.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00ꢀ7.90 (m, 12 H), 7.84 (dd, J =
1.2, 8.0 Hz, 2 H), 7.67ꢀ7.63 (m, 1 H), 7.61 (m, 1 H), 7.56ꢀ7.51 (m, 4 H), 7.48ꢀ7.33 (m,
13 H), 7.30 (m, 2 H), 5.90 (t, J = 9.6 Hz, 1 H), 5.65 (t, J = 8.0 Hz, 1 H), 5.60 (t, J =
10.0 Hz, 1 H), 5.55 (dd, J = 8.0, 10.0 Hz, 1 H), 5.40ꢀ5.34 (m, 1 H), 5.30 (dd, J = 6.4,
8.0 Hz, 1 H), 5.25ꢀ5.20 (m, 1 H), 4.86 (d, J = 7.6 Hz, 1 H), 4.58 (dd, J = 3.2, 12.0 Hz,
1 H), 4.49 (dd, J = 7.2, 12.0 Hz, 1 H), 4.35 (dd, J = 4.8, 11.6 Hz, 1 H), 4.20 (d, J = 6.4
Hz, 1 H), 4.16ꢀ4.11 (m, 1 H), 3.99 (t, J = 7.2 Hz, 1 H), 3.40 (dd, J = 8.0, 11.6 Hz, 1 H),
3.01 (dd, J = 4.4, 11.2 Hz, 1 H), 2.43 (d, J = 8.0 Hz, 1 H), 2.31 (dd, J = 8.0, 13.6 Hz, 1
H), 1.98 (s, 3 H), 1.96 (s, 3 H), 1.43 (s, 3 H), 1.41 (s, 3 H), 1.30 (s, 3 H), 1.12 (s, 3 H),
0.98 (s, 3 H), 0.56 (s, 3 H), 0.55 (s, 3 H), 0.37 (d, J = 4.4 Hz, 1 H), 0.03 (d, J = 4.8 Hz,
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1 H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.0, 165.9, 165.8, 165.6, 165.5, 165.2,
164.9 (2 C), 102.4, 101.6, 87.3, 85.8, 83.2, 81.8, 77.7, 75.5, 73.1, 72.2, 70.9, 70.7,
70.2, 69.7, 63.9, 61.7, 57.4, 50.6, 46.6, 46.0, 43.8, 41.6, 37.8, 32.5, 31.9, 31.1, 31.0,
29.7 (2 C), 29.4, 28.7, 27.1, 26.9, 26.7, 26.0, 23.9, 22.9, 22.7, 22.6, 21.6, 21.5, 21.0,
19.0, 18.9, 15.6, 14.1; HRMS (ESIꢀTOF) m/z: [M+NH4]+ calcd for C94H104O23N
1614.6994; found 1614.7008.
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3ꢀOꢀtertꢀButyldimethylsilyꢀ6,16ꢀdiꢀOꢀpivaloylꢀ25ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀ
glucopyranosyl)ꢀcycloastragenol (25). Except for the catalyst amounts (Ph3PAuNTf2,
0.2 equivalents), similar procedure as that used for the synthesis of 20 was applied to
afford 25 (160 mg, 92%) as a white solid: [α]D25 = 40.3 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 8.02ꢀ7.96 (m, 4 H), 7.91 (dd, J = 1.2, 8.0 Hz, 2 H), 7.86 (dd, J = 1.2,
8.4 Hz, 2 H), 7.54ꢀ7.48 (m, 4 H), 7.43ꢀ7.34 (m, 7 H), 7.31 (t, J = 8.0 Hz, 1 H), 5.90 (t,
J = 9.6 Hz, 1 H), 5.53 (dd, J = 9.2, 10.0 Hz, 1 H), 5.48 (dd, J = 7.6, 9.2 Hz, 1 H), 5.35
(d, J = 8.0 Hz, 1 H), 5.23ꢀ5.18 (m, 1 H), 4.76 (dd, J = 6.8, 14.4 Hz, 1 H), 4.60 (dd, J =
2.8, 12.0 Hz, 1 H), 4.44 (dd, J = 7.2, 12.0 Hz, 1 H), 4.13ꢀ4.08 (m, 1 H), 3.72 (dd, J =
4.8, 8.4 Hz, 1 H), 3.20 (m, 1 H), 2.42 (d, J = 7.6 Hz, 1 H), 2.14ꢀ2.06 (m, 2 H), 1.37 (s,
3 H), 1.33 (s, 3 H), 1.18 (s, 9 H), 1.17 (s, 9 H), 1.16 (s, 3 H), 1.13 (s, 3 H), 0.98 (s, 3
H), 0.86 (s, 12 H), 0.80 (s, 3 H), 0.56 (d, J = 4.8 Hz, 1 H), 0.27 (d, J = 4.8 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 178.0, 177.7, 165.9, 165.8, 165.4, 164.9, 134.2, 134.1,
133.5, 133.2, 133.1 (2 C), 129.8 (2 C), 129.7 (2 C), 129.6, 129.3, 129.2, 129.0, 128.8,
128.4, 128.3 (2 C), 96.2, 86.0, 84.1, 80.1, 78.3, 76.1, 73.1, 72.1 (2 C), 70.5, 69.8, 63.9,
57.8, 49.1, 46.8, 46.3, 45.2, 43.2, 41.9, 38.6, 38.5, 38.2, 32.6, 32.1, 31.2, 30.5, 27.8,
27.4, 27.2 (2 C), 25.9, 25.5, 24.0, 21.7, 20.6, 19.7, 19.6, 18.1, 15.4, ꢀ3.9, ꢀ4.9; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C80H107O16Si 1351.7323; found 1351.7331.
6,16ꢀDiꢀOꢀpivaloylꢀ25ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)ꢀcycloastra
genol (26). Similar procedure as that used for the synthesis of 9 was adopted to
convert 25 to 26 (91 mg, 83%) as a white solid: [α]D25 = 20.5 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.00ꢀ7.96 (m, 4 H), 7.91 (dd, J = 1.2, 8.0 Hz, 2 H), 7.85 (dd, J =
1.2, 8.0 Hz, 2 H), 7.54ꢀ7.49 (m, 3 H), 7.45ꢀ7.33 (m, 7 H), 7.31ꢀ7.27 (m, 2 H), 5.91 (t,
J = 9.6 Hz, 1 H), 5.54 (t, J = 10.1 Hz, 1 H), 5.48 (dd, J = 8.0, 9.6 Hz, 1 H), 5.27 (d, J
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= 8.0 Hz, 1 H), 5.23ꢀ5.18 (m, 1 H), 4.78ꢀ4.73 (m, 1 H), 4.59 (dd, J = 3.2, 12.0 Hz, 1
H), 4.44 (dd, J = 7.2, 11.6 Hz, 1 H), 4.14ꢀ4.08 (m, 1 H), 3.72 (dd, J = 4.8, 8.4 Hz, 1
H), 3.24 (dd, J = 4.8, 11.6 Hz, 1 H), 2.43 (d, J = 8.0 Hz, 1 H), 2.16 (dd, J = 7.6, 13.6
Hz, 1 H), 2.05ꢀ2.01 (m, 1 H), 1.36 (s, 3 H), 1.33 (s, 3 H), 1.18 (s, 12 H), 1.17 (s, 9 H),
1.11 (s, 3 H), 1.00 (s, 3 H), 0.91 (s, 3 H), 0.89 (s, 3 H), 0.56 (d, J = 4.8 Hz, 1 H), 0.30
(d, J = 4.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 178.1, 177.7, 166.0, 165.8, 165.4,
164.9, 133.5, 133.2 (2 C), 133.1, 129.8 (2 C), 129.7 (2 C), 129.6 (2 C), 128.9, 128.8,
128.4, 128.3 (2 C), 96.2, 86.0, 84.1, 80.1, 77.9, 76.1, 73.1, 72.1, 72.0, 70.4, 69.9, 63.9,
57.8, 49.2, 46.8, 46.3, 45.4, 43.7, 41.3, 38.6, 38.5, 38.3, 32.3 (2 C), 31.3, 30.0, 28.0,
27.3, 27.2, 27.1, 26.9, 26.1, 25.9, 25.6, 23.8, 22.0, 20.8, 19.8, 19.7, 15.0; HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C74H93O16 1237.6458; found 1237.6468.
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3ꢀOꢀ(2,3,4ꢀTriꢀOꢀbenzoylꢀβꢀDꢀxylopyranosyl)ꢀ6,16ꢀdiꢀOꢀpivaloylꢀ25ꢀOꢀ(2,3,4,6ꢀtet
raꢀOꢀbenzoylꢀβꢀ ꢀglucopyranosyl)ꢀcycloastragenol (27). Except for the catalyst
D
amounts (Ph3PAuNTf2, 0.2 equivalents), similar procedure as that used for the
synthesis of 20 was applied to afford 27 (361 mg, 83%) as a white solid: [α]D25 = 25.2
(c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02ꢀ7.94 (m, 10 H), 7.92 (dd, J = 1.2,
8.0 Hz, 2 H), 7.86 (dd, J = 1.2, 8.0 Hz, 2 H), 7.55ꢀ7.43 (m, 7 H), 7.41ꢀ7.27 (m, 14 H),
5.91 (t, J = 10.0 Hz, 1 H), 5.80 (t, J = 8.0 Hz, 1 H), 5.52ꢀ5.42 (m, 3 H), 5.32ꢀ5.27 (m,
2 H), 5.23ꢀ5.18 (m, 1 H), 4.80 (d, J = 6.4 Hz, 1 H), 4.65ꢀ4.58 (m, 2 H), 4.42ꢀ4.33 (m,
2 H), 4.14ꢀ4.09 (m, 1 H), 3.73 (dd, J = 4.8, 8.4 Hz, 1 H), 3.62 (dd, J = 7.6, 12.0 Hz, 1
H), 3.15 (dd, J = 4.4, 11.2 Hz, 1 H), 2.44 (d, J = 7.6 Hz, 1 H), 2.13ꢀ2.03 (m, 2 H),
1.35 (s, 3 H), 1.33 (s, 3 H), 1.19 (s, 3 H), 1.17 (s, 9 H), 1.13 (s, 3 H), 1.08 (s, 9 H),
0.97 (s, 3 H), 0.78 (s, 3 H), 0.64 (s, 3 H), 0.52 (d, J = 4.8 Hz, 1 H), 0.26 (d, J = 4.8 Hz,
1 H); 13C NMR (100 MHz, CDCl3) δ 178.0, 177.5, 166.0, 165.9, 165.6 (2 C), 165.4,
165.1, 164.9, 133.6, 133.4, 133.3, 133.2 (2 C), 133.1, 129.9, 129.8, 129.7 (2 C), 129.6
(2 C), 129.4, 129.2, 129.1, 128.9, 128.8, 128.5, 128.4 (2 C), 128.3 (2 C), 102.6, 96.2,
88.6, 86.1, 84.2, 80.2, 76.1, 73.1, 72.1 (2 C), 71.2, 71.0, 70.4, 69.6, 69.3, 63.9, 61.7,
57.8, 49.2, 46.8, 46.3, 45.2, 42.9, 41.4, 38.5, 38.3, 32.5, 31.8, 31.1, 28.6, 27.4, 27.2,
27.1, 26.6, 26.2, 25.9, 25.6, 24.0, 21.9, 20.7, 19.7, 19.6, 15.6; HRMS (ESIꢀTOF) m/z:
[M+NH4]+ calcd for C100H116O23N 1699.7967; found 1699.7990.
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Cycloastrgenol 25ꢀOꢀglucoside (1). To a solution of 20 (20 mg, 0.017 mmol) in dry
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MeOH (2 mL) was added freshly prepared NaOMe (Na was dissolved in dry MeOH
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at 0 C) at room temperature. The resulting solution was stirred at the same
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temperature for 15 h, at which time TLC showed that the reaction reached completion.
The pH value of the reaction mixture was adjusted with H+ resin to 6ꢀ7. Filtration and
concentration yield a residue which was further subjected to silica gel
chromatography (CH2Cl2/MeOH = 5 : 1) to deliver 1 (9.2 mg, 84%) as a white solid:
[α]D25 = 21.4 (c 1.0, CHCl3); 1H NMR (400 MHz, C5D5N) δ 5.10 (d, J = 8.0 Hz, 1 H),
4.95ꢀ4.88 (m, 2 H), 4.47 (dd, J = 2.8, 11.6 Hz, 1 H), 4.34 (dd, J = 4.8, 11.6 Hz, 1 H),
4.25ꢀ4.16 (m, 2 H), 4.09 (dd, J = 9.2, 16.0 Hz, 1 H), 3.93ꢀ3.89 (m, 2 H), 3.83ꢀ3.77 (td,
J = 4.4, 10.0 Hz, 1 H), 3.70 (dd, J = 4.4, 11.2 Hz, 1 H), 2.87ꢀ2.80 (m, 1 H), 2.47 (d, J
= 7.6 Hz, 1 H), 1.92 (s, 3 H), 1.68 (s, 3 H), 1.43 (s, 3 H), 1.38 (s, 6 H), 1.30 (s, 3 H),
0.96 (s, 3 H), 0.62 (d, J = 4.8 Hz, 1 H), 0.34 (d, J = 3.6 Hz, 1 H); 13C NMR (100 MHz,
C5D5N) δ 98.6, 87.0, 81.8, 78.3, 78.0, 77.8, 75.0, 73.3, 71.1, 68.0, 62.5, 57.9, 53.7,
46.8, 45.9, 45.8, 44.9, 42.2, 38.5, 34.8, 33.2, 32.5, 31.2, 30.7, 29.6, 29.2, 27.6, 26.0,
25.7, 25.4, 22.8, 21.4, 20.6, 19.9, 15.9; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C36H61O10 653.4259; found 653.4260.
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Astramembrannin (2). Similar procedure as that used for the synthesis of 1 was
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applied to convert 21 to 2 (25.3 mg, 86%) as a white solid: [α]D = 57.2 (c 0.5,
1
CH3OH); H NMR (400 MHz, C5D5N) δ 6.55 (bs, 1 H), 5.68 (bs, 1 H), 5.05 (dd, J =
6.8, 14.0 Hz, 1 H), 4.93 (d, J = 7.2 Hz, 1 H); 4.40 (dd, J = 4.8, 11.2 Hz, 1 H),
4.27ꢀ4.22 (m, 1 H), 4.19 (t, J = 8.4 Hz, 1 H), 4.09ꢀ4.05 (m, 1 H), 3.91 (dd, J = 5.6, 8.8
Hz, 1 H), 3.81ꢀ3.72 (m, 2 H), 3.66 (dd, J = 4.0, 11.6 Hz, 1 H), 3.15 (dd, J = 10.8, 20.4
Hz, 1 H), 2.55 (d, J = 7.6 Hz, 1 H), 2.45ꢀ2.42 (m, 1 H), 2.35ꢀ2.28 (m, 1 H), 2.00 (s, 3
H), 1.58 (s, 3 H), 1.43 (s, 3 H), 1.34 (s, 3 H), 1.32 (s, 3 H), 1.30 (s, 3 H), 1.01 (s, 3 H);
0.58 (d, J = 4.0 Hz, 1 H), 0.30 (d, J = 4.0 Hz, 1 H); 13C NMR (100 MHz, C5D5N) δ
107.4, 88.5, 87.0, 81.5, 78.3, 75.4, 73.2, 71.0, 67.8, 66.8, 58.1, 53.8, 46.8, 46.4, 45.9,
44.8, 42.5, 38.4, 34.7, 33.2, 32.3, 30.4, 30.1, 29.3, 28.7, 28.3, 28.0, 26.9, 26.2, 26.0,
21.3, 20.8, 20.0, 16.4; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C35H58O9Na
645.3973; found 645.3974.
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Astragaloside IV (3). Similar procedure as that used for the synthesis of 1 was
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applied to convert 24 to 3 (12.97 mg, 76%) as a white solid: [α]D = 16.3 (c 0.4,
1
CH3OH); H NMR (400 MHz, C5D5N) δ 6.55 (bs, 1 H), 5.81 (d, J = 2.8 Hz, 1 H),
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4.93 (d, J = 8.0 Hz, 1 H), 4.88 (d, J = 7.2 Hz, 1 H), 4.52 (dd, J = 2.8, 11.6 Hz, 1 H),
4.39ꢀ4.31 (m, 2 H), 4.27ꢀ4.21 (m, 3 H), 4.19 (t, J = 8.8 Hz, 1 H), 4.06 (m, 2 H),
3.94ꢀ3.87 (m, 2 H), 3.83 (td, J = 3.6, 8.4 Hz, 1 H), 3.74 (t, J = 10.4 Hz, 1 H), 3.56 (dd,
J = 4.0, 11.6 Hz, 1 H), 3.18 (dd, J = 11.2, 20.8 Hz, 1 H), 2.55 (d, J = 7.6 Hz, 1 H),
2.41ꢀ2.27 (m, 4 H), 2.06 (s, 3 H), 1.60 (s, 3 H), 1.43 (s, 3 H), 1.39 (s, 3 H), 1.31 (s, 6
H), 0.95 (s, 3 H), 0.61 (d, J = 3.6 Hz, 1 H), 0.22 (d, 4.0 Hz, 1 H); 13C NMR (100 MHz,
C5D5N) δ 107.5, 105.0, 88.3, 87.0, 81.4, 79.1, 79.0, 78.3, 77.9, 75.4, 73.2, 71.6, 71.0,
66.8, 62.9, 58.0, 52.3, 46.0, 45.5, 44.8, 42.4, 34.7, 34.4, 33.2, 32.0, 30.0, 28.8, 28.6,
28.4, 28.0, 26.9, 26.2, 26.0, 20.9, 19.6, 16.4; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C41H69O14 785.4682; found 785.4675.
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Isoastragaloside IV (4). To a solution of 27 (70 mg, 0.042 mmol) in dry THF (2.0
o
mL) was added LiAlH4 (25 mg, 0.67 mmol) under N2 atmosphere at 0 C. After the
addition was completed, the ice bath was removed and the stirring was continued for
another 3.7 h at room temperature. The reaction mixture was then chilled to 0 oC, and
H2O was added slowly to quench the reaction. Then the volatile solvent was removed
under reduced pressure to yield a residue, which was further coꢀevaporated with
toluene for three times. The resulting residue was dissolved in dry pyridine (2.0 mL),
o
to which Ac2O (2.0 mL) was added dropwise at 0 C. The reaction mixture was
warmed to room temperature, and the stirring was continued for another 24 h. General
procedure was adopted to get the crude product which was further subjected to the
silica gel chromatography (petroleum ether/ethyl acetate = 2 : 1) to afford acetylated
intermediate. The acetylated intermediate was not characterized and put to the next
saponification step directly.
To a solution of above obtained acetylated intermediate in dry MeOH (3 mL) was
added freshly prepared MeONa at room temperature. The mixture was stirred at the
same temperature for another 18 h, then the reaction was quenched with H+ resin.
Filtration and concentration afforded a residue which was further purified by reverse
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phase C18 chromatography (MeOH/H2O = 3 : 1) to afford 4 (30 mg, 92%) as a white
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1
solid: [α]D = 7.9 (c 0.25, CH3OH); H NMR (400 MHz, C5D5N) δ 5.08 (d, J = 7.6
Hz, 1 H), 4.93 (d, J = 7.2 Hz, 1 H), 4.45 (dd, J = 3.6, 11.6 Hz, 1 H), 4.40 (dd, J = 4.8,
11.2 Hz, 1 H), 4.32 (dd, J = 4.8, 11.6 Hz, 1 H), 4.25ꢀ4.15 (m, 4 H), 4.09ꢀ4.00 (m, 3 H),
3.92ꢀ3.88 (m, 2 H), 3.81ꢀ3.72 (m, 2 H), 3.64ꢀ3.61 (m, 1 H), 2.85 (dd, J = 11.6, 19.6
Hz, 1 H), 2.48 (d, J = 7.6 Hz, 1 H), 2.00 (s, 3 H), 1.67 (s, 3 H), 1.42 (s, 3 H), 1.35 (s, 3
H), 1.33 (s, 3 H), 1.29 (s, 3 H), 0.94 (s, 3 H), 0.56 (d, J = 3.2 Hz, 1 H), 0.28 (d, J = 4.0
Hz, 1 H); 13C NMR (100 MHz, C5D5N) δ 107.4, 98.6, 88.4, 87.0, 81.8, 78.3, 77.8,
75.4, 75.0, 73.3, 71.1, 71.0, 67.7, 66.8, 62.5, 57.9, 53.8, 46.6, 45.9, 45.8, 45.0, 42.5,
38.4, 34.8, 33.2, 32.2, 30.3, 30.1, 29.3, 28.7, 27.6, 26.0, 25.7, 25.4, 22.8, 21.3, 20.7,
19.8, 16.4; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C41H68O14Na 807.4501; found
807.4498.
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Acknowledgements:
This work was financially supported by the National Natural Science Foundation of
China (21372252 and 21572081). The Scientific Research Fund of Jiangxi Provincial
Education Department (GJJ150328) was also appreciated.
Supporting Information
13C NMR spectra comparison between synthetic 1ꢀ4 with those either reported in
1
literatures or acquired with authentic sample, copies of H and 13C for all new
compounds
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