Total synthesis of bidensyneosides A2 and C: Remarkable protecting group effects in glycosylation

Article abstract of DOI:10.1016/j.tet.2004.08.012

Bidensyneosides are a group of five recently identified polyacetylenic glucosides from Bidens parviflora WILLD, a traditional Chinese medicinal plant that contains rich bioactive natural products. It was shown that bidensyneosides inhibited both histamine

Full text of DOI:10.1016/j.tet.2004.08.012

Tetrahedron 60 (2004) 9405–9415
Total synthesis of bidensyneosides A2 and C: remarkable
protecting group effects in glycosylation
†
*
Benjamin W. Gung and Ryan M. Fox
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA
Received 12 May 2004; revised 3 August 2004; accepted 5 August 2004
Available online 8 September 2004
Abstract—Bidensyneosides are a group of five recently identified polyacetylenic glucosides from Bidens parviflora WILLD, a traditional
Chinese medicinal plant that contains rich bioactive natural products. It was shown that bidensyneosides inhibited both histamine release and
nitric oxide production. The synthesis of bidensyneoside A2 (2) and C (4) as well as 3-deoxybidensyneoside C (5) are described. These
syntheses establish a synthetic entry to the bidensyneosides and confirm the stereochemistry at C3. Furthermore, a remarkable protecting
group effect on orthoester formation was observed during the glycosylation reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Bidensyneosides are a group of five new polyacetylenic
glucosides (see Fig. 1) isolated from the traditional Chinese
medicinal plant Bidens parviflora WILLD,1 which contains
rich bioactive natural products.2 It was shown that
bidensyneosides inhibit both histamine release and nitric
oxide production.1 The structures of bidensyneosides have
been assigned based on spectroscopic analysis, physico-
chemical properties and application of the Mosher ester
method. Assays have been performed to identify the
biological activity of bidensyneosides, but no attempt at
their synthesis has been reported.
The bidensyneosides are glucosides with a 10-carbon
polyacetylenic side chain. These five natural products differ
from one another primarily in the oxidation degree of this
side chain. In the most potent antiallergic agent, bidensy-
neoside C (4), the side chain contains hydroxyl groups at C3
and C10 while bidensyneosides A1, A2, and B lack a C10
hydroxyl group. Here we describe initial synthetic efforts in
the polyacetylenyl glucoside area, which lead to the first
total synthesis of bidensyneoside A2 (2) and C (4) as well as
3-deoxybidensyneoside C (5). These syntheses establish a
synthetic entry to the bidensyneosides, and furthermore,
confirm the stereochemistry at C3.
Figure 1. Structures of bidensyneosides from Bidens parviflora WILLD.
Since the bidensyneosides differ among themselves mainly
in the aglycon side chain, the development of a strategy
allowing for the convergent assembly of different side chain
analogs was of importance in our synthetic planning. The
consideration of a mild glycosylation step, which would
allow the attachment of functionalized side chain, led to the
retrosynthetic intermediates 6, 7, and 8 (Scheme 1).
Keywords: Total synthesis; Natural product; Bidensyneosides; Glycosyla-
tion; Protecting group effect.
* Corresponding author. Tel.: C1-513-529-2825; fax: C1-513-529-5715;
e-mail: gungbw@muohio.edu
† Beckman predoctoral scholarship recipient.
We chose thioglucosides as the glycosylation donors
because it is known that these donors are stable, and they
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.012

9406
B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
Scheme 1.
couple with a variety of acceptors under mild conditions.3,4
The endiyne side chain was envisioned to arise from a
copper-catalyzed coupling of intermediates 7 and 8, and the
chiral acetylenic diol 7 was envisaged to arise from an
enzymatic resolution of a racemate, which could be
prepared from a 3-alkoxy propanal and ethynylmagnesium
bromide. The enzymatic resolution of acetylenic alcohols
has been studied5,6 and should provide both enantiomers,
thereby allowing verification of the C3 stereochemistry.
TBS protecting group was achieved in THF with the
HF$pyridine complex. To avoid the loss of the product, the
work-up consisted of adding solid NaHCO3 and evaporating
the solvent to a slurry, which was transferred to a silica gel
column and eluted with a mixed solvent system (MeOH/
CHCl3, 10:90) giving 51% of 5 as a white solid.
The synthetic sample gave identical 1H and 13C NMR
spectra as the reported natural product.1 Five UV absorp-
tions were reported for 3-deoxybidensyneoside C (328, 283,
267, 252, and 239 nm),1 but we observed only four (282,
266, 252, and 240 nm). Considering reported UV spectra for
other endiynes and those reported for the other four
bidensyneosides,1 we believe that the 328 nm absorption
is spurious.
2. Results and discussion
2.1. Preparation of 3-deoxybidensyneoside C 5
As a preliminary study, we first carried out the glycosylation
reaction between glucose pentacetate and 4-pentyn-1-ol in
the presence of BF3$OEt2.7 The desired product 10 was
obtained in 30% yield (Scheme 2).
2.2. Synthesis of bidensyneoside C 4
The stereo center on the side chain of this substance was
introduced by using a convenient enzymatic resolution
approach (Scheme 3). The THP and TBS protected
aldehyde 14 were prepared from 1,3-propanediol (13).
The low yield of the desired product 10 is possibly due to
anchimerically-assisted deglycosylation, as reported for
4-pentenyl glucosides.8 For the preparation of compound 5,
nevertheless, we could easily prepare enough material to
continue with the synthesis. Bromo enyne 11 was prepared
from commercially available (E)-2-penten-4-yn-1-ol via (1)
hydroxyl protection as the t-butyldimethylsilyl (TBS)
ether,9 and (2) bromination with NBS in the presence of
AgNO3.10 The coupling of bromo alkyne 11 and glucoside
10 was carried out under Cadiot–Chodkiewicz conditions.11
The copper-promoted coupling reaction, which was carried
out in a mixture of EtNH2 and MeOH, proceeded
concurrently with the removal of acetate groups by
EtNH2, leading to the polar glucoside 12 in 31% yield.
Attempted coupling with the unprotected bromo enyne 8
resulted in loss of product during work-up due to difficulties
in separating the extremely polar 5 from solvent. The
problem was alleviated by using a TBS ether protecting
group. Diyne 12 could be extracted from the aqueous
solution and purified on a silica gel column. Removal of the
Oxidation of 14 under the conditions of Swern12 and in situ
addition of ethynylmagnesium bromide to the resulting
aldehyde afforded the racemic propargyl alcohol 15 in 61%
yield.13 The current preparation of 15 employs less
expensive reagents and requires fewer steps than a previous
reported procedure.14
The hydroxyl protecting group at C1 of rac-15 has a
profound influence on the lipase-mediated kinetic resol-
ution. The TBS ether group, unlike the THP, provides the
steric bulk required for an efficient resolution and material
of greater than 95% ee was obtained when this ether was
treated with Amano lipase AK (from pseudomonas sp) in
the presence of vinyl acetate in hexanes.5,6 The progress of
the enzymatic resolution was monitored carefully by H
NMR spectroscopy and the reaction was terminated after
50% of rac-15 was consumed. After separation of the
1
Scheme 2.

B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
9407
Scheme 3.
dimethyl(methylthio) sulfonium triflate (DMTST).16
Although DMTST is less active than other thiophiles,
such as NIS/TfOH, it does not produce a nucleophile as a
byproduct.4 We thus decided to increase the reactivity of the
glucoside donor by replacing some of the acetate protecting
groups with TBS ethers. Thioglucoside 6a was deacetylated
with K2CO3 in MeOH (Scheme 4) and the crude tetraol 17
was treated with either 1 or 2 equiv of TBSCl and imidazole
in DMF. This led to the selective formation of either the
6-TBS ether 18a or the 3,6-di TBS ether 18b, respectively.
Bidensyneosides have the b-configuration at the anomeric
carbon. A C2-acetate group is necessary to provide
neighboring group assistance for control of stereochemistry
in glycosylation.17 Therefore, the free hydroxyl groups of
18a and 18b were acetylated. According to a study by
Wong, replacing a C6 acetate group with TBS increases the
glycosyl donor reactivity by a factor of 3–5!.18
Scheme 4.
alcohol R-15 from the acetate 16 by column chromato-
graphy, both enantiomers were obtained in high optical
purity as confirmed by the 1H NMR spectra of their
O-methyl mandelic esters.15 No diastereomeric isomer was
When thioglucoside donor 6b and (R)-7 were allowed to
react in the presence of DMTST for 1 h at room
temperature, we were surprised to isolate the orthoester
19a in 74% yield, rather than the normal anomeric coupling
product (Scheme 5). The structure of 19a was determined by
a battery of NMR spectroscopy methods, including 1H, 13C,
DEPT 13C, and 2D COSY and HMBC spectra. We expected
to see four carbonyl groups in the 13C NMR spectrum, but
saw only three and one unexpected peak at 121 ppm
1
detectable by 500 MHz H NMR analysis. The final two
steps in the preparation of the side chain involved the
acylation of the secondary OH group in R-15 and the
removal of the TBS ether with HF$pyridine complex to
afford the optically pure alcohol (R)-7.
The thioglucoside 6a with four acetate groups was
‘disarmed’ or inert in the presence of the promoter
Scheme 5.

9408
B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
Figure 2. Comparison of the NMR data of 19a and 21.
indicating an orthoester. The normal glycosylation products
have a chair conformation with large vicent coupling
constants. The small coupling constants between H2 and
H3 (J23Z2.9 Hz) and between H3 and H4 (J34Z2.9 Hz) is
consistent with a twist boat or ‘skew’ conformation for 19a,
Figure 2, due to the constraint imposed by the bicyclic
structure. Previous studies of carbohydrates containing
orthoesters suggested a similar conformation.19,20
from a single protecting group at C3. Although the
formation of orthoesters is quite common in glycosylation
reactions, we believe this is the first time that a single
hydroxyl protecting group has been shown to effectively
alter the outcome of the glycosylation reaction. Currently
we believe this difference is related to the relative stability
of the glycosylation intermediate, the oxycarbenium ion. It
appears that donor 6b with a C3 acetate group produces a
less stable oxycarbenium ion and requires neighboring
group stabilization and thus the formation of the orthoester.
Donor 6c with a TBS ether group should yield a more stable
oxycarbenium ion which then reacts directly with the
acceptor. An alternative explanation is that both reactions
proceed through the initial formation of the orthoester,
which rearranges more rapidly in the case of 6c to the
glycoside.22
The exclusive formation of the orthoester 19a was
reproducible from 6b and (R)-7. When the S-enantiomer
of 7 was used as the acceptor, the normal glycosylation
product 20 was also isolated in addition to the orthoester,
but the yield of the reaction was only 26%. The difference
between R- and S-7 appears to be an effect of matching and
mismatching pairs with regard to the glucoside donor 6b.
Therefore, we decided to use the more reactive donor 6c to
couple with alcohol 7 even though it should be possible to
transform orthoester 19a to the diastereomer of 20 under
acidic conditions.20
The copper promoted coupling reaction (Cadiot–Chokwicz
reaction) between the terminal alkyne 21 and the bromo
alkyne 8 was carried out under the conditions discussed
earlier (Scheme 2). This reaction furnished bidensyneoside
C in its protected form. Interestingly, only the C3 acetate
group was removed during the reaction; the two acetate
groups on the glucose ring remained intact. Apparently the
steric bulk of the TBS ethers in 21 prevents EtNH2 from
attacking these esters. Removal of the protecting groups was
undertaken in the sequence shown in Scheme 6. If the
acetates were removed first, it was difficult to isolate the
The reaction was instantaneous when glucosyl donor 6c was
allowed to react with the chiral alcohol R-7 in the presence
of DMTST (Scheme 6). Within 5 min at 0 8C, TLC analysis
indicated no starting material remaining and the glycosyl-
ation product 21 was isolated in 68% yield with no
orthoester formation. The dramatic difference in glycosyl-
ation results observed between donor 6b and 6c originates
Scheme 6.

B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
9409
Scheme 7.
final product after removal of the TBS ethers. The
spectroscopic data of the synthetic sample are consistent
with that reported for the natural product.
of the orthoester while an electron-releasing TBS group led
to the normal glycosylation product. Based on this study, a
change of protecting groups effectively alters the outcome
of the glycosylation reaction. In accord with our recent
observation, a propargylic oxygen substitution in the
bromoalkyne enhances the copper-catalyzed cross coupling
reaction to produce conjugated diynes.
2.3. Synthesis of bidensyneoside A2 2
With the key intermediate 21 in hand, we were eager to
expand our synthetic route to other members of the
bidensyneosides. The commercial availability of (Z)-3-
penten-1-yne prompted us to prepare bidensyneoside A2 (2)
as a test for our methodology. It turns out that the more
practical route for compound 2 is to prepare bromoalkyne
23 because of the volatility of (Z)-3-penten-1-yne
(Scheme 7).
4. Experimental
4.1. General
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware with magnetic stirring.
Reagents were purchased from commercial sources, and
used directly without further purification. Methylene
chloride was dried over P2O5 and freshly distilled before
use. Purification of reaction products was carried out by
flash chromatography using silica gel 40–63 mm (230–400
mesh), unless otherwise stated. Reactions were monitored
In the bromination reaction of the terminal alkyne 21, the
preferred solvent was DMF, instead of acetone, to minimize
the breakage of the glycosydic bond. The copper-catalyzed
coupling of bromoalkyne 23 with (Z)-3-penten-1-yne
proceeded smoothly to produce the protected bidensyneo-
side A2 in 86% yield. This is consistent with our recent
observation that a propargylic oxygen substitution in the
bromoalkyne enhances the rate of the copper-catalyzed
cross coupling reaction to produce conjugated diynes.21
Without a propargylic oxygen substitution, homocoupling
of the bromoalkyne sometimes dominates. The removal of
the TBS ether and the acetate protecting group was
performed in that order affording compound 2 in 85%
yield for two steps. The synthetic sample was identified by
spectroscopic methods and the results are consistent with
the reported natural product.
1
by H NMR and/or thin-layer chromatography. Visualiza-
tion was accomplished with UV light, staining with 5%
KMnO4 solution followed by heating or with p-anisalde-
hyde (200 ml of 95% EtOH, 10 ml of H2SO4, and 10 ml of
p-anisaldehyde). Chemical shifts are recorded in ppm (d)
using tetramethylsilane (H, C) as the internal reference.
Data are reported as: (sZsinglet, dZdoublet, tZtriplet, qZ
quartet, mZmultiplet; integration; coupling constant(s) in
Hz). Optical rotations were measured using Autopol III.
Melting points were measured with a Gallenkamp melting
point apparatus. Infrared spectra were recorded on a Perkin
Elmer 1600 series FTIR. High-resolution mass spectra were
recorded at Ohio State University. Lipase AK from
pseudomonas sp5,6 was purchased from Amano Enzyme
Inc. All new compounds were determined to be O95% pure
3. Conclusions
The total synthesis of bidensyneoside A2 (2) and C (4) was
achieved in 7 linear steps starting from glucose pentacetate
in w14% overall yield and 3-deoxybidensyneoside C (5) in
three steps and 4.7% overall yield. These syntheses
represent the first synthetic entry to the bidensyneosides
and confirm the stereochemistry at C3 of bidensyneoside C.
Glycoside formation was found to be highly dependent on
the nature of the protecting groups on the glucose. Exclusive
formation of the normal glycosylation product or the
orthoester was observed, respectively, depending on the
characteristic of the protecting group at C3 of the glucoside.
The electron-withdrawing acetate group led to the formation
1
by H NMR spectroscopy.
4.1.1. 4-Pentynyl tetra-acetyl-b-D-glucopyranoside (10).
A solution of glucose penta-acetate 9 (1.95 g, 5.0 mmol) in
CH2Cl2 (10 ml) was stirred with BF3$Et2O (5.5 mmol) at
room temperature for 1 h. Next, 4-pentyne-1-ol (0.63 g,
7.5 mmol) was added and the mixture was stirred for 4 h.
After consumption of the starting material, the mixture was
cooled to 0 8C and stirred with saturated aq. NaHCO3 for
30 min. The resulting mixture was extracted three times
with diethyl ether. Then the combined extracts were washed

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B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
with water, brine and dried over MgSO4. The resulting
solution was filtered, concentrated and purified over silica
gel. (50% EtOAc/hexanes) giving a yellow syrup (632 mg,
30%).
1654, 1077. HRMS: calcd for C22H36O7SiCNa, 463.2128,
found MCNa: 463.2155.
4.1.4. 3-Deoxybidensyneoside B (5). To a solution of
24 mg (0.055 mmol) 12 in 4 ml THF and at 0 8C was added
55 ml HF$pyridine. After the addition, the mixture was
allowed to warm to room temperature and stirred for an
additional 16 h. To the mixture was added solid NaHCO3
and the solvent was evaporated to w1 ml. The solution was
directly purified over silica gel (30% MeOH/CHCl3) giving
a white solid (mp 158–161 8C, 9.5 mg, 51%).
[a]DZ10.60 (MeOH, cZ6.6), 1H NMR (200 MHz, CDCl3):
d 1.67 (2H, m), 1.87 (1H, t, JZ2.6 Hz), 1.91–1.99 (12H,
4 s), 2.16 (2H, dt, JZ7.1, 2.6 Hz), 3.56 (2H, m), 3.87 (1H,
dt, JZ9.7, 5.4 Hz), 4.00 (1H, m), 4.18 (1H, dd, JZ12.3,
4.6 Hz), 4.42 (d, 1H, JZ7.9 Hz), 4.89 (1H, t, JZ9.3 Hz),
4.99 (1H, t, JZ9.6 Hz), 5.23 (1H, t, JZ9.4 Hz), 13C NMR
(50 MHz, CDCl3): d 51.11 (CH2), 20.97–21.10 (CH3), 28.53
(CH2), 62.28 (CH2), 68.70 (CH2), 68.75 (CH), 69.27, 71.62
(CH), 72.10 (CH), 73.11 (CH), 83.73, 101.37 (CH), 169.74,
169.78, 170.63, 171.03. IR: n cmK1 3282, 2117, 1755.
HRMS: calcd for C19H26O10CNa, 437.1424, found MC
Na, 437.1446.
[a]DZK15.2 (MeOH, cZ0.14), 1H NMR (500 MHz,
Methanol-d4): d 1.86 (2H, m), 2.50 (2H, JZ7.12 Hz), 3.19
(1H, dd, JZ9.1, 7.8 Hz), 3.29 (2H, m), 3.36 (1H, t, JZ
8.8 Hz), 3.66(1H, dt, JZ10.0, 6.2 Hz), 3.69, (1H, dd, JZ
11.8, 5.4 Hz), 3.88 (1H, dd, 11.8, 2.1 Hz), 3.98 (1H, dt, JZ
10.0, 6.1 Hz), 4.14 (2H, dd, JZ4.8, 2.1 Hz), 4.27 (1H, d,
JZ7.8 Hz), 5.78 (1H, d, JZ15.9 Hz), 6.36 (1H, dt, JZ15.9,
4.8 Hz), 13C NMR (75 MHz, Methanol-d4): d 16.82 (CH2),
29.81 (CH2), 62.69 (CH2), 62.75 (CH2), 66.13 (C), 69.21
(CH2), 71.64 (CH), 74.06, 75.13 (CH), 75.24, 77.93 (CH),
78.07 (CH), 84.33, 104.45 (CH), 109.13 (CH), 147.07 (CH).
IR: n cmK1 3213, 2228, 2140, 1627, 1159, 1030, 1009,
UV/Vis: l(max)nm: 282, 266, 252, 240. HRMS: Calculated
C16H22O7CNaZ349.1263, found C16H22O7CNaZ
349.1252.
4.1.2. Silane, (1,1-dimethylethyl)dimethyl[5-bromo-(2E)-
2-penten-4-ynyloxy] (11). To a suspension of NBS
(541 mg, 3.04 mmol) and the TBS ether of 2-penten-4-yn-
1-ol (510 mg, 2.6 mmol), in 20 ml acetone was added
AgNO3 (44 mg, 0.26 mmol). The mixture was stirred for
1 h, and then it was diluted with 50 ml Et2O and 50 ml
NaHCO3. The solution was extracted three times with Et2O
and the combined organic layers were dried over MgSO4.
The product was purified over silica Gel (2% EtOAc/
hexanes) giving a yellow oil (411 mg, 58%).
1H NMR (300 MHz, CDCl3): d 0.05 (6H, s), 0.86 (9H), 4.17
(2H, ddd, JZ14.1, 4.9, 2.2 Hz), 5.70 (1H, dt, JZ15.8,
2.2 Hz), 6.23 (1H, dt, JZ15.7, 4.1 Hz), 13C NMR (75 MHz,
CDCl3): d K4.98 (CH3), 18.73, 26.25 (CH3), 49.53, 63.06
(CH2), 78.84, 108.55 (CH), 144.52 (CH). IR: n cmK1 3400,
3039, 2167, 1638, 1133.
4.1.5. (C)-3R-5-tert-butyldimethylsilyloxy-1-pentyn-3-ol
(R-15). A solution of racemic 15 (2.62 g, 12.19 mmol) in
˚
100 ml of hexanes was added 3 g of molecular sieves (4 A)
and vinyl acetate (6.29 g, 73.17 mmol). Next, lipase AK
from pseudomonas sp5,6 (2.62 g) was added and the mixture
was stirred at room temperature. When H NMR analysis
1
indicated that the ratio of acylated alcohol to free alcohol
was approximately 1:1 the mixture was filtered over a pad of
Celite, washed with hexanes and purified over silica gel
(15% EtOAc/hexanes) giving a yellow oil (1.06 g, 40.5%,
(R)-15 and a light yellow oil (1.25 g, 40%, (S)-16.
4.1.3.
[10-tert-Butyldimethylsilyloxy-8-decen-4,6-
diynyl]-b-D-glucopyranoside (12). To a 10 ml flask
equipped with a stirring bar under an atmosphere of
nitrogen was added NH2OH$HCl (24 mg, 0.34 mmol),
methanol (1 ml), compound 10 (200 mg, 0.48 mmol) and
70% aq EtNH2 solution (1 ml). The mixture was cooled to
0 8C and CuCl (2.4 mg, 0.024 mmol) was added followed
by slow addition of compound 11 (146 mg, 0.53 mmol). The
reaction was stirred for 30 min, and then allowed to warm to
room temperature. A KCN/NH4Cl solution (prepared from
5 g of KCN and 20 g of NH4Cl in 300 ml of H2O)11 was
added to the reaction flask. The resulting mixture was then
extracted seven times with EtOAc. The combined extracts
were concentrated, and purified over silica gel (10% MeOH/
CHCl3) giving a yellow oil (66 mg, 31%).
(R)-15: [a]DZC14.8 (CHCl3, cZ8.25), (S)-16: [a]DZ
1
K51.4 (MeOH, cZ1.52), H NMR (200 MHz, CDCl3): d
0.06 (3H), 0.07 (3H), 0.88 (9H), 1.90 (2H, m), 2.44 (1H, d,
JZ2.1 Hz), 3.55 (1H, d, JZ6.2 Hz), 3.84 (1H, m), 4.03
(1H, m), 4.60 (1H, m), 13C NMR (200 MHz, CDCl3): d
K5.14 (CH3), 18.5, 26.25 (CH3), 38.67 (CH2), 61.51 (CH2),
62.28 (CH), 73.25, 84.79. IR: n cmK1 3437, 3033, 2111,
1654. HRMS: calcd for C11H22O2SiCNa, 237.1287, found
MCNa, 237.1290.
4.1.6. (C)-3R-3-Acetoxy-1-tert-butyldimethylsilyl-4-
pentyn-1-ol (R)-(C)-16. To a solution of R-15 (1.06 g,
4.86 mmol) in 5 ml pyridine was added DMAP (5 mg) and a
solution of acetic anhydride (0.74 ml, 7.40 mmol) in 3 ml of
pyridine. The mixture was heated to 60 8C and stirred for
4 h.19 After TLC analysis indicated the completion of the
reaction, the solution was diluted with 2 N HCl (5 ml) and a
50:50 Et2O/hexanes solution (5 ml). The mixture was
extracted three times with a mixture of Et2O/hexanes and
the combined organic extracts were washed three times with
water, and once with brine. The organic layer was dried over
Na2SO4. The solvents were removed under reduced pressure
[a]DZK7.7 (MeOH, cZ0.9), 1H NMR (300 MHz, CDCl3):
d 0.10 (2!CH3, s), 0.94 (3!CH3, s), 1.85 (2H, m), 2.50
(2H, t, JZ7.1 Hz), 3.18 (1H, t, JZ8.6 Hz), 3.28 (2H, m),
3.37 (1H, m), 3.66 (2H, m), 3.88 (1H, dd, JZ11.7, 1.8 Hz),
3.97 (1H, dt, JZ10.0, 6.1 Hz), 4.24 (3H, dd, JZ4.5, 2.9 Hz,
and d, JZ7.4 Hz), 5.78 (1H, d, JZ15.7 Hz), 6.34 (1H, dt,
JZ15.7, 4.2 Hz), 13C NMR (75 MHz, CDCl3): d K5.31
(CH3), 16.82 (CH2), 19.16, 26.31 (CH3), 29.81 (CH2), 62.74
(CH2), 63.85 (CH2), 66.17, 69.21 (CH2), 71.62 (CH), 74.06,
75.11 (CH), 75.33, 77.91 (CH), 78.05 (CH), 84.30, 104.46
(CH), 108.46 (CH), 146.81 (CH). IR: n cmK1 3402, 2930,

B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
9411
and the residue was purified over silica gel (15% EtOAc/
hexanes) giving a light yellow oil (1.08 g, 85%).
4.1.9. p-Tolyl 3,6-O-bis(tert-butyldimethylsilyl)-1-thio-b-
D-glucopyranoside (18b). To a dry 250 ml round bottom
flask was added p-tolyl-2,3,4,6-terta-acetyl-1-thio-b-D-
glucopyranoside (6b) (12.31 g, 26.72 mmol), 200 ml
MeOH, and K2CO3 (184 mg, 1.34 mmol). The reaction
was stirred at room temperature for 2 h at which point the
methanol was removed by vacuum and the white residue
was subject to high vacuum overnight. The mass of the flask
indicated complete removal of ethyl acetate and methanol
after 10 h. Then, the residue was dissolved in 67 ml of DMF
and TBSCl was added (8.46 g, 56.1 mmol) at 0 8C. Next,
imidazole (4.36 g, 64.12 mmol) was added in three portions
over 10 min. The solution was stirred at room temperature
for 5 h, and diluted with 25 ml of 0.5 N HCl. The resulting
mixture was extracted three times with Et2O, and the
combined organic extracts were washed with aq. NaHCO3,
brine and dried over MgSO4. After removing the solvents
under reduced pressure, the residue was purified over silica
gel (50% EtOAc/hexanes) giving a syrup (6.23 g, 50%).
[a]DZC55.3 (MeOH, cZ1.25), 1H NMR (200 MHz,
CDCl3): d 0.00 (6H, s), 0.84 (9H, s), 1.95 (2H, m), 2.03
(3H, s), 2.41 (1H, d, JZ2.1 Hz), 3.69 (2H, m), 5.43 (1H, dt,
JZ2.1, 6.9 Hz), 13C NMR (50 MHz, CDCl3): d K5.08
(CH3), 18.64, 21.34 (CH3), 26.26 (CH3), 37.95 (CH2), 58.93
(CH2), 61.40 (CH), 73.99, 81.58, 170.13. IR: n cmK1 3447,
3311, 2123, 1747, 1231. HRMS: calcd for C13H24O3SiC
Na, 279.1392, found MCNa, 279.1389.
4.1.7. (C)-3(R)-3-Acetoxy-4-pentyn-1-ol (R)-(C)-7. To a
solution of (R)-16 (689 mg, 2.68 mmol) in 40 ml THF was
added at 0 8C HF$pyridine complex (2.68 ml) at 0 8C. The
mixture was allowed to warm to room temperature and
stirred for 18 h. After completion, the solution was diluted
with Et2O, and washed with NaHCO3, brine, and dried over
Na2SO4. The solution was concentrated and purified over
silica gel (50% EtOAc/hexanes) giving a clear oil (320 mg,
84%).
[a]DZK33.6 (CHCl3, cZ3.62), 1H NMR (200 MHz,
CDCl3): d 0.08 (3H, s), 0.12 (3H, s), 0.89 (18H, s), 2.31
(3H, s), 3.13–3.54 (4H, m), 3.85 (2H, d, JZ4.5 Hz), 4.44
(1H, d, JZ9.6 Hz), 7.08 (2H, d, JZ7.9 Hz), 7.42 (2H, d,
JZ8.0 Hz), 13C NMR (50 MHz, CDCl3): d K4.95 (CH3),
K4.14 (CH3), K3.95 (CH3), 18.75 (C), 18.80, 21.60 (CH3),
26.32 (CH3), 26.39 (CH3), 64.61 (CH2), 72.61 (CH), 72.76
(CH), 79.35 (CH), 79.79 (CH), 89.10 (CH), 128.99, 130.13
(CH), 133.40 (CH), 138.54. IR: n cmK1 3592, 3054, 1493,
1265, 1134, 1072. HRMS: calcd for C25H46O5SSi2CNa,
537.2502, Found MCNa, 537.2508.
[a]DZC103.6 (MeOH, cZ2.70), 1H NMR (200 MHz,
CDCl3): d 2.00 (2H, m), 2.05 (3H, s), 2.32 (1H, s), 2.47 (1H,
d, JZ2.1 Hz), 3.69 (2H, m), 5.49 (1H, dt, JZ2.1, 6.7 Hz),
13C NMR (50 MHz, CDCl3): d 21.36 (CH3), 37.86 (CH2),
58.68 (CH2), 61.70 (CH), 74.56, 81.18, 170.67. IR: n cmK1
3479, 3303, 2118, 1752, 1631. HRMS: calcd for C7H10O3C
Na, 165.0528, Found MCNa, 165.0536, Deprotection of
(S)-(K)-16 gave (S)-(K)-7 with [a]DZK96.6 (MeOH, cZ
40).
4.1.10. p-Tolyl 2,3,4-O-tris(acetyl)-6-O-(tert-butyl-
dimethylsilyl)-1-thio-b-D-glucopyranoside (6b). To a
round bottom flask equipped with a stirring bar under an
atmosphere of nitrogen was added pyridine (13 ml),
compound 18a (2.17 g, 5.42 mmol), a solution of Ac2O
(2.21 g, 21.68 mmol) in 15 ml pyridine, and 5 mg of
DMAP.19 The flask was then heated to 60 8C for 4 h and
diluted with 2 N HCl (60 ml), and 60 ml of a 50/50 Et2O/
hexanes solution. The resulting mixture was extracted three
times with Et2O and the combined ether extracts were
washed three times with water, once with brine, and dried
over Na2SO4. The solution was then filtered and the solvent
removed under reduced pressure, and purified over silica gel
column giving a white solid (mp 123–125 8C, 2.74 g, 96%).
4.1.8. p-Tolyl 6-O-(tert-butyldimethylsilyl)-1-thio-b-D-
glucopyranoside (18a). To a dry 25 ml round bottom
flask was added p-tolyl-2,3,4,6-terta-acetyl-1-thio-b-D-
glucopyranoside (6a, 0.66 g, 1.45 mmol), 14 ml MeOH,
and K2CO3 (10 mg, 0.072 mmol). The reaction was stirred
at room temperature for 2 h at which point the methanol was
removed by vacuum and the white residue was subject to
high vacuum overnight. The mass of the flask indicated
complete removal of the acetates and methanol. Then, the
residue was dissolved in DMF (5 ml) and TBSCl was added
(285 mg, 1.89 mmol) at 0 8C. Next, imidazole (130 mg,
1.90 mmol) was added in three portions over 10 min. The
solution was stirred at room temperature for 1.5 h, and then
diluted with 5 ml of 0.5 N HCl. The resulting mixture was
extracted three times with Et2O, and then the combined
organic extracts were washed with NaHCO3, brine and dried
over MgSO4. After removing the solvents under reduced
pressure, the residue was purified over silica gel (70%
EtOAc/hexanes) giving a clear syrup (203 mg, 35%).
[a]DZK4.53 (MeOH, cZ2.56), 1H NMR (200 MHz,
CDCl3): d 0.03 (3H, s), 0.05 (3H, s), 0.87 (9H, s), 1.93
(3H, s), 1.96 (3H, s), 2.03 (3H, s), 2.30 (3H, s), 3.50 (1H,
ddd, JZ2.7, 4.2, 9.7 Hz), 3.68 (2H, m), 4.64 (1H, d, JZ
9.9 Hz), 4.86 (1H, t, JZ9.7 Hz), 4.97 (1H, t, JZ9.6 Hz),
5.16 (1H, t, JZ9.2 Hz), 7.05 (2H, d, JZ8.0 Hz), 7.35 (2H,
d, JZ8.1 Hz), 13C NMR (50 MHz, CDCl3): d K5.07 (CH3),
18.70, 21.07 (CH3), 21.21 (CH3), 21.60 (CH3), 26.24 (CH3),
62.73 (CH2), 68.85 (CH), 70.37 (CH), 74.89 (CH), 79.26
(CH), 86.04 (CH), 128.26, 130.83 (CH), 133.88 (CH),
138.83, 169.64, 169.66, 170.75. IR: n cmK1 2930, 2857,
1757, 1374, 837, 810, 779. HRMS: calcd for C25H38O8-
SSiCNa, 549.1954, Found MCNa: 549.1963.
[a]DZK36.1 (MeOH, cZ1.14), 1H NMR (200 MHz,
Methanol-d4): d 0.10 (3H, s), 0.11 (3H, s), 0.95 (9H, s),
2.33 (3H, s), 3.18–3.34 (4H, m), 3.79 (1H, dt, JZ11.3,
2.3 Hz), 3.98 (1H, d, JZ11.0 Hz), 4.54 (1H, d, JZ9.6 Hz),
7.12 (2H, d, JZ8.1 Hz), 7.48 (2H, d, JZ8.2 Hz), 13C NMR
(50 MHz, Methanol-d4): d K5.87 (CH3), K5.81 (CH3),
18.35, 20.34 (CH3), 25.62 (CH3), 63.30 (CH2), 70.13 (CH),
72.70 (CH), 78.74 (CH), 81.22 (CH), 88.62 (CH), 129.56
(CH), 130.47, 132.46 (CH), 137.51. IR: n cmK1 3392, 2928,
1641, 1493, 1071. HRMS: calcd for C19H32O5SSiCNa,
423.1637, Found MCNa: 423.1639.
4.1.11. p-Tolyl 2,4-O-bis(acetyl)-3,6-O-bis(tert-butyl-
dimethylsilyl)-1-thio-b-D-glucopyranoside (6c). To a

9412
B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
round bottom flask was added 30 ml of pyridine, compound
18b (6.2 g, 13.13 mmol), a solution of Ac2O (5.36 g,
52.5 mmol) in 40 ml pyridine, and 5 mg of DMAP. The
mixture was then heated to 60 8C for 4 h and diluted with
2 N HCl (60 ml), and 60 ml of a 50/50 Et2O/hexanes
solution. The resulting mixture was extracted three times
with Et2O and the combined ether extracts were washed
three times with water, once with brine, and dried over
Na2SO4. The solution was then filtered, concentrated, and
purified over silica gel giving a white solid (mp 104–107 8C,
6.80 g, 87%).
20,30,40-O-tri(acetyl)-60-O-(tert-butyl dimethyl silyl)-b-D-
gluco-pyranoside (20). To a 10 ml round bottom flask was
added 4 ml of dry CH2Cl2, 6b (103 mg, 0.20 mmol), (S)-7
(42 mg, 0.30 mmol) and 0.4 g of molecular sieves. The
mixture was stirred for 20 min at room temperature. While
the mixture was stirring, dimethyldisulfide (55 mg,
0.59 mmol) and MeOTf (97 mg, 0.59 mmol) were allowed
to mix in a separate vial. After a solid was formed, it was
dissolved in 1.5 ml CH2Cl2. The mixture of 6b and (K)-7
was then cooled to 0 8C and the DMTST solution was
slowly added. The mixture was stirred at 0 8C for 30 min,
then 1 h at room temperature. Next, 0.6 ml Et3N was added
to the mixture, which prompted a precipitate to form. The
mixture was then filtered and diluted with CH2Cl2. The
organic solution was washed with NaHCO3, brine, and dried
over Na2SO4. Finally, the mixture was filtered, and the
solvents removed under reduced pressure. The residue was
purified over silica gel (15% EtOAc/hexanes) giving a
yellow oil (12 mg, 11%, 19b) and a clear oil (16 mg, 15%,
20).
[a]DZK9.27 (CHCl3, cZ8.19), 1H NMR (200 MHz,
CDCl3): d 0.0–0.03 (12H, three singlet’s), 0.79 (9H, s),
0.86 (9H, s), 2.04 (3H, s), 2.10 (3H, s), 2.29 (3H, s), 3.40
(1H, ddd, JZ9.4, 5.9, 3.2 Hz), 3.61 (2H, m), 3.80 (1H, t, JZ
8.9 Hz), 4.53 (1H, d, JZ10.1 Hz), 4.84 (1H, t, JZ10.0 Hz),
4.88 (1H, t, JZ10.1 Hz), 7.05 (2H, d, JZ8.0 Hz), 7.36 (2H,
d, JZ8.1 Hz), 13C NMR (50 MHz, CDCl3): d K5.03 (CH3),
K4.83 (CH3), K4.06 (CH3), K4.02 (CH3), 18.19, 18.78,
21.57 (CH3), 21.73 (CH3), 21.90 (CH3), 25.90 (CH3), 26.32
(CH3), 63.69 (CH2), 72.08 (CH), 73.02 (CH), 74.97 (CH),
79.90 (CH), 87.43 (CH), 130.03 (CH), 130.45, 132.49 (CH),
138.07, 169.84. IR: n cmK1 2926, 1736, 1222, 1132, 1051.
HRMS: calcd for C29H50O7SSi2CNa, 621.2714, Found
MCNa, 621.2718.
19b: [a]DZC12.7, (MeOH, cZ0.1), 1H NMR: (300 MHz,
CDCl3): d 0.03 (3H, s), 0.03 (3H, s), 0.87 (9H, s), 1.68 (3H,
s), 2.07 (2H, m), 2.08 (3H, s), 2.08 (3H, s), 2.07 (3H, s), 2.46
(1H, d, JZ2.2 Hz), 3.60 (2H, m), 3.70 (1H, m), 3.72 (2H,
m), 4.29 (1H, ddd, JZ5.2, 3.1, 0.9 Hz), 4.95 (1H, ddd, JZ
9.0, 2.5, 0.9 Hz), 5.16 (1H, t, JZ2.8 Hz), 5.44 (1H, dt, JZ
2.1, 6.9 Hz), 5.68 (1H, d, JZ5.2 Hz), 13C NMR: (75 MHz,
CDCl3): d K4.96 (2 CH3), 18.73, 20.98 (CH3), 21.21 (CH3),
21.29 (2 CH3), 26.24 (CH3), 34.90 (CH2), 59.42 (CH2),
63.37 (CH2), 68.52 (CH), 70.06 (CH), 70.41 (CH), 73.49
(CH), 80.96, 97.50 (CH), 121.56, 169.66, 170.01, 170.13.
IR: n cmK1 2930, 2255, 1742, 1371, 1239, 911, 937, 779,
732. HRMS: calcd for C25H40O11SiCNa, 567.2238, found
MCNa: 567.2241.
4.1.12. Orthoester (19a). To a 10 ml round bottom flask
was added 4 ml dry CH2Cl2, compound 6b (103 mg,
0.20 mmol), compound (R)-7 (42 mg, 0.30 mmol), and
0.4 g of molecular sieves. The mixture was stirred for
20 min at room temperature. While the mixture was stirring,
dimethyldisulfide (55 mg, 0.59 mmol) and MeOTf (97 mg,
0.59 mmol) were allowed to mix in a separate vial to form a
solid. After the mixture had fully crystallized, it was
dissolved in 1.5 ml CH2Cl2. The mixture of 6b and (R)-7
was then cooled to 0 8C and the DMTST solution was
slowly added. The mixture was stirred at 0 8C for 30 min,
then 1 h at room temperature. Next, 0.6 ml of Et3N was
added to the mixture, which prompted a precipitate to form.
The mixture was then filtered and diluted with CH2Cl2. The
organic solution was washed with aq. NaHCO3, brine, and
dried over Na2SO4. Finally, the mixture was filtered, and the
solvents removed under reduced pressure. The residue was
purified over silica gel (15% EtOAc/hexanes) giving a
yellow oil (79 mg, 74%).
1
20: [a]DZK13.5, (MeOH, cZ0.15), H NMR (500 MHz,
CDCl3): d 0.02 (3H, s), 0.03 (3H, s), 0.86 (9H, s), 1.97 (3H,
s), 1.99 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.09 (2H, m), 2.44
(1H, d, JZ2.1 Hz), 3.52 (1H, ddd, JZ9.9, 5.2, 2.7 Hz), 3.63
(1H, m), 3.68 (2H, m), 3.99 (1H, dt, JZ10.0, 5.6 Hz), 4.92
(1H, dd, JZ8.1, 9.7 Hz), 4.98 (1H, t, JZ9.7 Hz), 5.17 (1H,
t, JZ9.5 Hz), 5.35 (1H, dt, JZ2.1, 6.6 Hz), 13C NMR
(75 MHz, CDCl3): d K4.97 (CH3), 18.70, 21.01 (CH3),
21.04 (CH3), 21.08 (CH3), 21.24 (CH3), 26.20 (CH3), 34.76
(CH2), 61.32 (CH), 62.84 (CH2), 65.67 (CH2), 69.38 (CH),
71.65 (CH), 73.53 (CH), 74.39, 75.18 (CH), 101.10 (CH),
169.78, 169.90, 170.82. IR: n cmK1 3019, 2121, 1756, 1371.
HRMS: calcd for C25H40O11SiCNa, 567.2238, Found MC
Na: 567.2244.
[a]DZC2.3, (MeOH, cZ1.7), 1H NMR: (300 MHz,
CDCl3): d 0.02 (3H, s), 0.03 (3H, s), 0.86 (9H, s), 1.68
(3H, s), 1.99 (2H, m), 2.04 (3H, s), 2.06 (3H, s), 2.07 (3H, s),
2.45 (1H, d, JZ2.2 Hz), 3.59 (2H, m), 3.7 (3H, m), 4.28
(1H, ddd, JZ5.3, 3.1, 0.9 Hz), 4.94 (1H, ddd, JZ9.0, 2.6,
0.9 Hz), 5.15 (1H, t, JZ2.8 Hz), 5.43 (1H, dt, JZ2.2,
6.9 Hz), 5.67 (1H, d, JZ5.3 Hz), 13C NMR: (75 MHz,
CDCl3): d K4.98 (CH3), K4.94 (CH3), 18.72, 20.96 (CH3),
21.23 (CH3), 21.31 (CH3), 26.23 (CH3), 34.87 (CH2), 59.42
(CH2), 61.38 (CH), 63.34 (CH2), 68.49 (CH), 70.02 (CH),
70.36 (CH), 73.44 (CH), 80.95, 97.49 (CH), 121.55, 169.65,
170.00, 170.11. IR: n cmK1 2930, 2255, 1742, 1371, 1239,
911, 937, 779, 732. HRMS: calcd for C25H40O11SiCNa,
567.2238, found MCNaZ567.2245.
4.1.14. (3R)-3-Acetoxy-4-pentynyl 20,40-O-bis(acetyl)-
30,60-O-bis(tert-butyldimethylsilyl)-b-D-glucopyranoside
(21). To a 25 ml round bottom flask was added 8 ml
dry CH2Cl2, compound 6c (289 mg, 0.48 mmol), compound
(C)-7 (103 mg, 0.72 mmol) and 0.8 g of molecular sieves.
The mixture was stirred for 20 min at room temperature.
While the mixture was stirring, dimethyldisulfide (136 mg,
1.44 mmol) and MeOTf (236 mg, 1.44 mmol) were allowed
to mix in a separate vial to form a solid. After the mixture
had fully crystallized, it was dissolved in 2.5 ml CH2Cl2.
The mixture was then cooled to 0 8C and the DMTST
solution was slowly added. The mixture was stirred at 0 8C
4.1.13. Orthoester (19b) and (3S)-3-acetoxy-4-pentynyl

B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
9413
for 30 min, then allowed to warm to room temperature. TLC
analysis indicated the disappearance of 6c. Next, 0.6 ml
Et3N was added to the mixture, which led to a precipitate.
The mixture was filtered and diluted with CH2Cl2. The
organic solution was then washed with aq. NaHCO3, brine
and dried over Na2SO4. The mixture was filtered, and the
solvents removed under reduced pressure. The residue was
purified over silica gel (15% EtOAc/hexanes) giving a
yellow oil (189 mg, 64%).
3.38 (1H, m), 3.61 (2H, m), 3.80 (2H, m), 4.02 (1H, m), 4.22
(2H, d, JZ3.2 Hz), 4.33 (1H, d, JZ8.1 Hz), 4.59 (1H, m),
4.80 (1H, t, JZ9.1 Hz), 4.84 (1H, dd, JZ9.0, 8.2 Hz), 5.79
(1H, d, JZ15.9 Hz), 6.39 (1H, dt, JZ15.9, 4.7 Hz), 13C
NMR (50 MHz, CDCl3): d K4.94 (CH3), K4.84 (CH3),
K4.11 (CH3), K4.03 (CH3), 18.19, 18.77, 21.73 (CH3),
25.87 (CH3), 26.26 (CH3), 36.76 (CH2), 61.59 (CH), 63.02
(CH2), 63.60 (CH2), 66.72 (CH2), 70.02, 72.38 (CH), 73.39
(CH), 74.25, 74.38 (CH), 75.67 (CH), 77.16, 82.74, 101.23
(CH), 108.93 (CH), 146.25 (CH), 169.95, 170.61. IR: n
cmK1 3429, 2233, 1754, 1373, 1063, 837. HRMS: calcd for
C32H54O10Si2CNa, 677.3153, found MCNa, 677.3196.
[a]DZC19.4 (MeOH, cZ2.3), 1H NMR (200 MHz,
CDCl3): d 0.00 (6H, s), 0.02 (6H, s), 0.78 (9H, s), 0.85
(9H, s), 1.99 (2H, m), 2.04 (3H), 2.07 (3H), 2.08 (3H), 2.42
(1H, d, JZ2.1 Hz), 3.37 (1H, m), 3.46 (1H, m), 3.59 (2H,
m), 3.80 (1H, t, JZ9.1 Hz), 3.94 (1H, dt, JZ9.9, 5.8 Hz),
4.28 (1H, d, JZ8.0 Hz), 4.79 (1H, t, JZ9.2 Hz), 4.84 (1H, t,
JZ9.0 Hz), 5.36 (1H, dt, JZ2.0, 6.6 Hz), 13C NMR
(50 MHz, CDCl3): d K4.94 (CH3), K4.83 (CH3), K4.14
(CH3), K4.03 (CH3), 18.17, 18.75, 21.33 (CH3), 21.61
(CH3), 21.74 (CH3), 25.88 (CH3), 26.25 (CH3), 35.17
(CH2), 61.08 (CH), 63.65 (CH2), 64.94 (CH2), 72.45 (CH),
73.47 (CH), 74.05, 74.48 (CH), 75.66 (CH), 81.11 (CH),
101.10 (CH), 169.82, 169.90, 170.16. IR: n cmK1 3303,
2126, 1752. HRMS: calcd for C29H52O10Si2CNa,
639.2997, found MCNa, 639.2953.
4.1.17. Bidensyneoside C (4). To a 100 ml round bottom
flask was added compound 22 (270 mg, 0.41 mmol),
HF$pyridine complex (5 ml), AcOH (4 ml) and THF
(35 ml). The mixture was stirred overnight and was diluted
with EtOAc and aq. NaHCO3. The mixture was then
saturated with NaCl and extracted 5 times with EtOAc. The
solvents were removed under reduced pressure and the
residue purified over silica gel (10% MeOH/CHCl3)
yielding a yellow/brown syrup (102 mg, 58%), which was
used in the next step without further identification. To a
solution of the syrup in 12 ml MeOH was added K2CO3
(1.6 mg). The mixture was stirred for 4 h. The reaction was
monitored by TLC and the appearance of a single polar spot
indicated the completion of the reaction. Then, about half of
the solvent was removed under vacuum and the residue was
purified over silica gel (35% MeOH/CHCl3) giving a light
brown oil (76 mg, 94%).
4.1.15. 5-Bromo-2-penten-4-yn-1-ol (8). To a suspension
of 2-penten-4-yn-1-ol (0.50 g, 6.09 mmol) and NBS (1.27 g,
7.13 mmol) in 50 ml acetone was added AgNO3 (104 mg,
0.61 mmol). The mixture was stirred for 1 h at room
temperature and then diluted with 50 ml of Et2O, and 50 ml
of water. The aqueous layer was extracted twice with Et2O
and then the combined organic extracts were dried over
MgSO4. The solvents were then removed under reduced
pressure and the residue purified over silica gel (30%
EtOAc/hexanes) giving a yellow oil (0.62 g, 63%).
[a]DZK50.84 (MeOH, cZ0.83), 1H NMR (500 MHz,
CD3OD): d 1.99 (2H, m), 3.19 (1H, t, JZ8.5 Hz), 3.30 (2H,
m), 3.37 (1H, m), 3.69 (1H, dd, JZ5.1, 11.7 Hz), 3.76 (1H,
dt, JZ10.0, 6.5 Hz), 3.88 (2H, dd, JZ1.2, 12.1 Hz), 4.02
(1H, dt, JZ10.1, 5.7 Hz), 4.29 (1H, d, JZ4.8 Hz), 4.68 (1H,
t, JZ6.6 Hz), 5.83 (1H, d, JZ15.9 Hz), 6.42 (1H, dt, JZ
15.9, 4.5 Hz), 13C NMR (125 MHz, Methanol-d4): d 38.88
(CH2), 60.15 (CH), 62.60 (CH2), 62.65 (CH2), 66.76 (CH2),
69.52, 71.51 (CH), 74.14, 75.03 (CH), 77.56, 77.84 (CH),
77.97 (CH), 84.31, 104.49 (CH), 108.54 (CH), 148.09 (CH).
IR: n cmK1 3302, 2885, 2233, 1629, 1414, 1368, 1161,
1071, UV/Vis: l(max)nm: 283, 267, 253, 240. HRMS:
Calculated for C16H22O8CNa, 365.1212, found
C16H22O8CNa, 365.1219.
1H NMR (200 MHz, CDCl3): d 2.16 (1H, s), 4.14 (2H, dd,
JZ4.9, 1.8 Hz), 5.68 (1H, dt, JZ15.9, 1.8 Hz), 6.27 (1H, dt,
15.9, 4.9 Hz), 13C NMR (50 MHz, CDCl3): d 50.47, 62.96
(CH2), 78.45, 110.09 (CH), 143.93 (CH). IR: n cmK1 3429,
3034, 2166, 1636, 620.
4.1.16. 30,60-O-Bis(tert-butyldimethylsilyl)-20,40-O-bis-
(acetyl) bidensyneoside C (22). To a 10 ml round bottom
flask was added compound 21 (189 mg, 0.3 mmol), 1 ml of
a 70% aq. EtNH2 solution, 1 ml MeOH, and NH2OH$HCl
(1 mg, 0.015 mmol). Next, the mixture was cooled to 0 8C
and CuCl (1.5 mg, 0.015 mmol) was added followed by
slow addition of 8 (54 mg, 0.33 mmol) (keeping the
bromoalkyne concentration low suppresses its homo-
coupling). The mixture was allowed to stir until 21 had
been consumed. Next, the mixture was quenched with a sat.
KCN/NH4Cl solution. The resulting mixture was extracted
three times with Et2O, and the combined extracts were
washed with a solution of NaHCO3, brine, and dried over
MgSO4. The solvents were removed under reduced pressure
and the residue was purified over silica gel (50% EtOAc/
hexanes) giving a yellow oil (110 mg, 56%).
4.1.18. (3R)-30-Acetoxy-50-bromo-40-pentynyl 2,4-O-
bis(acetyl)-3,6-O-bis(tert-butyldimethylsilyl)-b-D-gluco-
pyranoside (23). A 10 ml round bottom flask euipped with a
stirring bar under an atmosphere of nitrogen was added 4 ml
DMF, compound 21 (200 mg 0.32 mmol), and NBS (75 mg
0.42 mmol). The solution was then cooled to 0 8C and
AgNO3 (4.6 mg 0.032 mmol) was added. The mixture was
allowed to warm to room temperature and after 1.5 h, 5 ml
cold water was added to the mixture. The resulting solution
was extracted with Et2O (3!5 ml). The combined extracts
were then washed with brine and dried over MgSO4. After
removal of solvent under reduced pressure, the crude
mixture was purified over silica gel column (15% EtOAc/
hexanes) giving a light yellow oil (140 mg, 63%).
[a]DZK31.8 (MeOH, cZ1.2), 1H NMR (200 MHz,
CDCl3): d (0.01, (6H, two singlets), 0.03 (6H, s), 0.78
(9H, s), 0.85 (9H, s), 1.86 (2H, m), 2.02 (3H, s), 2.10 (3H, s),
[a]DZC18 (CHCl3, cZ0.17), 1H NMR (500 MHz,
CDCl3): d 0.04 (3H, s), 0.05 (3H, s), 0.07 (3H, s), 0.08

9414
B. W. Gung, R. M. Fox / Tetrahedron 60 (2004) 9405–9415
(3H, s), 0.84 (9H, s), 0.94 (9H, s), 2.07 (2H, m), 2.09 (3H, s),
2.11 (3H, s), 2.13 (3H, s), 3.41(1H, ddd, JZ9.7, 6.1,
3.6 Hz), 3.52 (1H, dt, JZ10.1, 6.7 Hz), 3.64, (1H, dd, JZ
11.6, 3.4 Hz), 3.68 (1H, dd, JZ11.4, 6.2 Hz), 3.83 (1H, t,
JZ9.1 Hz), 3.96 (1H, dt, JZ10.1, 5.7 Hz), 4.32 (1H, d, JZ
8.0 Hz), 4.85 (1H, t. JZ9.1 Hz), 4.88 (1H, t, JZ8.4 Hz),
5.42 (1H, t, JZ6.6 Hz), 13C NMR (75 MHz, CDCl3): d
K4.97 (CH3), K4.86 (CH3), K4.16 (CH3), K4.05 (CH3),
18.17, 18.73, 21.27 (CH3), 21.59 (CH3), 21.73 (CH3), 25.87
(3!CH3), 26.24 (3!CH3), 35.22 (CH2), 46.67, 61.47
(CH), 63.66 (CH2), 64.91 (CH2), 72.46 (CH), 73.47 (CH),
74.05 (CH), 75.69 (CH), 77.55, 101.14 (CH), 169.74,
169.84, 170.05. IR: n cmK1, 2977, 2219, 1751, 1735, 1217,
1111. HRMS: calcd for C29H51BrO10Si2CNa, 717.2102,
Found MCNa, 717.2089.
extracted with EtOAc (5!5 ml). The solvent was removed
under reduced pressure. The residue was then dissolved in
MeOH (1 ml) and transferred into a 5 ml round bottom flask
in the absence of light. Next, K2CO3 (0.2 mg 1.4 mmol) was
added and the solution was stirred at room temperature for
4 h until TLC analysis indicated a single spot. Next,
approximately half of the MeOH was removed under
reduced pressure and the resulting solution was purified
over silica gel using mixed solvents (MeOH/H2O/CHCl3)
giving a light brown residue (3.9 mg, 85%).
[a]DZK152.5 (MeOH, cZ0.012), 1H NMR (500 MHz,
Methanol-d4): d 1.88 (3H, dd, JZ7.02, 1.63 Hz), 1.97 (2H,
m), 3.16 (1H, dd, JZ7.9, 8.9 Hz), 3.26 (2H, m), 3.34 (1H,
m), 3.67 (1H, dd, JZ11.7, 5.0 Hz), 3.73 (1H, dt, JZ10.0,
6.6 Hz), 3.85 (1H, dd, JZ11.7, 1.9 Hz), 4.00 (1H, dt, JZ
10.1, 5.9 Hz), 7.26 (1H, d, JZ7.8 Hz), 4.66 (1H, t, JZ
6.6 Hz), 5.53 (1H, dm JZ10.9 Hz), 6.20 (1H, dq, JZ10.8,
6.9 Hz), 13C NMR (75 MHz, Methanol-d4): d 16.42 (CH3),
38.97 (CH2), 60.22 (CH), 62.73 (CH2), 66.80 (CH2), 69.45,
71.61 (CH), 75.11 (CH), 75.96, 77.96 (CH), 78.07 (CH),
78.46, 85.15, 104.59 (CH), 109.70 (CH), 144.00 (CH). IR: n
cmK1 3330, 2918, 2231, 1611, 1162, 1071, UV/Vis:
l(max)nm: 282, 266, 252, 240. HRMS: Calculated for
C16H22O7CNa 349.1263, found 349.1267.
4.1.19. (8Z)-(30R)-30,Hydroxy-80-decen-40,60-diynyl 3,6-
O-bis(tert-butyldimethylsilyl)-2,4-O-bis(acetyl)-b-D-
glucopyranoside (24). In the absence of light, a 5 ml round
bottom flask equipped with a stir bar under an atmosphere of
nitrogen was added MeOH (0.5 ml), EtNH2 (0.5 ml), Z-3-
pentene-1-yne (3 mg, 0.044 mmol) and NH2OH–HCl
(0.5 mg 0.007 mmol) at 0 8C in an ice bath. Next CuCl
(0.2 mg, 2.2 mmol) was added followed by slow addition
over 5 min of a solution of 23 (0.5 ml, 2.2 mmol). After 1 h
at 25 8C, TLC analysis indicated the completion of the
reaction. The mixture was then cooled to 0 8C and diluted
with 2 ml EtOAc and 3 ml of a KCN/NH4Cl solution. The
aqueous layer was extracted with EtOAc (3!3 ml) and the
combined extracts were washed with aq. NaHCO3 and
brine. The resulting solution was dried over MgSO4 and
purified over silica gel column (20% EtOAc/hexanes)
giving a light yellow oil (12 mg, 86%).
Acknowledgements
This research is supported in part by a grant from the
National Institutes of Health (GM60263) and the Beckman
Foundation. Acknowledgment is also made to the donors of
the Petroleum Research Fund (PRF#36841-AC4)
administered by the American Chemical Society. We
thank Robert Falconer and Amanda Jones for preparing
some of the starting materials.
[a]DZK9.4 (MeOH, cZ0.2), 1H NMR (300 MHz, CDCl3):
d 0.01 (3H, s), 0.02 (3H, s), 0.03 (6H, s), 0.79 (9H, s), 0.86
(9H, s), 1.89 (3H, dd, JZ6.9, 1.7 Hz), 2.05 (3H, s), 2.10
(2H, m), 2.12 (3H, s), 3.39 (1H, ddd, JZ9.7, 5.9, 3.5 Hz),
3.59 (1H, dd, JZ11.4, 3.5 Hz), 3.64 (1H, dd, JZ11.4,
6.0 Hz), 3.80 (1H, dt, JZ9.7, 5.4 Hz), 3.81 (1H, t, JZ
9.1 Hz), 4.04 (1H, dt, JZ9.5, 4.5 Hz), 4.34 (1H, d, JZ
8.1 Hz), 4.62 (1H, m), 4.80 (1H, dd, JZ9.9, 9.1 Hz), 4.84
(1H, dd, JZ9.2, 8.1 Hz), 5.49 (1H, dd, JZ10.8, 1.6 Hz),
6.15 (1H, dq, JZ10.8, 6.9 Hz), 13C NMR (75 MHz,
CDCl3): d K4.97 (CH3), K4.87 (CH3), K4.15 (CH3),
K4.06 (CH3), 16.87 (CH3), 18.18, 18.74, 21.69 (2!CH3),
25.86 (3!CH3), 26.23 (3!CH3), 36.74 (CH2), 61.72 (CH),
63.60 (CH2), 66.77 (CH2), 70.10, 72.37 (CH), 73.40 (CH),
74.33 (CH), 75.69 (CH), 76.00, 82.14, 83.23, 101.24 (CH),
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