Assembly of digitoxin by gold(I)-catalyzed glycosidation of glycosyl o-alkynylbenzoates

Article abstract of DOI:10.1021/jo201850z

Digitoxin, a clinically important cardiac trisaccharide, was assembled efficiently from digitoxigenin and 3,4-di-O-tert-butyldiphenylsilyl-d- digitoxosyl o-cyclopropylethynylbenzoate in 9 steps and 52% overall yield via alternate glycosylation and protecting group manipulation. The present synthesis showcases the advantage of the gold(I)-catalyzed glycosylation protocol in the synthesis of glycoconjugates containing acid-labile 2-deoxysugar linkages.

Full text of DOI:10.1021/jo201850z

Article
pubs.acs.org/joc
Assembly of Digitoxin by Gold(I)-Catalyzed Glycosidation of Glycosyl
o-Alkynylbenzoates
Yuyong Ma,† Zhongzhen Li,‡ Hefang Shi,‡ Jian Zhang,† and Biao Yu*,†
†State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
‡Key Laboratory of Marine Drugs, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, China
S
* Supporting Information
ABSTRACT: Digitoxin, a clinically important cardiac trisac-
charide, was assembled efficiently from digitoxigenin and 3,4-
di-O-tert-butyldiphenylsilyl-D-digitoxosyl o-cyclopropylethynyl-
benzoate in 9 steps and 52% overall yield via alternate
glycosylation and protecting group manipulation. The present
synthesis showcases the advantage of the gold(I)-catalyzed
glycosylation protocol in the synthesis of glycoconjugates
containing acid-labile 2-deoxysugar linkages.
transport activity of the enzyme Na/K-ATPase in myocardiac
cells.3 Over the years, the anticancer effect of digitoxin on
patients has also attracted attention,4 and that has trigged
current research efforts in this direction.5 On the structure−
activity relationship (SAR) of cardiac glycosides, the steroidal
aglycone is the pharmacophore but itself is largely inactive,
while the sugar moiety determines the potency of the cardiac
glycosides and their pharmacokinetics as well.1
INTRODUCTION
■
Cardiac glycosides constitute a family of the steroid glycosides
bearing characteristically a lactone, either a butenolide or a α-
pyrone, at C-17 and a mono- or oligosaccharide residue, which
consists mostly of deoxysugars, at C-3 of the steroid nucleus.1 It
has been recognized since ancient times that they can enhance
the force and velocity of the contraction of the heart, slow the
rate of atrioventricular conduction, and cause toxic and lethal
effects at high doses. Among cardiac glycosides, digitoxin (1,
Figure 1) is structurally the prototype, which in homogeneous
Although glycosylation of the digitoxigenin (2) to access to
the digitoxin analogues with varied sugar moieties have been
intensively studied,6 assembly of the native trisaccharide
digoxose onto digitoxigenin has been realized in only three
reports.7−9 Wiesner and co-workers achieved the first synthesis
of digitoxin (1), employing sequential glycosylation of a furyl
precursor of digitoxigenin with 4-O-benzyl-3- O-(N-methyl-
carbamoyl)-D-digitoxose (p-TsOH, benzene, CH2Cl2, rt; 47.6%,
β/α = 3/1), ethyl 3-O-(p-methoxybenzoyl)-4-O-(p-nitrobenzo-
yl)-1-thio-digitoxoside (HgCl2, CdCO3, CH2Cl2, DMF, rt;
60.9%, β/α >25/1), and ethyl 3,4-di-O-(p-methoxybenzoyl)-1-
thio-digitoxoside (HgCl2, CdCO3, CH2Cl2, DMF, rt; 57.8%, β
only).7 Of these donors the protecting groups on the 3-OH
facilitated formation of the β-glycosidic linkages via 1,3-
participation, while those on the 4-OH (of the first two
donors) were selectively removable to ensure the next
glycosylation. The butenolide residue in digitoxin was finally
elaborated from the furyl moiety via oxidation, which was found
vulnerable under the alkaline conditions for removal of the N-
methylcarbamoyl group. McDonald et al. accomplished the
synthesis of digitoxin (1) via acid-catalyzed coupling of
Figure 1. Digitoxin (1) and its retrosynthesis with digitoxosyl o-
alkynylbenzoates as glycosylation donors.
form is a widely prescribed drug for treating congestive heart
failure and cardiac arrhythmia.2 Digitoxin and congeners exert
their predominant action through inhibition of the ion
Received: September 9, 2011
Published: November 4, 2011
© 2011 American Chemical Society
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Scheme 1. Preparation of the Digitoxosyl o-Cyclopropylethynylbenzoates 8−10
digitoxigenin with a trisaccharide glycal (1 mol % Ph3PHBr,
CHCl3; 82%, β/α = 3/2), which was fabricated by an iterative
tungsten-catalyzed endoselective alkynol cyclomerization meth-
odology.8 More recently, O’Doherty and Zhou developed
another de novo approach to the synthesis of digitoxin (1),
featuring iterative application of palladium-catalyzed glycosyla-
tion (with pyranose derivatives), reductive 1,3-transposition,
diastereoselective dihydroxylation, and regioselective protec-
tion.9 This recent synthesis requires 15 steps from digitoxigenin
(2) and a chiral pyranone, which is not only the shortest but
also the most stereocontrolled synthesis among the three
approaches to the synthesis of digitoxin (1).
After the Wiesner synthesis of digitoxin (1) in 1985, the
scenario of the glycoconjugate synthesis has changed
dramatically.10 Numerous new and powerful glycosylation
protocols have been developed.11 A recent addition is with
glycosyl o-alkynylbenzoates as donors and Au(I) as catalyst.12
We envisioned the efficient assembly of digitoxin (1) with this
new glycosylation method, because the digitoxosyl (2,6-
dideoxy-D-ribo-hexosyl) o-alkynylbenzoates would be stable
for convenient handling (in comparison to other types of the
favorable donors, such as the corresponding 2,6-dideoxy-
hexosyl halides, imidates, and phosphites), and their mild and
neutral activation conditions would secure the acid-labile β-
digitoxosyl linkages staying intact. In fact, glycosylation of the
extremely acid-labile substrates, such as the N-Boc-protected
purine, the dammarane, and the lupane derivatives, has been
achieved effectively with this method.13
Through modification of literature approaches, methyl 4,6-O-
benzylidene-2-deoxy-α-D-ribo-hexopyranoside (3) was readily
prepared from methyl α-D-glucopyranoside in four steps with
74% overall yield, i.e., 4,6-O-benzylidene protection (PhCH-
(OMe)2, TsOH, DMF, 40 °C), 2,3-di-O-tosyl ester formation
(TsCl, CH2Cl2, KOH, rt), conversion into 2,3-anhydro-
allopyranoside (NaOMe, CH2Cl2, MeOH, rt),15 and reduction
(LiAlH4, THF, 50 °C).16,17 The resulting 3-OH in 3 was then
protected with MBz group to provide 4 (97%); this axial 3-OH
was rather hindered so that forced conditions (MBzCl,
pyridine, DMAP, toluene, 100 °C) were required to ensure
the completion of the transformation. Compound 4 was
subjected to cleavage of the 4,6-O-benzylidene group (TsOH,
MeOH, rt) to give diol 5 (86%). Treatment of 5 with iodine in
the presence of PPh3 and imidazole (toluene, 70 °C) afforded
the desired 6-iodide 6a in only 64% yield; the major byproduct
(in 28% yield) was determined to be the 6-iodo-4-O-p-
methoxybenzoyl derivative 6b, in that the MBz group migrated
from the 3-OH to the 4-OH. Isomers 6a and 6b were difficult
to separate on silica gel in large scale; in addition, migration of
the MBz group also proceeded during the subsequent removal
of the 6-iodide under radical conditions. Therefore, the mixture
of 6a and 6b, without separation, was treated with Bu3SnH and
AIBN (toluene, 100 °C) followed by acetylation to provide 7a
and 7b in 67% and 33% yield, respectively, which were easily
separable on silica gel. Alternatively, after removal of the 6-
iodide, MBz protection of the 3- or 4-OH group gave 7c in 98%
yield. Methyl digitoxosides 7a−7c were subjected to hydrolysis
with 25% HOAc to give the corresponding digitoxoses, which
were then condensed with o-cyclopropylethynylbenzoic acid18
(EDCI, DMAP, DIPEA, CH2Cl2, rt) to afford the desired
digitoxosyl o-cyclopropylethynylbenzoates 8−10 in good yields,
in that the β-anomers were dominant with the α-anomers being
isolated in less than 5% yields.
RESULTS AND DISCUSSION
■
Stereoselective glycosylation with D-digitoxosyl donors (2-
deoxy-D-pyranosyl donors in general) to assemble the β-D-
digitoxoside linkage could resort to 1,3-participation.14 Thus, D-
digitoxosyl o-cyclopropylethynylbenzoates (8−10) equipped
with a p-methoxybenzoyl (MBz) or acetyl group at the 3-OH
were desired as the donors and were prepared as shown in
Scheme 1.
The glycosidic couplings of digitoxigenin 219 with digitoxosyl
o-cyclopropylethynylbenzoates 8−10 were examined under the
action of Ph3PAuOTf (0.1 equiv) in a mixed solvent of CH2Cl2
and toluene at rt, the typical glycosylation conditions for
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glycosyl o-alkynylbenzoates (Scheme 2). The coupled glyco-
sides 11−13 were furnished in excellent yields (>97%).
189a nearly quantitatively in 5 days. Reactions at >80 °C led to
decomposition of the substrate. At this stage, the corresponding
α anomer could be easily removed by chromatography on silica
gel. Diol 18 was then subjected to selective protection of the
axial 3′-OH with an acetyl group via 3′,4′-orthoester formation
and subsequent cleavage (CH3C(OMe)3, TsOH, rt),9,22 leading
to monosaccharide 199a in 98% yield.
Scheme 2. Glycosylation of Digitoxigenin (2) with
Digitoxosyl o-Cyclopropylethynylbenzoates 8−10
Glycosylation of digitoxigenin 3′-O-acetyl-β-D-digitoxoside 19
with 3,4-di-O-TBDPS-D-digitoxosyl o-cyclopropylethynylben-
zoate 17 under normal conditions (0.1 equiv Ph3PAuOTf,
CH2Cl2, −40 °C) afforded the desired β-disaccharide 20 in
high yields (∼80%) without detection of the corresponding α-
isomer. However, this reaction was poorly reproducible;
disaccharide 24 was isolated as the major byproduct (up to
64%), which was derived plausibly via glycal formation (from
17) followed by a Ferrier-type glycosylation.23 To our delight,
replacement of CH2Cl2 with toluene as the solvent completely
avoided this side reaction, leading to β-disaccharide 20 nearly
quantitatively.
However, the β/α selectivities were only moderate (∼2.0:1).
Variation of the reaction conditions, e.g., the solvent (dichloro-
methane, toluene, diethyl ether, 1,2-dichloroethane), temper-
ature (−40 °C to rt), and replacement of Ph3PAuOTf with
Ph3PAuNTf2, did not improve the β selectivity.
A worthwhile attempt to achieve the β-selective digitoxoside
formation was to increase the steric hindrance of the 3-O-
protecting group in the digitoxosyl donor. Therefore, 3,4-di-O-
tert-butyldiphenylsilyl-D-digitoxosyl o-cyclopropylethynylben-
zoate 17 was prepared (Scheme 3). Thus, 4,6-O-benzylidene
4 was treated with NBS in the presence of AIBN (BaCO3,
CCl4, reflux) to provide the 6-bromo-4-O-benzoate 14 in
excellent yield (97%).17c Treatment of 14 with LiAlH4 in THF
at 50 °C afforded digitoxoside 15,17c in that the 6-bromide, 4-
O-Bz, and 3-O-MBz groups were cleaved cleanly. Blocking the
3,4-OHs with a TBDPS group gave 16 quantitatively under
forced conditions.20 Methyl digitoxoside 16 was then converted
conveniently into the desired digitoxosyl o-cyclopropylethynyl-
benzoate 17 (74%, β/α = 8.6:1) via hydrolysis and ester
formation.
Gratifyingly, glycosylation of digitoxigenin (2) with 3,4-di-O-
TBDPS-D-digitoxosyl o-cyclopropylethynylbenzoate 17 under
normal conditions (0.1 equiv Ph3PAuOTf, CH2Cl2, rt) led to
the coupled glycoside nearly quantitatively in high β/α
selectivity (ca. β/α = 6.6:1 as measured by 1H NMR) (Scheme
4). The β and α anomers were inseparable on silica gel and
therefore were subjected directly to the next step for removal of
the 3,4-di-O-TBDPS group. These two TBDPS groups were
quite resistant to cleavage (e.g., HF·pyridine, THF, 50 °C), and
under some conditions (e.g., TBAF, THF, rt) the butenolide
moiety in the aglycone did not survive. Fortunately, under the
action of NH4F·HF in the presence of NMP in DMF at 70
°C,8b,21 the TBDPS groups were cleaved slowly to give diol
Digitoxigenin disaccharide 20 was then subjected to removal
of the 3″,4″-O-TBDPS groups with NH4F·HF in the presence of
NMP in DMF. The disaccharide was considerably more robust
than the monosaccharide (cf., →18), and thus the reaction was
performed at 80 °C to provide the corresponding 3″,4″-diol
nearly quantitative in 3 days. Selective protection of the axial 3″-
OH with an acetyl group under similar conditions as for 18→
19 gave 3′,3″-di-O-acetyl-disaccharide 219a (98%).
Applying the above glycosylation conditions (0.1 equiv
Ph3PAuOTf, toluene, −40 °C) to the coupling of digitoxigenin
disaccharide 21 with 3,4-di-O-TBDPS-D-digitoxosyl o-cyclo-
propylethynylbenzoate 17 provided the desired trisaccharide 22
in 97% yield with completely β selectivity. Removal of the
3‴,4‴-O-TBDPS groups on 22 under similar conditions as on
the disaccharide substrate 20 required longer time (5 days),
leading to diol 239a in 91% yield. Finally, the remaining 3′,3″-di-
O-acetyl groups were removed with LiOH in MeOH and H2O
at rt to furnish the target digitoxin (1) in 74% yield. The
1
analytical data (optical rotation, H, and 13C NMR) of the
synthetic compound 1 were in good agreement with those
reported for the natural product.
Scheme 3. Preparation of the Digitoxosyl o-Cyclopropylethynylbenzoate 17
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Scheme 4. Efficient Assembly of Digitoxin (1)
concentrated. The residue was purified by silica gel column
In conclusion, digitoxin (1), a clinically important cardiac
trisaccharide, has been assembled efficiently in 9 steps and 52%
overall yield from digitoxigenin and 3,4-di-O-tert-butyldiphe-
nylsilyl-D-digitoxosyl o-cyclopropylethynylbenzoate (17) via
alternate glycosylation and protecting group manipulation.
The digitoxosyl o-cyclopropylethynylbenzoate 17, readily
prepared from methyl α-D-glucopyranoside in 10 steps and
50% overall yield, was stable and could be activated by a
catalytic amount of Ph3PAuOTf to afford the β-digitoxosides in
excellent yields and β/α selectivity. These results demonstrate
that the present gold(I)-catalyzed glycosylation protocol is a
favorable method for the synthesis of glycoconjugates
containing 2-deoxy-sugars, in that the deoxysugar o-alkynyl-
benzoates donors are stable and the acid-labile deoxysugar
linkages remain intact during the glycosylation.
chromatograph (petroleum ether/acetone, 2:1) to provide 5 (8.1 g,
1
86%) as a colorless syrup: [α]25 = 115.4 (c 3.4, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2
H), 5.39 (q, J = 3.2 Hz, 1 H, H-3), 4.72 (d, J = 4.0 Hz, 1 H, H-1), 4.05
(m, 1 H, H-5), 3.88−3.80 (m, 6 H, H-4, H-6, H-6′, 3-OMBz-Me), 3.35
(s, 3 H, 1-OMe), 3.22 (brs, 1 H, -OH), 2.77 (brs, 1 H, -OH), 2.24 (dd,
J = 15.4, 2.6 Hz, 1 H, H-2), 1.98 (dt, J = 15.4, 3.6 Hz, 1 H, H-2′); 13
C
NMR (100 MHz, CDCl3) δ 166.6, 163.4, 131.8, 122.6, 113.5, 97.0 (C-
1), 69.4 (C-3), 67.8 (C-5), 67.1 (C-6), 62.5 (C-4), 55.3 (4-OMBz-
Me), 55.1(1-OMe), 33.2 (C-2); HRMS (ESI) calcd for C15H20O7Na
[M + Na]+ 335.1107, found 335.1103.
Methyl 2,6-Dideoxy-6-iodo-3-O-(p-methoxybenzoyl)-α-D-
ribo-hexopyranoside (6a) and Methyl 2,6-Dideoxy-6-iodo-4-
O-(p-methoxybenzoyl)-α-D-ribo-hexopyranoside (6b). Diol 5
(8.99 g, 28.7 mmol), PPh3 (11.39 g, 43.4 mmol), and imidazole
(5.91 g, 88.2 mmol) were dissolved in dry toluene (150 mL). After 30
min of stirring at 70 °C, I2 (9.57 g, 37.6 mmol) was added under an Ar
atmosphere. The mixture was stirred at 70 °C for an additional 1 h and
then concentrated and diluted with EtOAc. The organic phase, after
being washed with aqueous 1 N HCl, saturated NaHCO3, and brine,
respectively, was dried over anhydrous Na2SO4 and then concentrated
in vacuo. The resulting yellow oil was purified carefully by silica gel
column chromatograph (petroleum ether/EtOAc, 4:1) to provide 6a
(7.77 g, 64%) and 6b (3.40 g, 28%) as white solids. 6a: [α]25D = 76.3
(c 3.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2
H), 6.92 (d, J = 8.8 Hz, 2 H), 5.37 (m, 1 H, H-3), 4.79 (d, J = 4.4 Hz,
1 H, H-1), 3.88−3.83 (m, 4 H, H-5, 3-OMBz-Me), 3.64 (m, 2 H, H-4,
H-6), 3.45 (s, 3 H, 1-OMe), 3.36 (dd, J = 10.4, 7.6 Hz, 1 H, H-6′), 2.72
(brs, 1 H, 4-OH), 2.24 (dd, J = 15.4, 2.6 Hz, 1 H, H-2), 2.03 (dt, J =
15.4, 4.4 Hz, 1 H, H-2′); 13C NMR (100 MHz, CDCl3) δ 166.7, 163.5,
131.8, 122.2, 113.6, 97.2 (C-1), 70.9 (C-4), 69.3 (C-3), 67.2 (C-5),
55.4 (1-OMe), 55.3 (3-OMBz-Me), 33.4 (C-2), 8.2 (C-6); HRMS
EXPERIMENTAL SECTION
■
Methyl 4,6-O-Benzylidene-2-deoxy-3-O-(p-methoxybenzo-
yl)-α-D-ribo-hexopyranoside (4). To a solution of compound 3
(10.64 g, 40 mmol) in toluene (60 mL) and pyridine (20 mL) at 100
°C were added p-methoxybenzoyl chloride (9.12 g, 80 mmol) and
DMAP (0.49 g, 4 mmol). After stirring at this temperature for 6 h, the
reaction mixture was diluted with MeOH (15 mL) and concentrated
under reduced pressure. The residue was diluted with EtOAc, and the
organic phase, after being washed with water and brine, respectively,
was dried over Na2SO4 and then concentrated in vacuo. The residue
was purified by silica gel column chromatograph (petroleum ether/
EtOAc, 5:1) to give 4 (15.69 g, 97%) as a white solid: [α]25D = 176.2
(c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 2
H), 7.38−7.40 (m, 2 H), 7.28−7.30 (m, 3 H), 6.93 (d, J = 8.8 Hz, 2
H), 5.61 (s, 1 H), 5.52 (d, J = 2.4 Hz, 1 H), 4.76 (d, J = 4.0 Hz, 1 H),
4.32−4.53 (m, 2 H), 3.84 (s, 3 H), 3.78 (m, 2 H), 3.37 (s, 3 H), 2.36
(dd, J = 15.5, 3.1 Hz, 1 H), 2.01 (dt, J = 15.6, 3.4 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 165.9, 163.3, 137.3, 131.8, 129.0, 128.2, 126.2,
123.2, 113.5, 101.9, 97.6, 69.5, 66.1, 58.9, 55.4, 55.3, 33.7; HRMS
(MALDI) calcd for C22H24O7Na [M + Na]+ 423.1420, found
423.1420.
(MALDI) calcd for C15H19IO6Na [M + Na]+ 445.0117, found
1
445.0119. 6b: [α]25 = 113.0 (c 1.4, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 8.02 (d, J = 9.2 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 4.92 (d,
J = 3.2 Hz, 1 H, H-1), 4.81 (dd, J = 9.8, 3.2 Hz, 1 H, H-4), 4.26 (m, 1
H, H-3), 4.16 (m, 1 H, H-5), 3.86 (s, 3 H, 4-OMBz-Me), 3.51 (s, 3 H,
1-OMe), 3.48 (dd, J = 10.6, 2.2 Hz, 1 H, H-6), 3.26 (dd, J = 10.8, 8.4
Hz, 1 H, H-6′), 2.18 (ddd, J = 14.8, 3.2, 1.2 Hz, 1 H, H-2), 2.06 (dt, J
= 14.8, 3.2 Hz, 1 H, H-2′); 13C NMR (100 MHz, CDCl3) δ 165.2,
163.7, 131.9, 121.8, 113.7, 98.9 (C-1), 74.0 (C-4), 65.7 (C-3), 65.4 (C-
5), 55.7 (1-OMe), 55.4 (4-OMBz-Me), 35.3 (C-2), 6.2 (C-6); HRMS
Methyl 2-Deoxy-3-O-(p-methoxybenzoyl)-α-D-ribo-hexopyr-
anoside (5). To a solution of 4 (12.0 g, 30 mmol) in methanol (50
mL) was added p-toluenesulfonic acid at rt until pH = 3. After stirring
at rt for 2 h, the mixture was neutralized with Et3N and then
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(MALDI) calcd for C15H19IO6Na [M + Na]+ 445.0117, found
445.0119.
DMAP (10 mg, 0.08 mmol), EDCI (154 mg, 0.8 mmol), and DIPEA
(0.26 mL) were added. After being stirred overnight at rt, the mixture
was diluted with CH2Cl2 and washed with 1 N 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 column chromatography (toluene/EtOAc, 7:1) to
Methyl 4-O-Acetyl-2,6-dideoxy-3-O-(p-methoxybenzoyl)-α-
D-ribo-hexopyranoside (7a) and Methyl 3-O-Acetyl-2,6-di-
deoxy-4-O-(p-methoxybenzoyl)-α-D-ribo-hexopyranoside
(7b). To a solution of the mixture of iodide 6a and 6b (0.46 g, 1.1
mmol), which was obtained from the above transformation, and AIBN
(0.016 g, 0.1 mmol) in dry toluene (90 mL) at 100 °C was added
Bu3SnH (0.8 mL, 3.0 mmol) under an Ar atmosphere. After 1 h of
stirring at this temperature, pyridine (10.0 mL) and Ac2O (0.8 mL, 8.8
mmol) were added into the mixture, and the stirring was continued for
another 5 h. The resulting mixture was concentrated in vacuo and
diluted with EtOAc. The organic phase, after being washed with 1 N
HCl, saturated aqueous NaHCO3, and brine, respectively, was dried
over anhydrous Na2SO4 and concentrated in vacuo. The resulting
yellow oil was purified by silica gel column chromatography
1
provide 8 (159 mg, 80%, β/α = 19/1) as a white solid. 8α: H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 7.2 Hz, 1
H), 7.47 (d, J = 7.2 Hz, 1 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.09 (t, J = 7.2
Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.42 (d, J = 3.6 Hz, 1 H), 5.68 (q, J
= 3.2 Hz, 1 H), 4.80 (dd, J = 10.0, 2.8 Hz, 1 H), 4.59 (m, 1 H), 3.83 (s,
3 H), 2.48 (dd, J = 15.6, 2.4 Hz, 1 H), 2.36 (dt, J = 15.6, 4.0 Hz, 1 H),
2.00 (s, 3 H), 1.46 (m, 1 H), 1.27 (d, J = 6.0 Hz, 3 H), 0.83 (m, 4 H);
13C NMR (100 MHz, CDCl3) δ 170.0, 165.6, 164.9, 163.4, 134.2,
131.91, 131.86, 131.5, 130.2, 126.8, 124.8, 122.3, 113.5, 99.7, 91.1,
74.2, 72.3, 65.8, 64.3, 55.4, 32.8, 20.8, 17.6, 8.86, 8.82, 0.92; HRMS
(ESI) calcd for C28H28O8Na [M + Na]+ 515.1676, found 515.1666.
8β: [α]25D = 47.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05
(d, J = 8.8 Hz, 2 H), 7.96 (d, J = 7.2 Hz, 1 H), 7.49 (d, J = 7.2 Hz, 1
H), 7.43 (td, J = 7.2, 1.2 Hz, 1 H), 7.31 (td, J = 7.2, 1.2 Hz, 1 H), 6.97
(d, J = 8.8 Hz, 2 H), 6.42 (dd, J = 9.2, 2.4 Hz, 1 H), 5.80 (q, J = 3.2
Hz, 1 H), 4.79 (dd, J = 9.2, 3.2 Hz, 1 H), 4.30 (m, 1 H), 3.89 (s, 3 H),
2.38 (m, 1 H), 2.26 (m, 1 H), 2.01 (s, 3 H), 1.52 (m, 1 H), 1.31 (d, J =
6.4 Hz, 3 H), 0.89 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 170.1,
165.2, 164.4, 163.7, 134.4, 132.0, 131.8, 130.7, 130.6, 127.0, 125.1,
122.0, 113.8, 98.7, 91.3, 74.4, 72.3, 69.6, 67.0, 55.5, 34.4, 20.8, 18.0,
8.8, 0.62; HRMS (ESI) calcd for C28H28O8Na [M + Na]+ 515.1676,
found 515.1666.
(petroleum ether/EtOAc, 5:1) to provide 7a (0.25 g, 67%) and 7b
1
(0.12 g, 33%) as white solids. 7a: [α]25 = 176.9 (c 2.2, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 2 H), 6.95 (d, J = 8.8
Hz, 2 H), 5.56 (m, 1 H, H-3), 4.77 (d, J = 2.8 Hz, 1 H, H-1), 4.72 (dd,
J = 9.8, 3.0 Hz, 1 H, H-4), 4.33 (m, 1 H, H-5), 3.87 (s, 3 H, 3-OMBz-
Me), 3.42 (s, 3 H, 1-OMe), 2.20 (dd, J = 15.0, 2.2 Hz, 1 H, H-2), 2.12
(dt, J = 15.0, 4.0 Hz, 1 H, H-2′), 1.99 (s, 3 H, 4-OAc), 1.22 (d, J = 6.4
Hz, 3 H, H-6); 13C NMR (100 MHz, CDCl3) δ 170.1 (4-OAc), 165.7,
163.4, 131.8, 122.8, 113.6, 97.1 (C-1), 72.6 (C-4), 66.1 (C-3), 61.7 (C-
6), 55.4 (3-OMBz-Me), 55.2 (1-OMe), 33.6 (C-2), 20.8 (4-OAc), 17.4
(C-6); HRMS (MALDI) calcd for C17H22O7Na [M + Na]+ 361.1258,
1
found 361.1258. 7b: [α]25 = 98.7 (c 1.3, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H),
5.36 (m, 1 H, H-3), 4.89 (dd, J = 9.4, 3.2 Hz, 1 H, H-4), 4.74 (d, J =
3.6 Hz, 1 H, H-1), 4.37 (m, 1 H, H-5), 3.86 (s, 3 H, 4-OMBz-Me),
3.39 (s, 3 H, 1-OMe), 2.21 (dd, J = 14.8, 2.0 Hz, 1 H, H-2), 2.10−2.05
(m, 4 H, H-2, 3-OAc), 1.26 (d, J = 6.0 Hz, 3 H, H-6); 13C NMR (100
MHz, CDCl3) δ 170.6 (3-OAc), 165.1, 163.6, 131.6, 122.1, 113.7, 97.1
(C-1), 72.3 (C-4), 61.7 (C-3), 62.2 (C-5), 55.4 (4-OMBz-Me), 55.2
(1-OMe), 33.2 (C-2), 21.2 (3-OAc), 17.5 (C-6); HRMS (MALDI)
calcd for C17H22O7Na [M + Na]+ 361.1258, found 361.1264.
3-O-Acetyl-2,6-dideoxy-4-O-(p-methoxybenzoyl)-D-ribo-hex-
opyranosyl o-Cyclopropylethynylbenzoate (9). Compound 9
(86 mg, 85%, trace α) was prepared from 7b following a procedure
1
similar to that for 7a→8. 9β: [α]25 = 38.8 (c 1.9, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.97−7.94 (m, 3 H), 7.49 (d, J = 7.6 Hz, 1 H),
7.43 (td, J = 7.6, 1.2 Hz, 1 H), 7.31 (td, J = 7.6, 1.2 Hz, 1 H), 6.93 (d, J
= 7.2 Hz, 2 H), 6.38 (dd, J = 8.8, 2.0 Hz, 1 H), 5.67 (m, 1 H), 4.97
(dd, J = 8.8, 3.2 Hz, 1 H), 4.34 (m, 1 H), 3.87 (s, 3 H), 2.33 (m, 1 H),
2.21 (m, 1 H), 2.11 (s, 3 H), 1.52 (m, 1 H), 1.34 (d, J = 6.0 Hz, 3 H),
0.89 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 169.8, 165.1, 164.4,
163.7, 134.3, 132.0, 131.6, 130.6, 127.0, 125.0, 121.9, 113.7, 99.7, 91.4,
74.3, 72.0, 70.0, 67.0, 55.4, 34.0, 20.9, 18.1, 8.8, 0.6; HRMS (ESI) calcd
for C28H28O8Na [M + Na]+ 515.1676, found 515.1689.
Methyl 2,6-Dideoxy-3,4-di-O-(p-methoxybenzoyl)-α-D-ribo-
hexopyranoside (7c). To a solution of the mixture of 6a and 6b
(10.56 g, 25.0 mmol) and AIBN (0.27 g, 1.7 mmol) in dry toluene
(150 mL) at 100 °C was added Bu3SnH (8.1 mL, 30.0 mmol) under
an Ar atmosphere. After 1 h of stirring at this temperature, pyridine
(100 mL) and p-methoxybenzoyl chloride (11.30 g, 74.2 mmol) were
added into the mixture, and the stirring was continued for another 5 h.
The resulting mixture was concentrated in vacuo and diluted with
EtOAc. The organic phase, after being washed with 1 N HCl, saturated
aqueous NaHCO3, and brine, respectively, was dried over anhydrous
Na2SO4 and concentrated in vacuo. The resulting yellow oil was
purified by silica gel column chromatography (toluene/EtOAc, 15:1)
2,6-Dideoxy-3,4-di-O-(p-methoxybenzoyl)-D-ribo-hexopyra-
nosyl o-Cyclopropylethynylbenzoate (10). Compound 10 (4.72
g, 90%, β/α = 17/1) was prepared from 7c following a procedure
1
similar to that for 7a→8. 10α: [α]25 = 151.4 (c 1.0, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2 H), 7.87 (d, J = 8.4
Hz, 2 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.37 (t, J
= 7.2 Hz, 1 H), 7.04 (t, J = 7.2 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 2 H),
6.73 (d, J = 8.4 Hz, 2 H), 6.48 (d, J = 3.2 Hz, 1 H), 5.78 (m, 1 H), 5.10
(dd, J = 9.8, 2.2 Hz, 1 H), 4.77 (m, 1 H), 3.80 (s, 3 H), 3.76 (s, 3 H),
2.57 (d, J = 14.4 Hz, 1 H), 2.42 (m, 1 H), 1.47 (m, 1 H), 1.34 (d, J =
6.0 Hz, 3 H), 0.84 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 165.2,
164.8, 164.5, 163.3, 163.1, 133.9, 131.59, 131.53, 131.46, 131.2, 129.9,
126.5, 124.5, 122.1, 121.6, 113.4, 113.2, 99.5, 90.9, 74.0, 72.0, 66.0,
64.4, 55.1, 32.6, 17.6, 8.65, 8.59, 0.4; HRMS (ESI) calcd for
to provide 7c (10.76 g, 98%) as a white solid: [α]25 = 226.6 (c 4.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 2 H),
7.85 (d, J = 8.8 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz,
2 H), 5.64 (m, 1 H), 5.01 (dd, J = 9.8, 3.0 Hz, 1 H), 4.81 (d, J = 3.6
Hz, 1 H), 4.50 (m, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.43 (s, 3 H),
2.29 (dd, J = 14.8, 2.8 Hz, 1 H), 2.18 (dt, J = 14.8, 4.0 Hz, 1 H), 1.28
(d, J = 6.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 165.5, 165.1,
163.4, 163.3, 131.7, 131.6, 122.9, 122.0, 113.50, 113.48, 97.1, 72.5,
66.6, 62.1, 55.29, 55.26, 55.15, 33.6, 17.5; HRMS (MALDI) calcd for
C23H26O8Na [M + Na]+ 453.1520, found 453.1512.
4-O-Acetyl-2,6-dideoxy-3-O-(p-methoxybenzoyl)-D-ribo-hex-
opyranosyl o-Cyclopropylethynylbenzoate (8). A solution of
methyl glycoside 7a (135 mg, 0.40 mmol) in 25% HOAc (8.0 mL) was
stirred at 100 °C for 4 h and was then concentrated in vacuo. The
residue was diluted with EtOAc, washed with saturated NaHCO3
solution and brine, respectively, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel column
chromatograph (petroleum ether/EtOAc, 2:1) to provide 4-O-acetyl-
2,6-dideoxy-3-O-(p-methoxybenzoyl)-D-ribo-hexopyranose as a color-
less syrup. The syrup was dissolved in anhydrous CH2Cl2 (2.0 mL) at
rt, to which 2-(cyclopropylethynyl)benzoic acid (97 mg, 0.48 mmol),
C34H32O9Na [M + Na]+ 607.1963, found 607.1939. 10β: [α]25
=
D
1
87.0 (c 3.6, CHCl3); H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 9.2
Hz, 2 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.49 (d, J
= 7.6 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 6.96
(d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.48 (dd, J = 8.8, 2.0
Hz, 1 H), 5.89 (m, 1 H), 5.09 (dd, J = 9.0, 2.6 Hz, 1 H), 4.47 (m, 1
H), 3.88 (s, 3 H), 3.82 (s, 3 H), 2.48 (m, 1 H), 2.35 (m, 1 H), 1.53
(m, 1 H), 1.37 (d, J = 6.0 Hz, 3 H), 0.90 (m, 4 H); 13C NMR (100
MHz, CDCl3) δ 165.1, 165.0, 164.3, 163.6, 163.5, 134.3, 132.0, 131.73,
131.69, 130.63, 130.59, 127.0, 125.0, 122.1, 121.8, 113.7, 113.6, 99.7,
91.4, 74.4, 72.2, 70.1, 67.3, 55.4, 55.3, 34.3, 18.1, 8.8, 0.6; HRMS (ESI)
calcd for C34H32O9Na [M + Na]+ 607.1963, found 607.1960.
Digitoxigenin 4-O-Acetyl-2,6-dideoxy-3-O-(p-methoxyben-
zoyl)-D-ribo-hexopyranoside (11). To a mixture of 2 (12 mg,
0.032 mmol), 8 (19 mg, 0.038 mmol), and 4 Å MS (100 mg) in dry
9752
dx.doi.org/10.1021/jo201850z|J. Org. Chem. 2011, 76, 9748−9756

The Journal of Organic Chemistry
Article
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2 H), 7.82 (d, J =
CH2Cl2/toluene (2 mL/1 mL) was added a solution of PPh3AuOTf in
CH2Cl2 (0.05 N, 0.08 mL). After stirring at rt for 3 h, the mixture was
filtered through Celite. After being concentrated, the residue was
purified by silica gel column chromatography (CH2Cl2/MeOH, 200:1
to 150:1) to provide 11β (14.3 mg, 66%) and 11α (7.2 mg, 33%) as
white solids. 11α: [α]25D = 102.0 (c 0.4, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.07 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.88 (s,
1 H), 5.50 (m, 1 H), 4.98 (dd, J = 18.0, 1.6 Hz, 1 H), 4.94 (d, J = 4.0
Hz, 1 H), 4.81 (dd, J = 18.0, 1.6 Hz, 1 H), 4.71 (dd, J = 9.6, 2.8 Hz, 1
H), 4.41 (m, 1 H), 3.96 (brs, 1H), 3.87 (s, 3 H), 2.78 (m, 1 H), 2.26
(dd, J = 15.0, 2.6 Hz, 1 H), 2.20−2.08 (m, 3 H), 2.00 (s, 3 H), 1.91−
1.22 (m, 20 H), 1.19 (d, J = 6.0 Hz, 3 H), 0.86 (s, 3H), 0.76 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 174.4, 170.2, 165.8, 163.4, 131.8,
122.9, 117.7, 113.5, 94.0, 85.6, 73.4, 72.9, 71.7, 66.7, 61.7, 55.4, 50.9,
49.6, 41.8, 40.0, 36.6, 35.6, 35.1, 34.0, 33.1, 32.3, 30.0, 26.9, 26.8, 24.0,
23.5, 21.3, 21.1, 20.8, 17.5, 15.7; HRMS (ESI) calcd for C39H52O10Na
8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 5.88
(s, 1 H), 5.75 (m, 1 H), 5.02−4.96 (m, 3 H), 4.80 (dd, J = 18.0, 1.4
Hz, 1 H), 4.20 (m, 1 H), 4.09 (brs, 1H), 3.89 (s, 3 H), 3.82 (s, 3 H),
2.78 (m, 1 H), 2.24−2.05 (m, 4 H), 1.92−1.36 (m, 20 H), 1.29 (d, J =
6.0 Hz, 3 H), 0.94 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.5, 174.4, 165.2, 165.1, 163.6, 163.5, 131.68, 131.65,
122.6, 122.1, 117.7, 113.8, 113.6, 96.3, 85.6, 73.4, 73.3, 72.8, 55.5, 55.4,
50.9, 49.6, 41.9, 40.1, 36.5, 36.3, 35.8, 35.2, 33.1, 30.2, 30.1, 26.9, 26.7,
26.6, 23.6, 21.4, 21.1, 18.2, 15.7; HRMS (ESI) calcd for C45H56O11Na
[M + Na]+ 795.3715, found 795.3735.
Methyl 4-O-Benzoyl-6-bromo-2,6-dideoxy-3-O-(p-methoxy-
benzoyl)-α-D-ribo-hexopyranoside (14). A mixture of 4 (1.80 g,
4.5 mmol), NBS (0.80 g, 4.5 mmol), AIBN (0.036 g, 0.23 mmol), and
BaCO3 (0.53 g, 2.7 mmol) in dry CCl4 (45 mL) was refluxed for 1 h
under argon. The mixture was then cooled to room temperature and
filtered through Celite. The filtrate was diluted with EtOAc and
washed with 1 N 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
[M + Na]+ 703.3453, found 703.3461. 11β: [α]25 = 20.1 (c 0.4,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 2 H),
6.96 (d, J = 8.8 Hz, 2 H), 5.88 (s, 1 H), 5.68 (m, 1 H), 4.98 (d, J =
17.6 Hz, 1 H), 4.97 (d, J = 7.6 Hz, 1 H), 4.80 (d, J = 18.0, 1.6 Hz, 1
H), 4.69 (dd, J = 9.6, 2.8 Hz, 1 H), 4.04 (m, 2 H), 3.88 (s, 3 H), 2.78
(m, 1 H), 2.19−1.99 (m, 4 H), 1.97 (s, 3 H), 1.90−1.35 (m, 20 H),
1.24 (d, J = 6.4 Hz, 3 H), 0.93 (s, 3H), 0.87 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 174.5, 170.1, 165.2, 163.6, 131.7, 122.5, 117.7, 113.8,
96.2, 85.6, 73.4, 73.3, 72.9, 68.2, 68.0, 55.5, 50.9, 49.6, 41.9, 40.0, 36.4,
36.3, 35.6, 35.2, 33.1, 30.2, 30.1, 26.9, 26.7, 26.6, 23.6, 21.4, 21.1, 20.8,
18.0, 15.7; HRMS (ESI) calcd for C39H52O10Na [M + Na]+ 703.3453,
found 703.3481.
column chromatography (toluene/EtOAc, 25:1) to provide 14 (2.09 g,
1
97%) as a white solid: [α]25 = 186.4 (c 0.9, CHCl3); H NMR (400
D
MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2 H), 7.88 (d, J = 8.0 Hz, 2 H),
7.52 (d, J = 7.4 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz,
2 H), 5.72 (m, 1 H), 5.20 (dd, J = 9.8, 3.0 Hz, 1 H), 4.92 (d, J = 4.0
Hz, 1 H), 4.61 (m, 1 H), 3.88 (s, 3 H), 3.64 (dd, J = 11.0, 2.2 Hz, 1
H), 3.54 (m, 1 H), 3.51 (s, 3 H), 2.31 (dd, J = 14.8, 2.4 Hz, 1 H), 2.23
(dt, J = 15.6, 3.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 165.5,
165.2, 163.5, 133.3, 131.8, 129.7, 129.2, 128.4, 122.6, 113.71, 113.66,
97.6, 70.5, 66.3, 65.5, 55.6, 55.4, 33.5, 32.9; HRMS (MALDI) calcd for
C22H23O7BrNa [M + Na]+ 501.0519, found 501.0505.
Methyl 2,6-Dideoxy-α-D-ribo-hexopyranoside (15). To a
solution of 14 (13.38 g, 27.9 mmol) in anhydrous THF (300 mL)
was added lithium aluminum hydride (10.60 g, 279 mmol). After
stirring at 50 °C for 5.5 h, the mixture was ice-cooled, to which were
added dropwise water (10.6 mL), 15% aq NaOH (10.6 mL), and
water (31.8 mL) successively. The resulting mixture was stirred at 50
°C for 1 h. The mixture was then filtered through a pad of Celite. The
filtrate was concentrated to give a residue, which was purified by silica
gel column chromatography (petroleum ether/EtOAc, 2:1) to afford
15 (4.13 g, 91%) as a colorless oil.
Methyl 3,4-Di-O-tert-butyldiphenylsilyl-2,6-deoxy-α-D-ribo-
hexopyranoside (16). To a solution of diol 15 (2.00 g, 12.3
mmol) and tert-butyldiphenylsilyl chloride (12.8 mL, 49.3 mmol) in
dry DMF (12.0 mL) was added imidazole (2.48 g, 36.9 mmol). After
being stirred at 100 °C for 12 h, the mixture was concentrated in
vacuo. The residue was diluted with ethyl actate and washed with
saturated H2O and brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by silica gel
column chromatography (petroleum ether/toluene, 2:1) to provide 16
(7.88 g, 100%) as a colorless syrup: [α]25D = 17.6 (c 3.9, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 6.4 Hz, 2 H), 7.71 (d, J = 6.8
Hz, 2 H), 7.66 (d, J = 6.8 Hz, 2 H), 7.59 (d, J = 7.2 Hz, 2 H), 7.41−
7.14 (m, 12 H), 4.40 (m, 1 H), 4.15 (m, 1 H), 4.02 (m, 1 H), 3.56 (m,
1 H), 3.30 (s, 3 H), 2.21 (m, 1 H), 1.63 (dt, J = 13.0, 3.8 Hz, 1 H),
1.09 (s, 9 H), 1.00 (s, 9 H), 0.66 (d, J = 10.8 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 136.22, 136.19, 136.1, 136.0, 134.4, 134.1, 134.0,
133.6, 129.55, 129.50, 129.48, 129.38, 127.4, 97.3, 75.0, 68.9, 54.7,
27.0, 26.9, 19.34, 19.32, 17.2; HRMS (MALDI) calcd for
C39H50O4Si2Na [M + Na]+ 661.3145, found 661.3117.
Digitoxigenin 3-O-Acetyl-2,6-dideoxy-4-O-(p-methoxyben-
zoyl)-D-ribo-hexopyranoside (12). Compound 12 (21.8 mg,
100%, β/α = 2.0/1) was prepared from 2 (12 mg, 0.032 mmol) and
9 (19 mg, 0.038 mmol) following a procedure similar to that for 8→
11. 12α: [α]25D = 70.0 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 8.8 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 5.89 (s, 1 H), 5.29
(m, 1 H), 4.99 (d, J = 18.0 Hz, 1 H), 4.93 (d, J = 2.8 Hz, 1 H), 4.87
(dd, J = 9.6, 2.8 Hz, 1 H), 4.81 (dd, J = 17.8, 1.0 Hz, 1 H), 4.42 (m, 1
H), 3.92 (brs, 1 H), 3.87 (s, 3 H), 2.79 (m, 1 H), 2.25 (dd, J = 14.8,
2.8 Hz, 1 H), 2.19−2.00 (m, 6 H), 1.99−1.25 (m, 20 H), 1.21 (d, J =
6.4 Hz, 3 H), 0.95 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.5, 170.5, 165.3, 163.6, 131.8, 122.1, 117.7, 113.7, 94.7,
85.6, 73.4, 72.7, 72.6, 67.5, 62.4, 55.5, 50.9, 49.6, 41.9, 40.0, 37.1, 35.7,
35.2, 33.8, 33.2, 32.4, 30.2, 26.9, 26.7, 24.8, 23.9, 21.3, 21.2, 17.5, 15.8;
HRMS (ESI) calcd for C39H52O10Na [M + Na]+ 703.3453, found
1
703.3482. 12β: [α]25 = 8.9 (c 0.7, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.91 (d, J = 9.2 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.88 (s,
1 H), 5.57 (m, 1 H), 4.99 (dd, J = 17.6 Hz, 1 H), 4.90 (dd, J = 9.0, 2.2
Hz, 1 H), 4.86 (dd, J = 9.4, 3.0 Hz, 1 H), 4.81 (dd, J = 18.0, 1.4 Hz, 1
H), 4.07 (m, 2 H), 3.86 (s, 3 H), 2.79 (m, 1 H), 2.21−2.04 (m, 6 H),
1.99 (dd, J = 9.2, 3.2 Hz, 1 H), 1.95−1.34 (m, 20 H), 1.26 (d, J = 6.0
Hz, 3 H), 0.94 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
174.5, 169.8, 163.6, 131.6, 122.1, 117.7, 113.7, 96.0, 85.6, 73.4, 73.1,
72.6, 68.4, 68.0, 55.4, 50.9, 49.6, 41.9, 40.6, 36.3, 36.2, 35.8, 35.2, 33.1,
30.1, 26.9, 26.6, 23.6, 21.4, 21.1, 21.0, 18.1, 15.8; HRMS (ESI) calcd
for C39H52O10Na [M + Na]+ 703.3453, found 703.3476.
Digitoxigenin 2,6-Dideoxy-3,4-di-O-(p-methoxybenzoyl)-β-
D-ribo-hexopyranoside (13). Compound 13 (24.0 mg, 97%, β/α
= 1.8/1) was prepared from 2 (12 mg, 0.032 mmol) and 10 (22 mg,
0.038 mmol) following a procedure similar to that for 8→11. 13α:
1
[α]25 = 134.4 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3) δ 8.05
D
(d, J = 8.8 Hz, 2 H), 7.89 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2
H), 6.84 (d, J = 8.8 Hz, 2 H), 5.87 (s, 1 H), 5.55 (m, 1 H), 5.01−4.96
(m, 3 H), 4.80 (d, J = 17.6 Hz, 1 H), 4.56 (m, 1 H), 3.98 (brs, 1H),
3.87 (s, 3 H), 3.83 (s, 3 H), 2.76 (m, 1 H), 2.37 (dd, J = 15.0, 2.6 Hz,
1 H), 2.20−2.08 (m, 3 H), 1.91−1.84 (m, 2 H), 1.77−1.16 (m, 21 H),
0.86 (s, 3H), 0.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.47,
174.46, 165.6, 165.3, 163.5, 163.3, 131.76, 131.74, 123.1, 122.2, 117.7,
113.6, 113.5, 94.1, 85.6, 73.4, 72.9, 71.8, 67.3, 62.2, 55.5, 55.4, 50.9,
49.6, 41.8, 40.0, 36.5, 35.6, 35.0, 34.0, 33.1, 32.3, 29.9, 26.9, 26.8, 24.1,
23.5, 21.3, 21.1, 17.7, 15.7; HRMS (ESI) calcd for C45H56O11Na [M +
3,4-Di-O-tert-butyldiphenylsilyl-2,6-deoxy-α-D-ribo-hexo-
pyranosyl o-Cyclopropylethynylbenzoate (17). Digitoxosyl o-
alkynylbenzoate 17 (5.38 g, 74%, β/α = 8.6:1) was prepared from 16
(4.42 g) following a procedure similar to that for 7a→8. 17α: [α]25
=
D
1
14.1 (c 0.4, CHCl3); H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6
Hz, 1 H), 7.70 (d, J = 6.8 Hz, 2 H), 7.63−7.57 (m, 6 H), 7.47 (d, J =
8.0 Hz, 1 H), 7.42−7.23 (m, 14 H), 6.04 (brs, 1 H), 4.17 (brs, 1 H),
4.12 (brs, 1 H), 3.64 (brs, 1 H), 2.46 (m, 1 H), 1.88 (m, 1 H), 1.26
(m, 1 H), 1.00−0.98 (m, 18 H), 0.86 (m, 4 H), 0.70 (d, J = 6.8 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 165.1, 136.2, 136.1, 136.0, 134.3,
Na]+ 795.3715, found 795.3735. 13β: [α]25 = 64.9 (c 0.4, CHCl3);
D
9753
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The Journal of Organic Chemistry
Article
134.1, 133.7, 133.5, 133.4, 131.8, 131.5, 130.6, 129.8, 129.6, 127.59,
127.56, 127.53, 127.50, 126.8, 124.8, 99.4, 91.0, 77.2, 74.6, 74.4, 68.5,
27.02, 26.99, 19.4, 19.2, 17.2, 8.8, 0.7; HRMS (ESI) calcd for
3 H), 0.73 (d, J = 8.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
174.7, 174.5, 170.2, 137.7, 136.1, 136.0, 135.9, 133.9, 133.72, 133.70,
133.4, 129.8, 129.54, 129.50, 128.9, 128.1, 127.6, 127.45, 127.35,
125.2, 117.5, 95.7, 85.4, 79.3, 75.7, 73.4, 72.8, 68.9, 50.8, 49.5, 41.6,
39.9, 36.1, 36.0, 35.6, 35.0, 32.9, 30.1, 30.0, 27.1, 27.0, 26.8, 26.5, 23.5,
21.3, 21.24, 21.21, 21.0, 19.5, 19.2, 18.4, 18.2, 15.7; HRMS (MALDI)
C50H56O5Si2Na [M + Na]+ 815.3559, found 815.3577. 17β: [α]25
=
D
−61.7 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.72−7.60 (m,
8 H), 7.44−7.20 (m, 15 H), 7.16 (t, J = 7.6 Hz, 1 H), 6.44 (m, 1 H),
4.32 (d, J = 8.4 Hz, 1 H), 4.12 (br, 1 H), 3.74 (br, 1 H), 2.54 (br, 1
H), 1.69 (m, 1 H), 1.28 (m, 1 H), 1.11−1.07 (m, 18 H), 0.83−0.81
(m, 7 H); 13C NMR (100 MHz, CDCl3) δ 163.9, 136.1, 135.9, 135.7,
134.2, 134.0, 133.6, 133.5, 133.3, 131.4, 131.3, 130.0, 129.7, 129.6,
129.5, 127.6, 127.54, 127.51, 127.3, 126.6, 125.0, 99.6, 74.4, 27.04,
27.00, 19.4, 19.2, 8.8, 0.6; HRMS (ESI) calcd for C50H56O5Si2Na [M +
Na]+ 815.3559, found 815.3596.
+
calcd for C69H92O11Si2Na [M + Na] 1175.6070, found 1175.6115.
Digitoxigenin 3″-O-Acetyl-2″,6″-dideoxy-β-D-ribo-hexopyra-
nosyl-(1→4)- 3′-O-acetyl-2′,6′-dideoxy-β-D-ribo-hexopyrano-
side (21). A mixture of 20 (103 mg, 0.089 mmol) and NH4F·HF
(825 mg, 14.5 mmol) in a mixed solvent of anhydrous DMF (10 mL)
and N-methylpyrrolidine (NMP, 5 mL) was kept at 80 °C for 3 days
under argon. The solvent was removed under reduced pressure. The
residue was diluted with ethyl acetate, which was washed with H2O
and brine, respectively. The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (CH2Cl2/MeOH, 40:1)
to provide the deprotected product (60 mg, 99%) as a white solid.
The above product (53 mg, 0.074 mmol) was dissolved in CH2Cl2
(2.0 mL), and to this solution were added trimethylorthoacetate (0.03
mL, 0.222 mmol) and a catalytic amount of p-toluenesulfonic acid (1
mg, 5.8 μmol). The mixture was stirred for 2 h, and TLC indicated
that the starting material was consumed. The solvent was removed
under reduced pressure, and the residue was dissolved in THF/H2O
(2 mL, 1:1). p-Toluenesulfonic acid (7 mg, 0.04 mmol) was added,
and the stirring was continued for 1 h. The reaction was quenched
with addition of satd NaHCO3 solution. The mixture was extracted
with CH2Cl2, and the combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (CH2Cl2/MeOH, 40:1) to afford
compound 21 (55 mg, 98%) as a white solid.
Digitoxigenin 2,6-Dideoxy-α/β-D-ribo-hexopyranoside (18).
To a mixture of 17 (127 mg, 0.16 mmol), digitoxigenin 2 (50 mg, 0.13
mmol), and 4 Å MS (200 mg) in dry CH2Cl2 (10 mL) was added a
solution of PPh3AuOTf in CH2Cl2 (0.3 mL, 0.05 M). After stirring at
rt for 2 h, the mixture was filtered through Celite. The filtrate was
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 4:1) to provide the
coupled glycoside as a colorless syrup (130 mg, 99%).
A mixture of the above product (130 mg, 0.13 mmol) and
NH4F·HF (340 mg, 14.5 mmol) in a mixed solvent of anhydrous
DMF (10 mL) and N-methylpyrrolidine (NMP, 5 mL) was kept at 70
°C for 5 days under argon. The solvent was removed under reduced
pressure, and the residue was diluted with ethyl acetate. The organic
layer, after being washed with H2O and brine, respectively, was dried
over Na2SO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (CH2Cl2/MeOH,
40:1) to provide 18β9a (57.6 mg, 86%) and 18α (8.7 mg, 13%) as
white solids. 18α: [α]25D = 73.0 (c 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.88 (s, 1 H), 4.994 (d, J = 18.0 Hz, 1 H), 4.993 (d, J = 2.8
Hz, 1 H), 4.81 (d, J = 18.0 Hz, 1 H), 4.01 (s, 1 H), 4.03 (m, 1H), 3.97
(m, 1 H), 3.78−3.71 (m, 2 H), 2.77 (m, 1 H), 2.54 (d, J = 8.8 Hz, 1
H), 2.20−2.08 (m, 3 H), 2.00−1.19 (m, 24H), 0.95 (s, 3H), 0.87 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 174.5, 117.7, 94.8, 85.5, 73.4,
72.7, 71.8, 67.6, 64.8, 50.8, 49.5, 41.7, 39.9, 37.1, 35.6, 35.4, 35.2, 33.1,
32.2, 30.1, 26.8, 26.5, 23.8, 23.6, 21.2, 21.1, 17.8, 15.7; HRMS (ESI)
Digitoxigenin 3‴,4‴-Di-O-tert-butyldiphenylsilyl-2‴,6‴-di-
deoxy-β-D-ribo-hexopyranosyl-(1→4)-3″-O-acetyl-2″,6″-di-
deoxy-β-D-ribo-hexopyranosyl−(1→4)-3′-O-acetyl-2′,6′-di-
deoxy-β-D-ribo-hexopyranoside (22). To a mixture of 17 (63 mg,
0.079 mmol), 21 (38 mg, 0.052 mmol), and 4 Å MS (200 mg) in dry
toluene (5.0 mL) was added a solution of PPh3AuOTf in CH2Cl2
(0.16 mL, 0.05 M) at −40 °C. After stirring for 2 h, the mixture was
filtered through Celite. The filtate was concentrated. The residue was
purified by silica gel column chromatography (toluene/EtOAc, 6:1) to
+
calcd for C29H44O7Na [M + Na] 527.2979, found 527.2987.
provide 22 (68 mg, 97%) as a white solid: [α]25 = 27.8 (c 0.5,
Digitoxigenin 3′-O-Acetyl-2,6-dideoxy-β-D-ribo-hexopyra-
noside (19). A round-bottom flask containing alcohol 18 (79 mg,
0.157 mmol) in CH2Cl2 (2.0 mL) was stirred at room temperature. To
this solution were added trimethylorthoacetate (0.06 mL, 0.470 mmol)
and a catalytic amount of p-toluenesulfonic acid (1.5 mg, 9.3 μmol).
The mixture was stirred for 2 h, and TLC indicated that the starting
material was consumed. The solvent was removed under reduced
pressure, and the residue was dissolved in THF/H2O (2 mL, 1:1). p-
Toluenesulfonic acid (15 mg, 0.093 mmol) was added, and the stirring
was continued for 1 h. The reaction was quenched by the addition of
satd NaHCO3 solution. The mixture was extracted with CH2Cl2, and
the combined organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (CH2Cl2/MeOH, 40:1) to afford
compound 199a (84 mg, 98%) as a white solid.
Digitoxigenin 3″,4″-Di-O-tert-butyldiphenylsilyl-2″,6″-di-
deoxy-β-D-ribo-hexopyranosyl-(1→4)-3′-O-acetyl-2′,6′-di-
deoxy-β-D-ribo-hexopyranoside (20). To a mixture of 17 (109
mg, 0.14 mmol), 19 (50 mg, 0.09 mmol), and 4 Å MS (200 mg) in dry
toluene (5.0 mL) was added a solution of PPh3AuOTf in CH2Cl2 (0.3
mL, 0.05 M) at −40 °C. After stirring for 2 h, the mixture was filtered
through Celite. After being concentrated, the residue was purified by
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.71−7.65 (m, 5 H), 7.47−
7.20 (m, 15 H), 5.87 (s, 1 H), 5.36 (brs, 1 H), 5.10 (brs, 1 H), 4.98 (d,
J = 17.6 Hz, 1 H), 4.82−4.71 (m, 3 H), 4.60 (d, J = 8.8 Hz, 1 H), 4.29
(brs, 1 H), 4.06 (m, 1 H), 3.99 (brs, 1H), 3.81 (m, 1 H), 3.66 (m, 1
H), 3.40 (d, J = 5.2 Hz, 1 H), 3.27 (d, J = 9.2 Hz, 1 H), 2.90 (m, 1 H),
2.78 (m, 1 H), 2.20−1.20 (m, 40 H), 1.08 (s, 9 H), 0.90 (s, 12 H),
0.87 (s, 3 H), 0.73 (d, J = 8.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 174.52, 174.48, 170.28, 170.26, 136.2, 136.1, 136.0, 134.1, 133.8,
133.5, 129.8, 129.63, 129.58, 127.7, 127.53, 127.50, 127.4, 117.7, 98.7,
95.9, 85.6, 79.6, 79.0, 75.8, 73.4, 73.0, 70.0, 69.03, 69.98, 50.9, 49.6,
41.8, 40.0, 36.2, 35.7, 35.6, 35.1, 33.1, 30.1, 29.7, 37.2, 27.1, 26.9, 26.6,
23.6, 21.4, 21.3, 21.1, 19.6, 19.3, 18.4, 18.2, 18.0, 15.7; HRMS
(MALDI) calcd for [C77H104O15Si2Na]+ 1347.6811, found 1347.6806.
Digitoxigenin 4″-Di-O-tert-butyldiphenylsilyl-2″,3″,6″-tri-
deoxy-β-D-erythro-hex-2-enopyranosyl-(1→4)-3′-O-acetyl-
2′,6′-dideoxy-β-D-ribo-hexopyranoside (24). To a mixture of 17
(161 mg, 0.20 mmol), 19 (74 mg, 0.14 mmol), and 4 Å MS (200 mg)
in dry CH2Cl2 (5.0 mL) was added a solution of PPh3AuOTf in
CH2Cl2 (0.4 mL, 0.05 M) at rt. After stirring for 2 h, the mixture was
filtered through Celite. The filtrate was concentrated. The residue was
purified by silica gel column chromatography (toluene/EtOAc, 7:1) to
provide 24 as a white solid (79 mg, 64%): [α]25 = 41.7 (c 2.2,
silica gel column chromatography (toluene/EtOAc, 7:1) to provide 20
D
1
as a white solid (103 mg, 98%): [α]25 = 19.8 (c 0.5, CHCl3); H
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.2 Hz, 4 H),
D
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 9.6 Hz, 2 H), 7.65 (m, 4 H),
7.48−7.30 (m, 12 H), 7.18 (t, J = 10.0 Hz, 2 H), 5.87 (s, 1 H), 5.15
(brs, 1 H), 4.98 (d, J = 24.0 Hz, 1 H), 4.81 (d, J = 12.8 Hz, 1 H), 4.79
(d, J = 23.6 Hz, 1 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.28 (brs, 1 H), 4.10
(m, 1 H), 3.97 (brs, 1 H), 3.70 (m, 1 H), 3.39 (d, J = 10.4 Hz, 1 H),
3.02 (d, J = 11.6 Hz, 1 H), 2.76 (m, 1 H), 2.18−1.20 (m, 29 H), 1.14
(d, J = 8.4 Hz, 3 H), 1.08 (s, 9 H), 0.91 (s, 3 H), 0.87 (s, 9 H), 0.87 (s,
7.44−7.35 (m, 6 H), 5.87 (s, 1 H), 5.74 (d, J = 10.4 Hz, 1 H), 5.48 (d,
J = 2.4 Hz, 1 H), 5.38 (d, J = 10.4 Hz, 1 H), 4.99 (d, J = 17.6 Hz, 1 H),
4.93 (brs, 1 H), 4.83−4.78 (m, 2 H), 4.04 (brs, 1H), 3.93 (d, J = 8.4
Hz, 1 H), 3.81 (m, 2 H), 3.55 (dd, J = 9.2, 2.8 Hz, 1 H), 2.77 (m, 1
H), 2.14 (m, 2 H), 2.08 (s, 3 H), 2.00−1.38 (m, 18 H), 1.32 (d, J = 5.6
Hz, 3 H), 1.30−1.19 (m, 4 H), 1.15 (d, J = 6.0 Hz, 3 H), 1.05 (s, 9 H),
0.92 (s, 3 H), 0.87 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 174.7,
9754
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Article
174.5, 170.2, 135.90, 135.86, 134.4, 133.9, 133.1, 129.8, 129.7, 127.7,
127.5, 124.9, 117.5, 95.8, 91.3, 85.5, 75.2, 73.4, 73.0, 70.9, 68.7, 68.2,
66.2, 50.8, 49.6, 41.7, 40.0, 36.3, 36.2, 35.7, 35.1, 33.0, 30.12, 30.10,
26.9, 26.8, 26.60, 26.56, 23.5, 21.3, 21.1, 19.3, 18.3, 18.0, 15.7; HRMS
(MALDI) calcd for C53H72O10SiNa [M + Na]+ 919.4787, found
919.4746.
Digitoxin (1). A mixture of 22 (25 mg, 0.019 mmol) and
NH4F·HF (412 mg, 7.23 mmol) in a mixed solvent of anhydrous
DMF (6 mL) and N-methylpyrrolidine (NMP, 3 mL) was kept at 80
°C for 5 days under argon. The solvent was removed under reduced
pressure. The residue was diluted with ethyl acetate, which was washed
with H2O and brine, respectively. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (CH2Cl2/MeOH, 40:1)
to provide 23 (14.5 mg, 91%) as a white solid.
To a solution of diacetate 23 (9.0 mg, 10.6 μmol) in MeOH/H2O
(2.5 mL, 4:1) at room temperature was added LiOH (3 mg, 0.125
mmol). The mixture was stirred for 3 h and was then quenched with
addition of the pH = 7.0 buffering solution (10 mL). The mixture was
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by
Natl. Acad. Sci. U.S.A. 2005, 102, 12305. (c) Langenhan, J. M.; Engle, J.
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1964, 29, 2016. (c) Meyer zu Reckendorf, M.; Wassiliadou-Micheli,
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silica gel column chromatography (EtOAc) to provide 1 (6.0 mg,
1
74%) as a white solid: [α]25 = 16.0 (c 0.5, CHCl3); H NMR (400
D
MHz, CDCl3) δ 5.87 (s, 1 H), 4.99 (d, J = 17.6, 1.8 Hz, 1 H), 4.92−
4.79 (m, 4 H), 4.24 (m, 2 H), 4.13 (m, 1 H), 4.02 (m, 1 H), 3.85−3.75
(m, 3 H), 3.31 (m, 1 H), 3.25−3.20 (m, 2 H), 3.04 (s, 1 H), 2.98 (s, 1
H), 2.77 (m, 1H), 2.43 (s, 1 H), 2.17−2.05 (m, 7 H), 1.90−1.36 (m,
22 H), 1.29 (d, J = 6.4 Hz, 3 H), 1.23 (d, J = 6.0 Hz, 6 H), 0.92 (s,
3H), 0.87 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 174.64, 174.58,
117.6, 98.25, 98.18, 95.4, 85.6, 82.5, 82.2, 73.5, 72.7, 72.5, 69.5, 68.2,
68.1, 66.4, 66.3, 50.9, 49.6, 41.8, 40.1, 37.8, 37.1, 36.7, 36.2, 35.7, 35.1,
33.2, 30.2, 29.7, 26.9, 26.6, 26.5, 23.4, 21.4, 21.1, 18.1, 15.7; HRMS
(MALDI) calcd for C41H64O13Na [M + Na]+ 787.4239, found
787.4275.
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(10) For recent reviews on the chemical synthesis of steroid and
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642. (b) Yu, B.; Zhang, Y.; Tang, P. Eur. J. Org. Chem. 2007, 5145.
(c) Pellissier, H. Tetrahedron 2004, 60, 5123.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) For a recent review on the glycosylation methods, see: Zhu, X.;
Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900.
(12) (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604.
(b) Li, Y.; Yang, X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem.Eur. J.
2010, 16, 1871. (c) Zhu, Y.; Yu, B. Angew. Chem., Int. Ed. 2011, 50,
8329.
AUTHOR INFORMATION
Corresponding Author
*E-mail: byu@mail.sioc.ac.cn.
■
(13) (a) Zhang, Q.; Sun, J.; Zhu, Y.; Zhang, F.; Yu, B. Angew. Chem.,
Int. Ed. 2011, 50, 4933. (b) Liao, J.; Sun, J.; Niu, Y.; Yu, B. Tetrahedron
Lett. 2011, 52, 3075. (c) Li, Y.; Sun, J.; Yu, B. Org. Lett. 2011, 13, 5508.
(14) For comprehensive reviews on the synthesis of the 2-deoxy-
glycosidic linkages, see: (a) Marzabadi, C. H.; Frank, R. W.
Tetrahedron 2000, 56, 8385. (b) Hou, D.; Lowary, T. L. Carbohydr.
Res. 2009, 344, 1901.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Basic
Research Program of China (2010CB529706) and the National
Natural Science Foundation of China (90713003 and
20932009).
(15) Brown, M. A.; Cox, P. J.; Howie, R. A.; Melvin, O. A.; Taylor,
O. J.; Wardell, J. L. J. Organomet. Chem. 1995, 498, 275.
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via Sonogashira coupling (Pd(PPh3)2Cl2, CuI, i-Pr2NH, rt, 100%) and
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