Catalytic stereoselective synthesis of β-digitoxosides: Direct synthesis of digitoxin and C1′-epi-digitoxin

Article abstract of DOI:10.1021/jo4021419

A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-d-digitoxosides from 6-deoxy-d-allals has been described. This β-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1′-epi-digitoxin.

Full text of DOI:10.1021/jo4021419

Article
pubs.acs.org/joc
Catalytic Stereoselective Synthesis of β‑Digitoxosides: Direct
Synthesis of Digitoxin and C1′-epi-Digitoxin
Kedar N. Baryal, Surya Adhikari, and Jianglong Zhu*
Department of Chemistry and School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street,
Toledo, Ohio 43606, United States
S
* Supporting Information
ABSTRACT: A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-D-digitoxosides from 6-deoxy-D-
allals has been described. This β-selective glycosylation was achieved probably because of the formation of corresponding α-
digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of
digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1′-epi-digitoxin.
sylation14 of parent digitoxin, replacement of the natural
INTRODUCTION
■
digoxose trisaccharide with monosaccharide moieties,15 as well
2-Deoxy sugars, especially 2,6-dideoxy sugars, exist in numerous
as incorporation of other type of sugars.16 Studies of their
bioactive natural products and clinical agents and influence
structure−activity relationship (SAR) indicated that their
antitumor activity was significantly affected by the stereo-
chemistry and length of the sugar subunit. To further explore
the role of sugar subunit and search for better analogues of
digitoxin and its congeners, we initiated our effort toward the
synthesis of digitoxin.
their chemical, physical, and biological activities.1 Among the
naturally occurring 2,6-dideoxy sugars, β-linked digitoxosides
are present in cardiac glycosides2 involved in clinic use, such as
digitoxin3 and digoxin.4 Digitoxin and its congeners are well-
known inhibitors of the enzyme Na+/K+-ATPase and used for
treating congestive heart failure and cardiac arrhythmia for a
long period of time.3 While their clinical use is limited because
of the high toxicity, it was recently discovered that these
molecules have also demonstrated interesting anticancer
activity5 and could be potential agents for neuroprotection.6
In previous reports, β-digitoxosides were stereoselectively
prepared from various thio-digitoxoside (Hg2+),7 6-deoxy-D-
allal (Ph3P·HBr),8 in situ generated digitoxosyl iodides,9
digitoxosyl o-alkynylbenzoates (cationic Au(I)),10 or via
palladium-catalyzed glycosylation followed by functional
group manipulations.11 Despite those remarkable accomplish-
ments, only one direct synthesis of digitoxin was achieved by
McDonald and co-workers thus far,8 in which Ph3P·HBr-
catalyzed glycosylation of digitoxigenin with digoxose trisac-
charide glycal afforded desired product in modest anomeric
selectivity (β/α = 3/2). Other syntheses of digitoxin from the
groups of Wiesner,7 O’Doherty,11 and Yu10 required iterative
glycosylation of costly digitoxigenin or its furan derivative7 with
various glycosyl donors, which led to the decreasing overall
efficiency of the total synthesis.
RESULTS AND DISCUSSION
■
Recently, transition-metal catalysis has been successfully
utilized in the stereoselective synthesis of oligosaccharides/
glycoconjugates including 2-deoxy sugars and has demonstrated
advantages over traditional glycosylations involving stoichio-
metric amount of electrophilic promoters.17,18 Among those
reports, the Toste glycosylation19 involving rhenium(V)-
catalyzed stereoselective synthesis of 2-deoxy-α-glycosides
from glycals bearing equatorial C3-substituents, such as D-
glucal (1), D-rhamnal (2), and D-galactal (3), was particularly
appealing (Scheme 1a), in that this rhenium catalysis enables
direct selective formation of 2-deoxy α-glycosides (4) with
essentially 100% atom-economic efficiency. Inspired by this
report, we wonder if glycals bearing axial C3-substituents, such
as 6-deoxy-D-allal (5), would be selectively converted to the
corresponding β-digitoxosides (6) under similar Re(V)
catalysis. Because of 1,3-diaxial interactions, the production of
corresponding α-digitoxosides (7) should be disfavored
(Scheme 1b).
In addition, extensive efforts have been reported for the
preparation of analogues of digitoxin and related cardiac
glycosides in order to improve their activity and/or to alleviate
their side effects. Among those studies, special attention has
been paid to the modification of the sugar subunit, such as
neoglycorandomization,12 regioselective acylation13 or glyco-
Initially, known 3-O-benzyl-4-O-tert-butyldimethylsilyl-6-
deoxy-D-allal (8)20 was chosen to react with diacetone-D-
Received: September 28, 2013
Published: December 2, 2013
© 2013 American Chemical Society
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Scheme 1. Re(V)-Catalyzed Stereoselective Synthesis of 2-Deoxy Glycosides from Glycals
a
Table 1. Optimization of Re(V)-Catalyzed Stereoselective Synthesis of 2-Deoxy β-D-Digitoxoside
b
c
entry
reaction condition
yield (β/α)
1
2
3
4
toluene, rt, 12 h
CH2Cl2, rt, 24 h
CH3CN, rt, 24 h
Benzene, rt, 12 h
85%, 3.6/1
31%, 5.6/1
21%, 4.6/1
92%, 4.3/1
a
Reactions were performed using 0.3 mmol of 8 (1.5 equiv), 0.2 mmol of 9 (1.0 equiv), and 1 mol % ReOCl3(SMe2)(OPPh3), in 0.5 mL of solvent
b
c
1
at room temperature unless otherwise noted. Combined isolated yield of α/β isomers. α/β Ratio was determined by H NMR analysis.
galactose (9) for our condition optimization (Table 1). It was
found that with the use of 1 mol % ReOCl3(SMe2)(OPPh3) in
toluene, the original optimal condition reported by Toste,19
disaccharide 10 was produced in 85% yield (β/α = 3.6/1)
(entry 1, Table 1). Use of more polar solvents, such as
dichloromethane and acetonitrile, significantly dropped the
yields, albeit slightly better β/α selectivity was observed (entries
2 and 3). It was found that reactions in those polar solvents
were sluggish, and significant amounts of side products were
detected, which was consistent with what Toste observed.19
Finally, it was discovered that use of benzene as solvent
afforded disaccharide 10 in 92% yield (β/α = 4.3/1) (entry 4).
With this optimal condition developed, we next investigated
the reaction scope using various 6-deoxy-D-allals (8 and 1121)
as well as primary and secondary alcohols (9, 12−1321) and
thiophenol as acceptors (Table 2). As shown in Table 2, a
number of digitoxosides and thio-digitoxosides have been
prepared in synthetically useful to excellent yields with good to
excellent β-selectivity. In particular, use of thiophenol
essentially gave rise to the desired thio-digitoxosides in
excellent yields with complete β selectivity. In general, this
type of glycosylation involving secondary alcohol acceptors
generally afforded higher β/α selectivity than the use of primary
alcohol acceptors. In addition, higher catalyst loading was
required for secondary alcohol acceptors, probably due to their
relatively lower reactivity as compared to the primary alcohols.
It was found that Ferrier rearrangement22 was the main side
reaction, which competes with the desired glycosylation
pathway. It is worth noting that glycosyl phenylsulfide 13
bearing C2-methoxy group serves as the precursor for its
corresponding glycal and can be converted into the glycal via
reductive lithiation and 1,2-elimination (vide infra). Accord-
ingly, Re(V)-catalyzed glycosylation between 6-deoxy D-allal 8
and acceptor 13 followed by tetra-n-butylammonium fluoride
(TBAF)-mediated desilylation afforded disaccharide 20 in 64%
yield over two steps together with a small amount of α-anomer
(β/α= 8.3/1).
Having established this optimal condition, we set forth to
apply this method to the direct synthesis of digitoxin (Scheme
2). Accordingly, disaccharide acceptor 20 reacted with 6-deoxy
D-allal 8 under Re(V) catalysis to give rise to β-linked
trisaccharide 21 in 75% yield together with a small amount of
its α-anomer (β/α = 7/1). Trisaccharide 21 was then subjected
to TBAF-mediated desilylation to furnish desired alcohol 22
(89% yield). Next, reductive debenzylation and concomitant
reductive lithiation−elimination23 of 22 furnished the free
trisaccharide glycal, which subsequently underwent global
protection as its tetra-TES ether 23 (73% yield overall).
Because of the insolubility of digitoxigenin in nonpolar solvent,8
Re(V)-catalyzed glycosylation of glycal 23 with digitoxigenin
(24) in benzene was very sluggish. Use of dichloromethane
instead of benzene as solvent for this Re(V) catalysis afforded
trace amount of desired product together with side products
from Ferrier rearrangement.22 Finally, employing the condition
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a b c
, ,
Table 2. Re(V)-Catalyzed Stereoselective Synthesis of β-D-Digitoxosides
a
Reactions were performed using glycal (1.5 equiv), acceptor (1.0 equiv), 1 mol % ReOCl3(SMe2)(OPPh3), in benzene at room temperature unless
b
c
d
e
otherwise noted. Isolated yield. α/β Ratio was determined by 1H NMR analysis. Glycal (1.0 equiv) and thiophenol (1.2 equiv) were used. Glycal
(1.0 equiv), acceptor (1.5 equiv), and 10 mol % ReOCl3(SMe2)(OPPh3) were used. 10 mol % ReOCl3(SMe2)(OPPh3) was used. 20 was obtained
f
in 64% yield over two steps (Re(V)-catalyzed glycosylation followed by TBAF-mediated desilylation).
Scheme 2. Direct Synthesis of Digitoxin
described by McDonald (Ph3P·HBr, CHCl3) provided the
desired glycosylation product in 61% yield as an inseparable
mixture of anomers (β/α = 1/5) in which α was found to be
the major compound probably due to the predominance of
anomeric effect over 1,3-diaxial interaction. Subsequent global
deprotection of TES ether of this anomeric mixture using
NH4F−HF in DMF/NMP (4 h)8 afforded a mixture of
digitoxin 25 (β-isomer) and C1′-epi-digitoxin 26 (C1′-α-
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Scheme 3. Revised Synthesis of Digitoxin
(toluene:EtOAc = 50:1) to afford 2.6 g (96% yield) of 1,5-anhydro-3-
O-benzyl-4-O-p-methoxybenzyl-D-ribo-hex-1-enitol. Next, to 1,5-anhy-
dro-3-O-benzyl-4-O-p-methoxybenzyl-D-ribo-hex-1-enitol (2.3 g, 6.4
mmol) in 21 mL of THF cooled at −78 °C was added LiDBB (21.3
mL, 0.4 M) dropwise. The resulting mixture was stirred for 15 min at
−78 °C. Saturated sodium bicarbonate (1 mL) was added. After THF
was removed under reduced pressure, the remaining aqueous mixture
was extracted with EtOAc (3 × 40 mL). Combined extracts were
washed sequentially with water (20 mL) and brine (20 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel flash column chromatography
(hexanes:EtOAc = 5:1 to 3:1) to afford 1.3 g of 1,5-anhydro-4-O-p-
methoxybenzyl-D-ribo-hex-1-enitol (81% yield). Next, to a mixture of
1,5-anhydro-4-O-p-methoxybenzyl-D-ribo-hex-1-enitol (1.3 g, 5.2
mmol) in 5 mL of DMF and imidazole (1.08 g, 15.8 mmol), tert-
butyldimethylsilyl chloride (1.59 g, 10.6 mmol) was added. The
reaction mixture was stirred at room temperature for 1 h before water
was added. The resulting mixture was extracted with EtOAc (3 × 30
mL), and combined organic extracts were sequentially washed with
water (2 × 50 mL) and brine (25 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated . Crude mixture was purified by silica
gel flash column chromatography (hexanes:ethyl acetate = 25:1) to
isomer) in a combined 90% yield. This mixture was further
separated by reverse phase HPLC (C18 column) to provide
pure digitoxin 25 (β-isomer) and C1′-epi-digitoxin 26 (C1′-α-
isomer).21 Our synthetic digitoxin was identical to the digitoxin
purchased from Sigma-Aldrich according to spectroscopic
analysis.
Because of the fact that poor β/α ratio was obtained in the
glycosylation between trisaccharide glycal 23 and digitoxigenin
(24), we decided to prepare corresponding TBS-protected
trisaccharide glycal 27 (Scheme 3). We hope that greater size of
TBS ether, as compared to TES ether, would lead to more
severe 1,3-diaxial interaction, which would disfavor the
formation of α-anomer and thus favor the production of β-
anomer. Accordingly, reductive debenzylation and concomitant
reductive lithiation−elimination23 of 21 followed by global silyl-
protection afforded trisaccharide glycal tetra-TBS ether 27
(63% yield overall).24 Next, use of the condition described by
McDonald (Ph3P·HBr, CHCl3)8 provided the glycosylation
product in 57% yield (β/α = 1.4/1) in which β was found to be
the major compound, probably because 1,3-diaxial interaction is
prodominant over anomeric effect because of the steric
bulkiness of TBS ether. Final global deprotection of TBS
ether using NH4F−HF in DMF/NMP at 80 °C (6 days)8
furnished the desired digitoxin 25 and its C1′-epi-digitoxin
(26) in 85% combined yield, which can be separated by reverse
phase HPLC (C18 column) as previously discussed.
access 1.8 g of 1,5-anhydro-3-O-tert-butyldimethylsilyl-2,6-dideoxy-4-
23
O-p-methoxybenzyl-D-ribo-hex-1-enitol (11) (94% yield): [α]D
=
232.0° (c = 1, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.27 (ovrlp, 2
H), 6.87 (d, J = 8.6 Hz, 2 H), 6.30 (d, J = 5.9 Hz, 1 H), 4.78 (t, J = 5.9
Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.39 (d, J = 11.4 Hz, 1 H), 4.28
(dd, J = 3.3, 5.7 Hz, 1 H), 4.14 (dd, J = 6.2, 9.7 Hz, 1 H), 3.83−3.77
(m, 3 H), 3.24 (dd, J = 3.5, 9.7 Hz, 1 H), 1.32 (d, J = 6.2 Hz, 3 H),
0.90 (s, 9 H), 0.13−0.05 (ovrlp, 6 H); 13C NMR (150 MHz, CDCl3) δ
159.5, 145.6, 130.7, 129.7, 114.0, 102.2, 79.0, 70.7, 70.0, 60.9, 55.6,
26.2, 18.5, 18.1, −3.6, −4.0; FT-IR (thin film) 3047, 2926, 2843, 1643,
1607, 1500, 1456, 1243, 1171, 1083 cm−1; ESIHRMS [M+Na]+
calculated for C20H32NaO4Si 387.1968, found 387.1963.
CONCLUSION
■
In conclusion, we have reported a mild and atom-economic
Re(V)-catalyzed stereoselective synthesis of β-D-digitoxosides
from 6-deoxy-D-allals. This β-selectivity may be resulted from
the disfavored production of corresponding α-digitoxosides by
1,3-diaxial interaction. In addition, this method has been
successfully applied to a direct synthesis of digitoxin, a potent
cardiac glycoside, and its C1′-epimer. Synthesis of digitoxin
analogues bearing diverse sugar subunits and investigations of
their biological activity are currently in progress and will be
reported in due course.
Phenyl 3-O-benzyl-6-deoxy-2-O-methyl-1-thio-α-D-ribo-hex-
opyranoside (13). To a solution of 1,2,4,6-tetra-O-acetyl-3-O-
benzylallopyranose25 (14.8 g, 33.8 mmol) and thiophenol (6.9 mL,
67.6 mmol) in 84 mL of dichloromethane cooled at 0 °C was added
boron trifluoride diethyl etherate (8.3 mL, 67.6 mmol) dropwise. The
reaction mixture was stirred at ambient temperature for 2 h before 100
mL of water was added. After separating organic layer, aqueous layer
was extracted with dichloromethane (3 × 100 mL). Combined extracts
were washed sequentially with water (100 mL), saturated sodium
bicarbonate (200 mL) and brine (200 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography (toluene:EtOAc =
50:1 to 5:1) to afford 11.5 g (70% yield) of an α/β mixture of phenyl
2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-D-ribo-hexopyranoside. To this α/
β mixture of phenyl 2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-D-ribo-hex-
opyranoside (9.0 g, 18.4 mmol) in 37 mL of methanol was added
sodium methoxide (683 μL, 3.6 mmol). The resulting mixture was
stirred at ambient temperature overnight and neutralized with Dowex-
50 in the H+ form. Solvent was evaporated after filtration, residue was
azeotroped with toluene and redissolved in 37 mL of N,N-
dimethylformamide and benzaldehyde dimethyl acetal (4.2 mL, 27.9
mmol), p-toluenesulfonic acid (106 mg, 0.56 mmol) was added. The
reaction mixture was stirred at ambient temperature overnight.
EXPERIMENTAL SECTION
■
1,5-Anhydro-3-O-tert-butyldimethylsilyl-2,6-dideoxy-4-O-p-
methoxybenzyl-D-ribo-hex-1-enitol (11). To a solution of 1,5-
anhydro-3-O-benzyl-D-ribo-hex-1-enitol20 (1.73 g, 7.9 mmol) in 16 mL
N,N-dimethylformamide cooled at 0 °C was added sodium hydride
(408 mg, 10.2 mmol) portionwise. The resulting mixture was stirred at
0 °C for 45 min, and p-methoxybenzyl chloride (1.1 mL, 8.3 mmol)
was added. The reaction mixture was warmed up and stirred at
ambient temperature for 1 h. Ice-cold water was added, and the
resulting mixture was extracted with EtOAc (3 × 30 mL). Combined
organic extracts were washed with water (2 × 50 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
crude residue was purified by silica gel flash column chromatography
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Saturated sodium bicarbonate (50 mL) was added, and aqueous layer
was extracted with ethyl acetate (3 × 50 mL). Combined organic
layers were washed sequentially with water (3 × 50 mL) and brine (50
mL), dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The residue was purified by silica gel flash column
chromatography (toluene:EtOAc = 25:1) to afford 6.5 g (78%
combined yield) of an α/β mixture of phenyl 3-O-benzyl-4,6-O-
benzylidene-1-thio-D-ribo-hexopyranoside.
mg, 0.2 mmol) in 0.5 mL of dry benzene (0.4 M based on limiting
reagent) cooled at 0 °C was added 1 mol % catalyst ReOCl3(SMe2)-
(OPPh3). The resulting mixture was stirred at ambient temperature for
12 h. After 100 μL of saturated sodium bicarbonate was added, the
resulting mixture was filtered through a pad of anhydrous sodium
sulfate, concentrated, and purified by silica gel flash column
chromatography (hexanes:EtOAc = 30:1 to 10:1) to afford 10 (109
mg, 92% combined yield) as α/β (1/4.3) mixture: [α]D23 = −1.0° (c =
1
To a solution of α/β mixture of phenyl 3-O-benzyl-4,6-O-
benzylidene-1-thio-D-ribo-hexopyranoside (6.5 g, 14.4 mmol) in 47
mL of N,N-dimethylformamide cooled at 0 °C was added sodium
hydride (1.14 mg, 28.5 mmol) portionwise. The resulting mixture was
stirred for 45 min at 0 °C before methyl iodide (1.4 mL, 21.4 mmol)
was added. The reaction mixture was stirred for 3 h, and then water
(50 mL) was added. The aqueous layer was extracted with ethyl
acetate (3 × 50 mL), and the combined organic layers were washed
sequentially with water (2 × 100 mL), brine (50 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel flash column chromatography
(hexanes:EtOAc = 40:1 to 1:1) to afford 3.85 g (58% yield) of phenyl
3-O-benzyl-4,6-O-benzylidene-2-O-methyl-1-thio-α-D-ribo-hexopyra-
noside and 1.92 g (29% yield) of its corresponding β-anomer. Next, to
phenyl 3-O-benzyl-4,6-O-benzylidene-2-O-methyl-1-thio-α-D-ribo-hex-
opyranoside (3.4 g, 7.3 mmol) in 72 mL of dichloromethane and 1.5
mL of water was added trifluoroacetic acid (842 μL, 11 mmol). The
reaction mixture was stirred at ambient temperature for 24 h before
solid sodium bicarbonate (1.2 g, 14 mmol) was added. The resulting
mixture was concentrated in vacuo and purified by silica gel flash
column chromatography (hexanes:EtOAc = 10:1) to furnish 2.45 g
(88% yield) of phenyl 3-O-benzyl-2-O-methyl-1-thio-α-D-ribo-hexo-
pyranoside.
1, CHCl3); H NMR (600 MHz, CDCl3) δ 7.40−7.21 (ovrlp, 5 H, α
and β), 5.55 (d, J = 5.0 Hz, 1 H, β), 5.50 (d, J = 5.0 Hz, 1 H, α), 4.89
(d, J = 9.5 Hz, 1 H, β), 4.81 (d, J = 4.2, 1 H, α) 4.69 (ovrlp, 1 H, α and
β), 4.62 (d, J = 11.9 Hz, 1 H, β), 4.60−4.54 (ovrlp, 1 H, α and β),
4.55−451 (m, 1 H, α), 4.32−4.18 (ovrlp, 5 H, α and β), 4.06−4.01
(m, 1 H, β), 4.01−3.96 (ovrlp, 1 H, α and β), 3.96−3.90 (m, 1 H, β),
3.80−3.74 (ovrlp, 1 H, α and β), 3.72−3.69 (m, 1 H, α), 3.68−3.59
(ovrlp, 1 H, α and β), 3.41 −3.36 (ovrlp, 1 H, α and β), 2.34 − 2.29
(m, 1 H, α) 2.29−2.24 (m, 1 H, β), 1.74 − 1.69 (m, 1 H, α), 1.66−
1.57 (ovrlp, 1 H, β), 1.54−1.49 (ovrlp, 3 H, α and β), 1.46−1.40
(ovrlp, 3 H, α and β), 1.32 (s, 9 H, α and β), 1.28 (s, 3 H, α), 1.24−
1.17 (ovrlp, 3 H, α and β), 0.95−0.85 (ovrlp, 9 H α and β), 0.09−0.00
(ovrlp, 6 H, α and β); 13C NMR (150 MHz, CDCl3) δ 139.4, 139.2,
128.6, 128.5, 127.9, 127.9, 127.8, 127.7, 127.5, 109.7, 109.3, 108.9,
108.9, 98.9, 97.0, 96.7, 96.6, 76.2, 75.7, 75.3, 74.3, 72.5, 71.8, 71.2,
71.1, 71.0, 70.8, 70.7, 70.3, 68.8, 68.0, 66.2, 65.7, 64.9, 36.3, 32.8, 26.5,
26.4, 26.3, 26.2, 25.3, 25.3, 24.8, 24.8, 18.8, 18.5, 18.5, 18.4, −3.6, −3.8,
−4.4, −4.5; FT-IR (thin film) 2913, 2871, 2355, 1461, 1384, 1316,
1254, 1212, 1171, 1072 cm−1; ESIHRMS [M+Na]+ calculated for
C31H50NaO9Si 617.3122, found 617.3119.
3-O-tert-Butyldimethylsilyl-2,6-dideoxy-4-O-p-methoxybenzyl-β-
D-ribo-hexapyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-α-D-galac-
topyranoside (14). Prepared according to general procedure from
compound 11 (109 mg, 0.3 mmol), diacetone-D-galactose 9 (52 mg,
0.2 mmol), and 1 mol % catalyst ReOCl3(SMe2)(OPPh3) at ambient
temperature in 12 h. Purification by silica gel flash column
chromatography (hexanes:EtOAc = 50:1 to 10:1) furnished 14 (70.6
mg, 57%) and its α-anomer (17.5 mg, 14%) (71% combined yield).
A mixture of phenyl 3-O-benzyl-2-O-methyl-1-thio-α-D-ribo-hexo-
pyranoside (2.1 g, 5.6 mmol), 2-aminoethyl diphenyl borinate26 (126
mg, 0.56 mmol) and p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) in
21 mL of acetonitrile and N,N-diisopropylethylamine (1.4 mL, 8.4
mmol) was stirred at ambient temperature for 22 h. The reaction was
quenched with saturated sodium bicarbonate (25 mL) and brine (20
mL), and organic layer was separated. The aqueous layer was extracted
with ethyl acetate (4 × 40 mL). Combined organic extracts were dried
over anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by silica gel flash column chromatography (hexanes:E-
tOAc = 4:1 to 2:1) to afford phenyl 3-O-benzyl-2-O-methyl-6-O-p-
toluenesulfonyl-1-thio-α-D-ribo-hexopyranoside. To a solution of this
tosylate in 27 mL of THF cooled at 0 °C was added lithium aluminum
hydride (3 mL, 4 M in diethyl ether) dropwise. The reaction mixture
was refluxed for 1 h before being cooled back to 0 °C. Saturated
ammonium chloride (1 mL) was added dropwise. After THF was
removed under reduced pressure, the residue was diluted with
methylene chloride (120 mL) and filtered through Celite. The filtrate
was washed with saturated sodium bicarbonate, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography (toluene:EtOAc =
10:1) to afford 1.7 g (84% over 2 steps) of phenyl 3-O-benzyl-6-deoxy-
2-O-methyl-1-thio-α-D-ribo-hexopyranoside (13): [α]D23 = 205.1° (c =
23
The β-anomer 14 is characterized as follows: [α]D = −0.8° (c = 1,
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.25−7.20 (m, 2 H), 6.89−
6.82 (m, 2 H), 5.54 (d, J = 5.1 Hz, 1 H), 4.88 (dd, J = 1.9, 9.4 Hz, 1
H), 4.61−4.54 (m, 2 H), 4.34 (d, J = 11.4 Hz, 1 H), 4.29 (dd, J = 2.4,
5.1 Hz, 1 H), 4.26−4.20 (m, 2 H), 4.04−3.96 (m, 2 H), 3.94−3.88 (m,
1 H), 3.80 (s, 3 H), 3.65 (dd, J = 7.1, 10.7 Hz, 1 H), 2.98 (dd, J = 2.4,
9.2 Hz, 1 H), 2.02 (ddd, J = 2.0, 4.0, 13.4 Hz, 1 H), 1.65−1.57 (ovrlp,
1 H), 1.52 (s, 3 H), 1.45 (s, 3 H), 1.32 (d, J = 4.2 Hz, 6 H), 1.21 (d, J
= 6.2 Hz, 3 H), 0.91−0.85 (s, 9 H), 0.07−0.01 (ovrlp, 6 H); 13C NMR
(150 MHz, CDCl3) δ 159.5, 130.6, 129.8, 114.0, 109.6, 108.9, 98.7,
96.7, 81.1, 71.8, 71.4, 71.0, 70.7, 68.8, 68.5, 67.9, 66.1, 55.6, 39.6, 26.4,
26.3, 26.2, 25.3, 24.7, 18.6, 18.5, −4.2, −4.5; FT-IR (thin film) 2926,
2895, 2843, 1607, 1461, 1373, 1301, 1249, 1171, 1072 cm−1;
ESIHRMS [M+Na]+ calculated for C32H52NaO10Si 647.3227, found
647.3217.
Phenyl 3-O-benzyl-4-O-tert-butyldimethylsilyl-2,6-dideoxy-1-
thio-β-D-ribo-hexapyranoside (15). Prepared according to general
procedure from compound 8 (70 mg, 0.21 mmol), thiophenol (26 μL,
0.25 mmol), and 1 mol % catalyst ReOCl3(SMe2)(OPPh3) at ambient
temperature in 3 h. Purification by silica gel flash column
chromatography (hexanes:EtOAc = 50:1) afforded 15 (87.5 mg,
1
1, CHCl3); H NMR (600 MHz, CDCl3) δ 7.58−7.53 (m, 2 H),
7.48−7.43 (m, 2 H), 7.40−7.35 (m, 2 H), 7.34−7.27 (m, 3 H), 7.26−
7.21 (m, 1 H), 5.54 (d, J = 5.5 Hz, 1 H), 5.20 (d, J = 11.6 Hz, 1 H),
4.58 (d, J = 11.6 Hz, 1 H), 4.21 (qd, J = 6.3, 9.7 Hz, 1 H), 4.08 (t, J =
2.6 Hz, 1 H), 3.68 (dd, J = 2.2, 5.5 Hz, 1 H), 3.54−3.48 (m, 3 H), 3.21
(ddd, J = 3.3, 9.7, 11.6 Hz, 1 H), 2.35 (d, J = 11.4 Hz, 1 H), 1.30 (d, J
= 6.2 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δ 138.6, 138.3, 131.4,
129.2, 128.9, 128.5, 128.2, 127.1, 86.4, 80.7, 76.7, 75.2, 72.1, 57.7, 17.7;
FT-IR (thin film) 3424, 2926, 1633, 1586, 1471, 1444, 1368, 1347,
1160, 1062 cm−1; ESIHRMS [M+Na]+ calculated for C20H24NaO4S
383.1293, found 383.1303.
23
1
94% yield): [α]D = 39.8° (c = 1, CHCl3); H NMR (600 MHz,
CDCl3) δ 7.50−7.45 (m, 2 H), 7.37−7.26 (m, 7 H), 7.25−7.21 (m, 1
H), 5.23 (dd, J = 1.9, 11.8 Hz, 1 H), 4.74 (d, J = 11.7 Hz, 1 H), 4.62
(d, J = 11.7 Hz, 1 H), 4.01 (dd, J = 6.3, 9.3 Hz, 1 H), 3.80 (q, J = 2.6
Hz, 1 H), 3.41 (dd, J = 2.7, 9.3 Hz, 1 H), 2.31−2.23 (m, 1 H), 1.85
(ddd, J = 2.4, 11.8, 13.8 Hz, 1 H), 1.26 (d, J = 6.2 Hz, 3 H), 0.92 (s, 9
H), 0.09 (s, 3 H), 0.06 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ
139.1, 135.1, 130.9, 129.1, 128.7, 127.9, 127.2, 79.8, 76.4, 75.5, 73.2,
72.9, 37.1, 26.2, 19.0, 18.4, −3.6, −4.5; FT-IR (thin film) 2947, 2871,
2843, 1581, 1467, 1352, 1249, 1202, 1124, 1088 cm−1; ESIHRMS [M
+Na]+ calculated for C25H36NaO3SSi 467.2052, found 467.2054.
Phenyl 3-O-tert-butyldimethylsilyl-2,6-dideoxy-4-O-p-methoxy-
benzyl-1-thio-β-D-ribo-hexapyranoside (16). Prepared according to
General Procedure for Rhenium(V)-Catalyzed Synthesis of
β-Digitoxosides and β-Thiodigitoxosides. 3-O-Benzyl-4-O-tert-
butyldimethylsilyl-2,6-dideoxy-β-D-ribo-hexapyranosyl-(1→6)-
1,2:3,4-di-O-isopropylidene-α-D-galactopyranoside (10). To a mix-
ture of glycal 8 (100 mg, 0.3 mmol) and diacetone-D-galactose 9 (52
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general procedure from compound 11 (73 mg, 0.2 mmol), thiophenol
(25 μL, 0.24 mmol), and 1 mol % catalyst ReOCl3(SMe2)(OPPh3) at
ambient temperature in 3 h. Purification by silica gel flash column
chromatography (hexanes:EtOAc = 50:1) afforded 16 (91 mg, 96%
yield): [α]D23 = 37.7° (c = 1, CHCl3); 1H NMR (600 MHz, CDCl3) δ
7.50−7.45 (m, 2 H), 7.32−7.27 (m, 2 H), 7.25−7.20 (m, 3 H), 6.86
(d, J = 8.6 Hz, 2 H), 5.23 (dd, J = 1.9, 11.6 Hz, 1 H), 4.57 (d, J = 11.2
Hz, 1 H), 4.36 (d, J = 11.4 Hz, 1 H), 4.26 (td, J = 2.1, 3.9 Hz, 1 H),
3.95 (dd, J = 6.2, 9.4 Hz, 1 H), 3.81 (s, 3 H), 3.00 (dd, J = 2.4, 9.4 Hz,
1 H), 2.04 (ddd, J = 2.0, 3.9, 13.5 Hz, 1 H), 1.85 (ddd, J = 2.2, 11.6,
13.5 Hz, 1 H), 1.24 (d, J = 6.2 Hz, 3 H), 0.91−0.83 (s, 9 H), 0.08−
0.02 (ovrlp, 6 H); 13C NMR (150 MHz, CDCl3) δ 159.5, 134.9, 131.3,
130.5, 129.8, 129.1, 127.3, 114.0, 80.7, 79.4, 71.7, 71.4, 66.1, 55.6, 40.3,
26.2, 18.8, 18.5, −4.1, −4.5; FT-IR (thin film) 2942, 2870, 1607, 1581,
1508, 1461, 1447, 1373, 1295, 1243 cm−1; ESIHRMS [M+Na]+
calculated for C26H38NaO4SSi 497.2158, found 497.2145.
Methyl 3-O-benzyl-4-O-tert-butyldimethylsilyl-2,6-dideoxy-β-D-
ribo-hexapyranosyl-(1→4)-6-deoxy-2,3-O-isopropylidene-α-L-man-
nopyranoside (17). Prepared according to general procedure from
compound 8 (100 mg, 0.3 mmol), 12 (98 mg, 0.45 mmol), and 10 mol
% catalyst ReOCl3(SMe2)(OPPh3) in 500 μL of benzene at ambient
temperature in 3 days. Purification by silica gel flash column
chromatography (hexanes:EtOAc = 70:1 to 20:1) afforded 17 (86
mg, 52% yield) and its α-anomer (4.4 mg). Compound 17 is
characterized as follows: [α]D23 = 6.4° (c = 1, CHCl3); 1H NMR (600
MHz, CDCl3) δ 7.41−7.35 (m, 2 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.27
(ovrlp, 1 H), 5.28−5.23 (m, 1 H), 4.84 (s, 1 H), 4.70 (d, J = 11.9 Hz, 1
H), 4.64 (d, J = 11.9 Hz, 1 H), 4.15−4.09 (m, 1 H), 4.07 (d, J = 5.5
Hz, 1 H), 3.93−3.85 (m, 1 H), 3.76 (d, J = 2.8 Hz, 1 H), 3.63−3.56
(m, 2 H), 3.40−3.33 (ovrlp, 4 H), 2.22 (td, J = 1.7, 13.6 Hz, 1 H),
1.56−1.48 (ovrlp, 4 H), 1.34 (s, 3 H), 1.32−1.26 (m, 3 H), 1.20 (d, J =
6.2 Hz, 3 H), 0.95−0.87 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H); 13C
NMR (150 MHz, CDCl3) δ 139.3, 128.6, 127.9, 127.7, 109.5, 98.3,
97.7, 78.8, 78.8, 76.5, 76.4, 75.7, 72.4, 70.4, 64.8, 55.1, 36.5, 28.2, 26.9,
26.2, 18.8, 18.4, 17.9, −3.7, −4.4; FT-IR (thin film) 2926, 2895, 2843,
1446, 1378, 1243, 166, 1140, 1093, 1015 cm−1; ESIHRMS [M+Na]+
calculated for C29H48NaO8Si 575.3016, found 575.3029.
Methyl 3-O-tert-butyldimethylsilyl-2,6-dideoxy-4-O-p-methoxy-
benzyl-β-D-ribo-hexapyranosyl-(1→4)-6-deoxy-2,3-O-isopropyli-
dene-α-L-mannopyranoside (18). Prepared according to general
procedure from compound 11 (1.8 g, 4.9 mmol), 12 (1.6 g, 7.4
mmol), and 10 mol % catalyst ReOCl3(SMe2)(OPPh3) in 4.9 mL of
benzene at ambient temperature in 60 h. Purification by silica gel flash
column chromatography (hexanes:EtOAc = 70:1 to 20:1) afforded 18
(1.86 g, 65% yield) and its α-anomer (142 mg). The β-anomer 18 is
characterized as follows: [α]D23 = 18.3° (c = 1, CHCl3); 1H NMR (600
MHz, CDCl3) δ 7.26−7.21 (m, 2 H), 6.89−6.83 (m, 2 H), 5.27 (dd, J
= 1.8, 9.5 Hz, 1 H), 4.83 (s, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.34 (d, J
= 11.4 Hz, 1 H), 4.26 (td, J = 2.1, 3.9 Hz, 1 H), 4.12−4.07 (m, 1 H),
4.07−4.03 (m, 1 H), 3.87 (dd, J = 6.2, 9.4 Hz, 1 H), 3.80 (s, 3 H),
3.61−3.50 (m, 2 H), 3.35 (s, 3 H), 2.98 (dd, J = 2.5, 9.3 Hz, 1 H), 1.98
(ddd, J = 1.9, 3.9, 13.2 Hz, 1 H), 1.57−1.47 (ovrlp, 4 H), 1.31 (s, 3 H),
1.28 (d, J = 6.1 Hz, 3 H), 1.20 (d, J = 6.2 Hz, 3 H), 0.94−0.88 (s, 9 H),
0.10−0.07 (m, 3 H), 0.07−0.02 (m, 3 H); 13C NMR (150 MHz,
CDCl3) δ 159.5, 130.7, 129.8, 114.0, 109.4, 98.3, 97.9, 80.9, 79.4, 78.8,
76.4, 71.1, 69.0, 66.1, 64.8, 55.6, 55.1, 39.9, 28.2, 26.7, 26.1, 18.7, 18.5,
17.9, −4.1, −4.6; FT-IR (thin film) 2926, 1607, 1508, 1461, 1378,
1301, 1249, 1145, 1093, 1041 cm−1; ESIHRMS [M+Na]+ calculated
for C30H50NaO9Si 605.3122, found 605.3113.
Phenyl 3-O-benzyl-2,6-dideoxy-β-D-ribo-hexapyranosyl-(1→4)-3-
O-benzyl-6-deoxy-2-O-methyl-1-thio-α-D-ribo-hexopyranoside (20).
To a solution of 8 (601 mg, 1.8 mmol) and 1321 (432 mg, 1.2 mmol)
in 2.4 mL of benzene at 0 °C was added 78 mg (10 mol %) of catalyst
ReOCl3(SMe2)(OPPh3). The reaction mixture was stirred for 3 days
before 200 μL of saturated sodium bicarbonate was added. The
resulting mixture was filtered through anhydrous sodium sulfate,
concentrated in vacuo, and purified by silica gel flash column
chromatography (hexanes:EtOAc = 70:1 to 5:1) to afford 19 (577
mg), its α-anomer (70 mg), and unreacted acceptor 13 (59.4 mg). The
β-anomer 19 was dissolved in 3.0 mL of THF at 0 °C, and tetra-n-
butylammonium fluoride (1.25 mL, 1 M in THF) was added. The
resulting mixture was stirred overnight before saturated sodium
bicarbonate was added. After THF was evaporated, the aqueous layer
was extracted with ethyl acetate (3 × 15 mL). Combined organic
extracts were washed sequentially with water (5 mL) and brine (2 ×
10 mL), dried over sodium sulfate, filtered, and concentrated. The
residue was purified by silica gel flash column chromatography
(toluene:EtOAc = 10:1) to afford 20 (448 mg, 64% yield over 2 steps)
(75% yield based on recovered alcohol 13). Compound 20 is
characterized as follows: [α]D = 167.8° (c = 1, CHCl3); H NMR
(600 MHz, CDCl3) δ 7.58−7.48 (m, 4 H), 7.40−7.35 (m, 2 H), 7.35−
7.29 (m, 4 H), 7.29−7.16 (ovrlp, 5 H), 5.50 (d, J = 5.7 Hz, 1 H), 4.90
(s, 2 H), 4.81 (dd, J = 1.7, 9.5 Hz, 1 H), 4.69 (d, J = 11.6 Hz, 1 H),
4.55−4.46 (ovrlp, 2 H), 4.32−4.26 (m, 1 H), 3.90 (d, J = 2.8 Hz, 1 H),
3.68−3.62 (m, 1 H), 3.60 (dd, J = 2.4, 5.7 Hz, 1 H), 3.38 (s, 3 H), 3.23
(dd, J = 2.6, 9.9 Hz, 1 H), 3.22−3.15 (m, 1 H), 2.28−2.21 (ovrlp, 2
H), 1.63−1.55 (ovrlp,1 H), 1.27 (d, J = 6.2 Hz, 3 H), 1.24 (d, J = 6.2
Hz, 3 H); 13C NMR (150 MHz, CDCl3) δ 139.8, 139.1, 138.2, 131.2,
129.0, 129.0, 128.4, 128.2, 128.1, 127.2, 126.8, 100.0, 86.8, 81.8, 79.5,
76.5, 76.2, 74.7, 72.8, 72.1, 71.0, 64.1, 57.2, 35.0, 18.7, 17.7; FT-IR
(thin film) 3445, 2916, 2874, 1643, 1586, 1498, 1451, 1368, 1321,
1171 cm−1; ESIHRMS [M+Na]+ calculated for C33H40NaO7S
603.2392, found 603.2411.
23
1
Phenyl 3-O-benzyl-4-O-tert-butyldimethylsilyl-2,6-dideoxy-β-D-
ribo-hexapyranosyl-(1→4)-3-O-benzyl-2,6-dideoxy-β-D-ribo-hexa-
pyranosyl-(1→4)-3-O-benzyl-6-deoxy-2-O-methyl-1-thio-α-D-ribo-
hexopyranoside (21). A mixture of compound 8 (1.1 g, 3.3 mmol)
and 20 (1.27 g, 2.2 mmol) was dissolved in 1.5 mL of benzene at 0 °C
before 10 mol % of catalyst ReOCl3(SMe2)(OPPh3) was added. The
reaction mixture was stirred for 60 h before 300 μL of saturated
sodium bicarbonate was added. The resulting mixture was filtered
through anhydrous sodium sulfate, concentrated in vacuo, and purified
by silica gel flash column chromatography (hexanes:EtOAc = 30:1 to
8:1) to afford 21 (1.51 g, 75% yield) and its α-anomer (215 mg). The
23
β-anomer 21 is characterized as follows: [α]D = 133.7° (c = 1,
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.56−7.50 (m, 4 H), 7.40−
7.25 (ovrlp, 15 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.21−7.19 (m, 1 H), 5.49
(d, J = 5.7 Hz, 1 H), 4.94−4.90 (m, 1 H), 4.90−4.85 (ovrlp, 3 H), 4.84
(d, J = 12.3 Hz, 1 H), 4.80 (d, J = 11.9 Hz, 1 H), 4.61 (dd, J = 12.2,
14.0 Hz, 2 H), 4.51−4.44 (m, 1 H), 4.30 (t, J = 2.4 Hz, 1 H), 4.07 (q, J
= 2.9 Hz, 1 H), 3.98−3.90 (m, 2 H), 3.79 (q, J = 2.8 Hz, 1 H), 3.59
(dd, J = 2.6, 5.7 Hz, 1 H), 3.39−3.34 (ovrlp, 4 H), 3.21 (ddd, J = 2.8,
6.4, 9.5 Hz, 2 H), 2.15 (ddd, J = 2.1, 3.6, 13.5 Hz, 1 H), 2.01 (ddd, J =
2.0, 3.5, 13.7 Hz, 1 H), 1.63 (ddd, J = 2.5, 9.7, 13.5 Hz, 1 H), 1.60−
1.54 (ovrlp, 1 H), 1.25−1.17 (ovrlp, 9 H), 0.94 (s, 9 H), 0.11 (s, 3 H),
0.10−0.09 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 140.0, 139.9,
139.3, 139.2, 131.2, 129.0, 128.7, 128.5, 128.2, 128.2, 128.0, 127.9,
127.8, 127.7, 127.1, 126.8, 100.4, 100.3, 86.8, 82.9, 81.9, 79.4, 76.8,
76.6, 75.8, 75.6, 74.7, 73.1, 73.1, 70.2, 68.9, 64.1, 57.1, 37.2, 37.1, 26.2,
19.0, 18.6, 18.4, 17.7, −3.6, −4.4; FT-IR (thin film) 2926, 2885, 1586,
1498, 1446, 1368, 1347, 1249, 1166, 1088 cm−1; ESIHRMS [M+Na]+
calculated for C52H70NaO10SSi 937.4357, found 937.4360.
2,6-Dideoxy-3,4-bis-O-(triethylsilyl)-β-D-ribo-hexapyranosyl-(1→
4)-2,6-dideoxy-3-O-triethylsilyl-β-D-ribo-hexapyranosyl-(1→4)-1,5-
anhydro-2,6-dideoxy-3-O-triethylsilyl-D-ribo-hex-1-enitol (23). To a
solution of 21 (1.51 g, 1.65 mmol) in 4 mL of THF was added tetra-n-
butylammonium fluoride (3.3 mL, 1 M in THF). The reaction mixture
was heated at 40 °C for 5 h before saturated sodium bicarbonate was
added. After evaporating THF, the aqueous layer was extracted with
ethyl acetate (3 × 50 mL). Combined organic extracts were washed
sequentially with water (2 × 50 mL), brine (2 × 50 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography (hexane:EtOAc =
10:1 to 2:1) to afford alcohol 22 (1.18 g, 89% yield). To this alcohol
22 (230 mg, 0.287 mmol) in 1 mL of THF cooled at −20 °C was
added LiDBB (7.1 mL, 0.4 M). The reaction mixture was stirred for 15
min at −20 °C before 500 μL of saturated sodium bicarbonate was
added. The resulting mixture was concentrated and purified by silica
gel flash column chromatography (CH2Cl2 to CH2Cl2/MeOH(20/1))
to afford corresponding tetra-ol. This tetra-ol was then dissolved in
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300 μL of N,N-dimethylformamide, imidazole (196 mg, 2.9 mmol)
and triethylsilyl chloride (322 μL, 1.9 mmol) were added. The reaction
mixture was stirred at room temperature for 45 min before water was
added. The resulting mixture was extracted with dichloromethane (4 ×
15 mL), and combined organic extracts were sequentially washed with
water (2 × 20 mL) and brine (20 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. This crude mixture was purified by
silica gel flash column chromatography (hexanes:CH2Cl2 = 10:1 to
3:1) to provide 174.4 mg of compound 23 (73% yield over 2 steps)
which is characterized as follows: [α]D = 98.8° (c = 1, CHCl3); H
NMR (600 MHz, CDCl3) δ 6.29 (d, J = 6.1 Hz, 1 H), 4.91 (dd, J =
1.7, 9.4 Hz, 1 H), 4.86 (dd, J = 2.0, 9.4 Hz, 1 H), 4.79 (t, J = 5.8 Hz, 1
H), 4.30−4.25 (m, 1 H), 4.21 (dd, J = 3.5, 5.7 Hz, 1 H), 4.13 (dd, J =
6.4, 10.5 Hz, 1 H), 4.00−3.95 (m, 1 H), 3.88−3.77 (m, 2 H), 3.44 (dd,
J = 3.5, 10.5 Hz, 1 H), 3.18 (dd, J = 2.4, 9.2 Hz, 1 H), 3.03 (dd, J = 2.8,
9.5 Hz, 1 H), 1.94−1.87 (ovrlp, 2 H), 1.71−1.64 (m, 1 H), 1.64−1.56
(ovrlp, 1 H), 1.29 (d, J = 6.4 Hz, 3 H), 1.15 (t, J = 5.9 Hz, 6 H), 1.02−
0.89 (m, 36 H), 0.70−0.51 (m, 24 H); 13C NMR (150 MHz, CDCl3)
δ 145.2, 103.2, 100.1, 82.9, 80.9, 75.7, 70.5, 69.6, 69.5, 69.2, 68.4, 64.4,
40.3, 39.8, 18.8, 18.3, 17.6, 7.3, 7.3, 7.2, 5.4, 5.3, 5.2; FT-IR (thin film)
2955, 2876, 1641, 1458, 1368, 1316, 1236, 1171, 1137, 1083 cm−1;
ESIHRMS [M+Na]+ calculated for C42H86NaO9Si4 869.5247, found
869.5250.
4.25 (d, J = 2.8 Hz, 1 H), 4.23−4.18 (m, 1 H), 4.15−4.11 (m, 1 H),
4.09−4.02 (m, 1 H), 3.98 (br. s., 1 H), 3.83−3.73 (ovrlp, 3 H), 3.33−
3.27 (m, 1 H), 3.23 (td, J = 2.4, 9.5 Hz, 2 H), 3.00 (s, 1 H), 2.81−2.74
(m, 1 H), 2.36 (s, 1 H), 2.19−2.02 (ovrlp, 6 H), 1.93 (td, J = 3.4, 14.3
Hz, 1 H), 1.91−1.79 (m, 4 H), 1.78−1.72 (m, 1 H), 1.72−1.31 (m, 17
H), 1.30−1.19 (ovrlp, 9 H), 0.91 (s, 3 H), 0.86 (s, 3 H); 13C NMR
(150 MHz, CDCl3) δ 174.9, 174.8, 118.1, 99.7, 98.5, 95.3, 85.9, 82.8,
82.7, 73.8, 73.1, 72.1, 69.8, 68.4, 68.3, 67.8, 66.7, 63.1, 51.2, 49.9, 42.1,
40.3, 38.2, 37.1, 37.0, 36.1, 36.0, 35.5, 33.5, 32.4, 30.4, 30.0, 27.2, 26.8,
24.1, 24.0, 21.6, 21.5, 18.5, 18.5, 18.1, 16.1; FT-IR (thin film) 3435,
2932, 2095, 1738, 1633, 1449, 1406, 1380, 1319, 1223 cm−1;
ESIHRMS [M+Na]+ calculated for C41H64NaO13 787.4245, found
787.4248.
23
1
3,4-Di-O-tert-butyldimethylsilyl-2,6-dideoxy-β-D-ribo-hexapyra-
nosyl-(1→4)-3-O-tert-butyldimethylsilyl-2,6-dideoxy-β-D-ribo-hexa-
pyranosyl-(1→4)-1,5-anhydro-3-O-tert-butyldimethylsilyl-2,6-di-
deoxy-D-ribo-hex-1-enitol (27). To a solution of 21 (274 mg, 0.30
mmol) in 1.0 mL of THF cooled at −20 °C was added LiDBB (6.6
mL, 2.64 mmol). The reaction mixture was stirred at −20 °C for 15
min and then quenched with 500 μL of saturated sodium bicarbonate,
concentrated, and purified by silica gel flash column chromatography
(CH2Cl2 to CH2Cl2/MeOH(20/1)). The resulting compound was
dissolved in 150 μL of N,N-dimethylformamide, imidazole (306 mg,
4.5 mmol) and tert-butylchlorodimethylsilane (452 mg, 3.0 mmol)
were added. The reaction mixture was stirred at room temperature for
several hours before being heated at 50 °C for 40 h. The reaction
mixture was quenched with water and extracted with dichloromethane
(4 × 20 mL). The combined organic layers were sequentially washed
with water (2 × 20 mL), brine (20 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by silica gel
flash column chromatography (hexanes:CH2Cl2 = 5:1) to afford 27
and its corresponding tri-TBS protected trisaccharide glycal. This tri-
TBS-protected trisaccharide glycal was resubjected for tert-butyldime-
thylsilyl-protection at 90 °C. After a total of three cycles, 160 mg (63%
yield overall) of 27 as well as 28 mg of tri-TBS-protected trisaccharide
Synthesis of Digitoxin (25) and C1′-epi-Digitoxin (26). To a
mixture of 23 (52 mg, 61 μmol) and digitoxigenin 24 (23 mg, 61
μmol) (this mixture was dried via azeotrope with benzene) in 2.3 mL
of dry chloroform was added 23 mg of freshly activated molecular
sieves. This mixture was stirred for 10 min, Ph3P·HBr (1 mg) was then
added, and the resulting mixture was stirred at ambient temperature
for 1 h. TLC analysis showed the reaction was incomplete. Therefore,
another batch of Ph3P·HBr (1 mg) was added, and the reaction was
continued to stir for another 2 h. The reaction mixture was quenched
with saturated sodium bicarbonate (1 mL), diluted with dichloro-
methane (70 mL). The organic layer was washed sequentially with
water (2 × 5 mL), brine (10 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by silica gel
flash column chromatography (hexanes:EtOAc = 20:1 to 10:1) to
afford 46 mg (61%) of the glycoconjugate as an inseparable α/β
mixture. To this α/β mixture (20 mg, 16 μmol) and ammonium
fluoride hydrogen fluoride (NH4F−HF, 132 mg, 2.3 mmol) was added
1.6 mL of DMF and 1.6 mL of NMP. The resulting mixture was stirred
at 70 °C for 4 h. The reaction mixture was cooled down to room
temperature, and solvents were removed by air flow. The residue was
diluted with dichloromethane (40 mL), and organic layer was washed
sequentially with water (2 × 10 mL), brine (10 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue was
purified by flash column chromatography (CH2Cl2/MeOH = 50/1 to
10/1) to afford 11 mg of a mixture of 25 and 26 (90% combined yield,
25/26 = 1/5). This α/β mixture was further purified by reverse phase
HPLC (C18 column, a gradient of 30 to 70% CH3CN in water over 20
min) to afford pure 25 and 26, which are characterized below.
Digitoxin (25). [α]D23 = 21° (c = 0.5, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 5.87 (s, 1 H), 4.99 (dd, J = 1.5, 18.2 Hz, 1 H), 4.90 (dt, J =
2.1, 9.9 Hz, 2 H), 4.86 (dd, J = 1.8, 9.5 Hz, 1 H), 4.81 (dd, J = 1.7, 18.1
Hz, 1 H), 4.27−4.22 (m, 2 H), 4.13 (br. S., 1 H), 4.02 (br. s., 1 H),
3.83 (qd, J = 6.1, 9.5 Hz, 1 H), 3.80−3.73 (m, 2 H), 3.34−3.29 (m, 1
H), 3.24 (dd, J = 3.0, 9.3 Hz, 1 H), 3.20 (dd, J = 3.0, 9.4 Hz, 1 H), 3.04
(s, 1 H), 2.97 (s, 1 H), 2.80−2.74 (m, 1 H), 2.30 (br. s., 1 H), 2.19−
2.02 (m, 5 H), 2.01−1.94 (m, 1 H), 1.90−1.79 (m, 2 H), 1.76−1.33
(m, 21 H), 1.29 (d, J = 6.2 Hz, 3 H), 1.22 (dd, J = 1.8, 6.2 Hz, 6 H),
0.91 (s, 3 H), 0.86 (s, 3H) ; 13C NMR (150 MHz, CDCl3) δ 174.9,
174.9, 118.0, 98.6, 98.5, 95.7, 86.0, 82.9, 82.5, 73.8, 73.1, 72.9, 69.8,
68.6, 68.4, 68.4, 66.8, 66.7, 51.3, 49.9, 42.2, 40.4, 38.1, 37.5, 37.0, 36.5,
36.1, 35.5, 33.5, 30.5, 30.1, 30.1, 27.2, 27.0, 26.9, 23.9, 21.7, 21.5, 18.5,
16.1; FT-IR (thin film) 3436, 2933, 1737, 1631, 1449, 1406, 1380,
1317, 1273, 1067 cm−1; ESIHRMS [M+Na]+ calculated for
C41H64NaO13 787.4245, found 787.4238.
23
glycal were obtained. Compound 27 is characterized as follows: [α]D
= 103.9° (c = 1, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.28 (d, J =
5.9 Hz, 1 H), 4.90 (dd, J = 1.7, 9.5 Hz, 1 H), 4.86 (dd, J = 1.8, 9.5 Hz,
1 H), 4.77 (t, J = 5.8 Hz, 1 H), 4.27−4.23 (m, 1 H), 4.19 (dd, J = 3.5,
5.7 Hz, 1 H), 4.13−4.06 (m, 1 H), 3.98−3.94 (m, 1 H), 3.86−3.80 (m,
1 H), 3.80−3.73 (m, 1 H), 3.43 (dd, J = 3.5, 10.5 Hz, 1 H), 3.16 (dd, J
= 2.4, 9.0 Hz, 1 H), 3.04 (dd, J = 2.8, 9.5 Hz, 1 H), 1.93 (ddd, J = 1.9,
4.0, 13.3 Hz, 1 H), 1.88 (ddd, J = 1.8, 3.9, 13.2 Hz, 1 H), 1.69−1.59
(ovrlp, 2 H), 1.28 (d, J = 6.2 Hz, 3 H), 1.13 (dd, J = 3.0, 6.3 Hz, 6 H),
0.94−0.84 (ovrlp, 36 H), 0.11−0.02 (ovrlp, 24 H); 13C NMR (150
MHz, CDCl3) δ 145.1, 103.3, 100.0, 100.0, 82.8, 80.7, 75.7, 70.3, 69.7,
69.3, 68.6, 64.5, 40.1, 39.7, 26.4, 26.3, 26.2, 19.0, 18.7, 18.5, 18.4, 18.4,
18.4, 17.6, −3.2, −3.8, −3.8, −4.0, −4.3, −4.4, −4.4, −5.1; FT-IR (thin
film) 2955, 2930, 2892, 2857, 1641, 1472, 1387, 1254, 1137, 1084
cm−1; ESIHRMS [M+Na]+ calculated for C42H86NaO9Si4 869.5247,
found 869.5267.
Synthesis of Digitoxin (25) and C1′-epi-Digitoxin (26). To a
mixture of 27 (51 mg, 60 μmol) and 24 (22 mg, 60 μmol) (this
mixture was dried via azeotrope with benzene) in 2.3 mL of dry
chloroform was added 23 mg of activated molecular sieves. This
mixture was stirred for 10 min, Ph3P.HBr (1 mg)5 was added, and the
resulting mixture was stirred at ambient temperature for 2 h. TLC
analysis showed the reaction was incomplete. Therefore, another batch
of Ph3P·HBr (3 mg) was added, and the reaction was continued to stir
for another 22 h. The reaction mixture was quenched with saturated
sodium bicarbonate (1 mL) and diluted with dichloromethane (70
mL). The organic layer was washed sequentially with water (2 × 5
mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by silica gel flash column
chromatography (hexanes:EtOAc = 20:1 to 10:1) to afford 42 mg
(57%) of the glycoconjugate as an inseparable α/β mixture. To this
mixture (25 mg, 20.4 μmol) and ammonium fluoride hydrogen
fluoride (NH4F−HF, 168 mg, 2.9 mmol) was added 2 mL of DMF
and 2 mL of NMP. The resulting mixture was stirred at 80 °C for six
days. The reaction mixture was cooled down to room temperature, and
23
1
C1′-epi-Digitoxin (26). [α]D = 56.5° (c = 0.5, CHCl3); H NMR
(600 MHz, CDCl3) δ 5.87 (s, 1 H), 5.02−4.96 (m, 1 H), 4.94 (d, J =
3.3 Hz, 1 H), 4.93−4.87 (ovrlp, 2 H), 4.81 (dd, J = 1.7, 18.2 Hz, 1 H),
12475
dx.doi.org/10.1021/jo4021419 | J. Org. Chem. 2013, 78, 12469−12476

The Journal of Organic Chemistry
Article
solvents were removed by air flow. The residue was diluted in
dichloromethane (40 mL), and organic layer was washed sequentially
with water (2 × 10 mL), brine (10 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by silica gel
flash column chromatography (CH2Cl2/MeOH = 50:1 to 10:1) to
afford 13.3 mg of anomeric mixture 25 and 26 (85% combined yield,
25/26 = 1.4/1).
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ASSOCIATED CONTENT
■
S
* Supporting Information
(16) (a) Iyer, A. K. V.; Zhou, M.; Azad, N.; Elbaz, H.; Wang, L.;
Rogalsky, D. K.; Rojanasakul, Y.; O’Doherty, G. A.; Langenhan, J. M.
ACS Med. Chem. Lett. 2010, 1, 326−330. (b) Wang, H.-Y. L.;
Rojanasakul, Y.; O’Doherty, G. A. ACS Med. Chem. Lett. 2011, 2, 264−
269. (c) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979−3981.
(17) (a) Li, X.; Zhu, J. J. Carbohydr. Chem. 2012, 31, 284−324.
(b) McKay, M. J.; Nguyen, H. M. ACS Catal. 2012, 2, 1563−1595.
(18) For our previous effort in this research field, see: (a) Adhikari,
S.; Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J. ACS Catal. 2013, 3, 57−60.
(b) Adhikari, S.; Li, X.; Zhu, J. J. Carbohydr. Chem. 2013, 32, 336−359.
(19) Sherry, B. D.; Loy, R. N.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 4510−4511.
1H and 13C NMR spectra for all new compounds, and select
1H−13C HSQC spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel.: +1-419-530-1501. Fax: +1-419-530-4033. E-mail:
Jianglong.Zhu@Utoledo.edu.
Notes
The authors declare no competing financial interest.
(20) Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J. Angew. Chem., Int. Ed.
2013, 52, 8012−8016 See Supporting Information for the preparation
of compound 8.
ACKNOWLEDGMENTS
■
(21) See Supporting Information for details.
Start-up funding from The University of Toledo is gratefully
acknowledged.
(22) (a) Ferrier, R. J. Top Curr. Chem. 2001, 215, 153−175.
(b) Rosati, O.; Curini, M.; Messina, F.; Marcotullio, M. C.; Cravotto,
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(23) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrier
̀
es, A.;
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