A divergent strategy for constructing a sugar library containing 2,6-dideoxy sugars and uncommon sugars with 4-substitution

Article abstract of DOI:10.1016/j.tet.2007.07.019

A practical strategy has been developed for delivering 2,6-dideoxy sugars and uncommon sugars with 4-substitution. This strategy employed Ferrier rearrangement reaction and BF₃·OEt₂-induced peroxidation to construct key intermediates 2,3-unsaturated glycosides and α,β-unsaturated lactones from peracetyl rhamnal. After further derivatization, four uncommon sugars with 4-substitution and eight uncommon sugar units with 3,4-disubstitution were successfully synthesized.

Full text of DOI:10.1016/j.tet.2007.07.019

Tetrahedron 63 (2007) 9705–9711
A divergent strategy for constructing a sugar library containing
2,6-dideoxy sugars and uncommon sugars with 4-substitution
*
Guisheng Zhang, Lei Shi, Qingfeng Liu, Jingmei Wang, Lu Li and Xiaobing Liu
School of Chemical and Environmental Sciences, Henan Normal University, 46 East Construction Road, Xinxiang,
Henan 453007, PR China
Received 28 May 2007; revised 5 July 2007; accepted 7 July 2007
Available online 13 July 2007
Abstract—A practical strategy has been developed for delivering 2,6-dideoxy sugars and uncommon sugars with 4-substitution. This strategy
employed Ferrier rearrangement reaction and BF3$OEt2-induced peroxidation to construct key intermediates 2,3-unsaturated glycosides and
a,b-unsaturated lactones from peracetyl rhamnal. After further derivatization, four uncommon sugars with 4-substitution and eight uncom-
mon sugar units with 3,4-disubstitution were successfully synthesized.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
in 15 steps.4 An alternative strategy is to start from non-
carbohydrate precursors. In this case, many researchers
have come up with different synthetic approaches. For ex-
ample, Nicolaou’s group synthesized L-vancosamine start-
ing from L-lactate in 11 steps,5a while McDonald and
Cutchins synthesized the same aminosugar by tungsten-
catalyzed alkynol cycloisomerization in nine steps.5b
MacMillan’s group developed a synthetic pathway for
stereoselectively constructing sugar derivatives starting from
b,g-oxyalaldehydes.6 O’Doherty’s group synthesized sugar
derivatives starting from furan alcohols.7 Wang’s group de-
veloped a systematic strategy for the synthesis of uncommon
sugars via ring-closing metathesis (RCM).8 In Wang’s
strategy, the intermediates six-membered b,g-unsaturated
lactones generated from RCM could be directly converted
to cis-3,4-difunctional uncommon sugar derivatives through
asymmetric dihydroxylation followed by reduction.8a These
intermediates could also be converted to a,b-unsaturated
lactones, which could be further modified to various uncom-
mon sugars.8b Wang’s strategy provided a synthetic pathway
to produce uncommon sugars systematically and revealed
the importance of a,b-unsaturated lactones in uncommon
sugar synthesis. However, the relatively high price of the chi-
ral starting materials and the Grubb’s catalysts, and the very
dilute conditions required by RCM reaction are the main
hurdles for this method to be utilized in large scale synthesis.
In order to address these drawbacks of the RCM strategy,
Wang’s group developed a practical method for the synthe-
ses of a,b-unsaturated lactones starting from furanaldehyde
in six steps.9
Uncommon sugars are derived from common sugars (e.g.,
D-glucose) by replacement of at least one hydroxyl group
or hydrogen atom with another functional group. They are
present in numerous biologically intriguing natural products
and have received special attention, due to the increased rec-
ognition of their vital roles in the biological function of
many natural products. The function of the uncommon sugar
moieties ranges from affecting the pharmacokinetics of the
drug to directly interacting with cellular targets like proteins,
RNA and DNA.1 They add important features to the shape
and the stereoelectronic properties of a molecule and often
play an essential role in the biological activities of many
natural product drugs. Areas in which their significance has
been well-established include cellular adhesion and cell–
cell recognition, fertilization, protein folding, neurobiology,
xenotransplantation and target recognition in the immune
response.2 By analyzing various glycosylated natural prod-
ucts and drugs, it was found that the majority of uncommon
sugars are 2,6-dideoxy sugars (uncommon sugars with 3,4-
disubstitution) and 2,3,6-trideoxy sugars (uncommon sugars
with 4-substitution) (e.g., daunorubicin and landomycin,
Fig. 1).
Many efforts have been focused on the total synthesis of
uncommon monosaccharides because of their biological
importance in natural products.3 Generally, uncommon
sugars were synthesized through multistep transformations
of relatively economical common sugars. For instance, start-
ing from methyl glucoside, L-vancosamine was synthesized
It has been indicated that structural modifications of sugar
moieties in some pharmaceuticals may enhance their phar-
macological profile.10 Lack of uncommon sugar sources is
Keywords: Uncommon sugars; Synthesis; Peracetyl rhamnal.
* Corresponding author. E-mail: zgs6668@yahoo.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.019

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G. Zhang et al. / Tetrahedron 63 (2007) 9705–9711
HO
O
O
OH
OH
O
OH
O
O
OH
O
HO
O
O
O
O
OH
HO
OMe
O
O
O
O
O
HO
O
O
O
HO
NH2
O
HO
Daunorubicin
Landomycin A
OH
Figure 1. Structure of daunorubicin and landomycin A.
the major disadvantage in the development of glycosylated
drugs. In our research, we plan to construct a diverse uncom-
mon sugar library to facilitate the systematic structure–activ-
ity relationship investigation of the potential anticancer
drugs. Therefore, it is necessary to develop a divergent and
practical method to deliver various uncommon sugars.
Most recently, we have reported a communication for the
preparation of 3-azido-2,3,6-trideoxy-L-hexoses (II-5–8)
from peracetyl rhamnal 1.13 Here, we present our more
detailed results on the preparation of uncommon sugar units
with 4-substitution (I-1–4, Scheme 2) and 2,6-dideoxy
sugars (II-1–4, Scheme 3).
Herein, we present our strategy (Scheme 1) to produce
uncommon sugars by employing Ferrier rearrangement
reaction and BF3$OEt2-induced peroxidation11 to construct
key intermediates 2,3-unsaturated glycoside (2) and a,b-
unsaturated lactone (4) from 3,4-di-O-acetyl-L-rhamnal (1).
This method is economic and practical for large scale manip-
ulations. Following this strategy, the corresponding D-series
of uncommon sugars can also be produced from 3,4-di-O-
acetyl-D-rhamnal (D-1), which could be readily prepared
from glucal.12 To demonstrate that this strategy is practicable,
four L-uncommon sugars with 4-substitution (I-1–4) and
eight L-uncommon sugars with 3,4-disubstitution (II-1–8)
were synthesized starting from 3,4-di-O-acetyl-L-rhamnal
(1) in 2–9 steps.
2. Results and discussion
We began our synthetic route with the Ferrier reaction of 1
and isopropanol in the presence of BF3$OEt2 in dichlorome-
thane at 0 ꢀC for 1.5 h. The key intermediate 2 was obtained
as an anomeric mixture (a/b>10:3 by NMR) in 80% yield.
Isopropanol was selected because the isopropoxy group on
the resulted uncommon sugars (I-1–4) is relatively reactive.
These isopropyl glycosides could be directly used as glyco-
syl donors or readily converted to other more active donors
such as thioglycosides.14 The compound 4, which is another
key intermediate for uncommon sugars with 3,4-disubstitu-
tion, was obtained by the deacetylation of lactone 3, which
OPri
OH
OPri
OH
OPri
OPri
OH
OH
O
O
O
O
N3
O
OPri
O
AcO
HO
N3
OAc
I-3
I-1
I-2
I-4
AcO
HO
OH
O
OH
O
O
O
O
2
OH
HO
HO
OH
II-2
O
HO
AcO
II-1
II-3
II-4
OH
OAc
1
N3
O
N3
OH
OH
O
O
HO
OH
O
4
HO
N3
II-5
N3
HO
II-6
II-7
II-8
OH
Scheme 1. The strategy to deliver uncommon sugars from peracetyl rhamnal.
1) K2CO3/ MeOH
O
O
OPri
i
2) DPPA, PPh3 , DEAD
PrOH, BF3OEt2
H2, Pd/C
82%
OPri
O
OPri
O
AcO
56%
80%
AcO
I-1
I-2
N3
AcO
2
OAc
1
1) K2CO3/ MeOH
2) HOAc, PPh3, DEAD
64%
1) K2CO3/ MeOH
2) DPPA, PPh3, DEAD
O
OPri
H2, Pd/C
OPri
O
OPri
O
I-4
N3
87%
55%
AcO
OAc
I-3
5
Scheme 2. Synthesis of uncommon sugars with 4-functionality.

G. Zhang et al. / Tetrahedron 63 (2007) 9705–9711
9707
O
O
OH
LiBr,AG 50W-X2
75%
K2CO3, MeOH
85%
HO
OH
O
AcO
HO
AcO
AcO
6
II-1
OAc
1
MCPBA,
BF3OEt2
90%
NaBH4, (PhSe)2,
AcOH, PrOH
O
O
O
O
O
O
O
O
i
OH
O
Na(CN)BH3
86%
K2CO3, MeOH
NaClO, pyridine
31%
OH
HO
85%
65%
HO
AcO
HO
80%
HO
II-3
3
O
O
4
OH
12
7
HOAc, PPh3, DEAD
1) PhCO3H, C6H6
O
O
1) NaBH4, (PhSe)2,
O
O
OH
2) K2CO3, MeOH
30%
i
AcOH, PrOH
OH
O
AcO
HO
2) Na(CN)BH3
55%
OH
8
9
II-4
K2CO3,
MeOH
91%
1) NaBH4, (PhSe)2,
AcOH, PrOH
O
O
O
O
i
PhCO3H, C6H6
OH
O
35%
HO
HO
2) Na(CN)BH3
48%
OH
II-2
10
HO
O
11
Scheme 3. Synthesis of 2,6-dideoxy sugars.
was generated via the reaction of glycal 1 with m-chloroper-
benzoic acid (m-CPBA) and BF3$OEt2 in dichloromethane
at ꢁ20 ꢀC in 90% yield.
exchange resin16 to give 3,4-di-O-acetyl-L-rhamnose 6 as
a mixture of a- and b-anomer, in a a/b ratio of 2:1, in
75% yield. Deacetylation of 6 with K2CO3 in methanol pro-
duced the 2,6-dideoxy sugar L-canarose II-1 in excellent
yield.
With large quantity of these two key intermediates in hand,
we turned our attention to the transformation of these
intermediates to the uncommon sugars. As outlined in
Schemes 2 and 3, starting from unsaturated glycoside 2
and unsaturated lactone 4, eight different L-uncommon
sugars (I-1–4, II-1–4) were successfully synthesized. Due
to the importance of aminosugar moiety in natural products
(e.g., daunorubicin), we strategically incorporated azido
group in our uncommon sugars, since the azido group can
be an excellent masking group for amino group and can be
amplified to diversified drug-resembling moieties (e.g.,
triazole ring).
The treatment of osmundalactone 4 with NaClO in pyridine
gave syn-epoxide 7 as the major product with the ratio of cis/
trans greater than 20:1 in 31% yield. Reductive opening
of epoxide ring of 7 with sodium phenylseleno(triiso-
propyloxy)-borate (NaBH4 and PhSeSePh in acetic acid)17
allowed the formation of 3,4-trans-dihydroxyl lactone.
Further reduction of the lactone with Na(CN)BH3 furnished
L-digitoxose (II-3) in 56% yield from two steps.
In order to synthesize the uncommon sugar L-boivinose
II-4, the lactone 4 was firstly converted to another lactone
8 by reaction with HOAc in the presence of DEAD and tri-
phenylphosphine as shown in Scheme 3. Epoxidation of 8
following the procedure for the preparation of epoxide 7
did not work well. However, PhCO3H worked well for the
conversion in benzene at 0 ꢀC. Epoxidation of 8 using per-
oxybenzoic acid proceeded stereoselectively from the less
hindered face of the molecule to afford the anti-epoxide
as the major product with the ratio of trans/cis greater
than 5:1. After removal of the acetyl group, the epoxide 9
was obtained in 30% yield from two steps. Finally, following
the same procedure for the preparation of D-digitoxose (II-3)
from epoxide 7, L-boivinose (II-4) was obtained in 55%
yield from 9.
As shown in Scheme 2, the uncommon sugars I-1–4 were
obtained by derivatization of the unsaturated glycoside 2
resulted from the Ferrier reaction of glycal 1. Hydrogenation
of glycoside 2 in the presence of Pd/C under H2 atmosphere
(30 psi) provided uncommon sugar I-1. Conversion of I-1 to
azido sugar I-2 was done by deacetylation with K2CO3 in
methanol, followed by Mitsunobu reaction15 in a total of
56% yield.
Glycoside 2 was deacetylated with K2CO3 in methanol,
subsequently treated with HOAc in the presence of diethyl
azodicarboxylate (DEAD) and triphenylphosphine in THF
at room temperature to give the glycoside 5 in 64% yield
from two steps. Following the same procedures for the prep-
aration of the uncommon sugar I-1 and azido sugar I-2, the
uncommon sugars I-3 and I-4 were obtained from the unsat-
urated glycoside 5 with good yield.
Meanwhile, the stereoselective approach to uncommon
sugar L-oliose II-2 was also achieved from lactone 8. De-
acetylation of 8 with K2CO3 in methanol gave another
lactone 10 in excellent yield. Following the procedure
for epoxidation of lactone 8, lactone 10 was epoxidized
to epoxide 11 in 35% yield. Following the same procedure
for the preparation of the D-digitoxose (II-3) from epoxide
The synthetic pathway of 2,6-dideoxy sugars (II-1–4) is
outlined in Scheme 3. Glycal 1 was treated with water in
the presence of lithium bromide and AG 50W-X2 cation

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G. Zhang et al. / Tetrahedron 63 (2007) 9705–9711
7, the epoxide 11 was reduced to L-oliose II-2 in 48%
yield from two steps.
be used for next reactions, they were not separated. HRMS
m/z calculated for C11H18O4Na 237.1097 (M+Na+), found
237.1099.
3. Conclusion
4.3. Synthesis of (5R,6S)-5-acetoxy-5,6-dihydro-
6-methylpyran-2-one, 3
In conclusion, we have demonstrated a concise and feasible
route to uncommon sugars. By employing the Ferrier reac-
tion and BF3$OEt2-induced peroxidation, we were able to
generate the 2,3-unsaturated glycosides and a,b-unsaturated
lactones in large scale. The efficiency of our diversity-
orientated synthesis was exemplified by the successful syn-
thesis of L-uncommon sugars. Combination of our previous
work,13 four L-uncommon sugars with 4-substitution (I-1–
4), four 2,6-dideoxy-L-sugars (II-1–4) and four 3-azido-
2,3,6-trideoxy-L-sugars (II-5–8) were delivered starting
from peracetyl L-rhamnal in 2–9 steps. Following the
procedures presented in Schemes 2 and 3, the corresponding
D-series of uncommon sugars could be prepared from 3,4-di-
O-acetyl-D-rhamnal. The syntheses of D-deoxy sugars are
currently undergoing in our laboratory.
A solution of m-CPBA (11 mmol) in dry CH2Cl2 (30 mL)
was added dropwise to a stirred solution of the glycal 1
(2.0 g, 9.3 mmol) in CH2Cl2 (30 mL) at ꢁ20 ꢀC. Subse-
quently, BF3$OEt2 (0.5 mL, 4 mmol) was added dropwise
and the mixture was stirred at ꢁ20 ꢀC for 1 h. Then the
reaction was quenched by the addition of saturated NaHCO3
(70 mL) containing Na2S2O3 (40 mg). The mixture was
extracted with CH2Cl2 and the combined organic layer
was dried over anhydrous Na2SO4. After removal of the sol-
vent under reduced pressure, the crude product was purified
by chromatography on silica gel (hexanes/EtOAc 6:1) to
give pure product (1.33 g, 90%). 1H NMR (400 MHz,
CDCl3) d 6.75 (dd, 1H, J¼9.9, 3.2 Hz), 6.07 (dd, 1H, J¼9.9,
1.5 Hz), 5.27–5.21 (m, 1H), 4.59 (quint, 1H, J¼6.6 Hz),
2.10 (s, 3H), 1.39 (d, 3H, J¼6.6 Hz); 13C NMR (100 MHz,
CDCl3) d 162.3, 143.1, 123.0, 76.6, 67.9, 21.0, 18.5;
HRMS m/z calculated for C8H10O4 170.0579 (M+), found
170.0580.
4. Experimental section
4.1. General remarks
4.4. Synthesis of (5R,6S)-5,6-dihydro-5-hydroxy-
6-methylpyran-2-one, 4
All solvents were of reagent grade materials purified by stan-
dard methods. All reagents were obtained from commercial
sources and used without further purification. The commer-
cial AG 50W-X2 (H+ form, moisture) resin was treated as
follows: the commercial resin (5 g) was washed with water
(3ꢂ15 mL) until the filtrate was colourless and then with
reagent grade acetonitrile (10ꢂ10 mL). It was then dried
over phosphorus pentoxide under vacuum to give dry resin
(1 g). The reactions, unless stated otherwise, were all carried
out under a positive pressure of argon and were monitored by
TLC on silica gel 60 F254 (0.25 mm, E. Merck). Column
chromatography was performed on silica gel 60 (230–400
mesh). The ratio between silica gel and crude product ranged
A solution of the L-erythro-enelactone 3 (1.30 g, 7.65 mmol)
and K2CO3 (0.5 g) in dry MeOH (20 mL) was stirred over-
night. After removal of the solvent under reduced pressure,
the crude product was purified by chromatography on silica
1
gel (hexanes/EtOAc 1:1) to give pure product (85%). H
NMR (400 MHz, CDCl3) d 6.86 (dd, 1H, J¼10.0, 2.0 Hz),
5.94 (dd, 1H, J¼9.5, 1.5 Hz), 4.39–4.34 (m, 1H), 4.23 (d,
1H, J¼9.0 Hz), 3.26 (br, 1H), 1.46 (d, 3H, J¼6.5 Hz); 13C
NMR (100 MHz, CDCl3) d 164.2, 149.9, 120.4, 79.5, 67.7,
18.3; HRMS calculated for C6H8O3 128.0473 (M+), found
128.0475.
1
from 100 to 50:1 (w/w). H and 13C NMR spectra were
recorded on Bruker AC-400 NMR spectrometer in solutions
of CDCl3 or CD3OD using tetramethylsilane as the internal
standard, d values are given in parts per million and coupling
constants (J) in hertz. Infrared absorption spectra were
recorded as neat films. The mass spectra and high-resolution
mass spectra were collected at the Zhengzhou University
Campus Instrumentation Center.
4.5. Synthesis of isopropanyl 3-O-acetyl-2,3,6-trideoxy-
L-threo-hex-2-enopyranoside, 5
A suspension of the glycoside 2 (1.64 g, 7.66 mmol) and
K2CO3 (0.5 g) in dry MeOH (20 mL) was stirred for 15 h.
The solvent was removed in vacuo to give the crude prod-
uct, which was purified by silica gel column chromato-
graphy (cyclohexane/EtOAc 10:1) to give the deacetylated
compound (1.14 g, 85% yield). The compound obtained
above (1.14 g, 6.5 mmol), AcOH (0.4 g, ca. 6.5 mmol)
and triphenylphosphine (1.71 g, 6.5 mmol) were dissolved
in dry THF (10 mL) and cooled to 0 ꢀC. Diethyl azodi-
carboxylate (1.14 g, ca. 6.5 mmol) in dry THF (3 mL) was
added dropwise to the resulted solution at 0 ꢀC. The reac-
tion mixture was stirred for 15 h and solvent was removed
in vacuo, diethyl ether (25 mL) was added to the residue
and the insoluble part was filtered off. After removal of sol-
vent, the crude product was purified by column chromato-
graphy (cyclohexane/EtOAc 16:1) to give 5 (1.05 g, 64%
yield from 2) as a colourless viscous liquid. It was a mixture
of a- and b-isomer. Since both the isomers were able to be
used for next reaction, they were not separated. HRMS m/z
4.2. Synthesis of isopropanyl 3-O-acetyl-2,3,6-trideoxy-
L-erythro-hex-2-enopyranoside, 2
3,4-Di-O-acetyl-L-rhamnal 1 (21.5 g, 0.1 mol) and isopropa-
nol (0.15 mol) were dissolved in dry dichloromethane
(100 mL) and boron trifluoride–ether (5 mL) was added at
0 ꢀC. Stirring was continued at 0 ꢀC for 1.5 h. TLC showed
that the glycal disappeared. After neutralization with satu-
rated NaHCO3, the reaction mixture was extracted with
dichloromethane, and the organic layer was dried over
MgSO4, then purified with silica gel chromatography (cyclo-
hexane/EtOAc 15:1) to give the product (17.2 g, 80% yield)
as a colourless viscous liquid. It was a mixture of a- and
b-isomer (a/b>10:3). Since both the isomers were able to

G. Zhang et al. / Tetrahedron 63 (2007) 9705–9711
9709
calculated for C11H18O4Na 237.1097 (M+Na+), found
237.1089.
4.9. Synthesis of (5S,6S)-5,6-dihydro-5-hydroxy-
6-methylpyran-2-one, 10
4.6. Preparation of 2-deoxy-3,4-di-O-acetyl-L-rhamno-
pyranose, 6
A solution of 8 (600 mg, 3.53 mmol) and K2CO3 (0.2 g) in
dry MeOH (20 mL) was stirred overnight and solvent was
removed in vacuo. Silica gel column chromatography (hex-
anes/EtOAc 1:1) of the crude product yielded 10 (411 mg,
AG 50W-X2 resin (0.3 g) and water (0.6 mL) were added to
a solution of 3,4-di-O-acetyl-L-rhamnal (0.4 g, 1.87 mmol)
and lithium bromide hydrate (0.5 g) in acetonitrile
(15 mL). The mixture was stirred at room temperature for
15 min. The reaction mixture was filtered, neutralized with
triethylamine and evaporated to dryness. The residue was
dissolved in dichloromethane and washed with water, ice-
cold 1 M hydrochloric acid and saturated sodium bicarbon-
ate solution. The colourless solid (a/b¼2:1) of compound 6
(325 mg, 75% yield) was obtained after purification on a col-
umn of silica gel using ethyl acetate/hexane (1:3) as eluent.
1H NMR (250 MHz, CDCl3) d 5.24 (d, J¼3.4 Hz, H-1a),
5.27–5.21 (m, H-3a), 4.92–4.86 (m, H-3b), 4.80 (dd,
J¼1.9, 9.4 Hz, H-1b), 4.63 (t, J¼9.6 Hz, H-4), 4.05–3.98
(m, H-5a), 3.43 (m, H-5b), 2.29–2.25 (m, H-2beq), 2.16–
2.12 (m, H-2aeq), 1.75–1.70 (m, H-2bax), 1.60 (m, H-
2aax), 1.11 (d, J¼6.2 Hz, H-6b), 1.05 (d, J¼6.2 Hz, H-6a).
1
91%). H NMR (400 MHz, CDCl3) d 6.98 (dd, 1H, J¼9.8,
5.8 Hz), 6.10 (d, 1H, J¼9.8 Hz), 4.52 (qd, J¼6.8 Hz,
2.8 Hz), 4.10–3.98 (m, 1H), 1.47 (d, 3H, J¼6.5 Hz); 13C
NMR (100 MHz, CDCl3) d 164.2, 148.9, 120.4, 79.6, 67.6,
18.0; HRMS m/z calculated for C6H8O3 128.0473 (M+),
found 128.0480.
4.10. Synthesis of isopropanyl 4-O-acetyl amicetoside, I-1
2,3-Unsaturated glycoside 2 (920 mg, 4.3 mmol) was dis-
solved in EtOAc (30 mL), palladium catalyst (10% Pd/C,
200 mg) was added and the reaction mixture was hydro-
genated at 30 psi overnight. Then, it was filtered through
a Celite bed, washed with EtOAc and the filtrate was concen-
trated under low pressure to give pure product (763 mg, 82%)
as a mixture of a- and b-anomer (a/b¼5:2), which could not
be separated by silica gel chromatography. The spectro-
1
4.7. Synthesis of (3S,4S,5R,6S)-3,4-epoxy-5-hydroxy-6-
methylpyran-2-one, 7
scopic data of the mixture: H NMR (250 MHz, CD3OD)
d 4.83 (d, 1H, J¼2.5 Hz, Ha-1), 4.49–4.38 (m, 1.4H, Ha-4,
Hb-1), 3.91–3.78 (m, 2.4H, Ha-5, Hb-4, Ha-secondary proton
on isopropyl), 3.33–3.28 (m, 0.8H, Hb-5, Hb-secondary pro-
ton on isopropyl), 2.13–1.31 (m, 9.8H, H-2, H-3, OAc),
1.20–1.04 (m, 12.6H, Me); HRMS m/z calculated for
C11H20O4Na 239.1253 (M+Na+), found 239.1256.
Lactone 4 (200 mg, 1.56 mmol) and pyridine (30 mL) were
placed in a 100 mL round bottom flask. After cooled to
ꢁ10 ꢀC, NaOCl solution (10–13%, 3 mL, 4 equiv) was
added into the flask in 10 min. The resulted mixture was
allowed to stir at ꢁ10 ꢀC for 1 h. The reaction was quenched
by the addition of saturated NH4Cl. The mixture was ex-
tracted with EtOAc. The combined organic layer was dried
over anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the crude product was purified by chroma-
tography on silica gel (hexanes/EtOAc 2:1) to give pure
product (70 mg, 31%). 1H NMR (400 MHz, CD3OD)
d 4.36–4.30 (m, 1H), 3.79 (d, 1H, J¼9.0 Hz), 3.65 (d, 1H,
J¼4.2 Hz), 3.62 (d, 1H, J¼4.2 Hz), 1.34 (d, 3H,
J¼6.3 Hz); 13C NMR (100 MHz, CD3OD) d 167.5, 73.4,
55.9, 50.4, 17.0. MS ES+ m/z 167 (M+Na); HRMS m/z cal-
culated for C6H8O4Na 167.0320 (M+), found 167.0329.
4.11. Synthesis of isopropanyl 4-azido-4-deoxy
rhodinoside, I-2
A solution of I-1 (212 mg, 0.98 mmol) and K2CO3 (0.1 g)
in dry MeOH (10 mL) was stirred overnight and solvent
was removed in vacuo. Silica gel column chromatography
(hexanes/EtOAc 3:1) of the crude product yielded the
deacetylated glycoside (145 mg, 85%). To a solution of
the glycoside (145 mg, 0.83 mmol) and Ph3P (655 mg,
2.50 mmol) in THF (10 mL) was slowly added DEAD
(0.40 mL, 2.50 mmol) at 0 ꢀC. After 3–5 min, diphenylphos-
phorylazide (DPPA, 0.54 mL, 2.50 mmol) was added by
dropwise and the resulting solution was allowed to slowly
warm up to room temperature and stirred overnight. The reac-
tion mixture was then concentrated to a small volume via an
atmospheric pressure distillation by means of a short path
apparatus fitted with a 15 cm Vigreux column and then chro-
matographed on a silica gel column with a 0–20% Et2O in
pentane gradient to afford the product (110 mg, 56% yield
4.8. Synthesis of (5S,6S)-5-acetoxy-5,6-dihydro-6-methyl-
pyran-2-one, 8
Diethyl azodicarboxylate (1.140 g, ca. 6.5 mmol) in dry
THF (2 mL) was added dropwise to the solution of 4
(0.832 g, 6.5 mmol) obtained above, AcOH (4.0 g, ca.
65 mmol) and triphenylphosphine (17.10 g, 65 mmol) in
dry THF (100 mL) at 0 ꢀC. The reaction mixture was stirred
for 15 h and solvent was removed in vacuo, diethyl ether
(50 mL) was added to the residue and the insoluble part
was filtered off. After removal of solvent, the crude product
was purified by silica gel column chromatography (hexanes/
EtOAc 6:1) to give 8 (0.884 g, 80%) as a colourless liquid.
1H NMR (400 MHz, CDCl3) d 6.82 (dd, 1H, J¼9.9,
2.2 Hz), 5.97 (dd, 1H, J¼9.9, 1.8 Hz), 4.38–4.30 (m, 1H),
4.25–4.19 (m, 1H), 2.11 (s, 3H), 1.47 (d, 3H, J¼6.3 Hz);
13C NMR (100 MHz, CDCl3) d 162.3, 140.8, 122.9, 76.6,
67.9, 20.9, 18.4; HRMS m/z calculated for C8H10O4
170.0579 (M+), found 170.0575.
1
from I-1) as a light-yellow oil. The data of IR, H and
13C NMR were identical with those reported in literature.8b
4.12. Synthesis of isopropanyl 4-O-acetyl rhodinoside, I-3
Following the same procedure described for I-1, the glyco-
side I-3 was obtained from 5 as a colourless oil (a/b¼5:1).
1
Selected data for a anomer: H NMR (250 MHz, CDCl3)
d 4.95 (d, 1H, J¼2.8 Hz, H-1), 4.80 (br, 1H, H-4), 4.08–
4.01 (quint, 1H, J¼6.6 Hz, H-5), 3.95–3.83 (sept, 1H,
J¼6.2 Hz, H-secondary proton on isopropyl), 2.21 (s, 3H),
2.07–1.21 (m, 4H), 1.21 (d, 3H, J¼6.3 Hz), 1.13 (d, 3H,

9710
G. Zhang et al. / Tetrahedron 63 (2007) 9705–9711
J¼6.0 Hz), 1.09 (d, 3H, J¼6.6 Hz); 13C NMR (63 MHz,
CDCl3) d 170.1, 94.4, 68.1, 65.1, 59.8, 24.3, 23.0, 22.7,
21.3, 21.1, 17.8; HRMS m/z calculated for C11H20O4Na
239.1253 (M+Na+), found 239.1254.
chromatography using EtOAc and methanol as the mobile
phase to give the pure compound 12 (99 mg, 65%). H
1
NMR (500 MHz, CD3OD) d 4.46 (dt, 1H, J¼6.9, 2.0 Hz),
4.18 (dd, 1H, J¼3.6, 1.8 Hz), 3.90 (dq, 1H, J¼6.9, 2.5 Hz),
2.91 (dd, 1H, J¼18.0, 6.6 Hz), 2.35 (dd, 1H, J¼18.0,
2.5 Hz), 1.25 (d, 3H, J¼6.6 Hz); 13C NMR (125 MHz,
CD3OD) d 167.5, 91.0, 69.3, 67.0, 37.9, 18.4; HRMS m/z
calculated for C6H10O4 146.0579 (M+), found 146.0586.
4.13. Synthesis of isopropanyl 4-azido-4-deoxy
amicetoside, I-4
Following the same procedure described for I-2, compound
I-4 was obtained from I-3 as a mixture of a- and b-anomer
(55%). The parent ion was not observed by HRMS, due to
the decomposition of this compound under the analysis
conditions. IR (neat, cmꢁ1) 2950, 2110 (N3 group), 1270,
1050; selected data for a anomer: 1H NMR (250 MHz,
CDCl3) d 4.85 (d, 1H, J¼2.4 Hz), 4.02–3.96 (qd, 1H, J¼
8.9, 6.3 Hz), 3.86–3.76 (sept, J¼6.1 Hz, 1H), 3.37 (m, 1H),
2.09 (m, 1H), 1.84 (m, 2H), 1.48 (m, 1H), 1.13 (d, J¼
6.1 Hz, 6H), 1.06 (d, J¼6.3 Hz, 3H); 13C NMR (63 MHz,
CDCl3) d 94.2, 67.6, 63.0, 59.8, 24.2, 23.0, 22.6, 21.2, 17.6.
Dihydroxylated lactone 12 (99 mg, 0.68 mmol) and AcOH/
AcONa (1.0 M, 25 mL) were added in a 50 mL round
bottom flask. Na(CN)BH3 (3.5 equiv) was added and the
reaction mixture was stirred at room temperature overnight.
The reaction mixture was then lyophilized and subjected to
silica gel column chromatography (CH2Cl2/EtOH 8:1) to
give the sugar L-digitoxose II-3 (87 mg, 86%), mixture of
1
a- and b-anomer. Selected data for a anomer: H NMR
(400 MHz, D2O) d 5.24 (t, 1H, J¼2.5 Hz), 4.28 (ddd, 1H,
J¼4.0, 2.5, 2.0 Hz), 3.96 (qd, 1H, J¼7.5, 3.0 Hz), 3.68 (dd,
1H, J¼17.0, 7.0 Hz), 2.02–2.00 (dd, 1H, J¼18.0, 2.0 Hz),
1.15 (d, 3H, J¼6.5 Hz); 13C NMR (100 MHz, D2O) d 91.0,
69.9, 67.2, 64.5, 32.0, 17.0. MS ES+ m/z 171 (M+Na)+.
4.14. Synthesis of L-canarose, II-1
A solution of 6 (232 mg, 1.0 mmol) and K2CO3 (0.1 g) in
dry MeOH (10 mL) was stirred overnight and solvent was
removed in vacuo. Silica gel column chromatography
(EtOH/CH2Cl2 1:10) of the crude product yielded II-1
(126 mg, 85%). Selected data for b-anomer: 1H NMR
(250 MHz, D2O) d 4.97 (d, 1H, J¼9.7 Hz), 3.49–3.43 (m,
1H), 3.21 (qd, 1H, J¼9.1, 6.2 Hz), 2.81 (t, 1H, J¼9.1 Hz),
2.05–2.01 (m, 1H), 1.29–1.25 (m, 1H), 1.04 (d, 3H,
J¼6.2 Hz); 13C NMR (63 MHz, D2O) d 92.6, 77.5, 68.5,
68.4, 40.6, 17.8. MS ES+ m/z 149 (M+H)+.
4.17. Synthesis of L-boivinose, II-4
A solution of the lactone 8 (727 mg, 4.28 mmol) in benzene
(10 mL) and perbenzoic acid in benzene (0.48 M, 10 mL)
was cooled to 0 ꢀC, mixed and kept at 0 ꢀC. At intervals,
aliquot portions were removed from the reaction solution
in order to follow the rate of consumption of the peracid.
After 30 h, the solution was washed with saturated K2CO3
solution twice and dried, and the solution was removed un-
der reduced pressure. The residue was dissolved in methanol
(10 mL) and K2CO3 (0.2 g) was added to the solution above.
The resulting mixture was stirred overnight and the solvent
was removed under reduced pressure. The crude product
was purified by chromatography on silica gel (hexanes/
EtOAc 2:1) to give the epoxide 9 (185 mg, w30%) with a
little unseparated contaminant. MS ES+ m/z 167 (M+Na)+.
4.15. Synthesis of L-oliose, II-2
Following the procedures described for epoxidation of 8
with peroxybenzoic acid, the lactone 10 was epoxidized to
11 in approximately 35% yield with a little unseparated con-
taminant. MS ES+ m/z 145 (M+H)+. The epoxide 11 was re-
duced following the procedures described for II-3 from 7 to
give the sugar L-oliose II-2 as a syrup (mixture of a- and b-
anomer) in 48% yield. Selected data for a anomer: 1H NMR
(500 MHz, D2O) d 5.22 (br, 1H), 4.15 (qd, 1H, J¼7.0,
2.0 Hz), 4.07 (dd, 1H, J¼6.5, 3.0 Hz), 3.68 (d, 1H,
J¼7.0 Hz), 1.83–1.81 (dd, 2H, J¼18.0, 2.0 Hz), 1.20 (d,
3H, J¼7.0 Hz); 13C NMR (125 MHz, D2O) d 92.5, 70.9,
67.2, 65.5, 32.4, 16.8. MS ES+ m/z 149 (M+H)+.
Following the procedures described for II-3 from 7, the
compound 9 obtained above was treated to give the sugar
L-boivinose II-4 (105 mg, 55%) as a mixture of a- and
b-anomer. Selected data for b-anomer: 1H NMR (250 MHz,
D2O) d 4.80 (dd, 1H, J¼9.8, 3.0 Hz), 3.66 (quint, 1H,
J¼6.2 Hz), 3.59 (m, 1H), 2.95–2.89 (m, 1H), 1.69–1.55
(m, 1H), 1.42–1.36 (m, 1H), 1.02 (d, 3H, J¼6.2 Hz); 13C
NMR (63 MHz, D2O) d 92.6, 69.5, 69.4, 68.9, 34.7, 16.8.
MS ES+ m/z 149 (M+H)+.
4.16. Synthesis of (4R,5S,6S)-dihydroxy-6-methyl-tetra-
hydropyran-2-one, 12, and L-digitoxose, II-3
To a stirred solution of PhSeSePh (1000 mg, 3.20 mmol) in
isopropanol (18 mL) was added in batches NaBH4 (245 mg,
6.30 mmol) at room temperature. After 8 min, AcOH
(63 mL, 1.05 mmol) was added into the mixture. The result-
ing mixturewas stirred for additional 10 min. Then a solution
of the epoxy lactone 7 (150 mg, 1.04 mmol) in isopropanol
(10 mL) was added to the mixture at 0 ꢀC. The reaction
was monitored via TLC (EtOAc/MeOH 5:2). The mixture
was stirred at 0 ꢀC for 1 h and subsequently diluted with
EtOAc. The organic solution was washed with brine and
dried over MgSO4. Evaporation of the solvent under reduced
pressure gave a residue that was purified by silica gel
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20672031) and a fund from the
Program for New Century Excellent Talents in University
of Henan Province (2006-HACET-06) to G.Z.
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