Bi(OTf)3-mediated intramolecular epoxide opening for bicyclic azepane synthesis

Article abstract of DOI:10.1080/07328303.2019.1581887

While an epoxide on a sugar-derived aziridine studying was opened, an unexpected formation of bicyclic compounds was observed. The structure of these bicycles depended on the nature of the protecting group on the nitrogen atom of the aziridine. These comp

Full text of DOI:10.1080/07328303.2019.1581887

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: https://www.tandfonline.com/loi/lcar20
Bi(OTf) -mediated intramolecular epoxide opening
3
for bicyclic azepane synthesis
Sha Zhu, Anh Tuan Tran, Yuki Hirokami, Geoffrey Gontard, Omar Khaled,
Yongmin Zhang, Atsushi Kato, Yves Blériot & Matthieu Sollogoub
To cite this article: Sha Zhu, Anh Tuan Tran, Yuki Hirokami, Geoffrey Gontard, Omar Khaled,
Yongmin Zhang, Atsushi Kato, Yves Blériot & Matthieu Sollogoub (2019): Bi(OTf) -mediated
3
intramolecular epoxide opening for bicyclic azepane synthesis, Journal of Carbohydrate Chemistry
To link to this article: https://doi.org/10.1080/07328303.2019.1581887
Published online: 25 Mar 2019.
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JOURNAL OF CARBOHYDRATE CHEMISTRY
https://doi.org/10.1080/07328303.2019.1581887
Bi(OTf) -mediated intramolecular epoxide opening for
3
bicyclic azepane synthesis
a
a
b
a
a
Sha Zhu , Anh Tuan Tran , Yuki Hirokami , Geoffrey Gontard , Omar Khaled ,
a
b
c
a
Yongmin Zhang , Atsushi Kato , Yves Bl eꢀ riot , and Matthieu Sollogoub
a
b
Sorbonne Universit ꢀe , CNRS, Institut Parisien de Chimie Mol ꢀe culaire, Paris, France; Department
c
of Hospital Pharmacy, University of Toyama, Toyama, Japan; IC2MP-UMR CNRS 7285, Universitꢀe
de Poitiers, Equipe “Synth ꢁe se Organique”, Groupe Glycochimie, Poitiers cedex 9, France
ABSTRACT
ARTICLE HISTORY
While an epoxide on a sugar-derived aziridine studying was
opened, an unexpected formation of bicyclic compounds was
observed. The structure of these bicycles depended on the
nature of the protecting group on the nitrogen atom of the
aziridine. These compounds appeared to be weak glycosidase
inhibitors.
Received 20 November 2018
Accepted 9 February 2019
KEYWORDS
Azasugar; Azepane;
Glycosidase inhibitors
GRAPHICAL ABSTRACT
Introduction
Glycosidases, enzymes that catalyze the hydrolysis of oligosaccharides, are
[
1]
involved in many therapeutic phenomena. Searching for new and efficient
inhibitors of such enzymes is thus the object of extensive research.
Iminosugars, sugar analogs in which the endocyclic oxygen atom is replaced
by a nitrogen atom, have been thoroughly studied and demonstrated high
[
2]
inhibition potential. Several applications of iminosugars for the treatment
[
3]
[4]
[5]
of lysosomal storage disorder,
HIV infection,
viral infection,
[
6]
[7]
Alzheimer disease or cancer have already been approved. Today, three
drugs, Zavesca , Glyset and Galafold , have been marketed for the treat-
ment of Gaucher, type II-diabetes and Fabry diseases, respectively.
Our group has been focused on the synthesis and evaluation of original
@
@
@
[
8]
[
9]
[10]
[11]
five (A), six (B),
bridged iminosugars (D, E)
proven to be interesting molecules notably as inhibitors of N-acetyl-
seven (C)-membered ring
and unnatural ether-
[
12]
as shown in Figure 1. Some of them have
CONTACT Matthieu Sollogoub,
matthieu.sollogoub@sorbonne-universite.fr
Sorbonne Universit ꢀe , CNRS,
Institut Parisien de Chimie Mol ꢀe culaire, UMR 8232, 4 place Jussieu, 75005 Paris, France.
ß 2019 Taylor & Francis Group, LLC

2
S. ZHU ET AL.
[
9–11]
glycosaminidases.
Numerous original molecules were disclosed
exploiting one key building block, the tribenzylated azacycloheptene F
Figure 1, due to its ability to be further functionalized either through dihy-
droxylation or epoxidation at the double bond. Thus, we have synthesized
numerous potent glycosidase inhibitors using a nucleophilic opening of
epoxyazepanes. We have previously synthesized b, c-trans-typed pentahy-
droxylated azepanes via epoxide opening with water under harsh acidic or
[
11]
basic conditions.
However, disappointing results both in terms of yields
and stereoselectivity hampered the use of this transformation to access imi-
nosugars. Hence, the improvement of this reaction is of interest. As the car-
bamate-based protecting group at the N-endocyclic position is not
compatible with the use of hydroxide or harsh basic conditions, we rea-
soned that activation of the epoxide by a Lewis acid should lower the acti-
vation energy of the reaction and favor the formation of products under
[
13]
milder conditions. A similar approach has been reported by Behr et al.
Results and discussion
Bismuth triflate (Bi(OTf) ) has been used as a Lewis acid catalyst in many
3
organic transformations and is very attractive due to its strong Lewis acidity
[
14]
together with low toxicity, low cost and good stability.
Taking into account
[
15]
that Bi(OTf) has been used as catalyst for epoxide opening, we envisaged
using Bi(OTf) in the presence of water to prepare 1,2-trans diols.
3
3
[
10]
[11]
Epoxidation of azacycloheptenes 1a
recently reported
ketone I gave epoxide 2a
and 1b
were first studied. We
with slow addition of
[
10]
[16]
that modified Shi’s procedure
[
10]
in a stereoselective manner (55%). This opti-
[
11]
mized procedure was also applied successfully to 1b, furnishing 2b
in a
could also stereoselectively
[
17]
6
0% yield. Interestingly, CF COCH /oxone
3 3
0
0
mediate the epoxidation but in favor of epoxides 2a (51%) and 2b (55%).
With these epoxides in hand, we treated them with Bi(OTf) (10 mol%) in
3
a mixture of toluene and water (9/1). Epoxide 2a was totally consumed after
Figure 1. Iminosugars reported by our groups.

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
ꢀ
1
h of stirring at 100 C. Interestingly, the expected b,c-dihydroxy azepanes
were not observed, but a bicyclic carbamate 3 was produced in a 50% yield
along with non-isolable side products (Table 1). The structure of 3 was con-
firmed by X-ray crystallography (CCDC 1015485) and its formation can be
rationalized by the nucleophilic addition of the carbamate on the closest car-
bon of the epoxide. Indeed, similar intramolecular epoxide opening has been
[
18]
reported by Hayes using Ti(OiPr) in stoichiometric quantity.
Rather than
4
problematic, this unexpected product is of interest as it demonstrated the
possibility for regioselective epoxide opening leading to b,c-trans-dihydrox-
yazepane. Better yields (60%) were obtained when the reaction was per-
formed in dried toluene (Table 1, entry 1). The same product was isolated
R
N
R
N
R
N
BnO
BnO
BnO
cond A or B
O
O
BnO
BnO
a: R = Boc
BnO
BnO
BnO
BnO
1
2a: R = Boc (55% Cond A) 2a’: R = Boc (51% Cond B)
2b: R = Cbz (60% Cond A) 2b’: R = Cbz (55% Cond B)
1
b: R = Cbz
O
O
O
O
O
O
O
F3C
CH3
I
II
Scheme 1. Epoxidation of Azacycloheptenes 1a and 1b. Conditions A: Oxone, ketone I,
ꢁ
ꢀ
4
ꢀ
M Na EDTA, 0 C. Conditions B: Oxone, ketone II, NaHCO ,
2 3
Bu NOH, NaHCO , CH CN/10
4
3
3
ꢁ
4
CH CN/4x10 M Na EDTA, 0 C.
3
2
Table 1. Synthesis of bicyclic carbamate 3.
Bi(OTf)3
BnO
O
BnO
N
BnO
R
O
O
O
OR
BnO
BnO
OBn
N
N
Bi(OTf)3 (0.2 eq)
Toluene, 1h
O
O
O
BnO
OH
BnO
BnO
2
3
ꢀ
a
Entry
Compound
R
Temperature ( C)
Yield of 3 (%)
1
2
3
4
2a
t-Bu
Bn
t-Bu
t-Bu
100
100
60
60
30
78
2b
2a
2a
b
RT
Traces
a
Isolated yield.
b
Reaction was carried out for 24 h.

4
S. ZHU ET AL.
when the reaction was performed with epoxide 2b but in lower yields (30%,
Table 1, entry 2). Lowering the temperature provided a satisfying 78% yield
(Table 1, entry 3). Only traces of product were observed when the reaction
was carried out at room temperature despite long reaction times.
Subsequently, the Bi(OTf) -mediated intramolecular epoxide opening was
3
0
0
also studied with epoxides 2a and 2b . Using the optimized conditions, the
expected cyclic carbamate 4 was not observed. While 2a gave an inseparable
mixture of compounds, reaction of 2b afforded two ether-bridged com-
0
0
pounds 5 (21%) and 6 (59%) (Scheme 2). The formation of these compounds
was probably resulted from the S 2 nucleophilic addition of C benzylether
N
8
on both carbons of the epoxide. We can suppose that nucleophilic attack
occurred preferentially on the sterically less hindered position (C ) leading
6
the formation of the major product. The intramolecular epoxide opening was
[
19]
also reported by Nemoto et al.
Hydrogenolysis of compounds 3, 5, 6 gave unprotected bicyclic
compounds 7, 8, 9 (Scheme 3). These three structurally original bicylic com-
pounds were evaluated as inhibitors of a panel of glycosidases. Interestingly,
derivatives 8 and 9 show weak but surprising specific inhibition activity
toward b-glucuronidase from E. coli with IC being 372 and 368 lM respect-
5
0
ively (Table 2).
In summary, Bi(OTf) can be used to access a variety of bicyclic com-
3
pounds from epoxy-azepanes, which were shown to be relatively weak glyco-
sidase inhibitors when deprotected. Other Lewis acids may be tried to assess
the generality of this reactivity.
Scheme 2. Bi(OTf) -mediated epoxide opening on compound 2b’.
3

JOURNAL OF CARBOHYDRATE CHEMISTRY
5
Cbz
N
O
Cbz
N
N
BnO
BnO
OH
O
O
O
BnO
BnO
OH
OH
BnO
3
BnO
BnO
6
5
H2, Pd/
MeOH, HCl
H2, Pd/
MeOH, HCl
75%
H2, Pd/
MeOH, HCl
84%
7
O
7
1%
H
N
H
N
N
HO
HO
O
O
OH
O
HO
HO
OH
OH
HO
HO
8
HO
9
Scheme 3. Hydrogenolysis of 3, 5, and 6.
Table 2. Glycosidase inhibitory activity of 7, 8, and 9.
Enzyme
7
8
9
a-Glucosidase
Yeast
Rice
a
b
NI (3.6%)
NI (31.7%)
NI (10.3%)
NI (0%)
NI (34.7%)
NI (28.7%)
NI (29.0%)
NI (5.2%)
NI (0%)
Rat intestinal maltase
b-Glucosidase
Almond
Bovine liver
a-Galactosidase
Coffee beans
b-Galactosidase
Bovine liver
a-Mannosidase
Jack bean
NI (0%)
NI (43.4%)
NI (10.4%)
NI (29.4%)
NI (5.1%)
NI (33.9%)
NI (2.3%)
NI (12.1%)
NI (0%)
NI (28.1%)
NI (11.3%)
NI (4.7%)
NI (2.5%)
NI (28.4%)
NI (0%)
NI (21.3%)
NI (27.0%)
NI (0%)
b-Mannosidase
Snail
NI (0%)
NI (0%)
a-L-Fucosidase
Bovine kidney
a-L-Rhamnosidase
Penicillium decumbens
b-Glucuronidase
E.coli
NI (9.4%)
NI (0%)
NI (23.2%)
NI (12.4%)
368
NI (11.1%)
NI (5.1%)
NI (6.5%)
372
a,a-Trehalase
Porcine kidney
Amyloglucosidase
Aspergillus niger
a
NI (0%)
NI (3.6%)
NI (0.1%)
NI (0%)
NI: No inhibition (less than 50% inhibition at 1000 lM).
b
(
): inhibition % at 1000 lM.
Experimental
Material and methods
All commercial reagents were used as supplied. TLC plates (Macherey-
Nagel, ALUGRAMVR SIL G/UV254, 0.2 mm silica gel 60 Å) were visualized
under 254 nm UV light and/or by dipping the TLC plate into a solution of
3
g of phosphomolybdic acid in 100 mL of ethanol followed by heating
with a heat gun. Flash column chromatography was performed using

6
S. ZHU ET AL.
Macherey-Nagel silica gel 60 (15–40 lm). NMR experiments were
1
recorded with a Bruker AM- 400 spectrometer at 400 MHz for H nuclei
1
3
and at 100 MHz for C nuclei. The chemical shifts are expressed in part
per million (ppm) using residual CHCl signal as internal reference (d
3
1
13
(
H) ¼ 7.26 ppm and d( C) ¼ 77.16 ppm) and the coupling constant J in
hertz (Hz). NMR multiplicities are reported using the following abbrevia-
tions: b ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quadruplet,
m ¼ multiplet. HRMS were recorded on a Bruker microTOF spectrom-
eter, using Tuning-Mix as reference. Optical rotations were measured on
a Perkin–Elmer 341 digital polarimeter or a Jasco P-2000 polarimeter
with a path length of 1 dm.
Compound 3. To a solution of 2a (136 mg, 0.25 mmol) and Bi(OTf)
3
ꢀ
(
33 mg, 0.05 mmol) in dry toluene (12 mL) was stirred at 60 C for 1 h.
After cooling to room temperature, the solvent was evaporated and the
residue was purified by chromatography (cyclohexane/AcOEt: 100/0–80/20)
to give 3 (95 mg, 78%) as white solid. Recrystallization with CH Cl /
2
2
Cyclohexane allowed obtaining the crystal which was analyzed by X-ray
ꢀ
24
1
analysis. Mp ¼ 139 C. [a] ¼ þ10.8 (c ¼ 0.55, CHCl ); H NMR
D
3
(
(
(
2
400 MHz, CDCl ) d 7.26–7.19 (m, 13H, H ), 7.11–7.09 (m, 2H, H ), 4.79
3
ar
ar
2
2
d, 1H, J ¼ 10.5 Hz, CH Ph), 4.75 (d, 1H, J ¼ 10.5 Hz, CH Ph), 4.56–4.53
2
2
2
m, 2H, CH Ph, H ), 4.41 (d, 1H, J ¼ 10.5 Hz, CH Ph), 4.32–4.29 (m, 2H,
2
6
2
xCH Ph), 4.17 (t, 1H, J
¼ J
¼ 9.5 Hz, H ), 4.06–4.04 (m, 1H,
2
H3–H4
H3–H2
3
H ), 3.68–3.58 (m, 5H, H , H , H , H , H ), 3.34 (ddd, 1H, J
H7b–H5
¼
5
8a
8b
2
4
7a
1
3
1
.0 Hz, JH7b–H6 ¼ 5.0 Hz, J
¼ 13.0 Hz, H ); C NMR (100 MHz,
7b
H7b–H7a
CDCl ) d 165.0 (CO), 138.0, 137.9, 137.5 (Cipso), 128.5, 128.4, 128.4, 128.1,
3
1
28.0, 127.9, 127.8, 127.6 (CH ), 81.8 (C ), 77.6 (C ), 75.5 (CH Ph), 74.9
ar 4 6 2
(
C ), 75.0, 73.2 (CH Ph), 69.6 (C ), 69.4 (C ), 61.2 (C ), 44.9 (C ). HRMS
3 2 8 5 2 7
þ
calcd for C H NO : [MH] : 490.2230 found 490.2222.
29
31
6
0
Compound 5 and 6. A mixture of 2b (90 mg, 0.155 mmol) and Bi(OTf)
(
3
ꢀ
20 mg, 0.031 mmol) in dry toluene (8.0 mL) was stirred at 100 C for 1 h.
After cooling to room temperature, the solvent was evaporated and the
residue was purified by chromatography (cyclohexane/AcOEt: 8/2–7/3 to
8
0) to give 5 (16 mg, 21%) as clear oil and 6 (44 mg, 59%). Compound 5
1
6
1
[
a] ¼ ꢁ28.5 (c ¼ 1.0, CH Cl ); H NMR (400 MHz, CDCl , 2 rotamers
D
2
2
3
in 1:0.8 ratio) d 7.38–7.23 (m, 27H, H ), 5.17 (s, 2H, CH Ph), 5.15 (s,
ar
2
1
4
J
.6H, CH Ph), 4.83–4.81 (m, 1H, H ), 4.68–4.61 (m, 3H, CH Ph),
2
2
2
.57–4.45 (m, 5H, CH Ph, H
0
), 4.37 (dd, 0.8H, J
0 0
¼ 6.5 Hz,
2
2
H7a –H6
0
0
¼ 14.0 Hz,
H7a
0
)
4.20
(dd,
1H,
JH7a–H6 ¼ 6.0 Hz,
H7a –H7b
JH7a–H7b ¼ 14.0 Hz, H ), 4.14 (brs, 1.8H, H , H
0
), 4.05–3.95 (m, 4.6H,
5
7a
5
H , H , H
0
, H , H
0
), 3.92-3.79 (m, 4.4H, H
0
, H , H
8b
0
, H , H ), 3.29
3
0
8
a
4
4
6
6
8a
8b
3

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
(
dd, 1H, JH7b-H6 ¼ 9.5 Hz, J
¼ 14.0 Hz, H ), 3.22 (dd, 0.8H,
7b
H7b–H7a
0
J
0
0
¼ 10.0 Hz, J
0
0
¼ 14.0 Hz, H
0
). 2.12 (s, 1.8H, OH, OH );
H7b –H6
3
H7b –H7a
7b
1
C NMR (100 MHz, CDCl , 2 rotamers in 1:0.8 ratio) d 155.8, 155.7
3
(
1
(
CO, Cbz), 137.7, 137.7, 137.4, 137.3, 136.3, 136.3 (Cipso), 128.6, 128.5,
28.4, 128.4, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6,
CH ), 78.6 (C ), 78.5 (C ), 77.6 (C ), 77.2 (C ), 77.2 (C ), 77.1 (C ),
0
0
0
5
ar
4
4
3
3
5
7
0.9, 70.7, 70.6 (C , C , 4xCH Ph), 67.7, 67.6 (CH Ph), 66.1 (C ), 65.6
6 2 2 8
0
6
(
C8
0
), 50.4 (C2 ), 50.0 (C ), 45.3 (C ), 44.9 (C ). HRMS calcd for
2 7 7’
0
þ
C H NNaO : [MNa] : 512.2049 found 512.2052. Compound 6
2
9
1
31
6
9
1
[
a] ¼ 229.9 (c ¼ 1.0, CHCl ); H NMR (400 MHz, CDCl , 2 rotamers
D
3
3
2
in 1:0.7 ratio) d 7.44–7.20 (m, 25.5H, H ), 5.25 (d, 1H, J ¼ 12.5 Hz,
ar
2
CH Ph), 5.21–5.17 (m, 1.7H, CH Ph), 5.12 (d, 0.7H, J ¼ 12.5 Hz,
2
2
2
CH Ph), 5.07–5.01 (m, 1.7H, CH Ph), 4.87 (d, 1H, J ¼ 11.0 Hz, CH Ph),
2
2
2
2
4
(
1
.70–4.61 (m, 3.4H, CH Ph, H ), 4.56 (d, 1H, J ¼ 11.5 Hz, CH Ph), 4.49
2
2
2
2
d, 0.7H, J ¼ 11.5 Hz, CH Ph), 4.41 (d, 1H, J ¼ 2.5 Hz, H
0
), 4.17–4.09 (m,
2
2
.7H, H , H
0
), 3.97–3.96 (m, 0.7H, H ), 3.90–3.88 (m, 1H, H ),
6 6
0
8
a
8a
3
.84–3.56 (m, 10.2H, H , H8
0
, H , H
0
, H , H
0
, H , H
0
, H , H , H ,
7a 7b
0
8
b
b
3
3
4
4
5
5
7a
1
3
H7b ); C NMR (100 MHz, CDCl , 2 rotamers in 1:0.7 ratio) d 158.8,
3
0
1
1
1
7
58.2 (CO, Cbz), 138.8, 138.7, 137.7, 137.6, 136.5, 136.4 (Cipso), 128.7,
28.6, 128.6, 128.6, 128.5, 128.5, 128.4, 128.1, 128.0, 127.9, 128.0, 127.9,
27.9, 127.8, (CH ), 85.3 (C
0
), 85.2 (C ), 83.6 (C ), 83.5 (C ), 75.7 (C3
0
0
),
), 70.8 (C ), 67.6
ar
4
4
5
5
5.6 (C ), 75.4, 75.3, 71.6, 71.5 (4xCH Ph), 71.3 (C
0
3
2
6
6
(
C8
0
), 67.5 (C ), 51.3 (C
0
), 51.0 (C ), 42.9 (C ), 42.7 (C ); HRMS calcd
7
0
8
2
2
7
þ
for C H NNaO : [MNa] : 512.2049 found 512.2042.
2
9
31
6
Compound 7. To a solution of 3 (11 mg, 0.022 mmol) in MeOH (2 mL)
was added aqueous HCl (1M, 0.1 mL) under argon. After adding Pd/C
(
10%, 10 mg), the argon was removed. The H was introduced and the
2
mixture was bubbled for 5 min. After stirring the solution for 24 under
H atmosphere, the mixture was filtered on micro-filter 0.3 mm). The
2
solvent was evaporated and the residue was purified by flash chromatog-
raphy (CH Cl /MeOH: 8.5/1.5) to give the desired product (3.5 mg, 71%).
2
2
2
2
1
[
1
a] ¼ þ2.8 (c ¼ 0.55, MeOH); H NMR (400 MHz, MeOD) d 4.61 (t,
D
H, J
JH5–H4
JH3–H2 ¼ J
¼ J
¼ 4.5 Hz, H ), 4.05 (ddd, 1H, J
¼ 1.0 Hz,
H6–H7a
H6–H5
6
H5–H7b
¼
2.5 Hz,
J
¼ 4.5 Hz,
H ),
(dd,
1H,
3.93
JH8a–H2 ¼ 3.0 Hz,
JH8b–H2 6.5 Hz,
¼ 12.5 Hz, H ), 3.53 (dd,
(t,
1H,
H5–H6
5
¼ 9.5 Hz,
H3),
3.74
3.86
(dd,
1H,
H3–H4
JH8a–H8b ¼ 11.5 Hz,
H ),
¼
8a
JH8b–H8a ¼ 11.5 Hz, H ), 3.56 (d, 1H, J
8b
H7a–H7b
7a
1
3
JH4–H5 ¼ 2.5 Hz, J
¼ 9.5 Hz, H ), 3.41–3.34 (m, 2H, H , H ).
C
H4–H3
4
2
7b
NMR (100 MHz, MeOD) d 168.0 (CO), 80.2 (C ), 72.8 (C ), 71.4 (C ),
6
4
5
6
8.5 (C ), 66.3 (C ), 62.8 (C ), 44.8 (C ) HRMS calcd for C H NO :
3 2 8 7 8 14 6
þ
[
MH] : 220.0821 found 220.0820.

8
S. ZHU ET AL.
Compound 8. To a solution of 5 (13 mg, 0.027 mmol) in MeOH (3 mL)
was added aqueous HCl (1M, 0.2 mL) was added under argon. After adding
Pd/C (10%, 13 mg), the argon was removed. The H was introduced and
2
the mixture was bubbled for 5 min. After stirring the solution for 24 h
under H atmosphere, the mixture was filtered on micro-filter 0.3 mm).
2
The solvent was evaporated to give the desired product (4.2 mg, 75%).
2
2
1
[
a] ¼ þ7.0 (C ¼ 0.3, MeOH); H NMR (400 MHz, D O) d 4.32 (ddd,
D
2
JH6–H5 ¼ 3.0 Hz, J
¼ 5.5 Hz, J
¼ 9.0 Hz, H ), 4.22–4.12 (m, 4H,
H6–H7a
H6–H7b
6
H , H , H , H ), 4.10 (d, 1H, J
¼ 3.0 Hz, H ), 4.00 (t,
8
a
8b
3
4
H5–H6
5
JH2–H8a ¼ J
¼ 4.0 Hz, H ), 3.54 (dd, 1H, J
¼ 5.5 Hz, J
¼
H2–H3
2
H7a–H6
H7a–H7b
1
3
1
3.5 Hz, H ), 3.15 (dd, 1H, J
¼ 9.0 Hz, J
¼ 13.5 Hz, H );
7b
C
7b
H7b–H6
H7b–H7a
NMR (100 MHz, D O) d 80.3 (C ), 71.3 (C ), 70.1 (C ), 67.5 (C ), 62.4
C ), 53.5 (C ), 42.8 0 (C ); HRMS calcd for C H NO : [MH] : 176.0917
1 2 7 7 14 4
2
5
4
3
6
þ
(
found 176.0920.
Compound 9. To a solution of 6 (15 mg, 0.031 mmol) in MeOH (3 mL)
was added aqueous HCl (1M, 0.2 mL) under argon. After adding Pd/C
(
10%, 15 mg), the argon was removed. The H was introduced and the mix-
2
ture was bubbled for 5 min. After stirring the solution for 24 under H2
atmosphere, the mixture was filtered on micro-filter 0.3 mm). The solvent
2
2
was evaporated to give the desired product (5.5 mg, 84%). [a] ¼ 215.8
D
1
(
C ¼ 0.3, MeOH); H NMR (400 MHz, D O) d 4.24 (dd, J
¼ 3.0 Hz,
2
H8a–H2
J
¼ 12.5 Hz, H ), 4.16–4.08 (m, 3H, H , H , H ), 3.88 (ddd, 1H,
H8a–H8b
8a
8b
3
6
JH5–H7a ¼ 1.0 Hz, J
¼ 2.5 Hz, J
¼ J
¼ 9.0 Hz, H ), 3.83–3.78 (m, 2H,
H5–H6
H5–H4
5
H , H ), 3.69 (t, 1H, J
¼ 9.0 Hz, H ), 3.62 (dd, 1H, J
7a
2
H4–H3
H4–H5
3
4
H7b–H6
1
¼
1.0 Hz, JH7b–H7a ¼ 14.5 Hz, H ); C NMR (100 MHz, D O) d 74.3 (C ),
7b
2
4
7
4.2 (C ), 72.6 (C ), 69.4 (C ), 62.2 (C ), 55.6 (C ), 39.0 (C ); HRMS calcd
5 3 6 8 2 7
þ
for C H NO : [MH] : 176.0917 found 176.0914.
7
14
4
Crystal data for 3. Colorless needles: C H NO , orthorhombic, P 2 2 2 ,
2
9
31
6
1 1 1
3
a ¼ 6.1055(3), b ¼ 13.7134(6), c ¼ 30.6466(16) Å, V ¼ 2566.0(2) Å , Z ¼ 4, T
ꢁ1
¼
200(2) K, l ¼ 5.233 mm , 10288 reflections measured, 4467 independ-
ent (R ¼ 0.0401), 3363 observed [I ꢂ 2r(I)], 326 parameters, final R indi-
int
ces R [I ꢂ 2 r (I)] ¼ 0.0482 and wR (all data) ¼ 0.1178, GOF on
1
2
2
ꢁ3
F ¼ 1.042, max/min residual electron density ¼ 0.13/ꢁ0.19 e.Å . CCDC
1
015485 contains the supplementary crystallographic data for this paper.
The data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
A single crystal of the compound was mounted onto a cryoloop.
Intensity data were collected at 200K with a BRUKER Kappa-APEXII dif-
fractometer with micro-focused Cu-Ka radiation (k ¼ 1.54178Å). Data col-
lection and data reduction were performed within APEX2 suite, with
SAINT and SADABS programs (BRUKER). In the WinGX suite of

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
[
20]
[21]
programs , the structure was solved with Sir92
program and refined
[
22]
by full-matrix least-squares methods using SHELXL-97
.
Acknowledgments
We thank Chinese Scholarship Council (CSC) for a PhD grant (SZ) and Lise-Marie
Chamoreau for X-ray diffraction.
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