Total synthesis of fuzinoside

Article abstract of DOI:10.1016/j.tet.2014.04.069

The first total syntheses of fuzinoside (1b) were achieved from d-galactose through two strategies (BCA and ABC) in 11 (total yield: 5.0%) and 15 (total yield: 3.7%) steps, respectively. Comparison of NMR data of synthetic compound 1b and those of the fuzinoside isolated from the lateral roots of Aconitum carmicaelii suggests that the structure reported in the literature^1,2 might not be accurate. The synthetic fuzinoside (1b) exhibited moderate cardiac activity in the isolated bullfrog heart assay.

Full text of DOI:10.1016/j.tet.2014.04.069

Tetrahedron 70 (2014) 4022e4030
Contents lists available at ScienceDirect
Tetrahedron
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Total synthesis of fuzinoside
,
a
a,
*
Ping He a, Xiao-Huan Li a, Qiao-Hong Chen b , Jing-Song Yang , Feng-Peng Wang
*
a Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3, Renmin Nan Road,
Chengdu 610041, PR China
b Department of Chemistry, California State University Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total syntheses of fuzinoside (1b) were achieved from D-galactose through two strategies (BCA
Received 26 December 2013
Received in revised form 8 April 2014
Accepted 24 April 2014
and ABC) in 11 (total yield: 5.0%) and 15 (total yield: 3.7%) steps, respectively. Comparison of NMR data of
synthetic compound 1b and those of the fuzinoside isolated from the lateral roots of Aconitum carmicaelii
suggests that the structure reported in the literature1,2 might not be accurate. The synthetic fuzinoside
(1b) exhibited moderate cardiac activity in the isolated bullfrog heart assay.
Available online 2 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Fuzinoside
D
-Galactose
Cardiac activity
1. Introduction
galactose (Scheme 1). The total yields for the syntheses of fuzino-
side via two synthetic routes are 5.0% and 3.7%, respectively.
Fuzinoside (1a), glycerol
b-D-galactofuranosyl-(1/3)-b-D-gal-
1
HO
HO
OH
OH
OH
OH
actofuranoside, was isolated from the lateral roots of Aconitum
carmicaelii in 2004.1,2 Fuzinoside has been demonstrated to have
apparent cardiotonic effect,1 which might be associated with its
ability to enhance the amount of calcineurin (CaN) based on the
in vivo data in rats.3 The extreme scarcity of fuzinoside precluded
a comprehensive evaluation of its biological profile and structur-
eeactivity relationship studies. Consequently, total synthesis of
fuzinoside is in need. It should be noted that the structure for
fuzinoside (1a)1,2 should be redrawn as 1b in correspondence with
O
O
O
O
O
2
O
4'
3
1'
HO
HO
2'
5'
6'
3'
OH
OH
HO
HO
HO
OH
O
O
4''
1''
HO
HO
2''
5'' 3''
6''
OH
OH
Fuzinoside
its name, glycerol 1-2-O-b-D-galactofuranosy-1-3-b-D-galactono-
1a
side. In the present paper, we wish to report the first total syntheses
of fuzinoside via two synthetic strategies. The first strategy is
designated as BCþA route: synthesis of a 1/3-disaccharide fol-
lowed by glycosylation with glycerine. The second strategy is des-
1b
Fuzinoside
(The structure in the literature)
ignated as ABþC route: synthesis of glycerol-
b-D-galactose via O-
2. Results and discussion
2.1. BCA synthetic strategy
glycosylation followed by incorporation of another molecular of
D
-
According to the method described in the literature,4,5 compounds
3 and 4 were made by treatment of glycerin with benzaldehyde di-
methyl acetal/TsOH and TrCl/pyridine, respectively. Thioglycoside 5
* Corresponding authors. Tel./fax: þ86 28 85501368; e-mail addresses: qchen@
csufresno.edu (Q.-H. Chen), wfp@scu.edu.cn (F.-P. Wang).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.069

P. He et al. / Tetrahedron 70 (2014) 4022e4030
4023
O
LG
O
PG
PG
OPG
OPG
OPG
PGO
O
OH
OH
O
O
O
PGO
PGO
OPG
A
HO
HO
OH
B+C
HO
O
HO
OH
HO
OPG
OPG
PGO
HO
LG
O
O
O
1b
PGO
PGO
PGO
PGO
OPG
OPG
A+B
C
PG = Protection Group
Scheme 1. Two synthetic strategies for fuzinoside.
LG = Leaving Group
was prepared in 40% yield from
D
-galactose using a four-step reaction
transferred product 5 instead of desired product 12 (Scheme 3).
Initially, we assumed this might be caused by high reaction tem-
perature or highly reactive TMSOTf. However, the same reaction
under much lower temperature (ꢀ20 ꢁC, ꢀ40 ꢁC, and ꢀ78 ꢁC) still
generated aglycone-transferred product 5. Meanwhile, less reactive
phenyl thiol ether protected compound 13 was treated with 11
under the same reaction conditions to yield aglycone-transferred
compound 15 instead of the expected compound 14 (Scheme 3).
At this point, we considered to replace the thioglycoside with
a benzyl protected glycoside, which might enable the glycosylation
procedure as described in the literature.6
Hydrolysis of 5 with 1% sodium methoxide in methanol at rt for
2e4 h afforded fully hydrolyzed product 6. Protection of C5eC6 diol
in 6 by reacting with 2,2-dimethoxypropane catalyzed by D-cam-
to proceed smoothly. Compound 16 (
b
/
a
¼6:1) was prepared from
phorsulfonic acid gave compound 7.6,7 Reaction of 7 in anhydrous
dichloromethane with 1.2 equiv of TBDPSCl in the presence of
DMAP and imidazole for 10 h yielded 2-O-TBDPS ether 8 (major
product, 74%) and 3-O-TBDPS ether 9 (minor product, 15%)8
(Scheme 2). Deprotection of C-1 of compound 5 with NBS/
EtOAceH2O yielded 10, which was treated with tri-
chloroacetonitrile in the presence of DBU to give 11.6 Unfortunately,
reaction of 8 and 11 catalyzed by TMSOTf9 only provided aglycone-
D-galactose according to the procedure described in the
literature.10 Deprotection of silyl groups in compound 16 with
TBAF/THF yielded compound 17. Conversion of 17 to ketal 18 by
reacting with 2,2-dimethoxypropane/D-CSA. Selective protection of
2-OH in compound 18 generated compound 19 in high yield by
treating with TBDPSCl/DMAP/imidazole in anhydrous dichloro-
methane overnight.
Scheme 2.

4024
P. He et al. / Tetrahedron 70 (2014) 4022e4030
Scheme 3.
Disaccharide 20 was prepared by condensing acceptor 19 and
donor 5 catalyzed by NIS/AgOTf. Its NMR spectra showed charac-
teristic signals for anomeric H-10 ( 5.27, s) and C-10 (
104.6, d),
indicating the trans-relationship of H-10 and H-20, and the existence
of
-configuration of H-10.11,12 TBDPS deprotection of disaccharide
chloride in pyridine yielded compound 26. Condensation of com-
pound 26 with compound 4 in the presence of NIS/AgOTf generated
compound 27 in 70% yield.
d
d
Its 1H NMR spectrum showed a singlet signal at dH 5.34 for H-1,
a
suggesting the trans-relationship of H-1 and H-2, and the a-ori-
20 followed by re-protection with benzoyl yielded compound 21,
which was converted to donor 22 through a sequential procedure
including debenzylation of 21 by catalytic hydrogenation and the
following reaction with trichloroacetonitrile. Donor 22 is very la-
bile, which was condensed immediately with acceptor 3 in the
presence of TMSOTf to generate disaccharide 23. Its NMR spectra
exhibited characteristic signals for anomeric H-1 (dH 5.79, s) and C-
1 (dC 104.9, d), suggesting the trans-relationship of H-1 and H-2,
entation of H-1.11,12 Removal of the levulinyl protecting group in
compound 27 with hydrazine acetate yielded compound 28 in 72%
yield. Unfortunately, attempt to connect compound 28 with 5 to
give the desired compound 29 in the presence of NIS/AgOTf
through a 1/3 glycosidic linkage failed (Scheme 5). This might be
caused by the steric hindrance of the substrate, as well as the lia-
bility of trityl protecting group under acidic conditions. Conse-
quently, we selected benzaldehyde glycerin acetal
3 as an
and the existence of
characteristic NMR signals for anomeric H-10 (
and C-10( 105.2, d) demonstrated the trans-relationship of H-10
and H-20, and the existence of
-configuration of H-
a
-configuration of H-1.11,12 Similarly, the
5.55, d, J1,2¼2.0 Hz)
alternative substrate due to its relative stability. Condensation of
compounds 26 and 3 in the presence of NIS/AgOTf yielded the
desired product 30 in 70% yield. Its 1H NMR spectrum showed
d
d
a
signals at
d
5.43 (s) for H-1 and at
d
104.6 (d) for C-1, indicating the
-orientation of
10.11,12 Deprotection of 23 through acid and base, respectively, fol-
lowed by purification by Sephadex LH-20 column yielded fuzino-
side (1b) in a total yield of 91% for two steps (Scheme 4). The NMR
spectra of 1b (Table 1) showed the characteristic signals for H-10
and C-10 (dH 5.21 s; dC 109.4 d) and H-100 and C-200 (dH 5.19 s; dC 109.2
trans-relationship between H-1 and H-2, and the
a
H-1.11e13 Removal of the levulinyl protecting group in compound 30
with hydrazine acetate yielded compound 31 in 72% yield. Con-
densation of compound 31 with 5 in the presence of NIS/AgOTf
generated disaccharide 23 with a 1/3 glycosidic bond. Depro-
tection of compound 23 using the above-mentioned procedure
(Scheme 4) yielded fuzinoside 1b (Scheme 6).
d), indicating the
glycosidic bond in fuzinoside can be established by the key HMBC
(Table 1) relationship between H-30 (dH 4.19 m) and C-100
dC 109.2
a
-orientation of both H-10 and H-100.11e13 The 1/3
(
After careful reading the literature1,2 and the original NMR
spectra in the associated Master Degree thesis, it was found: (1)
that the structure of fuzinoside in the literature (1a)1,2 does not
match with its name. Only the redrawn structure 1b can match the
d). The disaccharide moiety and glycerin in fuzinoside was con-
nected through C-10 of the disaccharide and C-2 of glycerin, based
on the critical HMBC relationship between H-2 (dH 3.85 m) and C-10
1a,2
1b
(
dC 109.4 d), as well as between H-10 (dH 5.21 s) and C-2 (dC 80.8 d).
name; (2) that neither DMSO-d6
nor CDCl3 was used as deu-
Collectively, the structure of the synthetic fuzinoside was de-
termined as 1b.
terated solvent in acquiring the NMR spectra for fuzinoside. The
solvent used should be D2O as noted in the figures in Ref. 1b; (3)
that the 1H(13C) NMR, DEPT, 1He1H COSY, and 1He13C COSY (no
HMBC) spectra of fuzinoside were included in Ref. 1b, but the 13C
NMR signals were not assigned. No spectra were shown in Refs. 1a
and 2. The connecting carbons of sugaresugar and sugareglycerol
were established based on the key HMBC correlations. All other
2.2. ABC synthetic strategy
Due to the existence of aglycone-transferred reactions when
treating compound 8 or compound 13 with compound 11 (Scheme
3), we attempted to overcome this problem by altering the con-
necting order of saccharides. Consequently, we designed an alter-
native ABC synthetic strategy, in which one saccharide unit was
first connected with glycerin followed by incorporation of the ter-
minal saccharide unit. Specifically, compound 24 was prepared in
95% yield by reacting intermediate 8 with levulinic acid in the
presence of DMAP and DCC at rt for 2e4 h. Deprotection of TBDPS in
24 followed by re-protection of the hydroxyl group with benzyl
signals were assigned based on the comparison with analogues
b-
methyl-
D
-furangalactose and glycerol. The 13C NMR data reported
in Refs. 1a, 1b, and 2 are almost in consistent to each other; (4) that
the chemical shifts of C-1 and C-3 for fuzinoside described in Refs.
1a and 2 didn’t show significant glycosidation shift. In reference to
the 13C NMR data for our synthetic fuzinoside, the signals for C-1
and C-600, and for C-3 and C-600 reported in Refs. 1 and 2 should be
switched; (5) that the coupling constant (J¼7.5 Hz) for the

P. He et al. / Tetrahedron 70 (2014) 4022e4030
4025
Scheme 4.
Table 1
from those (after above-mentioned re-assignments) for the fuzi-
noside isolated from nature.1,2
NMR data for fuzinoside (1b) (D2O; 1H: 400 MHz; 13C: 100 MHz)
No.
1b
1a1a
The structure of the synthetic fuzinoside 1b in this paper was
confirmed by extensive interpretation of 1H, 13C NMR, DEPT, 2D
NMR (HMQC, HMBC, 1He1H COSY), and HRESIMS data. There-
fore, the structure of fuzinoside reported in the literature1,2
might be wrong. The structure of fuzinoside isolated from A.
carmicaelii needs to be verified. The test of isolated bullfrog
heart showed that the synthetic fuzinoside (1b) exhibited ap-
parently cardiac activity with average rate of amplitude increase
as 28%.14
dC
dH mult
COSY
2
HMBC
(H/C)
dH multa
dC
1
62.8 t
3.67 m (hidden)
3.75 m (hidden)
3.85 m (hidden)
3.71 m (hidden)
5.21 s
2
67.9 at
80.7 d
2
3
10
80.8 d
63.6 t
109.4 d
1, 3
2
20, 30
1, 3, 10
2
2, 40
67.2b
t
d
5.0,
108.6 d
J¼7.5 Hz
20
30
40
50
60
100
81.9 d
84.8 d
83.9 d
72.7 d
64.9 t
4.31 br s
4.19 m
4.16 m
3.85 m (hidden)
3.72 m (hidden)
5.19 s
10, 30, 40
10, 20, 40
30, 50
60
10, 30
100, 20
30
82.3 d
85.4 d
83.7 d
74.8 d
63.9 bt
108.9 d
60
3. Conclusion
50
50, 40
300, 400
109.2 d
200, 300
d
5.05,
(1) The total syntheses of fuzinoside (1b) from D-galactose were
J¼7.5 Hz
achieved through two synthetic strategiesdBCA synthetic strategy
(11 steps, 5.0% total yield) and ABC synthetic strategy (15 steps, 3.7%
total yield). (2) Glycosylation of thioglycosides is readily to produce
aglycone-transferred products.15,16 When compared with benzalde-
hyde glycerin acetal 3, the 1,3-trityl selectively protected saccharide
can be easily made, but no subsequent glycosidation reaction hap-
pened due to the instability of the trityl group. (3) The structure of
fuzinoside isolated from the lateral roots of A. carmicaelii1,2 might be
wrong based on the comparison of the NMR data of our synthetic
fuzinoside (1b) and those reported in the literature. The further
confirmation of the structure of fuzinoside isolated from A. carmicaelii
200
300
400
500
600
83.4 d
78.7 d
85.1 d
72.7 d
65.0 t
4.14 m (hidden)
4.10 m
3.98 m
3.93 m
3.72 m (hidden)
100, 300
200, 400
300, 500
600
300
82.7 d
78.0 d
83.3 d
73.5 d
100, 200
300
600
400, 500
500
62.6a
t
a, b: Assignments may be interchangeable, respectively.
anomeric protons in fuzinoside reported in Refs. 1 and 2 is not in
consistent with the data (J ¼ 0e2 Hz) summarized in the
literature;11,13 and (6) that the 13C NMR signals for C-50, C-60, C-4,00
and C-600 for our synthetic fuzinoside 1b are significantly different

4026
P. He et al. / Tetrahedron 70 (2014) 4022e4030
Scheme 5.
Scheme 6. Total synthesis of fuzinoside (ABC strategy).
is in progress in our laboratory. The synthetic fuzinoside (1b) showed
hydroxytetrahydrofuran-3-yloxy)tetrahydrofuran-3,4-diol
(fuzino-
moderate cardiac activity in the isolated bullfrog heart assay.
side, 1b). Compound 23 (100 mg, 0.09 mmol) was added to a so-
lution of 5% CF3COOH in dichloromethane (5 mL, v/v%). The mixture
was stirred at rt for 1 h prior to the addition of sodium methoxide
solution (0.1 mol/L in MeOH) until pH ꢂ 10. After stirring for 3 h, the
reaction mixture was concentrated under vacuum. The crude
4. Experimental section
4.1. General methods
product was purified by Sephadex LH-20 column (100 g, MeOH) to
25
give compound 1b (36 mg, 91%). [
a
]
D
ꢀ104.7 (c 1.2, MeOH); 1H
Reagents and solvents were purchased from commercial sup-
pliers and used without further purification unless otherwise
noted. Anhydrous THF was distilled from sodium and benzophe-
none. Anhydrous dichloromethane was distilled from calcium hy-
dride. Column chromatography was performed on silica gel
(200e300 mesh). All 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Varian INOVA-400/54 spectrometer in
CDCl3 or D2O or CD3COCD3, with tetramethylsilane as an internal
standard. ESI-MS was recorded on Finnigan LCQ or VG-Autospec-
3000 apparatus. HRMS was recorded on Bruker BioTOFQ apparatus.
(400 MHz, D2O) and 13C NMR (100 MHz, D2O) see Table 1; 13C NMR
(100 MHz, DMSO-d6) d: 107.9 (d), 107.2 (d), 82.4 (d), 82.3 (d), 82.2
(d), 81.1 (d), 80.7 (d), 78.9 (d), 76.9 (d), 70.6 (d), 70.2 (d), 63.0 (t),
63.0 (t), 61.4 (t), 61.1 (t); HRESIMS m/z 439.1376 [MþNa]þ, calcd for
C15H28O13Na, 439.1428.
4.1.2. 2-Phenyl-1,3-dioxan-5-ol (3). The mixture of propane-1,2,3-
triol (2, 7.42 g, 80.6 mmol), benzaldehyde dimethyl acetal
(13.7 mL, 99.3 mmol), and p-toluenesulfonic acid (650 mg,
3.7 mmol) in anhydrous dichloromethane (100 mL) was stirred at rt
overnight and extracted with dichloromethane (120 mL ꢃ 3). The
combined organic extracts were rinsed with saturated aqueous
4.1.1. (2S,3S,4S,5S)-2-((S)-1,2-Dihydroxyethyl)-5-((2S,3S,4S,5R)-2-
((S)-1,2-dihydroxyethyl)-5-(1,3-dihydroxypropan-2-yloxy)-4-

P. He et al. / Tetrahedron 70 (2014) 4022e4030
4027
NaHCO3 solution, water, and brine, and dried over anhydrous
Na2SO4. After drying over anhydrous Na2SO4 and concentration
under vacuum, the crude product was purified by column chro-
matography petroleum ether/EtOAc (3:1, v/v) to give the compound
127.9 ꢃ 2 (d), 127.8 ꢃ 2 (d), 109.6 (s), 96.1 (d), 84.9 (d), 81.8 (d), 80.2
(d), 75.1 (d), 65.4 (t), 26.8 ꢃ 3 (q), 26.2 (q), 25.4 (q), 21.0 (q), 19.1 (s).
4.1.5. (R)-1-((2S,3R,4R,5S)-3,4-Bis(benzoyloxy)-5-(2,2,2-trichloro-1-
iminoethyl)tetrahydrofuran-2-yl)ethane-1,2-diyl dibenzoate (11). To
a solution of compound 5 (369 mg, 0.53 mmol) in ethyl acetate
(25 mL) were added NBS (738 mg, 4.15 mmol) and water (5 mL).
The reaction mixture was stirred at rt for 5 h before being quenched
with saturated aqueous Na2S2O3 solution. The organic layer was
rinsed with water and brine, and dried over anhydrous Na2SO4.
After concentration under vacuum, the crude product was purified
by column chromatography, eluting with petroleum ether/EtOAc
(8:1, v/v) to give the unstable compound 10 (243 mg, 80%) as
a colorless syrup. Trichloroacetonitrile (0.6 mL, 3.0 mmol) was
added to a solution of compound 10 (700 mg, 1.21 mmol) in dry
dichloromethane (40 mL) under argon at 0 ꢁC. After stirring for
3 (5.01 g, 35%) as a white solid. 1H NMR (400 MHz, CDCl3)
d:
7.51e7.34 (m, 5H), 5.56 (s, 1H), 4.15e4.20 (m, 5H); 13C NMR
(100 MHz, CDCl3)
d
: 137.7 (s), 129.0 (d), 128.3 ꢃ 2 (d), 125.8 ꢃ 2 (d),
110.6 (d), 72.2 ꢃ 2 (t), 63.9 (d).
4.1.3. 1,3-Bis (trityloxy)propan-2-ol (4). To a solution of propane-
1,2,3-triol (2, 275 mg, 2.98 mmol) in dry pyridine (5 mL) was added
triphenylmethyl chloride (2.03 g, 7.3 mmol) at 0 ꢁC. The reaction
mixture was stirred for 14 h and then diluted with water (20 mL). The
subsequent mixture was extracted with dichloromethane (20 mL ꢃ
3). The combined organic extracts were dried over anhydrous Na2SO4
and concentrated under vacuum. The crude product was purified by
column chromatography petroleum ether/EtOAc (4:1, v/v) to afford
compound 4 (1.50 g, 35%) as a white solid. 1H NMR (400 MHz, CDCl3)
10 min, DBU (50 mL, 0.34 mmol) was added. The reaction mixture
was stirred at 0 ꢁC for 30 min and concentrated under vacuum at rt.
The crude residue was purified by column chromatography, eluting
with petroleum ether/EtOAc/Et3N (10:1:0.5%, v/v/v), to afford
compound 11 (580 mg, 67%) as a labile colorless syrup.
d
: 7.22e7.42 (m, 30H), 3.97 (m,1H), 3.30e3.34 (m, 2H), 3.23e3.27 (m,
2H); 13C NMR (100 MHz, CDCl3)
d: 143.7 ꢃ 6 (s), 128.6 ꢃ 12 (d), 127.7
ꢃ 12 (d), 126.9 ꢃ 6 (d), 86.5 (s), 70.1 (d), 64.3 ꢃ 2 (t).
4.1.4. (2R,3R,4S,5S)-4-(tert-Butyldiphenylsilyloxy)-2-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)-5-(p-tolylthio)tetrahydrofuran-3-ol (8)
and (2S,3S,4S,5S)-4-(tert-butyldiphenylsilyloxy)-5-((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)-2-(p-tolylthio)tetrahydrofuran-3-ol (9). To a solu-
tion of compound 5 (21.3 g, 30.3 mmol) in methanol/dichloro-
methane (v/v ¼ 2:1, 300 mL) was added MeONa (5.0 g, 92 mmol).
The reaction mixture was stirred at rt for 3 h prior to removal of the
solvent under vacuum. Purification of the crude residue via column
chromatography, eluting with dichloromethane/MeOH (15:1, v/v),
afforded compound 6 (7.4 g, 86%) as a colorless syrup. To a solution
of compound 6 (1.0 g, 3.5 mmol) in dry dichloromethane (50 mL)
was added 2,2-dimethoxypropane (0.6 mL, 4.9 mmol), and the re-
4.1.6. (2R,3S,4S,5S)-2-(Benzyloxy)-5-((S)-1,2-dihydroxyethyl)tetra-
hydrofuran-3,4-diol (17). To a solution of compound 16 (570 mg,
0.78 mmol) in THF (10 mL) was added TBAF (3.5 mL, 1 M in THF).
The reaction mixture was stirred at rt for 4 h prior to removal of the
solvent under vacuum. The crude product was purified by column
chromatography, eluting with dichloromethane/MeOH (20:1, v/v),
to afford compound 17 (123 mg, 58%) as a colorless syrup. 1H NMR
(400 MHz, C3D6O)
(ABq, J¼12 Hz, 2H), 4.63 (d, J¼6.8 Hz, 1H), 4.06e4.12 (m, 3H), 4.02
(m, 1H), 3.76 (m, 1H), 3.65 (m, 2H); 13C NMR (100 MHz, C3D6O)
d: 7.25e7.38 (m, 5H), 4.97 (s, 1H, H-1), 4.74, 4.51
d
:
138.6 (s), 129.0 ꢃ 2 (d), 128.5 ꢃ 2 (d), 128.1 (d), 108.6 (s), 85.6 (d),
82.4 (d), 79.2 (d), 72.5 (d), 69.2 (t), 64.2 (t).
action mixture was stirred at rt for 15 min prior to the addition of D-
camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was
stirred for 2 h prior to being quenched with triethylamine. After
removing the solvent under vacuum, the crude product was purified
by column chromatography, eluting with petroleum ether/EtOAc
(2:1, v/v), to give compound 7 (1.0 g, 80%) as a colorless syrup. Im-
idazole (444 mg, 6.53 mmol) and DMAP (119 mg, 0.97 mmol) were
added to a solution of compound 7 (1.07 g, 2.97 mmol) in dry
dichloromethane (50 mL) at 0 ꢁC. The reaction mixture was kept
stirring for 30 min prior to the addition of TBDPSCl (0.92 mL,
3.55 mmol). The subsequent reaction mixture was stirred overnight
at rt prior to being extracted with dichloromethane (60 mL ꢃ 3). The
combined extracts were rinsed with water and brine, and dried over
anhydrous Na2SO4. After concentration under vacuum, the crude
product was purified by column chromatography, eluting with pe-
troleum ether/EtOAc (7:1, v/v), to give compounds 8 (1.21 g, 72%) and
9 (0.24 g, 15%) as colorless syrups. Compound 8: 1H NMR (400 MHz,
4.1.7. (2R,3S,4S,5R)-2-(Benzyloxy)-5-((S)-2,2-dimethyl-1,3-dioxolan-
4-yl)tetrahydrofuran-3,4 -diol (18). The mixture of compound 17
(290 mg, 1.07 mmol), 2,2-dimethoxypropane (0.6 mL, 4.9 mmol),
and (D)-camphorsulfonic acid (40 mg, 0.17 mmol) in anhydrous
dichloromethane (100 mL) was stirred at rt for 2 h and quenched
with Et3N (1 mL). The solvent was evaporated under vacuum. The
crude product was purified by column chromatography (petroleum
ether/EtOAC¼2:1, v/v) to give the product 18 (286 mg, 86%) as
a colorless syrup. 1H NMR (400 MHz, CDCl3)
d: 7.26e7.37 (m, 5H),
5.12 (s, 1H), 4.78, 4.56 (ABq, J¼11.6 Hz, 2H), 4.33 (dt, J1¼1.6 Hz,
J2¼8 Hz, 1H), 4.05e4.13 (m, 2H), 4.00e4.04 (m, 3H), 1.39, 1.42 (s,
each 3H); 13C NMR (100 MHz, CDCl3)
d
: 136.9 (s), 128.5 ꢃ 2 (d),
127.9 ꢃ 2 (d), 127.9 (d), 110.1 (s), 107.6 (d), 85.6 (d), 78.5 (d), 78.2 (d),
75.6 (d), 69.2 (t), 65.4 (t), 25.4 ꢃ 2 (q); ESIMS m/z: 311 [MþH]þ.
4.1.8. (2R,3R,4S,5R)-5-(Benzyloxy)-4-(tert-butyldiphenylsilyloxy)-2-
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydrofuran-3-ol (19). This
compound was prepared from the reaction of compound 18
(280 mg, 0.9 mmol), imidazole (107 mg, 1.57 mmol), and TBDPSCl
(0.3 mL, 1.16 mmol) in dry dichloromethane (15 mL), using the
similar procedure as described for the synthesis of compound 8.
The crude residue was purified by column chromatography, eluting
with petroleum ether/EtOAc (10:1, v/v), to give the product 19
CDCl3)
d
: 7.73 (d, J¼7.2 Hz, 4H), 7.49e7.42 (m, 6H), 7.28 (d, J¼7.6 Hz,
2H), 7.09 (d, J¼7.6 Hz, 2H), 5.38 (d, J¼2.8 Hz, 1H), 4.37 (m, 1H), 4.26
(m,1H), 4.02e4.05 (m, 3H), 4.00 (m,1H), 2.33 (s, 3H),1.48(s, 3H),1.41
(s, 3H) 1.48(s, 3H),1.13 (s, 9H); 13C NMR (100 MHz, CDCl3)
d: 137.5 (s),
135.7 ꢃ 2 (d),135.2 ꢃ 2 (d),133.0 (s),132.7 ꢃ 2 (d),132.4 (s),130.0 (d),
129.9 (d),129.6 (s),129.4 ꢃ 2 (d),127.8 ꢃ 2 (d),127.7 ꢃ 2 (d),109.5 (s),
92.7 (d), 83.7 (d), 83.7 (d), 78.9 (d), 75.1 (d), 65.2 (t), 26.7 ꢃ 3 (q), 26.2
(q), 25.2 (q), 20.9 (q), 19.0 (s). Compound 9: 1H NMR (400 MHz,
(380 mg, 79%) as a white solid. 1H NMR (400 MHz, CDCl3)
d:
CDCl3)
d
: 7.75e7.69 (m, 4H), 7.48e7.39 (m, 8H), 7.13 (d, J¼7.6 Hz, 2H),
7.17e7.64 (m, 15H), 5.00 (s, 1H, H-1), 4.66, 4.34 (ABq, J¼12 Hz, 2H),
4.40 (d, J¼12 Hz, 1H), 4.17 (d, J¼8.0 Hz, 1H), 4.03 (m, 2H), 3.86 (m,
1H), 3.69 (dd, J1¼1.2 Hz, J2¼10.0 Hz,1H) 1.49 (s, 3H),1.41 (s, 3H),1.07
5.46 (s,1H, H-1), 4.34 (d, 2H, J¼11.6 Hz), 4.19 (s, 3H), 4.07 (s, 3H), 3.96
(d, J¼11.6 Hz, 2H), 3.82 (t, J¼8.0 Hz, 1H), 3.73 (t, J¼8.0 Hz,1H), 3.28 (t,
J¼7.6 Hz, 1H), 2.33 (s, 3H), 1.29 (s, 3H), 1.22 (s, 3H), 1.16 (s, 9H); 13
C
(s, 9H); 13C NMR (100 MHz, CDCl3)
d
: 137.1 (s), 135.6 ꢃ 4 (d), 132.7 ꢃ
NMR (100 MHz, CDCl3)
d: 136.7 (s), 135.9 ꢃ 2 (d), 135.7 ꢃ 2 (d), 133.3
2 (s), 130.1 (d), 130.0 (d), 128.4 ꢃ 2 (d), 127.9 ꢃ 2 (d), 127.8 ꢃ 2 (d),
(s),133.0 (s), 132.7 (s), 131.2 ꢃ 2 (d), 130.1 (d), 130.0 (d), 129.6 ꢃ 2 (d),
127.8 ꢃ 2 (d), 127.7 (d), 109.9 (s), 107.0 (d), 87.9 (d), 81.9 (d), 78.9 (d),

4028
P. He et al. / Tetrahedron 70 (2014) 4022e4030
76.5 (d), 68.9 (t), 65.7 (t), 26.8ꢃ3 (q), 26.7 (q), 25.2 (q), 19.0 (s); MS
(ESI) m/z: 549 [MþH]þ.
tetrahydrofuran-3-yloxy)-5-((S)-1,2-bis(benzoyloxy)ethyl)tetrahy-
drofuran-3,4-diyl dibenzoate (23, method A). A suspension of com-
pound 21 (50 mg, 0.05 mmol) and Pd/C (10%, 50 mg) in dry THF
(10 mL) was hydrogenated under hydrogen at 60 ꢁC for 24 h. After
removal of the insoluble material by filtration, the filtrate was
concentrated in vacuo. The residue was dissolved in dry dichloro-
4.1.9. (2S,3S,4R,5S)-2-((2S,3R,4S,5R)-5-(Benzyloxy)-4-(tert-butyldi-
phenylsilyloxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydrofu-
ran-3-yloxy)-5-((S)-1,2-bis(benzoyloxy)ethyl)tetrahydrofuran-3,4-
diyl dibenzoate (20). To a solution of the receptor 19 (35 mg,
0.06 mmol) and the donor 5 (53 mg, 0.07 mmol) in dry dichloro-
methane (5 mL), to which was added trichloroacetonitrile (15
0.15 mmol) under argon at 0 ꢁC. The reaction mixture was kept
stirring for 10 min before the addition of DBU (5 L, 0.04 mmol).
mL,
ꢀ
methane (10 mL) was added 4 A molecular sieves (150 mg). The
m
reaction mixture was kept stirring for 10 min at 0 ꢁC prior to the
addition of NIS (20 mg, 0.09 mmol). The reaction mixture was
stirred for additional 30 min before AgOTf (4 mg, 0.02 mmol) was
added. The subsequent reaction mixture was kept stirring for 4 h
prior to being quenched with Et3N (3 mL). The mixture was diluted
with dichloromethane (10 mL) and then filtrated. The filtrate was
rinsed with saturated aqueous Na2S2O3 solution, water, and brine,
and then dried over anhydrous Na2SO4. After removal of solvents
under vacuum, the crude residue was purified by column chro-
matography, eluting with petroleum ether/EtOAc (8:1, v/v) to afford
compound 20 (43 mg, 64%) as a white solid. 1H NMR (400 MHz,
The subsequent mixture was stirred for 40 min prior to removal of
solvents under vacuum. The crude residue was purified by column
chromatography, eluting with PE/EtOAC/Et3N (9:1:0.5%, v/v/v), to
give the product 22 (63 mg, 72%) as a labile colorless syrup. To
a solution of compound 22 (40 mg, 0.04 mmol) and 3 (15 mg,
ꢀ
0.08 mmol) in dry dichloromethane (5 mL) was added 4 A molec-
ular sieves (100 mg). After stirring under argon at 0 ꢁC for 10 min,
TMSOTf (5 mL, 0.02 mmol) was added into the reaction mixture. The
mixture was stirred for additional 2 h prior to being quenched with
Et3N. The subsequent mixture was diluted with dichloromethane
(10 mL) and filtered. The filtrate was rinsed with saturated aqueous
NaHCO3 solution, water, and brine, and dried over anhydrous
Na2SO4. After removal of solvents under vacuum, the crude residue
was purified by column chromatography, eluting with cyclohexane/
CDCl3)
d
: 8.04 (dd, J1¼0.8 Hz, J2¼8.4 Hz, 2H), 7.96 (m, 4H), 7.89 (d,
J¼8.4 Hz, 2H), 7.16e7.64 (m, 27H), 5.97 (m, 1H), 5.59 (d, J¼4.4 Hz,
1H), 5.27 (s, 1H), 5.07 (s, 1H), 4.75 (m, 2H), 4.70 (d, J¼6.8 Hz, 1H),
4.54 (t, J¼4.4 Hz, 1H), 4.65, 4.34 (ABq, J¼11.6 Hz, 2H), 4.07 (m, 2H),
3.98 (t, J¼8.0 Hz, 1H), 3.89 (t, J¼7.6 Hz, 1H), 1.43, 1.37 (s, each 3H),
EtOAc (7:1, v/v), to afford compound 23 (28 mg, 66%) as a white
20
solid. [
a
]
D
ꢀ193.6 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d:
1.04 (s, 9H); 13C NMR (100 MHz, CDCl3)
d: 166.0 (s), 165.6 (s), 165.4
7.89e8.05 (m, 10H), 7.23e7.59 (m, 20H), 5.98 (m, 1H), 5.79 (s, 1H),
5.66 (d, J¼4.4 Hz, 1H), 5.60 (s, 1H), 5.55 (d, J¼2.0 Hz, 1H), 5.49 (s,
1H), 4.65e4.72 (m, 2H), 4.61 (t, J¼4.4 Hz, 1H), 4.27e4.44 (m, 4H),
4.11 (m, 1H), 4.04 (dd, J1¼1.6 Hz, J2¼10.8 Hz, 1H), 3.95 (m, 1H), 3.90
(m, 1H), 3.74 (br s, 1H), 1.39, 1.29 (s, each 3H); 13C NMR (100 MHz,
(s), 164.8 (s), 137.8 (s), 135.8 (d), 135.7 (d), 135.6 (d), 133.4 (d), 133.2
(d), 133.0 (d), 132.6 (s), 132.6 (s), 129.9 (d), 129.9 (d), 129.8 (d), 129.6
(d), 129.4 (s), 128.8 (s), 128.8 (s), 128.3 (d), 128.3 (d), 128.3 (d), 128.1
(d), 127.9 (s), 127.8 (s), 127.8 (d), 127.7 (d), 127.4 (d), 127.3 (d), 109.8
(s), 107.4 (d), 104.6 (d), 83.8 (d), 83.6 (d), 82.1 (d), 81.4 (d), 81.1 (d),
77.1 (d), 76.0 (d), 70.4 (d), 68.4 (t), 65.5 (t), 63.4 (t), 26.8 ꢃ 3 (q), 26.7
(q), 25.2 (q), 19.0 (s); ESIMS m/z: 1127 [MþH]þ.
CDCl3) d: 165.9 (s), 165.6 (s), 165.5 (s), 165.3 (s), 165.2 (s), 138.0 (s),
133.4ꢃ2 (d), 133.2 (d), 133.1 (d), 133.0 (d), 129.9 ꢃ 2 (d), 129.9 ꢃ 4
(d), 129.8 ꢃ 2 (d), 129.6 ꢃ 2 (d), 129.4 (s), 129.3 (s), 129.2 (s), 128.8
(d), 128.8 (s), 128.8 (s), 128.4 ꢃ 2 (d), 128.4 ꢃ 2 (d), 128.3 ꢃ 5 (d),
128.1 (d), 126.1 ꢃ 2 (d), 105.2 (d), 104.9 (d), 101.4 (d), 83.1 (d), 82.5
ꢃ 2 (d), 82.1 (d), 81.4 (d), 77.5 (d), 75.6 (d), 70.4 (d), 68.3 (d), 70.5 (t),
68.3 (t), 65.6 (t), 63.5 (t), 26.5 (q), 25.4 (q); ESIMS m/z: 1065
[MþH]þ; HRESIMS m/z 1087.3368 [MþNa]þ, calcd for C60H56O18Na,
1087.3364.
4.1.10. (2S,3S,4R,5S)-2-((2S,3R,4S,5R)-4-(Benzoyloxy)-5-(benzy-
loxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydrofuran-3-
yloxy)-5-((S)-1,2-bis(benzoyloxy)ethyl)tetrahydrofuran-3,4-diyl di-
benzoate (21). TBAF (30 mg, 0.09 mmol) was added to a solution
of compound 20 (100 mg, 0.9 mmol) in THF (10 mL) at 0 ꢁC, and
the reaction mixture was stirred at the same temperature for 1 h.
The reaction was quenched with water, and the subsequent mix-
ture was extracted with dichloromethane (10 mL ꢃ 3). The com-
bined organic extracts were dried over anhydrous Na2SO4 and
concentrated under vacuum. This crude product was directly used
for the next step reaction without further purification. To a solu-
tion of the crude product achieved above in dry pyridine (5 mL)
was added benzyl chloride (0.1 mL, 0.1 mmol), and the mixture
was stirred at rt for 2 h. After removal of the solvent, the crude
product was purified by column chromatography, eluting with
petroleum ether/EtOAc (9:1, v/v), to give compound 21 (63 mg,
4.1.12. (2S,3S,4R,5S)-2-((2S,3R,4S,5R)-4-(Benzoyloxy)-2-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-5-(2-phenyl-1,3-dioxan-5-yloxy)tet-
rahydrofuran-3-yloxy)-5-((S)-1,2-bis(benzoyloxy)ethyl)tetrahy-
drofuran-3,4-diyl dibenzoate (23, method B). A mixture of
receptor 31 (147 mg, 0.3 mmol), donor 5 (327 mg, 0.47 mmol),
ꢀ
and 4 A molecular sieves (150 mg) in dry dichloromethane
(10 mL) was stirred under argon at 0 ꢁC for 10 min. NIS (136 mg,
0.6 mmol) was then added and the subsequent mixture was kept
stirring for an additional 30 min. To the reaction mixture was
added AgOTf (13 mg, 0.05 mmol). The subsequent mixture was
stirred for 4 h prior to using the work-up procedure as described
in method A to afford compound 23 (217 mg, 67%) as a white
solid.
72%) as a white solid. [
CDCl3)
a
]
20 ꢀ35.2 (c 0.5, CHCl3); 1H NMR (400 MHz,
D
d
: 8.0e8.04 (m, 10H), 7.22e7.58 (m, 20H), 6.02 (m, 1H), 5.76
(s, 1H), 5.67 (d, J¼4.8 Hz, 1H), 5.57 (d, J¼1.2 Hz, 1H), 5.46 (s, 1H),
5.31 (s, 1H), 4.84 (d, J¼12.4 Hz, 1H), 4.62e4.76 (m, 4H), 4.32 (d,
J¼5.2 Hz, 1H), 4.28 (t, J¼6.0 Hz, 1H), 4.19 (t, J¼5.6 Hz, 1H), 3.93 (m,
1H), 3.89 (m, 1H), 1.40, 1.30 (s, each 3H); 13C NMR (100 MHz,
4.1.13. (2S,3R,4S,5S)-4-(tert-Butyldiphenylsilyloxy)-2-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)-5-(p-tolylthio)tetrahydrofuran-3-yl 4-
CDCl3)
d
: 165.9 (s), 165.5 (s), 165.4 (s), 165.3 (s), 165.2 (s) 137.4 (s),
oxopentanoate (24). To a solution of compound 8 (240 mg,
133.4 (d), 133.4 (d), 133.2 (d), 133.1 (d), 133.0 (d), 129.6 (d), 129.3
(s), 129.2 (s), 129.1 (s), 128.8 (s), 128.7 (s), 128.4 (d), 128.5 (d), 127.5
(d), 127.4 (d), 109.8 (s), 105.1 (d), 105.1 (d), 83.0 (d), 82.2 (d), 81.9
(d), 81.9 (d), 81.2 (d), 77.3 (d), 75.4 (d), 70.3 (d), 68.6 (t), 65.4 (t),
63.3 (t), 26.3 (q), 25.2 (q); HRESIMS m/z 1015.3149 [MþNa]þ, calcd
for C57H52O16Na, 1015.3153.
0.42 mmol), levulinic acid (105 mg, 0.90 mmol), and DCC (297 mg,
1.44 mmol) in dry dichloromethane (10 mL) was added DMAP
(10 mg, 0.08 mmol). The reaction mixture was stirred at rt for 3 h
and filtered. The filtrate was concentrated under vacuum. The crude
residue was purified by column chromatography, eluting with pe-
troleum ether/EtOAc (7:1, v/v), to afford compound 24 (268 mg,
95%) as a colorless syrup. 1H NMR (400 MHz, CDCl3)
d: 7.60e7.66
4.1.11. (2S,3S,4R,5S)-2-((2S,3R,4S,5R)-4-(Benzoyloxy)-2-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-5-(2-phenyl-1,3-dioxan-5-yloxy)
(m, 2H), 7.42 (m, 2H), 7.34e7.40 (m, 4H), 7.14 (d, J¼8.4 Hz, 2H), 7.02
(d, J¼8.0 Hz, 2H), 5.25 (d, J¼2.0 Hz, 1H), 5.09 (q, J1¼2.0, J2¼3.6 Hz,

P. He et al. / Tetrahedron 70 (2014) 4022e4030
4029
1H), 4.41 (m, 1H), 4.31 (t, J¼2.4 Hz, 1H), 4.10 (m, 1H), 4.03 (m, 1H),
3.94 (m, 1H), 2.64 (m, 1H), 2.43 (m, 1H), 2.33 (m, 1H), 2.29 (s, 3H),
2.15 (s, 3H), 1.42, 1.38 (s, each 3H),1.07 (s, 9H); 13C NMR (100 MHz,
HRESIMS m/z 1003.4032 [MþNa]þ, calcd for C62H60O11Na,
1003.4033.
CDCl3)
d
: 206.0 (s), 171.4 (s), 137.4 (s), 135.8 (d), 135.8 (d), 132.6 (d),
4.1.17. (2R,3S,4R,5R)-2-(1,3-Bis(trityloxy)propan-2-yloxy)-5-((S)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxytetrahydrofuran-3-yl ben-
zoate (28). To a solution of compound 27 (750 mg, 0.76 mmol) in
dichloromethane/methanol (30 mL, v/v¼3:1) was added hydrazine
acetate (176 mg, 1.92 mmol), and the mixture was stirred at rt for
3 h prior to being quenched with water (30 mL). The mixture was
extracted with dichloromethane (30 mLꢃ3), and the combined
organic extracts were rinsed with brine and dried over anhydrous
Na2SO4. After removal of organic solvents under vacuum, the crude
residue was purified by column chromatography, eluting with pe-
troleum ether/EtOAc (4:1, v/v), to give compound 28 (486 mg, 72%).
132.5 (s), 132.4 (s), 130.1 (s), 129.9 (d), 129.8 (d), 129.4 (d), 127.8 (d),
127.7 (d), 109.7 (s), 93.9 (d), 83.1 (d), 81.5 (d), 79.8 (d), 75.5 (d), 65.5
(t), 37.7 (t), 29.7 (q), 27.7 (t), 26.7 (q), 26.3 (q), 25.2 (q), 21.0 (q), 18.9
(s); ESIMS m/z: 663 [MþH]þ.
4.1.14. (2S,3S,4S,5S)-2-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-
hydroxy-5-(p-tolylthio) tetrahydro-furan-3-yl-4-oxopentanoate
(25). To a solution of compound 24 (690 mg, 1.04 mmol) in dry
THF (10 mL) was added TBAF (200 mg, 0.63 mmol) at 0 ꢁC and the
reaction mixture was stirred for 1 h. The solvent was removed
under vacuum. Chromatography of the crude residue, eluting with
PE/EtOAc (5:1, v/v), gave compound 25 (370 mg, 84%) as a colorless
1H NMR (400 MHz, CDCl3)
d
: 7.93 (dd, J1¼1.6 Hz, J2¼6.8 Hz, 2H),
7.17e7.59 (m, 33H), 5.51 (s,1H), 5.08 (d, J¼1.6 Hz,1H), 4.14e4.20 (m,
syrup. 1H NMR (400 MHz, CDCl3)
d
: 7.38 (d, J¼8.0 Hz, 2H), 7.12 (d,
2H), 3.80 (dd, J1¼7.2 Hz, J2¼6.8 Hz,1H), 3.24e3.35 (m, 5H),1.36,1.35
J¼7.6 Hz, 2H), 5.46 (s, 1H), 4.98 (br s, 1H), 4.48 (t, J¼7.2 Hz, 1H), 4.27
(m, 2H), 4.16 (d, J¼10.4 Hz, 1H), 4.07 (t, J¼7.2 Hz, 1H), 3.99 (t,
J¼7.2 Hz, 1H), 2.81 (m, 2H), 2.63 (t, J¼6.4 Hz, 2H), 2.33 (s, 3H), 2.20
(s, each 3H); 13C NMR (100 MHz, CDCl3)
d: 166.5 (s), 143.8 (s), 143.7
(s), 133.5 (d), 129.7 (d), 128.9 (s), 128.6 (d), 128.4 (d), 127.7 (d), 126.9
(d), 126.8 (d), 109.7 (s), 104.5 (d), 86.7 (s), 86.7 (s), 85.7 (d), 84.0 (d),
77.5 (d), 75.7 (d), 74.7 (d), 65.4 (t), 63.9 (t), 63.4 (t), 26.5 (q), 26.6 (q);
HRESIMS m/z 905.3670 [MþNa]þ, calcd for C57H54O9Na, 905.3666.
(s, 3H), 1.39, 1.38 (s, each 3H); 13C NMR (100 MHz, CDCl3)
d: 206.4
(s), 172.2 (s), 137.4 (s), 132.0 (d), 130.9 (s),129.7 (d), 95.2 (d), 81.9 (d),
80.8 (d), 79.3 (d), 75.4 (d), 65.5 (t), 37.8 (t), 29.7 (q), 27.9 (t), 25.6 (q),
25.4 (q), 21.0 (q).
4.1.18. (2R,3S,4R,5S)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-
oxopentanoyloxy)-2-(2-phenyl-1,3-dioxan-5-yloxy)tetrahydrofuran-
3-yl benzoate (30). This compound was prepared from 26 (100 mg,
0.19 mmol) and 3 (72 mg, 0.4 mmol), using the same reagents and
4.1.15. (2S,3S,4R,5S)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-
oxopentanoyloxy)-2-(p-tolyl-thio)tetrahydrofuran-3-yl
benzoate
(26). Benzyl chloride (0.8 mL, 80 mmol) was added to a solution of
compound 25 (3.3 g, 7.78 mmol) in anhydrous pyridine (10 mL) at
0 ꢁC. The mixture was stirred at rt for 2 h. After removal of solvents
under vacuum, the crude residue was purified by column chro-
matography, eluting with petroleum ether/EtOAc (6:1, v/v), to af-
ford compound 26 (3.9 g, 95%) as a colorless syrup. 1H NMR
procedure as described for the synthesis of compound 27. The
20
product 30 was obtained as a colorless syrup (75 mg, 67%). [a]
D
ꢀ27.2 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 8.04 (dd,
J1¼1.6 Hz, J2¼6.8 Hz, 2H), 7.31e7.60 (m, 10H), 5.56 (s, 1H), 5.45 (s,
1H), 5.43 (s, 1H), 5.21 (d, J¼4.4 Hz, 1H), 4.41 (m, 3H), 4.24 (t,
J¼5.2 Hz, 1H), 4.04e4.17 (m, 4H), 3.89e3.93 (m, 1H), 2.58e2.79 (m,
4H), 2.12 (s, 3H), 1.44, 1.38 (s, each 3H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d
: 8.13 (d, J¼7.6 Hz, 2H), 8.04 (d, J¼7.6 Hz, 2H),
7.63e7.42 (m, 3H), 7.13 (d, J¼7.6 Hz, 2H), 5.62 (s, 1H), 5.46 (s, 1H),
5.34 (d, J¼2.2 Hz, 1H), 4.47 (m, 1H), 4.38 (m, 1H), 4.09 (t, J¼7.6 Hz,
1H), 3.96 (t, J¼8.0 Hz, 1H), 2.79 (m, 2H), 2.64 (m, 2H), 2.32 (s, 3H),
d: 206.4 (s),171.8 (s),165.1 (s),138.1 (s),133.4 (d),129.8 (d),129.0 (s),
128.9 (d), 128.4 (d), 128.2 (d), 126.0 (d), 109.8 (s), 104.6 (d), 101.1 (d),
83.4 (d), 82.0 (d), 77.3 (d), 75.5 (d), 70.5 (t), 68.5 (d), 68.4 (t), 65.6 (t),
37.7 (t), 29.6 (q), 27.9 (t), 26.3 (q), 25.2 (q); HRESIMS m/z 607.2158
[MþNa]þ, calcd for C31H36O11Na, 607.2155.
2.17 (s, 3H), 1.41, 1.37 (s, each 3H); 13C NMR (100 MHz, CDCl3)
d:
206.3 (s), 171.7 (s), 165.2 (s), 138.0 (s), 138.8 (d), 133.6 (d), 133.0 (d),
130.2 (d), 129.9 (d), 129.8 (d), 129.5 (s), 129.0 (s), 128.8 (d), 128.8 (d),
109.8 (s), 91.4 (d), 82.2 (d), 81.9 (d), 77.8 (d), 75.1 (d), 65.5 (t), 37.9
(t), 29.8 (q), 28.0 (t), 26.3 (q), 25.3 (q), 21.2 (t); ESIMS m/z: 450
[MþH]þ.
4.1.19. (2R,3S,4R,5R)-5-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-
hydroxy-2-(2-phenyl-1,3-dioxan-5-yloxy)tetrahydrofuran-3-yl ben-
zoate (31). This compound was prepared from 30 (750 mg,
1.28 mmol) and hydrazine acetate (176 mg, 1.92 mmol) in
dichloromethane, using the same procedure as described for the
The NMR data of known compounds 24, 25, and 26 are in con-
sistent with those reported in the literature.8
synthesis of compound 28. The product 31 was obtained as a col-
4.1.16. (2R,3S,4R,5S)-2-(1,3-Bis(trityloxy)propan-2-yloxy)-5-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)-4-(4-oxopentanoyloxy)tetrahydrofuran-
3-yl benzoate (27). To a solution of compound 26 (100 mg,
0.19 mmol) and compound 4 (230 mg, 0.4 mmol) in anhydrous
orless syrup (449 mg, 72%). [
a
]
ꢀ53.1 (c 0.5, CHCl3); 1H NMR
20
D
(400 MHz, CDCl3)
d
: 8.03 (dd, J1¼1.2 Hz, J2¼7.2 Hz, 2H), 7.33e7.60
(m, 8H), 5.57 (s, 1H), 5.53 (s, 1H), 5.26 (d, J¼4.4 Hz, 1H), 4.39 (dd,
J1¼3.6 Hz, J2¼10.8 Hz, 2H), 4.26 (t, J¼6.8 Hz, 1H), 4.21 (m, 2H), 4.17
(m, 2H), 4.02 (m, 2H), 1.45, 1.38 (s, each 3H); 13C NMR (100 MHz,
ꢀ
dichloromethane (15 mL) was added 4 A molecular sieves (150 mg).
The mixture was stirred at 0 ꢁC for 10 min prior to the addition of
NIS (50 mg, 0.22 mmol). The subsequent reaction mixture was
stirred for an additional 30 min before AgOTf (4 mg, 0.02 mmol)
was added. The reaction mixture was stirred at 0 ꢁC for 4 h prior to
being quenched with Et3N. After diluting the mixture with
dichloromethane (20 mL) and filtration, the filtrate was rinsed with
saturated aqueous Na2S2O3 solution, water, and brine, and dried
over anhydrous Na2SO4. After removal of the organic solvents un-
der vacuum, the crude product was purified by column chroma-
CDCl3) d: 166.6 (s), 137.8 (s), 133.6 (d), 129.8 (d), 129.0 (d), 129.0 (s),
128.5 (d), 128.2 (d), 126.0 (d), 126.0 (d), 109.9 (s), 104.2 (d), 101.4 (d),
85.8 (d), 84.8 (d), 77.6 (d), 76.2 (d), 70.7 (t), 68.6 (d), 68.4 (t), 65.4 (t),
26.5 (q), 25.4 (q); HRESIMS m/z 509.1788 [MþNa]þ, calcd for
C26H30O9Na, 509.1788.
Acknowledgements
We are grateful to the National Natural Science Foundation of
tography, eluting with petroleum ether/EtOAc (3:1, v/v), to give
China (No. 81072550) for financial support of this research.
20
compound 27 (3.9 g, 95%) as a colorless syrup. [
a]
ꢀ8.6 (c 0.35,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
: 8.01e7.15 (m, 35H), 5.37 (s,
Supplementary data
1H), 5.34 (s, 1H), 5.21 (d, J¼4.8 Hz, 1H), 4.32e4.36 (m, 1H),
4.08e4.12 (m, 2H), 4.01 (t, J¼8.0 Hz, 1H), 3.81 (t, J¼8.0 Hz, 1H),
3.22e3.37 (m, 4H), 2.42e2.67 (m, 4H), 2.02 (s, 3H), 1.37 (s, 6H);
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.069.

4030
P. He et al. / Tetrahedron 70 (2014) 4022e4030
8. Zhu, S.-Y.; Yang, J.-S. Tetrahedron 2012, 68, 3795e3802.
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