Stereoselective glycosylation of endo-glycals by microwave- and AlCl 3-assisted catalysis

Article abstract of DOI:10.1016/j.tet.2011.05.124

α-2-Deoxyglycosides were synthesized in good to excellent yields by microwave-assisted reaction of endo-glycals with various O-nucleophiles in the presence of catalytic amount of AlCl₃. These glycosyl additions occurred with high α-stereoselect

Full text of DOI:10.1016/j.tet.2011.05.124

Tetrahedron 67 (2011) 6362e6368
Contents lists available at ScienceDirect
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Stereoselective glycosylation of endo-glycals by microwave- and AlCl3-assisted
catalysis
,
b
a
a
b,
*
Hui-Chang Lin a , Jia-Fu Pan , Yen-Bo Chen , Zi-Ping Lin , Chun-Hung Lin
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan
b Institute of Biological Chemistry, Academia Sinica, No. 128, Academia Road, Section 2, Nan-Kang, Taipei 11529, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-2-Deoxyglycosides were synthesized in good to excellent yields by microwave-assisted reaction of
Received 16 February 2011
Received in revised form 26 May 2011
Accepted 31 May 2011
endo-glycals with various O-nucleophiles in the presence of catalytic amount of AlCl3. These glycosyl
additions occurred with high
a
-stereoselectivity and were complete in 5e35 min in 65e93% yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 6 June 2011
Keywords:
2-Deoxyglycoside
Microwave
Glycosylation
endo-Glycal
Lewis acid
1. Introduction
by AlCl3-catalyzed additions of endo-galactals. Several issues were
addressed in depth, including the effects of Lewis acid, the sub-
stituent at C3-position and nucleophile substrates, plus the mech-
anistic study.
Many biologically important natural products1 contain one or
more 2-deoxyglycosides in their scaffolds, such as anthracyclin an-
tibiotics,2 aureolic acids,3 avermectins,4 orthosomycins,5 cardiac
glycosides,6 and angucycline.7 Because the moiety of 2-deoxygly-
cosides was essential for their biological activities, many methods
have been developed to synthesize 2-deoxyglycosides.8e10 For in-
stance, they can be prepared by formation of 2-iodo-2-deoxygly-
coside, followed by dehalogenation.8 Likewise, similar procedures
also include the formation of 2-chloro-2-deoxyglycoside and sub-
sequent radical dechlorination,9 as well as the preparation of
2-deoxy-2-phenylthio-glycoside followed by the reduction of Raney
Nickel.10 Previous reports indicated that acid-catalyzed addition to
glycals represents the most direct method that can be operated
under various conditions, including hydrogen bromide,11 triphe-
nylphosphine hydrogenbromide,12 Dowex-50 [Hþ] in the presence
of LiBr,13 CeCl3$7H2O/NaI,14 LaCl3$7H2O/NaI,15 TMSOTfeNEt3,16 BCl3
(or BBr3),17 ceric ammonium nitrate,18 GaCl3,19 and Rhenium(V)
[ReOCl3(SMe2)(OPPh3)].20 We recently applied microwave-assisted
2. Result and discussion
3,4,6-Tri-O-benzyl-
D
-galactal (1), prepared from 3,4,6-tri-O-
acetyl-
D
-galactal based on a reported procedure,22 first reacted
with cyclohexanol under a solvent-free condition. Several Lewis
acids (0.2 equiv) were examined as the catalyst, including alumi-
num chloride (AlCl3), samarium chloride (SmCl3), iron chloride
(FeCl3), cerium chloride (CeCl3), zinc chloride (ZnCl2), tin chloride
(SnCl2), and europium trifluoromethanesulfonate (Eu(OTf)3). The
reactions were carried out at 50 ꢀC in an open vessel with 100 W of
microwave energy that was generated by the CEM ‘Discover’ Fo-
cused MicrowaveÔ Synthesis System. Most of the reactions were
complete within 10 min, as shown in Table 1. Among the reactions,
the use of AlCl3 was found to provide the desired product, cyclo-
hexyl 2-deoxy-
yield (90%) with high stereoselectivity (ratio of
a
-galactopyranoside (5), in the highest isolated
eanomers: 8/1).
glycosylation of hex-1-en-3-uloses to synthesize
a-2-deoxyulo-
-O-2-deoxyglycoside
a/b
sides.21 Herein we present the synthesis of
a
The same condition applied to other alcohol nucleophiles also led
to similar yields and excellent stereoselectivity (see entries vevii in
Table 2). Interestingly, formation of the rearranged product (6) was
also observed in the presence of several Lewis acids (see entries
ivevii in Table 1), indicating that the glycosylations likely occurs via
two different reaction routes, such as protonation and allylic
* Corresponding authors. Tel.: þ886 2 27890110; fax: þ886 2 26514705 (C.-H.L.);
tel.: þ886 4 22053366x5612; fax: þ886 4 22078083 (H.-C.L.); e-mail addresses:
huichang@mail.cmu.edu.tw, lhc550005@yahoo.com.tw (H.-C. Lin), chunhung@
gate.sinica.edu.tw (C.-H. Lin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.124

H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
6363
Table 1
Effect of Lewis acid on the glycosylations of endo-glycal 1 with cyclohexanola
BnO
BnO OBn
O
BnO
BnO
OBn
O
OBn
O
Lewis acid (cat)
microwave
OH
+
+
BnO
O
O
1
5
6
Entry
Lewis acid (cat)
Time (min)
Protonationþrearrangement
products (yield,
ratio)b
a/b
i
ii
AlCl3
SmCl3
CeCl3
FeCl3
ZnCl2
SnCl2
Eu(OTf)3
AlCl3
d
5
5
10
5
10
25
20
60
20
5 (90%, 8/1)þ6 (0%)
5 (88%, 8/1)þ6 (0%)
5 (88%, 7/1)þ6 (0%)
5 (78%)cþ6 (11%)
5 (52%)cþ6 (34%)
5 (72%)cþ6 (18%)
5 (81%)cþ6 (12%)
iii
iv
v
vi
vii
viii
ix
5 (92%, 4/1)dþ6 (0%)
5 (0%)bþ6 (0%)
a
The glycosyl additions were all under a solvent-free condition in the presence of cyclohexanol (>30 equiv).
b
c
All the reactions were carried out at 50 ꢀC with 100 W of microwave energy.
The
a
-anomer is predominant with
a/b
ratio of 5/1 to 8/1 on the basis of 1H NMR integration.
d
The reaction was carried out without microwave heating in a CH2Cl2 solution containing AlCl3 (1.0 equiv) and cyclohexanol at room temperature.
Table 2
Glycosylations of glycals 1e4 with various alcoholsa
BnO
XO
BnO
BnO
XO
OBn
O
OBn
O
OBn
O
AlCl3 (cat)
50 oC, 100 W
+
ROH
+
OR
OR
see the table for
protonation products
1, X = Bn; 2, X = Ac;
3, X = H; 4, X = CO tBu;
6
2
Entry
Donor
Acceptor (ROH)
Time (min)
Protonationþrearrangement
products (yield,
a/b)
i
ii
1
2
3
4
1
1
1
Cyclohexanol
Cyclohexanol
Cyclohexanol
Cyclohexanol
n-Octanol
5
5
10
5
5
5
5 (90%, 8/1), d(0%)
7 (85%, 9/1), d(0%)
8 (81%, 8/1), d(0%)
9 (69%)bþ6 (10%)b
iii
iv
v
vi
vii
10 (94%, 6/1), d(0%)
11 (95%, 7/1), d(0%)
12 (92%, 10/1), d(0%)
Benzyl alcohol
Isopropanol
5
a
The glycosyl additions were all under a solvent-free condition in the presence of AlCl3 (0.2 equiv) and excessive alcohol nucleophile (>30 equiv).
b
The a-anomer is predominant with a/b
ratio of 5/1 to 8/1 on the basis of 1H NMR integration.
rearrangement.25 Apparently the presence of AlCl3 allows the for-
mer pathway only.
isopropylidene-
a
-
D
-galactopyranoside (13), there was no reaction
in the absence of solvent. But the addition of CH2Cl2 led to forma-
tion of the desired product 21 in 82% yield (see entry i in Table 3).
The same glycosyl donor (1) further reacted with several O-nucle-
ophiles in 0.5 mL CH2Cl2, including sugars 14e17 (entries iiev in
Table 3), and amino acid derivatives 18e20 (entries vieviii in Table
Although both AlCl3 and the microwave energy were used for
these reactions, each one was found to play a different role.
Without the microwave heating, the reaction of compound 1 with
cyclohexanol took much longer time for completion (see entry viii
in Table 1). The resulting stereoselectivity was lower than that
observed in the aforementioned examples, indicating that micro-
wave energy is necessary for accelerating the reaction and en-
hancing the selectivity. In contrast, there was no reaction in the
absence of AlCl3 (entry ix in Table 1), indicating that the glycosyl-
ation reactions require Lewis acid to take place.
3), to give 2-deoxy- -galactoside products 22e28 in moderate to
D
good yields, as shown in Table 3. As a result, we demonstrated that
this AlCl3- and microwave-assisted glycosylation is useful for for-
mation of various glycosides, glycopeptides and glycolipids.
We previously investigated trifluoroacetic acid (TFA)-catalyzed
glycosylations of endo- and exo-glycals where these reactions were
also found to proceed via two pathways, such as Ferrier rear-
rangement and protonation.24 The results indicated that protecting
group and allylic substituent (equivalent to C3-substituent in this
study) are critical to determine the favored reaction route. In-
terestingly we discovered that the usage of AlCl3 not only becomes
an additional factor, but also leads to exclusive formation of 2-
deoxygalactosides via the protonation pathway.
Furthermore, we examined how C3-substituents of endo-gal-
actal affect the glycosylation reaction, including benzyl (com-
pounds 1), acetate (2), hydroxyl (3) and tert-butyl carbonate groups
(4). The exclusive formation of 2-deoxy-
see entries ieiii) was still observed with high stereoselectivity
(ratio of -anomers: 8/1 to 9/1), except for the reaction of com-
D
-galactosides (5, 7, and 8,
a/b
pound 4 that generated both the desired product 9 (69%) and the
minor rearranged product (10%). It seemed that the change on C3-
substituent did not make significant difference.
The aforementioned reactions were carried out under solvent-
free conditions. When the acceptor substrate no longer exists as
liquid or oil, usage of solvent is required to promote the reactivity.
For instance, when the glycosyl donor 1 reacted with 1,2:3,4-di-O-
The reactions all displayed high
a-stereoselectivity, i.e., the
nucleophiles attacked from the bottom face of the sugar ring. This
result is not only consistent with the anomeric effect, but also fa-
vorable by the less steric hindrance (i.e., the axial hydroxyl group at
C4-position prefers
a-stereoselectivity). In contrast, the reactions of
tri-O-benzyl- -glucal with alcohol substrates (analogues to those of
D

6364
H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
Table 3
80% yield, as shown in Scheme 1. After deprotection under basic
condition, the product was subjected to another glycosylation with
Glycosylations of glycals 1 with various alcohols
BnO
BnO
BnO OBn
O
OBn
O
the glycosyl donor 2 to give the trisaccharide 31 in 54% yield as
ROH
AlCl3/CH2Cl2
50oC, 100 W
a mixture of a/b anomers (ratio of 96/4). Both glycosylation addi-
BnO
tions were carried out with 0.2 equiv of AlCl3 at 50 ꢀC with 100 W of
microwave energy.
1
OR
b
Entry
Acceptor (ROH)a
Time (min)
15
Products (yield, a/b)
OBn
O
BnO
AcO
OH
O
OH
O
BnO
AcO
OBn
O
cata. AlCl3/CH2Cl2
O
MeO
MeO
13
O
+
i
21 (82%, 94/6)
22 (76%, 92/8)
O
O
50 oC, 100 W
O
O
MeO
OMe
MeO
MeO
30 min
80%
2
14
MeO
OMe
29
OH
O
MeO
MeO
14
ii
15
20
MeO
OBn
O
BnO
AcO
OMe
OBn
O
BnO
HO
OBn
O
BnO
1. 2
HO
O
K2CO3
O
cata. AlCl /CH Cl
2
2.
3
50 oC, 100 W
80 min
2
O
O
O
15
MeOH
rt, 4 h
95%
O
O
iii
23 (71%, 95/5)
MeO
MeO
MeO
MeO
O
O
54%
MeO
OMe
MeO
OMe
30
31
Scheme 1.
OH
O
CH3O2CO
16
iv
15
35
24 (72%, 93/7)
25 (65%, 94/6)
In order for examining the mechanistic detail, 3,4,6-tri-O-ben-
zyl- -galactal 1 was treated with deuterium butanoxide. In-
O
D
O
triguingly the resulting product (32, in 88% yield) contained the
deuterium exclusively at the C2-equatorial position. Since it was
a solvent-free operation, deuterium chloride was rationalized to
result from the reaction of deuterium butanoxide with AlCl3
(Scheme 2). Therefore, the benzyl group at C4 appeared to prevent
the protonation from the top face of the sugar ring, but we cannot
rule out the possibility that the steric hindrance is owing to the
coordination of Lewis acid with the benzyl groups and the ring
oxygen. Following the protonation with deuterium chloride, the
oxocarbonium ion (33) then formed as the intermediate to react
with the activated butanoxide (the nucleophile, see Scheme 2).
Under such circumstances, anomeric effect or/and the aforemen-
OBn
O
HO
17
v
BnO
BnO
OMe
OH
CO2Me
vi
15
15
26 (83%, 94/6)
27 (78%, 93/7)
18
BocHN
HN
O
(CH2)13CH3
viii
19
tioned hindrance plays a role in favoring the a-glycosyl addition to
generate the desired 2-deoxyglycoside 32.
HO
CO2Me
BnO
BnO
BnO OBn
O
OBn
O
Me
FmocHN
OH
AlCl3(cat)
50 oC, 100W
5 min
+
OD
BnO
20
vii
20
28 (74%, 92/8)
D
O
CO2Me
32
1
88%
a
The glycosyl additions were all catalyzed by AlCl3 (0.2 equiv) with 2 equiv of the
Mechanism:
acceptor was dissolved in 0.5 mL CH2Cl2.
b
The a-anomer is predominant with a/b
ratio of 92/8 to 95/5 on basis of 1H NMR
+
AlCl3
DOBu
DCl
Bn
+
Cl2Al OBu
Cl
integration.
Bn
O
Bn
Bn
O
O
OBn
O
O
O
BnO
AlCl3
AlCl3
BuO Al Cl
Cl
compound 1) offered similar reactivity and yield, but with lower
stereoselectivity (ratio of -anomers: 1.5/1 to 3/1). Furthermore,
Bn
Bn
O
O
O
AlCl3
+
BnO
a/b
D
Cl
D
D
33
OBu
the product structure and stereochemistry were rigorously de-
termined by using DEPT and COSY, in agreement with previous
reports.20,23 For example, the 1H NMR spectrum of compound 21
showed the characteristic signals, such as the resonance of the new
32
1
Scheme 2.
In conclusion, a-2-deoxygalactosides were successfully synthe-
anomeric proton at
(dd). In the corresponding 13C NMR spectrum,
assigned for C1 and C2 of 2-deoxy- -galactoside, respectively.
d
5.03, H2a at
d
2.22 (ddd) and H2b at
d 2.02
sized byglycosyl additionofendo-galactals withseveralnucleophiles,
including simple alcohols, sugars, and amino acid derivatives. The
synthesis was operated in the presence of AlCl3 to occur via tandem
protonation and glycosylation under microwave-assisted condition.
This developed method was also applied for preparing the tri-
saccharide 31 with high stereoselectivity in a high overall yield.
d
96.3 and 31.3 were
D
Our developed method was further applied for the rapid as-
sembly of trisaccharide 31. As previously described (see entry ii of
Table 3), the addition of alcohol 14 to the CH2Cl2 solution of 3-O-
acetyl-4,6-di-O-benzyl- -galactal 2 afforded the disaccharide 29 in
D

H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
6365
3. Experimental section
3.1. General procedure
H2a), 1.97 (3H, s, CH3), 1.82e1.70 (3H, m, H2b, H20), 1.69e19 (8H, m,
cyclohexyl); 13C NMR (CDCl3, 100 MHz)
170.34, 138.48, 138.09,
128.32, 128.31, 128.27, 128.26, 128.06, 128.05, 127.60, 127.59, 127.58,
127.57, 95.24, 74.75, 74.64, 73.80, 73.29, 69.82, 69.16, 69.11, 33.38,
31.50, 31.08, 25.65, 24.22, 23.97, 21.12; HRMS (ESI) for C28H36O6Naþ
[MþNaþ] calcd 491.2410, found: 491.2407. Anal. Calcd for C28H36O6;
C: 71.77; H: 7.74. Found: C: 72.01; H: 7.76.
d
All purchased chemicals were of reagent grade. All reactions
were carried out under a nitrogen atmosphere and monitored by
TLC analysis (layer thickness: 250 mm). Column chromatography
was carried out with silica gel 60 (70e230 mesh for gravity column,
or 230e400 mesh for flash column). Commercially available re-
agents were directly used without further purification unless oth-
erwise noted. Dichloromethane, ethyl acetate, hexanes, and
methanol were purchased from Mallinckrodt Chemical Co. The
following compounds were purchased from Acros Chemical Co,
including benzyl alcohol, n-octanol, cyclohexanol, isopropanol,
3.2.3. Cyclohexyl-2-deoxy-4,6-di-O-benzyl-
(8). Pale yellow oil; [a]
D
a
-
D
-lyxo-hexopyranoside
þ23.5 (c 0.022, CHCl3); IR (CHCl3)
3400e3200, 2960, 1633, 1240, 1020 cmꢁ1 1H NMR (CDCl3,
400 MHz)
7.35e7.25 (10H, m, ArH), 5.07 (1H, d, J1,2a¼2.8 Hz, H1),
25
;
d
4.73 (1H, d, J¼11.6 Hz, PhCH2), 4.62 (1H, d, J¼11.6 Hz, PhCH2), 4.57
(1H, d, J¼11.6 Hz, PhCH2), 4.50 (1H, d, J¼12.0 Hz, PhCH2), 4.06 (2H,
m, H3, H5), 3.80 (1H, d, J4,3¼2.4 Hz, H4), 3.68 (1H, dd, J6a,5¼8.0 Hz,
J6a,6b¼10.2 Hz, H6a), 3.60 (1H, dd, J6b,5¼6.4 Hz, J6b,6a¼10.2 Hz, H6b),
3.54e3.50 (1H, m, H10), 1.90 (1H, ddd, J2a,1¼2.8 Hz, J2a,2b¼12.4 Hz,
J2a,3¼12.8 Hz, H2a), 1.87e1.81 (2H, m, H2a0,H2b), 1.73e1.19 (9H, m,
iodomethane, tri-O-acetyl-
carbonate, sodium hydride, AlCl3, SmCl3, FeCl3, CeCl3, ZnCl2, SnCl2,
Eu(OTf)3, 1,2:3,4-di-O-isopropylidene- -galactopyranose, N-tert-
butoxycarbonyl- -serine methyl ester, N-(9-fluorenylmethoxycar-
bonyl)- -threonine methyl ester. Proton NMR spectra were recor-
ded at a Bruker spectrometer (200 or 400 MHz) with CDCl3 (dH 7.24)
and DMSO-d6 dH 2.50) as the internal standard; Carbon-13 NMR
D-galactal, benzyl chloride, potassium
a-D
L
L
cyclohexyl); 13C NMR (CDCl3, 100 MHz)
d 138.49, 137.98, 128.56,
128.55, 128.38, 128.37, 127.99, 127.98, 127.90, 127.89, 127.69, 127.68,
95.41, 76.68, 75.13, 74.59, 73.40, 69.24, 69.14, 65.80, 35.08, 33.41,
31.54, 25.68, 24.25, 23.99; HRMS (ESI) for C26H34O5Naþ [MþNaþ]
calcd 449.2304, found: 449.2310. Anal. Calcd for C26H34O5; C:
73.21; H: 8.03. Found: C: 73.23; H: 8.05.
(
spectra were recorded at 50 or 100 MHz with CDCl3 [dC 77.0 (central
line of a triplet)]. Splitting patterns are shown by the abbreviations,
such as s (singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet). Microwave irradiation experiments were performed
using a single-mode Discover System from ‘Discover’ Focused
MicrowaveTM Synthesis System.
3.2.4. Cyclohexyl-2-deoxy-3-O-tert-butoxycarbonyl-4,6-di-O-ben-
25
zyl-
a
-
D
-lyxo-hexopyranoside (9). Pale yellow oil; [
a]
þ23.6 (c
1H
d 7.33e7.24 (10H, m, ArH), 5.13 (1H, d,
D
0.018, CHCl3); IR (CHCl3) 2991, 1750, 1648, 1230, 1060 cmꢁ1
;
3.2. Typical procedure of solvent-free glycosylation for
NMR (CDCl3, 400 MHz)
preparing 2-deoxygalacoside derivatives 5, 7e12
J1,2a¼2.8 Hz, H1), 5.07 (1H, ddd, J3,4¼3.2 Hz, J3,2b¼4.4 Hz,
J3,2a¼12.8 Hz, H3), 4.76 (1H, d, J¼11.5 Hz, PhCH2), 4.50 (1H, d,
J¼11.6 Hz, PhCH2), 4.48 (1H, d, J¼10.0 Hz, PhCH2), 4.41 (1H, d,
J¼12.0 Hz, PhCH2), 4.07 (1H, dd, J5,6a¼6.0 Hz, J5,6b¼6.4 Hz, H5), 3.99
(1H, br s, H4), 3.55e3.49 (3H, m, H6, H10), 2.29 (1H, ddd,
J2a,1¼2.8 Hz, J2a,2b¼12.4 Hz, J2a,3¼12.8 Hz, H2a), 1.89e184 (3H, m,
H2b, H20), 1.70 (2H, br s, H60), 1.49 (9H, s, 3ꢂ CH3), 1.48e1.23 (6H, m,
endo-Galactal (e.g., 1e4, 1.0 equiv) was mixed with alcohol sub-
strate (30 equiv) and AlCl3 (0.2 equiv), and then treated with 100 W
of microwave energy at 50 ꢀC for 5e10 min. The reaction mixture
was concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography with EtOAc/hexanes (1:5) to
give the desired product (e.g., 5, 7e12) in 70e90% yield.
cyclohexyl); 13C NMR (CDCl3, 125 MHz)
d 152.93, 138.37, 138.19,
128.43, 128.42, 128.29, 128.26, 128.23, 128.15, 127.83, 127.63, 127.55,
127.52, 95.21, 82.19, 74.69, 74.55, 73.36, 73.26, 72.74, 69.42, 69.30,
33.39, 31.51, 31.09, 27.81, 27.80, 27.79, 25.67, 24.24, 23.98; HRMS
(ESI) for C32H44O11Naþ [MþNaþ] calcd 549.2828, found: 549.2819.
Anal. Calcd for C32H44O11; C: 70.70; H: 7.74. Found: C: 70.74; H: 7.77.
3.2.1. Cyclohexyl-2-deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyrano-
25
side (5). Pale yellow oil; [
a]
D
þ21.5 (c 0.037, CHCl3); IR (CHCl3)
2931, 1650, 1254, 1040 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.34e7.23
(15H, m, ArH), 5.13 (1H, d, J1,2a¼3.6 Hz, H1), 4.93 (1H, d, J¼12.0 Hz,
PhCH2), 4.62 (1H, d, J¼9.6 Hz, PhCH2), 4.60 (2H, br s, CH2Ph), 4.51
(1H, d, J¼11.6 Hz, PhCH2), 4.43 (1H, d, J¼11.6 Hz, PhCH2), 3.98 (1H,
dd, J3,4¼6.4 Hz, J3,2a¼12.8 Hz, H3), 3.95(2H, br, H4, H5), 3.61 (1H, dd,
J6a,5¼7.2 Hz, J6a,6b¼9.6 Hz, H6a), 3.57 (1H, dd, J6b,5¼6.0 Hz,
J6b,6a¼9.6 Hz, H6b), 3.54e3.51 (1H, m, H10), 2.22 (1H, ddd,
J2a,1¼3.6 Hz, J2a,2b¼12.4 Hz, J2a,3¼12.8 Hz, H2a), 1.94 (1H, dd,
J2b,3¼4.4 Hz, J2b,2a¼12.4 Hz, H2b), 1.84 (2H, br s, H20), 1.70 (2H, br s,
H60), 1.52 (1H, br s, H3a0), 1.23 (5H, m, Cyclohexyl); 13C NMR (CDCl3,
3.2.5. Octyl-2-deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexopyranoside
(10). Pale yellow oil; [
a
]
D
25 þ29.4 (c 0.009, CHCl3); IR (CHCl3) 2935,
1631, 1250, 1050 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.27e7.16 (15H,
m, ArH), 4.88 (1H, d, J1,2a¼3.2 Hz, H1), 4.85 (1H, d, J¼12.0 Hz,
PhCH2), 4.53 (1H, d, J¼12.0 Hz, PhCH2), 4.52 (2H, br s, CH2Ph), 4.43
(1H, d, J¼12.0 Hz, PhCH2), 4.34 (1H, d, J¼12.0 Hz, PhCH2), 3.87e3.81
(3H, m, H3, H4, H5), 3.55e3.46 (3H, m, H6, H1a0), 3.30e3.25 (1H, m,
H1b0), 2.17e2.10 (1H, m, H2a), 1.92e1.89 (1H, m, H2b), 1.48e1.43
(2H, m, H20), 1.24e1.19 (10H, m, H30eH70), 0.80 (3H, t, J¼6.4 Hz,
100 MHz)
d 138.99, 138.65, 138.22, 128.36, 128.35, 128.34, 128.19,
128.18, 128.17, 128.16, 128.15, 127.65, 127.64, 127.60, 127.59, 127.45,
127.44, 127.31, 95.57, 75.05, 74.45, 74.26, 73.39, 73.22, 70.45, 69.84,
69.66, 33.48, 31.73, 31.62, 25.71, 24.33, 24.07; HRMS (ESI) for
C33H40O5Naþ [MþNaþ] calcd 539.2773, found: 539.2770. Anal.
Calcd for C33H40O5; C: 76.71; H: 7.80. Found: C: 76.75; H: 7.83.
CH3); 13C NMR (CDCl3, 100 MHz)
d 138.92, 138.57, 138.14, 128.32,
128.31, 128.30, 128.17, 128.16, 128.15, 128.14, 128.13, 128.12, 127.70,
127.69, 127.68, 127.58, 127.42, 127.41, 127.28, 127.27, 127.26, 97.68,
74.91, 74.23, 73.41, 73.07, 70.41, 69.76, 69.60, 67.47, 31.80, 31.27,
29.51, 29.37, 29.22, 26.20, 22.62, 14.06; HRMS (ESI) for C35H46O5Naþ
[MþNaþ] calcd 569.3243, found: 569.3247. Anal. Calcd for
C35H46O5; C: 76.89; H: 8.48. Found: C: 76.93; H: 8.51.
3.2.2. Cyclohexyl-2-deoxy-3-O-acetyl-4,6-di-O-benzyl-
a-
D
-lyxo-hex-
25
opyranoside (7). Pale yellow oil; [
(CHCl3) 2929, 1741, 1644, 1238, 1049 cmꢁ1
400 MHz)
a]
þ43.6 (c 0.024, CHCl3); IR
D
;
1H NMR (CDCl3,
7.34e7.25 (10H, m, ArH), 5.24 (1H, ddd, J3,4¼2.8 Hz,
d
3.2.6. Benzyl-2-deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranoside
25
J3,2b¼4.8 Hz, J3,2a¼12.4 Hz, H3), 5.12 (1H, d, J1,2a¼3.2 Hz, H1), 4.67
(1H, d, J¼11.6 Hz, PhCH2), 4.54 (1H, d, J¼11.6 Hz, PhCH2), 4.53 (1H, d,
J¼12.0 Hz, PhCH2), 4.44 (1H, d, J¼11.6 Hz, PhCH2), 4.11 (1H, dd,
J5,6a¼6.4 Hz, J5,6b¼6.8 Hz, H5), 3.93 (1H, br, H4), 3.61e3.51 (3H, m,
H6, H10), 2.25 (1H, ddd, J2a,1¼3.2 Hz, J2a,2b¼12.4 Hz, J2a,3¼12.4 Hz,
(11). Pale yellow oil; [
a]
D
þ30.1 (c 0.013, CHCl3); IR (CHCl3) 2955,
1650, 1235,1022 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.27e7.12 (20H,
m, ArH), 4.98 (1H, d, J1,2a¼3.2 Hz, H1), 4.84 (1H, d, J¼11.6 Hz,
PhCH2), 4.56 (2H, br s, PhCH2), 4.50 (2H, br s, CH2Ph), 4.41 (1H, d,
J¼11.6 Hz, PhCH2), 4.37 (1H, d, J¼12.4 Hz, PhCH2), 4.33 (1H, d,

6366
H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
0
0
0
J¼12.4 Hz, PhCH2), 3.89e3.84 (3H, m, H3, H4, H5), 3.52e3.45 (2H,
m, H6), 2.21e2.12 (1H, m, H2a), 1.95 (1H, dd, J2b,3¼3.6 Hz,
J1 ,2 ¼3.6 Hz, H1 ), 4.62 (1H, d, J¼11.6 Hz, PhCH2), 4.59 (2H, br s,
PhCH2), 4.50 (1H, d, J¼11.6 Hz, PhCH2), 4.43 (1H, d, J¼11.6 Hz,
J2b,2a¼12.4 Hz, H2b); 13C NMR (CDCl3, 100 MHz)
d
138.90, 138.53,
PhCH2), 3.95e3.88 (3H, m, H3, H4, H5), 3.79 (1H, dd, J6a ,5 ¼5.2 Hz,
0
0
0
0
0
138.13, 137.87, 128.52, 128.40, 128.39, 128.38, 128.37, 128.36, 128.35,
128.22, 128.21, 128.20, 128.19, 127.94, 127.93, 127.76, 127.75, 127.62,
127.49, 127.33,127.32, 126.94, 97.11, 74.85, 74.28, 73.46, 73.05, 70.47,
70.11, 69.59, 68.90, 31.13; HRMS (ESI) for C34H36O5Naþ [MþNaþ]
calcd 547.2460, found: 547.2462. Anal. Calcd for C34H36O5; C: 77.84;
H: 6.92. Found: C: 77.87; H: 6.97.
J6a ,6b ¼11.6 Hz, H6a ), 3.62 (3H, s, OCH3), 3.59e3.54 (4H, m, H6a,
H6b, H50, H6b0), 3.51e3.42 (7H, m, H30, OCH3), 3.33 (3H, s, OCH3),
0
0
0
0
0
3.17 (1H, dd, J2 ,1 ¼3.6 Hz, J2 0,3 ¼9.6 Hz, H2 ), 3.09 (1H, dd,
0
0
0
0
J4 ,3 ¼9.2 Hz, J4 ,5 ¼9.2 Hz, H4 ), 2.23 (1H, ddd, J2a,1¼3.2 Hz,
J2a,2b¼12.4 Hz, J2a,3¼12.8 Hz, H2a), 2.04 (1H, dd, J2b,3¼3.6 Hz,
J2b,2a¼12.4 Hz, H2b); 13C NMR (CDCl3, 100 MHz)
d 138.86, 138.39,
138.13, 128.38, 128.37, 128.34, 128.33, 128.20, 128.19, 128.18, 128.17,
127.70, 127.62, 127.54, 127.53, 127.47, 127.37, 127.36, 98.05, 97.23,
83.61, 81.85, 79.51, 74.36, 74.25, 73.34, 72.94, 70.27, 69.98, 69.63,
69.44, 65.82, 60.81, 60.29, 58.92, 54.96, 31.01; HRMS (ESI) for
C37H48O10Naþ [MþNaþ] calcd 675.3145, found: 675.3146. Anal.
Calcd for C37H48O10; C: 68.08; H: 7.41. Found: C: 68.12; H: 7.42.
3.2.7. Isopropyl-2-deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyrano-
25
side (12). Pale yellow oil; [
a]
D
þ130.3 (c 0.014, CHCl3); IR (CHCl3)
2934, 1641, 1242, 1034 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.41e7.28
(15H, m, ArH), 5.15 (1H, d, J1,2a¼3.2 Hz, H1), 4.99 (1H, d, J¼11.6 Hz,
PhCH2), 4.68 (1H, d, J¼11.6 Hz, PhCH2), 4.67 (2H, br s, CH2Ph), 4.57
(1H, d, J¼11.6 Hz, PhCH2), 4.49 (1H, d, J¼11.6 Hz, PhCH2), 4.05e4.00
(3H, m, H3, H4, H5), 3.97e3.91 (1H, m, H1a0), 3.69 (1H, dd,
J6a,5¼7.2 Hz, J6a,6b¼9.6 Hz, H6a), 3.62 (1H, dd, J6b,5¼6.0 Hz,
J6b,6a¼9.6 Hz, H6b), 2.34e2.27 (1H, m, H2a), 2.03e1.98 (1H, m,
H2b), 1.24 (3H, d, J¼6.4 Hz, CH3), 1.18 (3H, d, J¼6.4 Hz, CH3); 13C
3.3.3. 2-Deoxy-3,4,6-tri-O-benzyl-
2,3-O-isopropylidene- -lyxono-1,4-lactone (23). Pale yellow oil;
þ0.1 (c 0.023, CHCl3); IR (CHCl3) 2936, 1742, 1649, 1236,
a-D-lyxo-hexopyranosyl-(1/5)-
D
25
[a]
D
1062 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 7.40e7.25 (15H, m, ArH),
NMR (CDCl3, 100 MHz)
d
138.97, 138.64, 138.17, 128.35, 128.34,
4.94 (1H, d, J¼11.6 Hz, PhCH2), 4.89 (1H, d, J1,2a¼2.8 Hz, H1),
0
0
128.33, 128.32, 128.17, 128.16, 128.15, 128.14, 127.69, 127.68, 127.59,
127.41,127.27,127.26,127.25, 95.56, 75.04, 74.25, 73.42, 73.14, 70.44,
69.75, 69.55, 68.03, 31.65, 23.32, 21.35; HRMS (ESI) for
C30H36O5Naþ [MþNaþ] calcd 499.2460, found: 499.2465. Anal.
Calcd for C30H36O5; C: 75.60; H: 7.61. Found: C: 75.63; H: 7.63.
4.69e4.58 (4H, 0 m, H3, PhCH2), 4.50 (1H, dd, J3 ,4 ¼3.6 Hz,
0
0
J3 ,2 ¼6.4 Hz, H3 ), 4.48 (1H, d, J¼11.6 Hz, PhCH2), 4.41 (1H, d,
0
0
0
J¼12 Hz, PhCH2), 4.31 (1H, d, J2 ,3 ¼6.4 Hz, H2 ), 3.85 (1H, br s, H4),
0
0
0
0
0
3.77 (1H, dd, J5a ,4 ¼1.2 Hz, J5a ,5b ¼11.2 Hz, H5a ), 3.69e3.63 (2H, m,
H40, H6a), 3.59e3.53 (3H, m, H5b0, H6b, H5), 2.18 (1H, ddd,
J2a,1¼2.8 Hz, J2a,3¼12.4 Hz, J2a,2b¼12.8 Hz, H2a), 1.88 (1H, dd,
J2b,3¼4.4 Hz, J2b,2a¼12.8 Hz, H2b), 1.46 (3H, s, CH3), 1.34 (3H, s, CH3);
3.3. Typical procedure of glycosylation for preparing 2-
deoxyglycoside derivatives (21e28)
13C NMR (CDCl3, 100 MHz)
d 173.94, 138.57, 137.81, 137.80, 128.59,
128.58, 128.44, 128.43, 128.27, 128.26, 128.25, 128.24, 127.93, 127.87,
127.86, 127.82, 127.63, 127.54, 127.53, 113.22, 99.01, 80.68, 78.00,
75.37, 74.26, 73.66, 72.95, 72.49, 70.92, 69.89, 69.57, 67.04, 30.38,
26.76, 25.56; HRMS (ESI) for C35H40O9Naþ [MþNaþ] calcd 627.2570,
found: 627.2560. Anal. Calcd for C35H40O9; C: 69.52; H: 6.67. Found:
C: 69.55; H: 6.71.
To a stirred solution of endo-galactal (e.g., 1, 1.0 equiv) in CH2Cl2
(2.0 mL) were added alcohol substrate (3 equiv) and AlCl3
(0.2 equiv). The reaction mixture was subjected to microwave ra-
diation of 100 W at 50 ꢀC for 15e35 min. Upon reaction completion,
the mixture was concentrated under reduced pressure and then
purified by silica gel chromatography with EtOAc/hexanes (1:5) to
give the desired glycoside product (e.g., 21e28) in 65e80% yield.
3.3.4. 2-Deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexopyranosyl-(1/3)-
5-O-carbomethoxy-1,2-O-isopropylidene- -xylofuranose (24). Pale
D
3.3.1. 2-Deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranosyl-(1/6)-
yellow oil; [
a
]
25 þ5.0 (c 0.043, CHCl3); IR (CHCl3) 2928, 1726, 1644,
D
1,2:3,4-di-O-isopropylidene-
D
-galactopyranose 21. Pale yellow oil;
1244, 1045 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
7.31 (15H, m, ArH),
25 þ2.4 (c 0.037, CHCl3); IR (CHCl3) 2923, 1649, 1230, 1028 cmꢁ1
;
5.85 (1H, d, J1 ,2 ¼3.6 Hz, H1 ), 5.08 (1H, d, J1,2a¼3.20 Hz, H1), 4.92
0
0
0
[a]
D
1H NMR (CDCl3, 400 MHz)
d
7.35e7.21 (15H, m, ArH), 5.51 (1H, d,
(1H, d, J¼11.6 Hz, PhCH2), 4.83 (1H, d, J2 ,1 ¼3.6 Hz, H2 ), 4.59 (2H, br
0
0
0
0
0
J1 ,2 ¼5.2 Hz, H1 ), 5.03 (1H, d, J1,2a¼2.8 Hz, H1), 4.92 (1H, d,
J¼11.6 Hz, PhCH2), 4.62 (1H, d, J¼11.6 Hz, PhCH2), 4.62e4.57 (3H, m,
H30, CH2Ph), 4.49 (1H, d, J¼12.0 Hz, PhCH2), 4.42 (1H, d, J¼12.0 Hz,
s, PhCH2), 4.58 (1H, d, J¼11.6 Hz, PhCH2), 4.50 (1H, d, J¼12.0 Hz,
0
0
PhCH2), 4.42 (1H,0d, J¼11.6 Hz, PhCH2), 4.41 0(1H, d0d, J4 ,3 ¼3.6 Hz,
0
0
J4 ,5a ¼6.8 Hz, H4 ), 4.32e4.30 (2H, m, H5a , H5b ), 4.14 (1H, d,
0
0
0
0
0
0
0
0
PhCH2), 4.30 (1H, dd, J2 1 ¼2.4 Hz, J2 3 ¼5.2 Hz, H2 ), 4.21 (1H, d0d,
J3 ,4 ¼2.8 Hz, H3 ), 3.88 (1H, dd, J5,6b¼4.8 Hz, J5,6a¼7.2 Hz, H5),
3.85e3.82 (2H, m, H3, H4), 3.79 (3H, s, OCH3), 3.60 (1H, dd,
J6a,5¼7.2 Hz, J6a,6b¼10.0 Hz, H6a), 3.46 (1H, dd, J6b,5¼4.8 Hz,
J6b,6a¼10.0 Hz, H6b), 2.21 (1H, ddd, J2a,1¼3.2 Hz, J2a,3¼12.4 Hz,
J2a,2b¼12.8 Hz, H2a), 1.96 (1H, dd, J2b,3¼4.4 Hz, J2b,2a¼12.8 Hz, H2b),
1.45 (3H, s, CH3), 1.14 (3H, s, CH3); 13C NMR (CDCl3, 100 MHz)
0
0
0
0 0
J4 3 ¼1.6 Hz, J4 5 ¼8.0 Hz, H4 ), 3.95e3.94 (4H, m, H3, H4, H5, H5 ),
3.74 (1H, dd, J6a,5¼6.8 Hz, J6a,6b¼10.4 Hz, H6a), 3.66 (1H, dd,
0
0
J6b,5¼6.4 Hz, J6b,6a¼10.4 Hz, H6b), 3.62 (1H, dd, J6a ,5 ¼7.6 Hz,
0
0
0
0
0
0
0
J6a ,6b ¼9.2 Hz, H6a ), 3.54 (1H, dd, J6b ,5 ¼5.6 Hz, J6b ,6a ¼9.2 Hz,
H6b0), 2.22 (1H, ddd, J2a,1¼2.8 Hz, J2a,3¼12.0 Hz, J2a,2b¼12.4 Hz, H2a),
2.02 (1H, dd, J2b,3¼4.0 Hz, J2b,2a¼12.4 Hz, H2b),1.51 (3H, s, CH3),1.42
(3H, s, CH3), 1.33 (6H, s, 2ꢂ CH3); 13C NMR (CDCl3, 100 MHz)
d
155.51, 138.61, 138.23, 137.95, 128.45, 128.44, 128.39, 128.38,
128.24, 128.23, 128.22, 128.21, 127.75, 127.74, 127.68, 127.64, 127.60,
127.39, 127.38, 111.78, 105.07, 100.14, 82.89, 82.17, 77.49, 74.24,
74.18, 73.60, 73.09, 71.19, 70.52, 70.35, 65.01, 54.94, 31.15, 26.72,
25.99; HRMS (ESI) for C37H44O11Naþ [MþNaþ] calcd 687.2781,
found: 687.2785. Anal. Calcd for C37H44O11; C: 66.85; H: 6.67.
Found: C: 66.87; H: 6.69.
d
138.95, 138.61, 138.14, 128.37,128.36, 128.35, 128.34, 128.21,
128.20, 128.18, 128.17, 127.81, 127.80, 127.61, 127.45, 127.44, 127.30,
127.29, 109.30, 108.51, 97.53, 96.35, 74.70, 74.30, 73.37, 72.91, 71.09,
70.68, 70.63, 70.41, 69.83, 69.20, 65.85, 65.54, 31.11, 26.11, 25.96,
24.93, 24.54; HRMS (ESI) for C39H48O10Naþ [MþNaþ] calcd
699.3125, found: 699.3125. Anal. Calcd for C39H48O10; C: 69.21; H:
7.15. Found: C: 69.26; H: 7.19.
3.3.5. 2-Deoxy-3,4,6-tri-O-benzyl-
2,3,6-tri-O-benzyl-1-O-methyl- -glucopyranose (25). Pale yellow
þ23.9 (c 0.038, CHCl3); IR (CHCl3) 2929, 1641, 1235,
1052 cmꢁ1 1H NMR (CDCl3, 400 MHz)
7.35e7.20 (30H, m, ArH),
a-D-lyxo-hexopyranosyl-(1/4)-
a-D
25
3.3.2. 2-Deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranosyl-(1/6)-
oil; [a]
D
25
1,2,3,4-tetra-O-methyl-
a
-
D
-glucopyranose (22). Pale yellow oil; [
a
]
;
d
þ23.9 (c 0.038, CHCl3); IR (CHCl3) 2932, 1632, 1240, 1051 cmꢁ1; 1DH
5.47 (1H, d, J1,2a¼3.2 Hz, H1), 4.99 (1H, d, J¼10.8 Hz, PhCH2), 4.88
(1H, d, J¼11.6 Hz, PhCH2), 4.73 (1H, d, J¼12.0 Hz, PhCH2), 4.65 (1H, d,
J¼11.2 Hz, PhCH2), 4.61 (1H, d, J¼10.4 Hz, PhCH2), 4.59 (1H, d,
NMR (CDCl3, 400 MHz)
d 7.34e7.22 (15H, m, ArH), 5.04 (1H, d,
J1,2a¼3.2 Hz, H1), 4.93 (1H, d, J¼11.6 Hz, PhCH2), 4.74 (1H, d,

H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
6367
0
0
0
J1 ,2 ¼3.6 Hz, H1 ), 4.58 (1H, d, J¼11.2 Hz, PhCH2), 4.54 (1H, d,
J¼12.0 Hz, PhCH2), 4.52 (1H, d, J¼11.6 Hz, PhCH2), 4.49 (1H, d,
J¼11.6 Hz, PhCH2), 4.38 (1H, d, J¼12.0 Hz, PhCH2), 4.37 (1H, d,
J¼12.0 Hz, PhCH2), 4.31 (1H, d, J¼11.6 Hz, PhCH2), 3.89e3.76 (4H, m,
H3, H30, H6a, H6b), 3.73e3.59 (4H, m, H40, H50, H6a0, H6b0),
3.51e3.43 (3H, m, H20, H4, H5), 3.39 (3H, s, OCH3), 2.12 (1H, ddd,
J2a,1¼3.2 Hz, J2a,2b¼12.4 Hz, J2a,3¼12.8 Hz, H2a), 1.87 (1H, dd,
J2b,3¼4.4 Hz, J2b,2a¼12.4 Hz, H2b); 13C NMR (CDCl3, 100 MHz)
PhCH2), 4.36e425 (3H, m, H10, H3a0, H3b0), 3.93 (2H, br s, H4, H5),
3.86 (1H, ddd, J3,4¼1.6 Hz, J3,2b¼3.6 Hz, J3,2a¼12.4 Hz, H3), 3.73 (3H,
s, OCH3), 3.58e3.52 (2H, m, H6a, H6b), 2.17 (1H, ddd, J2a,1¼3.2 Hz,
J2a,3¼12.4 Hz, J2a,2b¼12.8 Hz, H2a), 1.85 (1H, dd, J2b,3¼4.0 Hz,
J2b,2a¼12.8 Hz, H2b), 1.24 (3H, d, J1 ,5 ¼6.4 Hz, CH3); 13C NMR (CDCl3,
0
0
100 MHz)
d 171.18, 156.59, 143.89, 143.71, 141.31, 141.30, 138.76,
138.31, 138.02, 128.40, 128.39, 128.36, 128.35, 128.19, 128.18, 128.14,
128.13, 127.72, 127.71, 127.70, 127.66, 127.65, 127.51, 127.50, 127.40,
127.39, 127.07, 127.06, 125.05, 119.98, 119.97, 119.96, 99.35, 75.10,
74.26, 74.25, 73.49, 72.89, 70.45, 70.38, 69.46, 67.14, 58.73, 52.38,
47.20, 31.26, 18.50; HRMS (ESI) for C47H49NO9Naþ [MþNaþ] calcd
794.3305, found: 794.3309. Anal. Calcd for C47H49NO9; C: 73.13; H:
6.40. Found: C: 73.17; H: 6.43.
d
138.78, 138.77, 138.45, 138.44, 138.04, 138.03, 128.45, 128.44,
128.43,128.42,128.41,128.40,128.39,128.38,128.33,128.32,128.31,
128.30, 128.29, 128.19, 128.13, 128.12, 127.92, 127.91, 127.90, 127.82,
127.81, 127.80, 127.63, 127.62, 127.61, 127.51, 127.50, 127.49, 127.30,
127.29, 99.68, 97.78, 82.05, 80.04, 75.91, 75.51, 74.48, 74.24, 73.46,
73.45, 73.26, 73.05, 72.78, 70.71, 70.39, 69.90, 69.55, 55.19, 31.60;
HRMS (ESI) for C55H60O10Naþ [MþNaþ] calcd 903.4084, found:
903.34088. Anal. Calcd for C55H60O10; C: 74.98; H: 6.86. Found: C:
75.02; H: 6.88.
3.3.9. 2-Deoxy-3,4,6-tri-O-benzyl-
3-acetyl-1,2,4-tri-O-methyl- -glucopyranose (29). Pale yellow oil;
þ61.0 (c 0.027, CHCl3); IR (CHCl3) 2960, 1741, 1642, 1248,
a-D-lyxo-hexopyranosyl-(1/6)-
a-D
25
[a]
D
1051 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 7.35e7.25 (10H, m, ArH),
3.3.6. 2-Deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranosyl-(1/O)-
5.26 (1H, ddd, J3,4¼3.2 Hz, J3,2b¼4.8 Hz, J3,2a¼12.4 Hz, H3), 5.04 (1H,
0
0
0
N-tert-butoxycarbonyl- -serine methyl ester (26). Pale yellow oil;
L
d, J1,2a¼3.2 Hz, H1), 4.78 (1H, d, J1 ,2 ¼3.6 Hz, H1 ), 4.67 (1H, d,
J¼11.6 Hz, PhCH2), 4.53 (1H, d, J¼11.6 Hz, PhCH2), 4.52 (1H, d,
J¼11.6 Hz, PhCH2), 4.44 (1H, d, J¼12.0 Hz, PhCH2), 4.08 (1H, dd,
J5,6a¼6.8 Hz, J5,6b¼6.4 Hz, H5), 3.94 (1H, br s, H4), 3.82 (1H, dd,
25
[
a
]
þ16.9 (c 0.052, CHCl3); IR (CHCl3) 2950, 1726, 1647, 1240,
D
1065 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d 7.37e7.23 (15H, m, ArH),
0
5.45 (1 H, d, JNH,2 ¼8.4 Hz, NH), 4.92 (1H, br s, H1), 4.90 (1H, d,
J¼11.6 Hz, PhCH2), 4.61e4.52 (3H, m, PhCH2), 4.52 (1H, d, J¼11.6 Hz,
PhCH2), 4.45e4.41 (2H, m, H20, PhCH2), 3.91e3.80 (5H, m, H1a0 H1b0,
H3, H6a, H6b), 3.71 (3H, s, OCH3), 3.58e3.56 (2H, m, H4, H5), 2.20
(1H, ddd, J2a,1¼2.8 Hz, J2a,2b¼12.4 Hz, J2a,3¼12.8 Hz, H2a), 1.93 (1H,
dd, J2b,3¼4.4 Hz, J2b,2a¼12.4 Hz, H2b), 1.44 (9H, s, CH3ꢂ3); 13C NMR
0
0
0
0
0
J6a ,5 ¼8.0 Hz, J6a ,6b ¼10.2 Hz, H6a ), 3.61e3.54 (7H, m, OCH3, H6a,
H6b, H6b0, H50), 3.53e3.47 (7H, m, 2ꢂ OCH3, H30), 3.39 (3H, s,
0
0
0
0
0
OCH3), 3.18 (1H, dd, J2 ,1 ¼3.6 Hz, J2 ,3 ¼9.6 Hz, H2 ), 3.12 (1H, dd,
0
0
0
0
0
J4 ,3 ¼9.2 Hz, J4 ,5 ¼9.6 Hz, H4 ), 2.26 (1H, ddd, J2a,1¼3.2 Hz,
J2a,3¼12.4 Hz, J2a,2b¼12.8 Hz, H2a), 1.98 (3H, s, CH3), 1.92 (1H, dd,
J2b,3¼3.6 Hz, J2b,2a¼12.8 Hz, H2b); 13C NMR (CDCl3, 100 MHz)
(CDCl3, 100 MHz)
d 171.06, 155.45, 138.74, 138.32, 137.98, 128.37,
128.36, 128.35, 128.34, 128.18, 128.17, 128.16, 128.15, 127.76, 127.75,
127.63, 127.53, 127.48, 127.36, 127.35, 98.83, 79.98, 74.27, 73.42,
72.69, 70.38, 70.21, 69.17, 68.51, 53.96, 53.37, 52.35, 30.95, 28.28,
28.27, 28.26; HRMS (ESI) for C36H45NO9Naþ [MþNaþ] calcd
658.2992, found: 658.3001. Anal. Calcd for C36H45NO9; C: 68.01; H:
7.13. Found: C: 68.06; H: 7.17.
d 170.22, 138.38, 138.01, 128.34, 138.33, 128.28, 128.27, 128.08,
128.07, 128.06, 128.05, 127.65, 127.64, 97.73, 97.27, 83.65, 81.80,
79.52, 74.74, 73.54, 73.27, 69.72, 69.51, 69.34, 68.93, 65.94, 60.76,
60.42, 58.94, 55.04, 30.44, 21.08; HRMS (ESI) for C32H44O11Naþ
[MþNaþ] calcd 627.2781, found: 627.2780. Anal. Calcd for
C32H44O11; C: 63.56; H: 7.33. Found: C: 63.59; H: 7.35.
3.3.7. 2-Deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranosyl-(1/O)-
3.3.10. 2-Deoxy-3,4,6-tri-O-benzyl-a-D-lyxo-hexopyranosyl-(1/6)-
N-(1-oxopentadecyl)- -serine methyl ester (27). Pale yellow oil;
L
3-hyroxy-1,2,4-tri-O-methyl-a-D-glucopyranose (30). Pale yellow
25
[
a]
þ42.5 (c 0.016, CHCl3); IR (CHCl3) 2950, 1750, 1645, 1244,
oil; [
a
]
D
25 þ45.4 (c 0.058, CHCl3); IR (CHCl3) 3400e3200, 1642, 1250,
D
1080 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
7.37e7.24 (15H, m, ArH),
1046 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 7.35e7.26 (10H, m, ArH),
0
0
0
0
6.51 (1H, d, JNH,2 ¼8.4 Hz, NH), 4.92e4.89 (2H, m, H1, PhCH2),
4.78e4.75 (1H, m, H20), 4.59 (1H, d, J¼11.2 Hz, PhCH2), 4.58 (2H, s,
PhCH2), 4.51 (1H, d, J¼11.6 Hz, PhCH2), 4.43 (1H, d0, J¼12.0 Hz,
4.99 (1H, d, J1,2a¼2.0 Hz, H1), 4.78 (1H, d, J1 ,2 ¼3.6 Hz, H1 ), 4.73
(1H, d, J¼11.6 Hz, PhCH2), 4.63 (1H, d, J¼11.2 Hz, PhCH2), 4.57 (1 H, d,
J¼11.6 Hz, PhCH2), 4.50 (1H, d, J¼12.0 Hz, PhCH2), 4.05e4.00 (2H, m,
H3, H5), 3.82e3.78 (2H, m, H4, H50), 3.69e3.57 (7H, m, H6a, H6b,
H6a0, H6b0, OCH3), 3.52e3.48 (7H, m, H3, OCH3), 3.37 (3H, s, OCH3),
0
0
0
0
PhCH2), 3.99 (1H, dd, J1a ,2 ¼3.6 Hz, J1a ,1b ¼10.8 Hz, H1a ), 3.88e3.77
(4H, m, H1b0, H3, H4, H5), 3.72 (3H, s, OCH3), 3.56 (1H, dd,
J6a,5¼8.4 Hz, J6a,6b¼9.6 Hz, H6a), 3.53 (1H, dd, J6b,5¼8.8 Hz,
J6b,6a¼9.6 Hz, H6b), 2.21 (1H, ddd, J2a,1¼2.8 Hz, J2a,3¼12.4 Hz,
J2a,2b¼12.8 Hz, H2a), 2.14e2.12 (2H, m, H30), 1.95 (1H, dd,
J2b,3¼4.4 Hz, J2b,2a¼12.8 Hz, H2b), 1.62e1.55 (2H, m, H40), 1.28 (22H,
3.17 (1H, dd, J2 ,1 ¼3.6 Hz, J2 ,3 ¼9.6 Hz, H20), 3.11 (1H, dd,
0
0
0
0
0
0
0
0
0
J4 ,3 ¼8.8 Hz, J4 ,5 ¼9.2 Hz, H4 ),1.93e1.80 (2H, m, H2a, OH),1.79 (1H,
d, J2b,2a¼10.0 Hz, H2b); 13C NMR (CDCl3, 100 MHz)
d 138.35, 137.86,
128.53, 128.52, 128.36, 128.35, 127.95, 127.94, 127.90, 127.89, 127.69,
127.68, 97.85, 97.23, 83.56, 81.81, 79.45, 76.24, 75.10, 73.32, 69.64,
69.29, 68.91, 65.91, 65.69, 60.74, 60.28, 58.89, 54.97, 34.32; HRMS
(ESI) for C30H42O10Naþ [MþNaþ] calcd 585.2676, found: 585.2673.
Anal. Calcd for C30H42O10; C: 64.04; H: 7.52. Found: C: 64.08; H:
7.55.
m, H50eH150), 0.88 (3H, d, J16 ,15 ¼7.2 Hz, CH3); 13C NMR (CDCl3,
0
0
100 MHz)
d 173.05, 170.78, 138.64, 138.30, 137.83, 128.40, 128.39,
128.38, 128.37, 128.23, 128.22, 128.21, 127.76, 127.75, 127.74, 127.57,
127.56, 127.34, 127.33, 127.32, 99.23, 74.25, 74.24, 73.49, 72.74,
70.49, 70.34, 69.62, 69.10, 52.52, 52.41, 36.30, 31.89, 31.07, 29.64,
29.63, 29.62, 29.50, 29.49, 29.43, 29.42, 29.33, 29.24, 25.45, 22.65,
14.08; HRMS (ESI) for C46H65NO8Naþ [MþNaþ] calcd 782.4608,
found: 782.4603. Anal. Calcd for C46H65NO8; C: 72.70; H: 8.62.
Found: C: 72.74; H: 8.64.
25
3.3.11. Trisaccharide (31). Pale yellow oil; [
a
]
þ16.3 (c 0.036,
1H NMR
7.35e7.23 (20H, m, ArH), 5.23 (1H, ddd,
D
CHCl3); IR (CHCl3) 2930, 1743, 1647, 1232, 1049 cmꢁ1
(CDCl3, 400 MHz)
;
d
J3,4¼2.8 Hz, J3,2b¼4.4 Hz, J3,2a¼9.60Hz, H3), 5.10 (1H, d, J1,2a¼3.2 Hz,
0
0
3.3.8. 2-Deoxy-3,4,6-tri-O-benzyl-
a
-
D
-lyxo-hexopyranosyl-(1/O)-
H1), 4.98 (1H, d, J1 ,2a ¼3.2 H0z0, H1 ), 4.83 (1H, d, J¼11.6 Hz, PhCH2),
00 00
N-(9-fluorenylmethoxycarbonyl)-
L
-threonine methyl ester (28). Pale
4.72 (1H, d, J1 ,2 ¼3.6 Hz, H1 ), 4.67 (1H, d, J¼11.6 Hz, PhCH2), 4.58
yellow oil; [
a]
25 þ11.3 (c 0.047, CHCl3); IR (CHCl3) 2936, 1745, 1645,
(1H, d, J¼11.6 Hz, PhCH2), 4.54 (1H, d, J¼12.0 Hz, PhCH2), 4.53 (1H, d,
J¼11.2 Hz, PhCH2), 4.52 (1H, d, J¼12.0 Hz, PhCH2), 4.44 (1H, d,
J¼11.6 Hz, PhCH2), 4.42 (1H, d, J¼12.0 Hz, PhCH2), 4.15e4.05 (2H, m,
D
1248, 1055 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.77 (2H, d, J¼7.6 Hz,
ArH), 7.63 (2H, m, ArH), 7.41e7.24 (19H, m, ArH), 5.41 (1H, d,
0
0
0
0
0
0
JNH,2 ¼9.6 Hz, NH), 4.93e4.90 (2H, m, H1, PhCH2), 4.61 (2H, br s,
H30, H5), 3.97 (1H, dd, J5 ,6a ¼6.0 Hz, J5 ,6b ¼6.4 Hz, H5 ), 3.94 (1H, br
PhCH2), 4.60 (1H, d, J¼11.6 Hz, PhCH2), 4.51e4.40 (4H, m, H20, H40,
s, H4), 3.83 (1H, br s, H40), 3.76 (1H, dd, J6a ,5 ¼4.8 Hz,
00 00

6368
H.-C. Lin et al. / Tetrahedron 67 (2011) 6362e6368
00
0
00
00
00
J6a ,6b ¼10.8 Hz, H6a ), 3.63e3.56 (8H, m, H6a, H6b, H6a , H6b ,
References and notes
H500, OCH3), 3.50e3.45 (8H, m, H6b0, H300, OCH3), 3.34 (3H, s, OCH3),
00
1. (a) He, X.; Agnihotri, G.; Liu, H.-W. Chem. Rev. 2000, 100, 4615e4662; (b)
Kirschning, A.; Bechthold, A. F. W.; Rohr, J. In Bioorganic Chemistry: Deoxysugars,
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and New York, NY, 1997; pp 1e84; (c) He, X. M.; Liu, H. W. Curr. Opin. Chem. Biol.
2002, 6, 590e597.
00 00
00 00
3.13 (1H, dd, J2 ,1 ¼4.0 Hz, J2 ,3 ¼9.6 Hz, H2 ), 3.07 (1H, d0d,
00
00 00
00 00
J4 ,3 ¼8.4 Hz, J4 ,5 ¼9.2 Hz, H4 ), 2.28e2.19 (2H, m, H2a, H2a ),
0
0
2.16e1.97 (4H, m,0 H2b, CH3), 1.80 (1H, dd, J2b ,3 ¼4.8 Hz,
J2b ,2a ¼12.4 Hz, H2b ); 13C NMR (CDCl3, 100 MHz)
d
170.21, 138.68,
0
0
2. (a) Kelly, T. R. Annu. Rep. Med. Chem. 1979, 14, 288e298; (b) Andrews, F. L.;
138.40, 138.08, 137.80, 128.58, 128.44, 128.35, 128.25, 128.03,
128.02, 127.93, 127.80, 127.69, 127.56, 97.95, 97.20, 96.73, 83.65,
81.87, 79.69, 76.16, 76.15, 74.49, 73.48, 73.33, 73.01, 72.89, 69.74,
69.70, 69.38, 69.23, 68.61, 65.94, 65.53, 60.78, 60.41, 58.89, 54.96,
34.83, 32.06, 29.68; HRMS (ESI) for C52H66O15Naþ [MþNaþ] calcd
953.4299, found: 953.4293. Anal. Calcd for C52H66O15; C: 67.08; H:
7.14. Found: C: 67.10; H: 7.18.
Larsen, D. S. Tetrahedron Lett. 1994, 35, 8693e8696.
3. (a) Remers, W. A. The Chemistry of Antitumor Antibiotics; Wiley-Interscience:
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York, NY, 1984; pp 553e606.
5. Wright, D. E. Tetrahedron 1979, 35, 1207e1237.
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York, NY, 1969; pp 3e21; (b) Albrecht, H. P. Cardiac glycosides In Naturally Oc-
curring Glycosides; Ikan, R., Ed.; Wiley: Chichester, UK, 1999; p 83; (c) Weymouth-
Wilson, A. C. Nat. Prod. Rep.1997, 14, 99e110; (d) Henderson, F. G. In Digitalis; Fish,
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3.3.12. Butyl-3,4,6-tri-O-benzyl-2-deoxy-2R-deuterium-a-D-lyxo-
hexopyranoside (32). Pale yellow oil; [
a
;
]
25 þ16.8 (c 0.064, CHCl3); IR
D
(CHCl3) 2924, 1646, 1248, 1051 cmꢁ1
1H NMR (CDCl3, 400 MHz)
8. (a) Costantino, V.; Imperatore, C.; Fattorusso, E.; Mangoni, A. Tetrahedron Lett.
2000, 41, 9177e9180; (b) Costantino, V.; Fattorusso, E.; Imperatore, C.; Mangon,
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15. Rani, S.; Agarwal, A.; Vankar, Y. D. Tetrahedron Lett. 2003, 44, 5001e5004.
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19. Yadav, J. S.; Subba Reddy, B. V.; Vijaya Bhasker, E.; Raghavendra, S.; Narsaiah, A.
V. Tetrahedron Lett. 2007, 48, 677e680.
d
7.34e7.21 (15H, m, ArH), 4.96 (1H, d, J1,2¼3.6 Hz, H1), 4.93 (1H, d,
J¼11.6 Hz, PhCH2), 4.62 (1H, d, J¼11.6 Hz, PhCH2), 4.59 (2H, s,
PhCH2), 4.51 (1H, d, J¼12.0 Hz, PhCH2), 4.42 (1H, d, J¼11.6 Hz,
PhCH2), 3.94e3.89 (3H, m, H3, H4, H5), 3.64e3.54 (3H, m, H6a, H6b,
H1a0), 3.38e3.33 (1H, m, H1b0), 2.21 (1H, dd, J2,1¼3.6 Hz,
J2,3¼12.4 Hz, H2), 1.55e1.49 (2H, m, H20), 1.37e1.25 (2H, m, H30),
0.90 (3H, t, J4 ,3 ¼7.6 Hz, H4 ); 13C NMR (CDCl3, 100 MHz)
d
138.88,
0
0
0
138.54, 138.11, 128.32, 128.31, 128.30, 128.17, 128.16, 128.14, 128.13,
127.69, 127.68, 127.59, 127.58, 127.43, 127.42, 127.27, 127.26, 97.63,
74.83, 74.21, 73.39, 72.99, 70.38, 69.74, 69.56, 67.11, 31.59, 19.39,
19.38, 13.86; HRMS (ESI) for C31H37DO5Naþ [MþNaþ] calcd
514.2680, found: 514.2688. Anal. Calcd for C31H37DO5; C: 75.73; H:
8.00. Found: C: 75.76; H: 7.01.
Acknowledgements
The authors thank the National Science Council of Taiwan
(NSC97-2113-M-039-001 for H.C.L. and NSC97-2628-M-001-016-
MY3 for C.H.L.) and China Medical University, Taiwan (CMU98-
NCTU-07) for financial support.
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Tetrahedron Lett. 2009, 50, 7327e7329.
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5071e5076.
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.05.124.