Synthesis of 4-O-[3-(aryl)prop-2-ynyl]-Neu5Ac2en and its 4-epi-analogs modified at C-4 by Sonogashira coupling reaction

Article abstract of DOI:10.1016/j.tet.2007.05.049

To explore new inhibitors of the sialidase of human parainfluenza virus type 1 (hPIV-1), a series of novel Neu5Ac2en derivatives were synthesized. Thus, 8,9-O-isopropylidene-4-O-2-propynyl-Neu5Ac2en methyl ester 8 was subjected to a Sonogashira coupling r

Full text of DOI:10.1016/j.tet.2007.05.049

Tetrahedron 63 (2007) 7571–7581
Synthesis of 4-O-[3-(aryl)prop-2-ynyl]-Neu5Ac2en and its
4-epi-analogs modified at C-4 by Sonogashira coupling reaction
Kazuki Sato,a Kiyoshi Ikeda,a, Takashi Suzuki,b,c Shinya Aoyama,b,c
*
Naoyoshi Maki,b,c Yasuo Suzukic,d and Masayuki Satoa
aDepartment of Organic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
bDepartment of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
cCREST, Japan Science and Technology Agency, Saitama, Japan
dDepartment of Biomedical Sciences, College of Life and Health Sciences, Chubu University,
1200 Matsumoto-cho, Kasugai-shi, Aichi 487-8501, Japan
Received 3 April 2007; revised 10 May 2007; accepted 11 May 2007
Available online 17 May 2007
Abstract—To explore new inhibitors of the sialidase of human parainfluenza virus type 1 (hPIV-1), a series of novel Neu5Ac2en derivatives
were synthesized. Thus, 8,9-O-isopropylidene-4-O-2-propynyl-Neu5Ac2en methyl ester 8 was subjected to a Sonogashira coupling reaction
with a variety of heteroaryl halides to produce a series of 4-O-(3-heteroaryl-2-propynyl) compound 9. Treatment of 9 with 80% acetic acid
followed by alkaline hydrolysis afforded deprotected Neu5Ac2en compounds. The 4-epi-analogs of this type of Neu5Ac2en were synthesized
in a similar manner. Compound 5d showed the most potent inhibitory activity (IC50 1.2 mM) against hPIV-1 sialidase.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
all of which cause a spectrum of illnesses in the upper and
lower respiratory tracts of children. At this time there are
no effective vaccines or specific therapies to control parain-
fluenza virus infections.
Sialic acids (Neu5Ac) are characterized as sugar carboxylic
acids with nine carbon atoms in a framework of sialic acid,
which are often involved in important cell surface communi-
cations.1 Modification of the functional groups on sialic
acids may lead to changes in the steric and/or electronic
properties of the molecules, which can be used to probe
space and charge requirements of sialic acid-recognizing
proteins.2 Among the diverse array of compounds related
to the sialic acid family, 5-acetamido-2,6-anhydro-3,5-di-
deoxy-D-glycero-D-galacto-non-2-enonic acid (Neu5Ac2en)
1 is known as an inhibitor of sialidases from both bacterial
and viral sources, occupying an important position in mod-
ern chemistry.3 A variety of Neu5Ac2en analogs have been
synthesized as competitive sialidase inhibitors. Among
them, zanamivir 2 has been used as anti-influenza virus
agent.4 Human parainfluenza viruses (hPIVs), which are
members of the Paramyxoviridae family, are important re-
spiratory tract pathogens of infants, children, and young
adults.5 Four different types of hPIVs have been identified,
We demonstrated that 4-O-thiocarbamoylmethyl-36 and the
4-O-ethyl-Neu5Ac2en derivative 47 have potential inhibi-
tory activities against the sialidase from hPIV-1. Small poly-
functionalized heterocyclic compounds play important roles
in the discovery process.8 As part of a program aimed at
identifying new inhibitors against the hPIV-1 sialidase, we
report herein the synthesis of a novel Neu5Ac2en 5 having
heterocycles using the Sonogashira coupling reaction9 as
the key reaction and their evaluation as inhibitors of hPIV-
1 HN sialidase activity. For further insight into the interac-
tion of the sialidase with substituent at C-4 of Neu5Ac2en
derivatives, the synthesis of the 4-epi-Neu5Ac2en deriva-
tives 6 modified at C-4 of 5 was also described (Fig. 1).
2. Results and discussion
2.1. Synthesis of 5
Keywords: 4-O-(3-Heteroaryl-2-propynyl)Neu5Ac2en; Sonogashira cou-
pling reaction; Sialidase inhibitor; Human parainfluenza virus type 1.
* Corresponding author. Tel./fax: +81 54 264 5108; e-mail: ikeda@ys2.
u-shizuoka-ken.ac.jp
Our initial focus was the synthesis of the products 5 using
a Sonogashira coupling reaction starting from the 4-O-2-
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.049

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K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
HO OH
HO
OH
HO OH
CO2H
O
HO
O
CO2H
HO
AcHN
O
CO2H
HO
AcHN
AcHN
O
HN
NH2
R
HO
NH2
R = -CH2C(=S)NH2 3, -CH2CH3
4
Neu5Ac2en 1
zanamivir 2
OH
O
HO
Ar
OH
O
CO2H
HO
HO
AcHN
CO2H
O
HO
O
AcHN
Ar
Ar = heteroaryl groups
6
5
Figure 1.
Me Me
OAc
AcO
O
O
O
CO2Me
AcO
AcHN
CO2Me
H
O
Neu5Ac
HO
5
AcHN
AcO
O
7
8
Scheme 1.
propynyl-Neu5Ac2en derivative 8,7 which was prepared
from Neu5Ac via 7 in seven steps (Scheme 1). Sonogashira
coupling reactions were performed using PdCl2(PPh3)2
(2 mol %), CuI (4 mol %), and Et3N (3.0 equiv) in CH3CN
under the method A conditions in Table 1.9
with 0.1 M KOH/MeOH (1:1) to give the target compounds
5a–f and 5h–j (Table 3). In the case of 9g, decomposition of
the starting material occurred with the treatment under
acidic conditions. Compounds 5b,c having a pyridyl group
were isolated as potassium salts.
When iodobenzene was used as an aryl halide, the corre-
sponding product 9a was obtained in 53% yield (Table 1,
entry 1). When 2-iodopyridine, 3-iodopyridine, and 2-iodo-
thiophene were used as heteroaryl halides under the same
conditions, the products 9b–d were obtained in 73, 93, and
83% yields, respectively (entries 2–4). However, the
coupling reaction of 8 with 3-bromothiophene led to the
recovery of 8 under the method A conditions (entry 5).
The reaction of 8 with bromothiophene by the combination
of PdCl2(CH3CN)2 (5 mol %), Cu(OAc)2$H2O (5 mol %),
PPh3 (10 mol %), and i-Pr2NH under the method B condi-
tions10 as an alternative procedure gave a poor yield of 9e
(entry 6). When iodothiophene as a heteroaryl halide was
used in method A, 9e was successfully obtained in 76% yield
(entry 7). In sharp contrast with the result of entry 8, the cou-
pling reaction of 8 with 2-bromo-1,3-thiazole under the
method B conditions afforded 9f in 59% yield (entry 9).
2.2. Synthesis of 6
We were interested in comparing the inhibitory activity
against the hPIV-1 sialidase between Neu5Ac2en 5 and 4-
epi-Neu5Ac2en derivatives 6 with an altered configuration
of 4-hydroxy group of Neu5Ac2en. As outlined in Scheme
2, the synthesis of compound 13 as the key intermediate
began with the known compound 11.11 Initially, the methyl
ester of Neu5Ac, derived from Neu5Ac, was treated with ace-
tic anhydride in the presence of concentrated sulfuric acid at
80 ꢀC for 3 h to give in 96% yield an inseparable mixture of
11a and 11b with an a/b ratio of 1:8, which was employed in
the subsequent step without further purification. Thus, Zem-
plen O-deacetylation of 11 with 0.1 M sodium methoxide in
MeOH followed by subsequent protection by 2,2-dimethoxy-
propane and Amberlite 120 (H+) in DMF afforded the 8,9-O-
isopropylidene compound 12 in 58% yield as a single
diastereomer after purification by silica gel column chroma-
tography. The J4,5 and J3,4 values (4.1 and 5.7 Hz, respec-
tively) of an 1H NMR spectroscopic analysis of 12
demonstrated the H-4,5 and H-3,4 relationships. Installation
of a propargyl group at the 4-hydroxyl group of 12 using
sodium hydride (2.0 equiv) and propargyl bromide
(1.3 equiv)inDMFgavethekeyintermediate13in39%yield.
For the synthesis of 9g–j having an additional substitution on
the heteroaryl five-membered ring, compound 8 successfully
underwent a Sonogashira coupling reaction with heteroaryl
halides under the method A conditions to afford 9g–j in
92, 55, 62, and 49% yields, respectively (Table 2).
The removal of the isopropylidene group of 9a–j, except for
9g, with 80% acetic acid at 80 ꢀC for 1 h gave the triols
10a–f and 10h–j, whose methyl ester group was hydrolyzed
The synthesis of 14a–c was performed using a Sonogashira
coupling reaction in a manner similar to the preparation of 9.

K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
Table 1. Synthesis of 9a–f by the Sonogashira coupling reaction Table 3. Synthesis of 5a–j
7573
HO
OH
HO
OH
O
O
O
O
O
O
CO2H
Ar
O
CO2Me
HO
AcHN
CO2Me
Ar
O
Ar-X
CO2Me
O
CO2Me
Ar
O
HO
O
HO
AcHN
HO
HO
AcHN
AcHN
AcHN
O
CH3CN
O
O
O
O
Ar
9
9a-j
10a-j
5a-j
8
Entry
1
Ar–X
Conditiona
A
Product
Yield (%)
53
Entry
1
Ar
Yield of 10 (%)
10a (82)
Yield of 5 (%)
5a (83)
9a
I
2
3
4
5
6
7
8
10b (91)
10c (83)
10d (98)
10e (89)
10f (83)
10h (95)
10i (80)
5b (quant.)a
5c (quant.)a
5d (66)
2
3
4
5
6
A
A
A
A
B
9b
73
93
83
N
I
I
N
9c
N
S
N
S
9d
I
5e (76)
Br
S
N
N.R.b
9e
S
S
5f (54)
Br
S
5
5h (98)
Ac
S
I
7
8
A
A
9e
76
5i (96)
CHO
S
S
N
N.R.b
Br
Br
S
9
10j (89)
5j (46)
CHO
O
a
N
The products were isolated as potassium salt.
9
B
9f
59
S
a
Method A: RX (1.1 equiv), Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol %), Et3N
(3 equiv). Method B: RX (1.1 equiv), PdCl2(CH3CN)2 (5 mol %),
Cu(OAc)2$H2O (5 mol %), PPh3 (10 mol %), i-Pr2NH (2 mL).
N.R.: no reaction.
The results are summarized in Table 4. When 2-iodothio-
phene and 3-iodothiophene were used as heteroaryl halides
under Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol %), and Et3N
(3 equiv) in CH3CN under the method A conditions, the cor-
responding products 14a,b were obtained in 64 and 73%
yield, respectively (Table 4, entries 1 and 2). In the case of
using 2-bromo-1,3-thiazole as a heteroaryl halide, the com-
bination of PdCl2(CH3CN)2 (5 mol %), Cu(OAc)2$H2O
(5 mol %), PPh3 (10 mol %), and i-Pr2NH under the method
B conditions gave 14c in 48% yield (entry 3).
b
Table 2. Synthesis of 9g–j by the Sonogashira coupling reaction
O
O
O
O
CO2Me
O
CO2Me
Ar
HO
Ar-X
CH3CN
O
HO
AcHN
AcHN
O
O
The deprotection of the isopropylidene group of 14a–c with
80% acetic acid at 80 ꢀC for 1 h afforded the triols 15a–c,
whose methyl ester group was hydrolyzed with 0.1 M KOH/
MeOH (1:1) to give the target compounds 6a–c (Table 5).
8
9
Entry
1
Ar–X
Conditiona
A
Product
Yield (%)
92
9g
I
Br
Br
Me
S
3. Biological evaluation
2
3
A
A
9h
9i
55
62
Ac
S
S
The behavior of synthesized compounds 5 and 6 toward
hPIV-1 sialidase was assayed by a fluorometric assay using
4-methylumbelliferyl N-acetyl-a-neuraminic acid as our
previously reported method.6b As may be seen in Table 6, in-
terestingly, 2-thienyl-Neu5Ac2en 5d exhibited the most po-
tent inhibitory activity (IC50 1.2 mM). Compounds 5e and 5f
had almost the same inhibitory effects. In the previous
study,6b 4-guanidino-Neu5Ac2en 2 had much lower inhibi-
tory activity toward hPIV-1 sialidase than that of 1 (IC50
CHO
4
A
9j
49
Br
CHO
O
a
Method A: RX (1.1 equiv), Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol %), Et3N
(3 equiv).

7574
K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
OAc
OAc
AcO
O
O
O
O
H
OH
O
O
O
c
a
b
O
CO2Me
AcO
AcHN
Neu5Ac
CO2Me
CO2Me
HO
AcHN
HO
AcHN
11
12
13
Scheme 2. (a) (i) MeOH, Amberlite IR120 (H+), rt, 15 h, quant.; (ii) Ac2O, H2SO4, 80 ꢀC, 3 h, 96% (11a/11b¼1:8). (b) (i) NaOMe, MeOH, 0 ꢀC, 1 h, quant.;
(ii) 2,2-dimethoxypropane, DMF, Amberlite IR120 (H+), rt, 12 h, 58%. (c) Propargyl bromide (1.3 equiv), NaH (2.0 equiv), DMF, 0 ꢀC, 1 h, 39%.
Table 4. Synthesis of 14a–c by the Sonogashira coupling reaction
Table 6. Inhibitory activities of 5a–f
Entry
Compound
IC50 (mM)a
O
O
H
O
O
Ar
Ar-X
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
15
88
14
1.2
2.5
3.1
O
O
CO2Me
CO2Me
O
O
HO
CH3CN
HO
AcHN
AcHN
14
13
Entry
1
Ar–X
Conditiona
Product
Yield (%)
64
a
Inhibitory activities were determined by the method according to Ref. 6b.
A
A
14a
I
S
I
5d showed the most potent inhibitory activity (IC50
1.2 mM) against hPIV-1 sialidase.
2
14b
14c
73
48
S
N
3
B
5. Experimental
5.1. General
Br
S
a
Method A: RX (1.1 equiv), Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol %), Et3N
(3 equiv). Method B: RX (1.1 equiv), PdCl2(CH3CN)2 (5 mol %),
Cu(OAc)2$H2O (5 mol %), PPh3 (10 mol %), i-Pr2NH (2 mL).
All melting points are uncorrected. Optical rotations were
measured with a JASCO P-1030 (Japan) digital polarimeter.
IR spectra were recorded on a SHIMADZU IRPrestige-21
30 mM). Compounds 6a–c as 4-epi-analogs of 5 exhibited
decreased sialidase inhibition compared with 5d, and com-
pound 5b was practically inactive against sialidase.
1
(Japan) spectrometer. H NMR spectra were recorded with
a JEOL ECA-500 (500 MHz) (Japan). 13C NMR spectra
were recorded with a JEOL ECA-500 (126 MHz) (Japan).
Chemical shifts are expressed in parts per million relative
to Me4Si (d¼0) in CDCl3 and in D2O referenced to HOD
(4.85 ppm) as internal standards. Fast atom bombardment
(FAB) mass spectra were obtained with a JEOL JMS-700
(Japan) mass spectrometer in the positive ion mode using
an NBA or thioglycerol matrix. High-resolution mass spec-
tra (HRMS) were recorded on a JEOL JMS-700 (Japan)
under FAB conditions. Column chromatography was
4. Conclusion
We have synthesized the novel Neu5Ac2en compounds 5
and 6 to develop hPIV-1 sialidase inhibitors. Sonogashira
coupling reactions of 8 and 14 with aryl or heteroaryl halides
and subsequent deprotection provided the new Neu5Ac2en
analogs 5 and 6, respectively. The 2-thienyl-Neu5Ac2en
Table 5. Synthesis of 6a–c
HO
OH
OH
HO
O
O
Ar
Ar
Ar
O
O
O
CO2H
CO2Me
O
CO2Me
O
O
HO
AcHN
HO
AcHN
HO
AcHN
14a-c
15a-c
6a-c
Entry
1
Ar
Yield of 15 (%)
15a (68)
Yield of 6 (%)
6a (60)
S
2
3
15b (79)
15c (53)
6b (99)
6c (94)
S
N
S

K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
7575
performed on Silica Gel 60 (70–230 mesh, Merck). Desalt-
ing was carried out with an ASAHI CHEMICAL Micro
Acylizer G1. All reactions were monitored using TLC
(Silica Gel 60F254, E. Merck, Germany) by charring after
spraying 5% H2SO4 in MeOH and then heating.
amorphous material. [a]2D4 +28 (c 0.66, CHCl3). IR (neat)
3298, 1729, 1632 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d 1.35, 1.39 (s, each 3H, Me2C), 2.04 (s, 3H, Ac), 3.57
(dd, 1H, J7,OH¼4.0 Hz, J7,8¼8.0 Hz, H-7), 3.79 (s, 3H,
OMe), 4.06–4.17 (m, 3H, H-6, H-9a, and H-9b), 4.21–4.26
(m, 1H, H-5), 4.33–4.37 (m, 1H, H-8), 4.46–4.55 (m, 4H,
H-4, OH, and OCH2C^), 5.74 (br, 1H, NH), 6.11 (d, 1H,
J3,4¼2.9 Hz, H-3), 7.28 (dd, 1H, J¼4.6, 7.5 Hz, Ar), 7.76
(dd, 1H, J¼1.7, 7.5 Hz, Ar), 8.57 (br, 1H, Ar), 8.69 (br,
1H, Ar). 13C NMR (126 MHz, CDCl3): d 23.4, 25.3, 27.1,
48.5, 52.6, 56.3, 67.3, 70.5, 72.9, 74.3, 77.5, 83.7, 88.2,
106.9, 109.3, 119.5, 123.2, 139.0, 146.2, 149.3, 152.5,
162.3, 172.4. Positive ion FABMS (NBA): m/z 461
[M+H]+, 483 [M+Na]+. FABHRMS calcd for C23H29N2O8
461.1924, found 461.1880.
5.2. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(phenyl)prop-2-ynyl]-D-
glycero-D-galacto-non-2-enonate (9a)
To a solution of 8 (80 mg, 0.21 mmol),7 PdCl2(PPh3)2 (2 mg,
0.004 mmol), and CuI (2 mg, 0.008 mmol) in CH3CN
(2 mL) were added Et3N (64 mg, 0.63 mmol) and iodobenz-
ene (47 mg, 0.23 mmol) under Ar. The mixture was stirred at
room temperature for 6 h, and then concentrated in vacuo.
The residue was purified by column chromatography using
CHCl3/MeOH (50:1 to 40:1, v/v) to give 6a (51 mg, 53%)
as an amorphous material. [a]2D4 +38 (c 0.80, CHCl3). IR
5.5. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(2-thienyl)prop-2-ynyl]-
D-glycero-D-galacto-non-2-enonate (9d)
(neat) 3298, 1730, 1633 cmꢁ1
.
1H NMR (500 MHz,
CDCl3): d 1.35, 1.39 (s, each 3H, Me2C), 2.02 (s, 3H, Ac),
3.57 (dd, 1H, J7,OH¼4.6 Hz, J7,8¼7.5 Hz, H-7), 3.79 (s,
3H, OMe), 4.06–4.09 (m, 2H, H-6 and H-9a), 4.14–4.21
(m, 2H, H-5 and H-9b), 4.35–4.38 (m, 1H, H-8), 4.48 (dd,
1H, J3,4¼2.3 Hz, J4,5¼9.8 Hz, H-4), 4.46, 4.54 (d, each 1H,
Jgem¼16.0 Hz, OCH2C^), 4.63 (d, 1H, OH), 5.68 (d, 1H,
J5,NH¼5.2 Hz, NH), 6.10 (d, 1H, H-3), 7.32–7.37 (m, 3H,
Ar), 7.45–7.47 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3):
d 23.3, 25.3, 27.1, 48.7, 52.5, 56.9, 67.4, 70.5, 72.7, 74.3,
77.6, 84.7, 87.3, 107.3, 109.3, 122.0, 128.6, 129.1, 131.9,
146.0, 162.3, 172.7. Positive ion FABMS (NBA): m/z 460
[M+H]+, 482 [M+Na]+. FAB HRMS calcd for C24H30NO8
460.1971, found 460.1992.
The reaction was carried out using 8 (139 mg, 0.36 mmol)
and 2-iodothiophene (84 mg, 0.40 mmol) in a manner simi-
lar to the preparation of 9a, to give 9d (140 mg, 83%) as an
amorphous material. [a]2D5 +27 (c 0.16, CHCl3). IR (neat)
3290, 1728, 1674 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d 1.35, 1.39 (s, each 3H, Me2C), 2.04 (s, 3H, Ac), 3.55
(dd, 1H, J7,OH¼4.6 Hz, J7,8¼8.0 Hz, H-7), 3.79 (s, 3H,
OMe), 4.06–4.09 (m, 2H, H-6 and H-9a), 4.14–4.20 (m,
2H, H-5 and H-9b), 4.34–4.38 (m, 1H, H-8), 4.46, 4.56 (d,
each 1H, Jgem¼16.6 Hz, OCH2C^), 4.46 (dd, 1H,
J3,4¼2.9 Hz, J4,5¼8.6 Hz, H-4), 4.63 (d, 1H, OH), 5.64 (d,
1H, J5,NH¼6.9 Hz, NH), 6.07 (d, 1H, H-3), 7.00 (dd, 1H,
J¼3.5, 5.2 Hz, Ar), 7.27 (dd, 1H, J¼1.2, 3.5 Hz, Ar), 7.31
(dd, 1H, J¼1.2, 3.5 Hz, Ar). 13C NMR (126 MHz, CDCl3):
d 23.3, 25.3, 27.1, 48.7, 52.5, 56.9, 67.4, 70.4, 72.8, 74.3,
77.7, 80.6, 88.8, 107.1, 109.3, 121.7, 127.3, 128.2, 133.2,
146.0, 162.3, 172.8. Positive ion FABMS (NBA): m/z 466
[M+H]+, 488 [M+Na]+. FABHRMS calcd for C22H28NO8S
466.1536, found 466.1544.
5.3. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(2-pyridyl)prop-2-ynyl]-
D-glycero-D-galacto-non-2-enonate (9b)
The reaction was carried out using 8 (80 mg, 0.21 mmol) and
2-iodopyridine (47 mg, 0.23 mmol) in a manner similar to
the preparation of 9a, to give 9b (70 mg, 73%) as an amor-
phous material. IR (KBr) 3257, 1735, 1637 cmꢁ1
.
1H
5.6. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(3-thienyl)prop-2-ynyl]-
D-glycero-D-galacto-non-2-enonate (9e)
NMR (500 MHz, CDCl3): d 1.36, 1.41 (s, each 3H, Me2C),
2.04 (s, 3H, Ac), 3.56–3.59 (m, 1H, H-7), 3.78 (s, 3H,
OMe), 4.03 (d, 1H, Jgem¼9.8 Hz, H-9a), 4.10–4.23 (m,
3H, H-5, H-6, and H-9b), 4.36–4.40 (m, 1H, H-8), 4.45,
4.56 (d, each 1H, Jgem¼17.2 Hz, OCH2C^), 4.64 (dd,
J3,4¼2.3 Hz, J4,5¼8.6 Hz, H-4), 4.80 (d, 1H, J7,OH¼4.0 Hz,
OH), 6.04 (d, 1H, H-3), 6.79 (br, 1H, NH), 7.29 (m, 1H, Ar),
7.44 (d, 1H, J¼7.5 Hz, Ar), 7.71 (dt, 1H, J¼1.7, 7.5 Hz, Ar),
8.53 (d, 1H, J¼4.6 Hz, Ar). 13C NMR (126 MHz, CDCl3):
d 22.8, 25.2, 26.9, 48.5, 52.3, 56.4, 67.1, 69.7, 72.3, 74.3,
77.7, 85.6, 86.3, 107.3, 109.0, 123.6, 126.8, 136.7, 142.0,
145.6, 149.6, 162.3, 173.3. Positive ion FABMS (NBA):
m/z 461 [M+H]+, 483 [M+Na]+. FAB HRMS calcd for
C23H29N2O8 461.1924, found 461.1883.
The reaction was carried out using 8 (147 mg, 0.38 mmol)
and 3-iodothiophene (88 mg, 0.42 mmol) in a manner simi-
lar to the preparation of 9a, to give 9e (136 mg, 76%) as an
amorphous material. [a]2D4 +41 (c 0.32, CHCl3). IR (neat)
3257, 1728, 1637 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d 1.35, 1.39 (s, each 3H, Me2C), 2.02 (s, 3H, Ac), 3.55
(dd, 1H, J7,OH¼4.6 Hz, J7,8¼8.0 Hz, H-7), 3.79 (s, 3H,
OMe), 4.06–4.09 (m, 2H, H-6 and H-9a), 4.14–4.20
(m, 2H, H-5 and H-9b), 4.34–4.38 (m, 1H, H-8), 4.47 (dd,
1H, J3,4¼2.3 Hz, J4,5¼8.0 Hz, H-4), 4.43, 4.51 (d, each 1H,
Jgem¼16.1 Hz, OCH2C^), 4.63 (d, 1H, OH), 5.71 (d,
1H, J5,NH¼6.9 Hz, NH), 6.09 (d, 1H, H-3), 7.13 (d, 1H,
J¼5.2 Hz, Ar), 7.30 (dd, 1H, J¼2.9, 5.2 Hz, Ar), 7.52 (d,
1H, J¼2.9 Hz, Ar). 13C NMR (126 MHz, CDCl3): d 23.3,
25.3, 27.1, 48.7, 52.5, 56.8, 67.4, 70.5, 72.7, 74.3, 77.6,
82.5, 84.5, 107.3, 109.3, 121.0, 125.9, 129.9, 130.0, 146.0,
162.3, 172.7. Positive ion FABMS (NBA): m/z 466
[M+H]+, 488 [M+Na]+. FABHRMS calcd for C22H28NO8S
466.1536, found 466.1482.
5.4. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(3-pyridyl)prop-2-ynyl]-
D-glycero-D-galacto-non-2-enonate (9c)
The reaction was carried out using 8 (117 mg, 0.31 mmol)
and 3-iodopyridine (70 mg, 0.34 mmol) in a manner similar
to the preparation of 9a, to give 9c (130 mg, 93%) as an

7576
K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
5.7. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(2-thiazolyl)prop-2-ynyl]-
D-glycero-D-galacto-non-2-enonate (9f)
H-4), 4.46 (dd, 1H, OH), 4.48, 4.55 (d, each 1H, Jgem
¼
16.6 Hz, OCH2C^), 5.57 (d, 1H, J5,NH¼6.9 Hz, NH), 6.08
(d, 1H, H-3), 7.23 (1H, J¼4.0 Hz, Ar), 7.55 (d, 1H, Ar).
13C NMR (126 MHz, CDCl3): d 23.2, 25.1, 26.7, 26.9, 48.2,
52.4, 56.2, 67.1, 70.2, 72.9, 74.0, 79.6, 91.9, 106.6, 109.1,
129.4, 131.9, 133.5, 145.2, 146.1, 162.0, 172.4, 190.0. Pos-
itive ion FABMS (NBA): m/z 508 [M+H]+. FABHRMS
calcd for C23H30NO9S 508.1641, found 508.1592.
To a mixture of 8 (130 mg, 0.34 mmol), PdCl2(CH3CN)2
(4 mg, 0.017 mmol), Cu(OAc)2 (3 mg, 0.017 mmol), and
PPh3 (5 mg, 0.034 mmol) in CH3CN (2 mL) were added
i-Pr2NEt (2 mL) and 2-bromo-1,3-thiazole (61 mg,
0.37 mmol) under Ar. The resulting mixture was stirred at
45 ꢀC for 6 h, and then concentrated in vacuo. The residue
was purified by column chromatography on silica gel using
CHCl3/MeOH (50:1 to 40:1, v/v) to give 9f (95 mg, 59%) as
5.10. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(50-formyl-20-thienyl)-prop-
2-ynyl]-D-glycero-D-galacto-non-2-enonate (9i)
an amorphous material. IR (neat) 3298, 1734, 1637 cmꢁ1
.
1H NMR (500 MHz, CDCl3): d 1.35, 1.39 (s, each 3H,
Me2C), 2.05 (s, 3H, Ac), 3.55 (dd, 1H, J7,OH¼4.6 Hz,
J7,8¼8.0 Hz, H-7), 3.78 (s, 3H, OMe), 4.03–4.12 (m, 2H,
H-6 and H-9a), 4.15–4.23 (m, 2H, H-5 and H-9b), 4.34–
4.38 (m, 1H, H-8), 4.55 (dd, 1H, J3,4¼2.3 Hz, J4,5¼8.6 Hz,
H-4), 4.48, 4.58 (d, each 1H, Jgem¼17.2 Hz, OCH2C^),
4.67 (d, 1H, OH), 6.04 (d, 1H, H-3), 6.38 (d, 1H,
J5,NH¼7.4 Hz, NH), 7.41 (d, 1H, J¼3.5 Hz, Ar), 7.83 (d,
1H, Ar). 13C NMR (126 MHz, CDCl3): d 23.1, 25.3, 27.1,
48.6, 52.5, 56.4, 67.3, 70.1, 72.9, 74.3, 77.7, 80.1, 90.2,
106.9, 109.2, 121.5, 143.6, 146.1, 147.7, 162.4, 173.1. Pos-
itive ion FABMS (NBA): m/z 467 [M+H]+. FABHRMS
calcd for C21H27N2O8S 467.1488, found 467.1500.
The reaction was carried out using 8 (168 mg, 0.44 mmol)
and 5-bromo-2-thiophenecarboxaldehyde (93 mg, 0.48 mmol)
in a manner similar to the preparation of 9a, to give 9i
(135 mg, 62%). IR (neat) 3273, 1732, 1653 cmꢁ1. [a]D23
1
+43 (c 0.75, CHCl3). H NMR (500 MHz, CDCl3): d 1.36,
1.39 (s, each 3H, Me2C), 2.06 (s, 3H, NAc), 3.56 (d, 1H,
J7,8¼13.8 Hz, H-7), 3.80 (s, 3H, OMe), 4.10–4.17 (m,
3H, H-6, H-9a, and H-9b), 4.23 (m, 1H, H-5), 4.35 (ddd,
1H, J8,9a¼5.7 Hz, J8,9b¼6.2 Hz, H-8), 4.45 (br, 1H, OH),
4.45 (dd, 1H, J3,4¼2.3 Hz, J4,5¼8.0 Hz, H-4), 4.48, 4.55 (d,
each 1H, Jgem¼16.6 Hz, OCH2C^), 5.59 (d, 1H, J5,NH
¼
6.9 Hz, NH), 6.08 (d, 1H, H-3), 7.32 (d, 1H, J¼3.5 Hz, Ar),
7.65 (d, 1H, Ar), 9.87 (s, 1H, CHO). 13C NMR (126 MHz,
CDCl3): d 23.3, 25.1, 27.0, 48.2, 52.5, 56.1, 67.2, 70.3,
73.1, 74.1, 77.4, 79.4, 93.1, 106.6, 109.2, 130.9, 133.5,
135.7, 144.4, 146.2, 162.1, 172.4, 182.4. Positive ion FABMS
(NBA): m/z 494 [M+H]+, 516 [M+Na]+. FABHRMS calcd
for C23H28NO9S 494.1485, found 494.1483.
5.8. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(50-methyl-20-thienyl)-prop-2-
ynyl]-D-glycero-D-galacto-non-2-enonate (9g)
The reaction was carried out using 8 (144 mg, 0.38 mmol)
and 2-iodo-5-methylthiophene (92 mg, 0.41 mmol) in a
manner similar to the preparation of 9a, to give 9g (166 mg,
92%). [a]2D5 +49 (c 0.19, CHCl3). IR (neat) 3196, 1732,
5.11. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(50-formyl-20-furyl)-prop-
2-ynyl]-D-glycero-D-galacto-non-2-enonate (9j)
1
1653 cmꢁ1. H NMR (500 MHz, CDCl3): d 1.34, 1.38 (s,
each 3H, Me2C), 2.02 (s, 3H, Ac), 2.45 (s, 3H, CMe), 3.53
(dd, 1H, J7,8¼7.5 Hz, J7,OH¼4.0 Hz, H-7), 3.76 (s, 3H,
OMe), 4.02–4.07 (m, 2H, H-6 and H-9a), 4.11–4.06 (m, 2H,
H-5 and H-9b), 4.34 (m, 1H, H-8), 4.42, 4.52 (d, each 1H,
The reaction was carried out using 8 (137 mg, 0.36 mmol)
and 5-bromo-2-furaldehyde (70 mg, 0.40 mmol) in a manner
similar to the preparation of 9a, to give 9j (84 mg, 49%).
[a]2D4 +27 (c 0.20, CHCl3). IR (neat) 3290, 1728,
1
Jgem¼16.6 Hz, OCH2C^), 4.44 (dd, 1H, J3,4¼2.3 Hz, J4,5
¼
1634 cmꢁ1. H NMR (500 MHz, CDCl3): d 1.30, 1.33 (s,
8.6 Hz, H-4), 4.69 (d, 1H, OH), 5.82 (d, 1H, J5,NH¼6.9 Hz,
NH), 6.05 (d, 1H, H-3), 6.63 (1H, J¼2.9 Hz, Ar), 7.05 (d,
1H, Ar). 13C NMR (126 MHz, CDCl3): d 15.5, 23.3, 25.3,
27.0, 48.6, 52.4, 57.0, 67.3, 70.2, 72.7, 74.2, 77.6, 81.0, 88.1,
107.4, 109.2, 119.1, 125.6, 133.5, 143.1, 145.8, 162.3, 172.9.
Positive ion FABMS (NBA): m/z 480 [M+H]+. FABHRMS
calcd for C23H30NO8S 480.1515, found 480.1590.
each 3H, Me2C), 2.04 (s, 3H, NAc), 3.54 (dd, 1H, J7,8
11.5 Hz, J7,OH¼4.6 Hz, H-7), 4.04–4.12 (m, 3H, H-6, H-
9a, and H-9b), 4.17 (m, 1H, H-5), 4.29 (ddd, 1H, J8,9a
¼
¼
5.2 Hz, J8,9b¼6.3 Hz, H-8), 4.51 (dd, 1H, J3,4¼2.3 Hz,
J4,5¼8.6 Hz, H-4), 4.44, 4.51 (d, each 1H, Jgem¼16.6 Hz,
OCH2C^), 4.62 (d, 1H, OH), 6.04 (d, 1H, H-3), 6.54 (d,
1H, J5,NH¼8.0 Hz, NH), 6.74 (d, 1H, J¼3.5 Hz, Ar), 7.21 (d,
1H, Ar), 9.53 (s, 1H, CHO). 13C NMR (126 MHz, CDCl3):
d 23.0, 25.1, 26.8, 48.2, 52.3, 55.9, 66.9, 69.7, 73.1, 74.2,
75.8, 77.4, 92.7, 107.0, 108.9, 117.8, 122.0, 140.6, 145.8,
152.2, 162.2, 172.9, 177.1. Positive ion FABMS (NBA):
m/z 478 [M+H]+, 500 [M+Na]+. FABHRMS calcd for
C23H28NO10 478.1713, found 478.1706.
5.9. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(50-acetyl-20-thienyl)-prop-2-
ynyl]-D-glycero-D-galacto-non-2-enonate (9h)
The reaction was carried out using 8 (128 mg, 0.33 mmol)
and 2-acetyl-5-bromothiophene (74 mg, 0.36 mmol) in
a manner similar to the preparation of 9a, to give 9h
(93 mg, 55%). [a]2D3 +7.6 (c 0.21, CHCl3). IR (neat) 3288,
1737, 1633 cmꢁ1. 1H NMR (500 MHz, CDCl3): d 1.36, 1.40
(s, each 3H, Me2C), 2.06 (s, 3H, NAc), 2.55 (s, 3H, CAc),
3.56 (dd, 1H, J7,8¼11.5 Hz, J7,OH¼4.6 Hz, H-7), 3.80 (s,
3H, OMe), 4.07–4.12 (m, 2H, H-6 and H-9a), 4.15–4.24 (m,
5.12. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(phenyl)prop-2-ynyl]-D-glycero-D-galacto-non-
2-enonate (10a)
A solution of 9a (51 mg, 0.11 mmol) in 80% AcOH (3 mL)
was stirred at 80 ꢀC for 1 h, and then evaporated. The residue
was purified by column chromatography on silica gel using
CHCl3/MeOH (9:1 to 6:1, v/v) to give 10a (38 mg, 82%) as
2H, H-5 and H-9b), 4.36 (ddd, 1H, J8,9a¼5.2 Hz, J8,9b
¼
8.0 Hz, H-8), 4.45 (dd, 1H, J3,4¼2.9 Hz, J4,5¼8.6 Hz,

K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
7577
an amorphous material. [a]2D5 +89 (c 0.18, CH3OH). IR
5.2 Hz, Ar), 7.22 (d, 1H, Ar), 7.24 (d, 1H, Ar). Positive ion
FABMS (NBA): m/z 426 [M+H]+, 448 [M+Na]+. FABHRMS
calcd for C19H24NO8S 426.1223, found 426.1187.
1
(neat) 3263, 1718, 1635 cmꢁ1. H NMR (500 MHz, D2O):
d 1.83 (s, 1H, Ac), 3.48–3.52 (m, 2H, H-7 and H-9a), 3.66
(s, 3H, OMe), 3.72 (d, 1H, Jgem¼12.1 Hz, H-9b), 3.77 (m,
1H, H-8), 4.09 (dd, J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.21
(d, 1H, H-6), 4.40 (d, each 1H, Jgem¼16.1 Hz, OCH2C^),
4.53 (d, 1H, H-4), 6.12 (s, 1H, H-3), 7.26–7.30 (m, 3H,
Ar), 7.37–7.39 (m, 2H, Ar). Positive ion FABMS (NBA):
m/z 420 [M+H]+, 442 [M+Na]+. FABHRMS calcd for
C21H26NO8 420.1658, found 420.1628.
5.16. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(3-thienyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonate (10e)
The reaction was carried out using 9e (59 mg, 0.13 mmol) in
a manner similar to the preparation of 10a, to give 10e
(48 mg, 89%) as an amorphous material. [a]2D5 +30 (c 0.22,
5.13. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(2-pyridyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonate (10b)
CH3OH). IR (neat) 3313, 1734, 1624 cmꢁ1 1H NMR
.
(500 MHz, D2O): d 1.85 (s, 1H, Ac), 3.51–3.57 (m, 2H, H-
7 and H-9a), 3.67 (s, 3H, OMe), 3.73 (dd, 1H, J8,9b
¼
2.3 Hz, Jgem¼12.0 Hz, H-9b), 3.78 (m, 1H, H-8), 4.10 (dd,
1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.24 (d, 1H, H-6),
4.39, 4.43 (d, each 1H, Jgem¼16.6 Hz, OCH2C^), 4.53 (dd,
The reaction was carried out using 9b (70 mg, 0.15 mmol) in
a manner similar to the preparation of 10a, to give 10b
(58 mg, 91%) as an amorphous material. [a]2D5 +12 (c 0.19,
1H, J ¼2.3 Hz, H-4), 6.12 (d, 1H, H-3), 7.07 (d, 1H, J¼
3,4
CH3OH). IR (neat) 3342, 1734, 1635 cmꢁ1
.
(500 MHz, D2O): d 1.82 (s, 1H, Ac), 3.49–3.54 (m, 2H, H-7,
1H NMR
4.6 Hz, Ar), 7.33 (m, 1H, Ar), 7.55 (d, 1H, J¼2.9 Hz, Ar).
Positive ion FABMS (NBA): m/z 426 [M+H]+, 448 [M+Na]+.
H-9a), 3.64 (s, 3H, OMe), 3.72 (dd, 1H, J8,9b¼2.3 Hz, Jgem
¼
12.0 Hz, H-9b), 3.77 (ddd, 1H, J8,9a¼5.7 Hz, J7,8¼8.6 Hz,
H-8), 4.07 (dd, 1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.20
(d, 1H, H-6), 4.40, 4.44 (d, each 1H, Jgem¼16.6 Hz,
OCH2C^), 4.50 (dd, 1H, J3,4¼2.3 Hz, H-4), 6.07 (d, 1H,
H-3), 7.28 (m, 1H, Ar), 7.42 (d, 1H, J¼8.0 Hz, Ar), 7.69 (dt,
1H, J¼1.7 Hz, Ar), 8.32 (d, 1H, J¼4.6 Hz, Ar). Positive ion
FABMS (NBA): m/z 421 [M+H]+, 443 [M+Na]+. FABHRMS
calcd for C20H25N2O8 421.1611, found 421.1585.
5.17. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(2-thiazolyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonate (10f)
The reaction was carried out using 9f (98 mg, 0.21 mmol) in
a manner similar to the preparation of 10a, to give 10f
(74 mg, 83%) as an amorphous material. [a]2D5 +52 (c 0.22,
CH3OH). IR (neat) 3392, 1734, 1624 cmꢁ1 1H NMR
.
(500 MHz, D2O): d 1.90 (s, 1H, Ac), 3.56–3.59 (m, 2H, H-7
and H-9a), 3.72 (s, 3H, OMe), 3.79 (dd, 1H, J8,9b¼2.3 Hz,
Jgem¼12.0 Hz, H-9b), 3.85 (m, 1H, H-8), 4.15 (dd, 1H,
J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.28 (d, 1H, H-6), 4.51,
4.54 (d, each 1H, Jgem¼17.2 Hz, OCH2C^), 4.56 (dd, 1H,
J3,4¼2.3 Hz, H-4), 6.14 (d, 1H, H-3), 7.59 (d, 1H, J¼
2.9 Hz, Ar), 7.76 (d, 1H, J¼3.4 Hz, Ar). Positive ion
FABMS (NBA): m/z 427 [M+H]+. FABHRMS calcd for
C18H23N2O8S 427.1175, found 427.1093.
5.14. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(3-pyridyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonate (10c)
The reaction was carried out using 9c (130 mg, 0.28 mmol)
in a manner similar to the preparation of 10a, to give 10c
(99 mg, 83%) as an amorphous material. [a]2D5 +40 (c 0.18,
CH3OH). IR (neat) 3298, 1734, 1637 cmꢁ1 1H NMR
.
(500 MHz, D2O): d 1.85 (s, 1H, Ac), 3.50–3.53 (m, 2H,
H-7, H-9a), 3.67 (s, 3H, OMe), 3.73 (dd, 1H, J8,9b¼2.3 Hz,
5.18. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(50-acetyl-20-thienyl)prop-2-ynyl]-D-glycero-
D-galacto-non-2-enonate (10h)
Jgem¼12.0 Hz, H-9b), 3.78 (ddd, 1H, J7,8¼8.6 Hz, J8,9b
¼
5.7 Hz, H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz,
H-5), 4.23 (d, 1H, H-6), 4.42, 4.46 (d, each 1H, Jgem
¼
16.1 Hz, OCH2C^), 4.52 (dd, 1H, J3,4¼2.3 Hz, H-4), 6.12
(d, 1H, H-3), 7.32 (dd, 1H, J¼5.2, 7.2 Hz, Ar), 7.81 (d,
1H, J¼8.1 Hz, Ar), 8.36 (br, 1H, Ar), 8.48 (br, 1H, Ar). Pos-
itive ion FABMS (NBA): m/z 421 [M+H]+. FABHRMS
calcd for C20H25N2O8 421.1611, found 421.1585.
The reaction was carried out using 9h (40 mg, 0.079 mmol)
in a manner similar to the preparation of 10a, to give 10h
(35 mg, 95%). [a]2D5 +12 (c 0.12, CH3OH). IR (neat) 3257,
1
1714, 1637 cmꢁ1. H NMR (500 MHz, CDCl3): d 1.89 (s,
3H, NAc), 2.47 (s, 3H, CAc), 3.49–3.56 (m, 2H, H-7 and
H-9a), 3.70 (s, 3H, OMe), 3.76 (dd, 1H, J8,9b¼2.9 Hz, Jgem
¼
5.15. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(2-thienyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonate (10d)
12.0 Hz, H-9b), 3.82 (ddd, 1H, J7,8¼9.2 Hz, J8,9a¼6.3 Hz,
H-8), 4.10 (dd, 1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.24
(d, 1H, H-6), 4.43–4.50 (m, 2H, 3H, H-4 and OCH2C^),
6.10 (d, 1H, J3,4¼2.3 Hz, H-3), 7.22 (d, 1H, J¼4.0 Hz, Ar),
7.68 (d, 1H, Ar). Positive ion FABMS (NBA): m/z 468
[M+H]+, 490 [M+Na]+.
The reaction was carried out using 9d (83 mg, 0.18 mmol) in
a manner similar to the preparation of 10a, to give 10d
(74 mg, 98%) as an amorphous material. [a]2D6 +33 (c 0.14,
CH3OH). IR (neat) 3265, 1734, 1624 cmꢁ1
.
1H NMR
5.19. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(50-formyl-20-thienyl)prop-2-ynyl]-D-glycero-
D-galacto-non-2-enonate (10i)
(500 MHz, D2O): d 1.99 (s, 1H, Ac), 3.51–3.57 (m, 2H, H-7
and H-9a), 3.70 (s, 3H, OMe), 3.78 (dd, 1H, J8,9b¼2.3 Hz,
Jgem¼12.0 Hz, H-9b), 3.89 (m, 1H, H-8), 4.15 (dd, 1H, J4,5
¼
8.6 Hz, J5,6¼10.9 Hz, H-5), 4.20 (d, 1H, H-6), 4.39, 4.46 (d,
each 1H, Jgem¼16.6 Hz, OCH2C^), 4.52 (dd, 1H,
J3,4¼2.3 Hz, H-4), 6.07 (d, 1H, H-3), 6.95 (dd, 1H, J¼4.0,
The reaction was carried out using 9i (42 mg, 0.085 mmol)
in a manner similar to the preparation of 10a, to give 10i
(31 mg, 80%). [a]2D5 +53 (c 0.19, CH3OH). IR (neat) 3265,

7578
K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
1
1734, 1624 cmꢁ1. H NMR (500 MHz, CDCl3): d 1.89 (s,
3H, NAc), 3.23–3.59 (m, 2H, H-7 and H-9a), 3.71 (s, 3H,
OMe), 3.76 (dd, 1H, J8,9b¼2.9 Hz, Jgem¼12.0 Hz, H-9b),
3.81 (ddd, 1H, J7,8¼9.2 Hz, J8,9b¼6.3 Hz, H-8), 4.13 (dd,
1H, J4,5¼9.2 Hz, J5,6¼10.9 Hz, H-5), 4.26 (d, 1H, H-6),
4.48, 4.51 (d, each 1H, Jgem¼16.6 Hz, OCH2C^), 4.52
(dd, 1H, J3,4¼2.3 Hz, H-4), 6.13 (d, 1H, H-3), 7.32 (d, 1H,
J¼3.5 Hz, Ar), 7.79 (d, 1H, Ar), 9.68 (s, 1H, CHO). Positive
ion FABMS (NBA): m/z 454 [M+H]+, 476 [M+Na]+.
H-3), 7.35 (dd, 1H, J¼5.2, 7.5 Hz, Ar), 7.53 (d, 1H, J¼
8.0 Hz, Ar), 7.77 (dd, 1H, Ar), 8.40 (d, 1H, Ar). Positive ion
FABMS (NBA): m/z 445 [M+H]+, 467 [M+K]+. FABHRMS
calcd for C19H22N2O8K 445.1013, found 445.1023.
5.23. Potassium 5-acetamido-2,6-anhydro-3,5-dideoxy-
4-O-[3-(3-pyridyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonate (5c)
The reaction was carried out using 10c (38 mg, 0.099 mmol)
in a manner similar to the preparation of 5b, to give 5c
(39 mg, 99%). [a]D25 +22 (c 0.26, CH3OH). 1H NMR
5.20. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(50-formyl-20-furyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonate (10j)
(500 MHz, D2O): d 1.88 (s, 3H, Ac), 3.51 (d, 1H, J7,8
¼
9.2 Hz, H-7), 3.53 (dd, 1H, J8,9a¼6.3 Hz, Jgem¼12.1 Hz,
H-9a), 3.78 (dd, 1H, J8,9b¼2.9 Hz, H-9b), 3.84 (ddd, 1H,
H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.18
(d, 1H, H-6), 4.45, 4.49 (d, each 1H, Jgem¼16.6 Hz,
OCH2C^), 4.52 (dd, 1H, J3,4¼2.3 Hz, H-4), 5.77 (d, 1H,
H-3), 7.35 (dd, 1H, J¼5.2, 8.0 Hz, Ar), 7.85 (m, 1H, Ar),
8.39 (dd, 1H, J¼1.8 Hz, Ar), 8.53 (d, 1H, Ar). Positive ion
FABMS (NBA): m/z 467 [M+K]+. FABHRMS calcd for
C19H22N2O8K 445.1013, found 445.1046.
The reaction was carried out using 9j (70 mg, 0.15 mmol) in
a manner similar to the preparation of 10a, to give 10j
1
(58 mg, 91%). IR (neat) 3246, 1734, 1616 cmꢁ1. H NMR
(500 MHz, CDCl3): d 1.91 (s, 3H, NAc), 3.54–3.59 (m, 2H,
H-7 and H-9a), 3.71 (s, 3H, OMe), 3.76–3.83 (m, 2H, H-8
and H-9b), 4.11 (dd, 1H, J4,5¼9.8, J5,6¼10.9 Hz, H-5),
4.25 (d, 1H, H-6), 4.46–4.52 (m, 3H, H-4 and OCH2C^),
6.09 (d, 1H, J3,4¼2.9 Hz, H-3), 6.82 (d, 1H, J¼3.4 Hz, Ar),
7.40 (d, 1H, Ar), 9.35 (s, 1H, CHO). Positive ion FABMS
(NBA): m/z 438 [M+H]+, 460 [M+Na]+. FABHRMS calcd
for C20H24NO10 438.1400, found 438.1353.
5.24. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(2-
thienyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-enonic
acid (5d)
5.21. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-
(phenyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonic acid (5a)
The reaction was carried out using 10d (41 mg, 0.099 mmol)
in amannersimilar tothe preparationof5a, togive5d(26 mg,
66%). [a]2D5 +23(c 0.15, CH3OH). 1H NMR (500 MHz, D2O):
d 1.89 (s, 3H, Ac), 3.53–3.56 (m, 2H, H-7 and H-9a), 3.76 (dd,
A solution of 10a (20 mg, 0.048 mmol) in 0.1 M KOH/
MeOH (1:1) (2 mL) was stirred at room temperature over-
night, and then adjusted to pH 2–3. The resin was filtered
off and the filtrate was evaporated. The residue was purified
by column chromatography on silica gel using CHCl3/
MeOH/H2O (65:35:5, v/v/v), and then desalted with an AC
Micro Acylizer G1. The resulting aqueous solution was con-
centrated to give 5a (16 mg, 83%) after lyophilization. [a]D25
+22 (c 0.22, CH3OH). 1H NMR (500 MHz, D2O): d 1.89 (s,
3H, Ac), 3.53–3.57 (m, 2H, H-7 and H-9a), 3.78 (dd, 1H,
1H, J8,9b¼2.3 Hz, Jgem¼12.0 Hz, H-9b), 3.84 (ddd, 1H, J7,8
¼
8.6 Hz, J8,9a¼5.7 Hz, H-8), 4.08 (dd, 1H, J4,5¼8.6 Hz,
J5,6¼10.9 Hz, H-5), 4.18, (d, 1H, H-6), 4.42, 4.46 (d, each
1H, Jgem¼16.6 Hz, OCH2C^), 4.49 (dd, 1H, J3,4¼2.3 Hz,
H-4), 5.75 (d, 1H, H-3), 6.97 (dd, 1H, J¼3.4, 5.2 Hz, Ar),
7.25 (d, 1H, Ar), 7.37 (d, 1H, Ar). Positive ion FABMS
(NBA): m/z 412 [M+H]+, 434 [M+Na]+. FABHRMS calcd
for C18H22NO8S 412.1066, found 412.1003.
J8,9b¼2.3 Hz, Jgem¼12.0 Hz, H-9b), 3.85 (ddd, 1H, J7,8
¼
5.25. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(3-
pyridyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-enonic
acid (5e)
9.2 Hz, J8,9a¼6.3 Hz, H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz,
J5,6¼10.9 Hz, H-5), 4.19 (d, 1H, H-6), 4.43, 4.47 (d, each
1H, Jgem¼16.1 Hz, OCH2C^), 4.52 (dd, 1H, J3,4¼2.3 Hz,
H-4), 5.79 (d, 1H, H-3), 7.30–7.36 (m, 3H, Ar), 7.43–7.45
(m, 2H, Ar). Positive ion FABMS (NBA): m/z 428 [M+Na]+.
The reaction was carried out using 10e (22 mg, 0.052 mmol)
in a manner similar to the preparation of 5a, to give 5e
(16 mg, 76%). [a]D25 +25 (c 0.11, CH3OH). 1H NMR
(500 MHz, D2O): d 1.90 (s, 3H, Ac), 3.53–3.57 (m, 2H,
H-7 and H-9a), 3.79 (dd, 1H, J8,9a¼2.9 Hz, Jgem¼12.1 Hz,
H-9b), 3.86 (m, 1H, H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz,
J5,6¼10.9 Hz, H-5), 4.20 (d, 1H, H-6), 4.42, 4.46 (d, each
1H, Jgem¼16.0 Hz, OCH2C^), 4.53 (dd, 1H, J3,4¼1.7 Hz,
H-4), 5.78 (d, 1H, H-3), 7.12 (d, 1H, J¼5.2 Hz, Ar), 7.37
(m, 1H, Ar), 7.59 (d, 1H, J¼2.3 Hz, Ar). Positive ion
FABMS (NBA): m/z 412 [M+H]+. FABHRMS calcd for
C18H22NO8S 412.1066, found 412.1122.
5.22. Potassium 5-acetamido-2,6-anhydro-3,5-dideoxy-
4-O-[3-(2-pyridyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonate (5b)
A solution of 10b (58 mg, 0.138 mmol) in 0.1 M KOH/
MeOH (1:1) (2 mL) was stirred at room temperature over-
night, and then evaporated. The residue was purified by col-
umn chromatography on silica gel with CHCl3/MeOH/H2O
(65:35:5, v/v), and then desalted with an AC Micro Acylizer
G1 to give 5b (60 mg, 99%) after lyophilization. [a]2D5 +17
(c 0.15, CH3OH). 1H NMR (500 MHz, D2O): d 1.86 (s, 3H,
5.26. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(2-
thiazolyl)prop-2-ynyl]-D-glycero-D-galacto-non-2-
enonic acid (5f)
Ac), 3.51 (d, 1H, J7,8¼9.2 Hz, H-7), 3.53 (dd, 1H, J8,9a
¼
6.3 Hz, Jgem¼12.0 Hz, H-9a), 3.78 (dd, 1H, J8,9b¼2.3 Hz,
H-9b), 3.84 (m, 1H, H-8), 4.12 (dd, 1H, J4,5¼8.6 Hz, J5,6
¼
10.9 Hz, H-5), 4.19 (d, 1H, H-6), 4.47, 4.51 (d, each 1H,
Jgem¼16.6 Hz, OCH2C^), 4.54 (d, 1H, H-4), 5.77 (s, 1H,
The reaction was carried out using 10f (74 mg, 0.17 mmol)
in a manner similar to the preparation of 5a, to give 5f

K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
7579
(39 mg, 54%). [a]D25 +8.1 (c 0.10, CH3OH). 1H NMR
(500 MHz, D2O): d 1.82 (s, 3H, Ac), 3.46–3.50 (m, 2H,
H-7 and H-9a), 3.72 (dd, 1H, J8,9a¼2.3 Hz, Jgem¼12.0 Hz,
H-9b), 3.79 (m, 1H, H-8), 4.06 (dd, 1H, J4,5¼9.2 Hz,
J5,6¼10.9 Hz, H-5), 4.15 (d, 1H, H-6), 4.47, 4.48 (d, each
1H, Jgem¼16.6 Hz, OCH2C^), 4.70 (m, 1H, H-4), 5.77 (d,
1H, J3,4¼2.3 Hz, H-3), 7.52 (d, 1H, J¼3.4 Hz, Ar), 7.70
(d, 1H, Ar). Positive ion FABMS (NBA): m/z 413 [M+H]+.
FABHRMS calcd for C17H21N2O8S 413.1019, found
413.1005.
was stirred for 2 h at the same temperature. The reaction
mixture was treated with Amberlite IRC-50 (5 g) and the
suspension was filtered and the filtrate was evaporated in
vacuo. The resulting residue was dissolved in 2,2-dimeth-
oxypropane (20 mL) and DMF (5 mL) containing Amberlite
IRA 120 (H+) (3 g), and the mixture was stirred for 12 h at
room temperature, filtered, and concentrated in vacuo.
Purification of the residue by column chromatography on sil-
ica gel with AcOEt yielded 12 (1.28 g, 58%). [a]2D4 ꢁ105
1
(c 1.63, CH3OH). H NMR (500 MHz, CDCl3): d 1.35,
1.40 (s, each 3H, Me2C), 2.10 (s, 3H, NAc), 2.74 (br, 1H,
OH-4), 3.50 (dd, 1H, J7,OH¼4.0 Hz, J7,8¼8.7 Hz, H-7),
3.78 (s, 3H, OMe), 3.93 (d, 1H, J5,6¼11.5 Hz, H-6), 4.09–
5.27. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(50-
acetyl-20-thienyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonic acid (5h)
4.18 (m, 3H, H-5, H-9a, and H-9b), 4.25 (ddd, 1H, J3,4
¼
5.7 Hz, J4,5¼4.1 Hz, J4,OH¼5.7 Hz, H-4), 4.41 (ddd, 1H,
J8,9a¼5.2 Hz, J8,9b¼6.3 Hz, H-8), 4.85 (d, 1H, OH-7), 6.11
(d, 1H, H-3), 6.53 (d, 1H, J5,NH¼7.5 Hz, NH). 13C NMR
(126 MHz, CDCl3): d 23.1, 25.2, 27.0, 47.7, 52.5, 61.2,
67.2, 69.6, 73.2, 74.1, 107.4, 109.1, 146.4, 162.5, 172.5. Pos-
itive ion FABMS (NBA): m/z 346 [M+H]+. FABHRMS
calcd for C15H24NO8 346.1502, found 346.1465.
The reaction was carried out using 10h (16 mg, 0.039 mmol)
in a manner similar to the preparation of 5a, to give 5h
(15 mg, 98%). H NMR (500 MHz, D2O): d 1.90 (s, 3H,
1
Ac), 2.50 (s, 3H, Ac), 3.51–3.57 (m, 2H, H-7 and H-9a),
3.78 (dd, 1H, J8,9b¼2.3 Hz, Jgem¼12.0 Hz, H-9b), 3.84
(ddd, 1H, J7,8¼9.2 Hz, J8,9a¼6.3 Hz, H-8), 4.10 (dd, 1H,
J4,5¼8.6 Hz, J5,6¼10.9 Hz, H-5), 4.19 (d, 1H, H-6), 4.43–
4.51 (m, 3H, H-4, OCH2C^), 5.75 (d, 1H, J3,4¼2.3 Hz,
H-3), 7.25 (d, 1H, J¼4.0 Hz, Ar), 7.37 (d, 1H, Ar). Positive
ion FABMS (NBA): m/z 476 [M+Na]+. FABHRMS calcd for
C20H23NO9SNa 476.0992, found 476.1044.
5.31. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-(prop-2-ynyl)-D-glycero-D-talo-
non-2-enonate (13)
Sodium hydride (31 mg, 1.3 mmol) at 0 ꢀC under Ar was
added to a solution of 12 (350 mg, 1.0 mmol). Propargyl bro-
mide (244 mg, 2.0 mmol) in DMF (5 mL) was added, and
the mixture was stirred for 1 h. After the addition of
MeOH (1 mL), the solvent was concentrated and dried.
The residue was chromatographed on silica gel using 50:1
CHCl3/MeOH to give 13 (151 mg, 39%). [a]2D4 ꢁ103
(c 0.29, CHCl3). 1H NMR (500 MHz, CDCl3): d 1.31, 1.35
(s, each 3H, Me2C), 2.05 (s, 3H, NAc), 2.52 (t, 1H, J¼
2.3 Hz, C^CH), 3.44 (dd, 1H, J7,OH¼3.5 Hz, J7,8¼8.0 Hz,
H-7), 3.73 (s, 3H, OMe), 3.96 (d, 1H, J5,6¼10.9 Hz, H-6),
4.05 (dd, 1H, J8,9a¼5.2 Hz, Jgem¼9.2 Hz, H-9a), 4.10–4.21
(m, 4H, H-4, H-5, H-9b, and OCH2C^C), 4.30 (dd, 1H,
Jgem¼16.1 Hz, OCH2C^), 4.33 (ddd, 1H, J8,9b¼2.3 Hz,
H-8), 4.73 (d, 1H, OH), 6.12 (d, 1H, J3,4¼5.2 Hz, H-3),
6.40 (d, 1H, J5,NH¼8.0 Hz, NH). Positive ion FABMS
(NBA): m/z 384 [M+H]+, 406 [M+Na]+. FABHRMS calcd
for C18H26NO8 384.1658, found 384.1681.
5.28. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(50-
formyl-20-thienyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonic acid (5i)
The reaction was carried out using 10i (18 mg, 0.04 mmol)
in a manner similar to the preparation of 5a, to give 5i
(17 mg, 96%). H NMR (500 MHz, D2O): d 1.92 (s, 3H,
1
Ac), 3.54 (d, 1H, J7,8¼9.2 Hz, H-7), 3.55 (dd, 1H, J8,9a
¼
6.3 Hz, Jgem¼12.0 Hz, H-9a), 3.79 (dd, 1H, J8,9b¼2.9 Hz,
H-9b), 3.86 (ddd, 1H, H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz,
J5,6¼10.9 Hz, H-5), 4.20 (d, 1H, H-6), 4.47–4.55 (m, 3H,
H-4, OCH2C^), 5.76 (d, 1H, J3,4¼2.3 Hz, H-3), 7.34 (d,
1H, J¼4.0 Hz, Ar), 7.81 (d, 1H, Ar), 9.69 (s, 1H, CHO). Pos-
itive ion FABMS (NBA): m/z 462 [M+Na]+.
5.29. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(50-
formyl-20-furyl)prop-2-ynyl]-D-glycero-D-galacto-
non-2-enonic acid (5j)
5.32. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(20-thienyl)prop-2-ynyl]-D-
glycero-D-talo-non-2-enonate (14a)
The reaction was carried out using 11j (20 mg, 0.046 mmol)
in a manner similar to the preparation of 5a, to give 5j (9 mg,
46%). 1H NMR (500 MHz, D2O): d 1.90 (s, 3H, Ac), 3.52 (d,
1H, J7,8¼9.2 Hz, H-7), 3.54 (dd, 1H, J8,9a¼6.3 Hz, Jgem
¼
The reaction was carried out using 13 (83 mg, 0.22 mmol)
and 2-iodothiophene (56 mg, 0.26 mmol) in a manner simi-
lar to the preparation of 9a, to give 14a (64 mg, 64%). H
12.0 Hz, H-9a), 3.78 (dd, 1H, J8,9b¼2.9 Hz, H-9b), 3.84
(ddd, 1H, H-8), 4.11 (dd, 1H, J4,5¼8.6 Hz, J5,6¼10.9 Hz,
H-5), 4.18 (d, 1H, H-6), 4.50 (dd, 1H, J3,4¼2.3 Hz, H-4),
4.51 (d, each 1H, Jgem¼17.2 Hz, OCH2C^), 5.74 (d, 1H,
H-3), 6.85 (d, 1H, J¼3.5 Hz, Ar), 7.43 (d, 1H, Ar), 9.37 (s,
1H, CHO). Positive ion FABMS (NBA): m/z 424 [M+H]+.
1
NMR (500 MHz, CDCl3): d 1.37, 1.41 (s, each 3H, Me2C),
2.07 (s, 3H, NAc), 3.51 (d, 1H, J7,8¼8.0 Hz, H-7), 3.79 (s,
3H, OMe), 4.04 (d, 1H, J5,6¼11.5 Hz, H-6), 4.11 (dd, 1H,
J8,9a¼5.2 Hz, Jgem¼8.6 Hz, H-9a), 4.18 (d, 1H, J8,9b
¼
6.3 Hz, H-9b), 4.20–4.24 (m, 1H, H-4), 4.25–4.27 (m, 1H,
H-5), 4.39–4.43 (m, 1H, H-8), 4.46, 4.59 (d, each 1H,
5.30. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-D-glycero-D-talo-non-2-enonate (12)
Jgem¼16.1 Hz, OCH2C), 4.77 (br, 1H, OH), 6.22 (d, 1H, J3,4¼
5.2 Hz, H-3), 6.39 (d, 1H, J5,NH¼8.0 Hz, NH), 6.99 (dd, 1H,
J¼4.0, 5.2 Hz, Ar), 7.24 (d, 1H, Ar), 7.30 (d, 1H, Ar). 13C
NMR (126 MHz, CDCl3): d 23.1, 25.2, 26.9, 46.6, 52.3,
56.3, 66.8, 67.1, 69.5, 73.8, 74.2, 80.8, 87.9, 103.7, 108.9,
To a solution of compound 11 (3.02 g, 6.38 mmol)11a in
MeOH (20 mL) was added a solution of NaOMe (0.035 g,
0.64 mmol) in MeOH (10 mL) at 0 ꢀC, and the mixture

7580
K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
121.5, 127.0, 127.9, 132.8, 147.1, 162.3, 172.2. Positive ion
FABMS (NBA): m/z 466 [M+H]+. FABHRMS calcd for
C22H28NO8S 466.1536, found 466.1482.
1H, Ar), 7.29 (d, 1H, Ar). Positive ion FABMS (NBA):
m/z 426 [M+H]+. FABHRMS calcd for C19H24NO8S
426.1223, found 426.1279.
5.33. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(30-thienyl)prop-2-ynyl]-D-
glycero-D-talo-non-2-enonate (14b)
5.36. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(30-thienyl)prop-2-ynyl]-D-glycero-D-talo-non-2-
enonate (15b)
The reaction was carried out using 13 (101 mg, 0.26 mmol)
and 3-iodothiophene (67 mg, 0.32 mmol) in a manner simi-
lar to the preparation of 9a, to give 14b (89 mg, 73%). [a]D24
ꢁ107 (c 0.22, CHCl3). 1H NMR (500 MHz, CDCl3): d 1.35,
1.40 (s, each 3H, Me2C), 2.05 (s, 3H, NAc), 3.50 (dd, 1H,
J7,8¼7.4 Hz, J7,OH¼2.3 Hz, H-7), 3.77 (s, 3H, OMe), 4.02
(d, 1H, J5,6¼10.9 Hz, H-6), 4.10 (dd, 1H, J8,9a¼5.2 Hz,
Jgem¼8.6 Hz, H-9a), 4.26 (dd, 1H, J4,5¼4.0 Hz, H-4),
4.15–4.23 (m, 1H, H-5 and H-9b), 4.39 (m, 1H, H-8),
4.42, 4.54 (d, each 1H, Jgem¼16.0 Hz, OCH2C^), 4.78 (d,
1H, OH), 6.23 (d, 1H, J3,4¼5.7 Hz, H-3), 6.42 (d, 1H,
J5,NH¼8.0 Hz, NH), 7.10 (dd, 1H, J¼1.2, 5.2 Hz, Ar), 7.28
(d, 1H, J¼2.9 Hz, Ar), 7.48 (d, 1H, Ar). 13C NMR
(126 MHz, CDCl3): d 23.3, 25.3, 27.1, 46.8, 52.5, 56.5,
66.9, 67.3, 69.7, 73.9, 74.3, 82.8, 83.8, 104.0, 109.1,
120.9, 125.8, 129.8, 129.9, 147.2, 162.5, 172.4. Positive
ion FABMS (NBA): m/z 466 [M+H]+. FABHRMS calcd
for C22H28NO8S 466.1536, found 466.1482.
The reaction was carried out using 14b (73 mg, 0.157 mmol)
in a manner similar to the preparation of 10a, to give 15b
(53 mg, 79%). [a]D24 ꢁ214 (c 0.74, CH3OH). 1H NMR
(500 MHz, D2O): d 1.83 (s, 3H, NAc), 3.48 (d, 1H,
J7,8¼9.8 Hz, H-7), 3.51 (dd, 1H, J8,9a¼5.8 Hz, Jgem
¼
12.0 Hz, H-9a), 3.57 (s, 3H, OMe), 3.72 (d, 1H, H-9a),
3.79 (br, 1H, H-8), 4.00 (d, 1H, J5,6¼3.5 Hz, H-6), 4.08 (d,
1H, J4,5¼11.5 Hz, H-5), 4.16 (dd, 1H, J3,4¼4.6 Hz, H-4),
4.23, 4.30 (d, each 1H, Jgem¼17.2 Hz, OCH2C^), 6.02 (d,
1H, H-3), 6.91 (d, 1H, J¼4.6 Hz, Ar), 7.10 (br, 1H, Ar),
7.32 (br, 1H, Ar). Positive ion FABMS (NBA): m/z 426
[M+H]+. FABHRMS calcd for C19H24NO8S 426.1223,
found 426.1135.
5.37. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(20-thiazolyl)prop-2-ynyl]-D-glycero-D-talo-non-2-
enonate (15c)
The reaction was carried out using 14c (41 mg, 0.088 mmol)
in a manner similar to the preparation of 10a, to give 15c
(20 mg, 53%). [a]D24 ꢁ30 (c 1.07, CH3OH). 1H NMR
(500 MHz, D2O): d 1.92 (s, 3H, NAc), 3.59–3.62 (m, 2H,
5.34. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-8,9-
O-isopropylidene-4-O-[3-(20-thiazolyl)prop-2-ynyl]-D-
glycero-D-talo-non-2-enonate (14c)
H-7 and H-9a), 3.74 (s, 3H, OMe), 3.82 (dd, 1H, J8,9a
2.3 Hz, Jgem¼12.0 Hz, H-9b), 3.89 (m, 1H, H-8), 4,22–
4.31 (m, 3H, H-4, H-5, and H-6), 4.56 (d, each 1H, Jgem
17.2 Hz, OCH2C^), 6.29 (d, 1H, J3,4¼5.8 Hz, H-3), 7.60
(d, 1H, J¼3.5 Hz, Ar), 7.77 (d, 1H, Ar). Positive ion FABMS
(NBA): m/z 427 [M+H]+. FAB HRMS calcd for
C18H23N2O8S 427.1175, found 427.1209.
¼
The reaction was carried out using 13 (151 mg, 0.39 mmol)
and 2-bromothiazole (71 mg, 0.43 mmol) in a manner simi-
lar to the preparation of 9f, to give 14c (70 mg, 48%). [a]D24
ꢁ101 (c 0.22, CHCl3). 1H NMR (500 MHz, CDCl3):
d 1.35, 1.39 (s, each 3H, Me2C), 2.08 (s, 3H, NAc), 3.49
(dd, 1H, J7,8¼8.0 Hz, J7,OH¼4.0 Hz, H-7), 3.77 (s, 3H,
OMe), 4.03 (d, 1H, J5,6¼11.5 Hz, H-6), 4.10 (dd, 1H,
¼
J8,9a¼5.2 Hz, Jgem¼8.6 Hz, H-9a), 4.15 (dd, 1H, J8,9b
¼
5.38. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(20-
thienyl)prop-2-ynyl]-D-glycero-D-talo-non-2-
enonic acid (6a)
6.3 Hz, H-9b), 4.20–4.25 (m, 1H, H-4), 4.27 (m, 1H, H-5),
4.39 (m, 1H, H-8), 4.48, 4.60 (d, each 1H, Jgem¼16.0 Hz,
OCH2C^), 4.75 (d, 1H, OH), 6.19 (d, 1H, J3,4¼5.7 Hz,
H-3), 6.40 (d, 1H, J5,NH¼8.0 Hz, NH), 7.40 (d, 1H, J¼
3.5 Hz, Ar), 7.83 (d, 1H, Ar). 13C NMR (126 MHz,
CDCl3): d 23.3, 25.3, 27.1, 46.7, 52.6, 55.9, 67.2, 67.3, 69.7,
73.9, 74.3, 80.4, 88.9, 103.2, 109.2, 121.4, 143.8, 147.4,
147.7, 162.3, 172.4. Positive ion FABMS (NBA): m/z 467
[M+H]+. FABHRMS calcd for C21H27N2O8S 467.1488,
found 467.1439.
The reaction was carried out using 15a (25 mg, 0.059 mmol)
in a manner similar to the preparation of 5a, to give 6a
(15 mg, 60%). [a]D24 ꢁ174 (c 0.17, CH3OH). 1H NMR
(500 MHz, D2O): d 1.90 (s, 3H, Ac), 3.55 (d, 1H, J7,8
¼
9.8 Hz, H-7), 3.58 (dd, 1H, J8,9a¼6.3, 12.0 Hz, H-9a), 3.81
(dd, 1H, J8,9b¼2.3 Hz, H-9b), 3.90 (ddd, 1H, H-8), 4.17 (d,
1H, J5,6¼12.1 Hz, H-6), 4.22–4.27 (m, 2H, H-4 and H-5),
4.49 (d, each 1H, Jgem¼17.2 Hz, OCH2C^), 5.99 (d,
J3,4¼5.2 Hz, H-3), 6.99 (dd, 1H, J¼4.0, 5.2 Hz, Ar), 7.26
(d, 1H, Ar), 7.39 (d, 1H, Ar). Positive ion FABMS (NBA):
m/z 412 [M+H]+. FABHRMS calcd for C18H22NO8S
412.1066, found 412.1081.
5.35. Methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-4-O-
[3-(20-thienyl)prop-2-ynyl]-D-glycero-D-talo-non-2-
enonate (15a)
The reaction was carried out using 14a (41 mg, 0.088 mmol)
in a manner similar to the preparation of 10a, to give 15a
(25 mg, 68%). [a]D24 ꢁ200 (c 1.20, CH3OH). 1H NMR
5.39. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(30-
thienyl)prop-2-ynyl]-D-glycero-D-talo-non-2-
enonic acid (6b)
(500 MHz, D2O): d 1.99 (s, 3H, NAc), 3.56 (d, 1H, J7,8
¼
9.2 Hz, H-7), 3.59 (dd, 1H, J8,9a¼5.7 Hz, Jgem¼12.0 Hz,
H-9a), 3.69 (s, 3H, OMe), 3.80 (d, 1H, H-9b), 3.87 (m,
1H, H-8), 4.14–4.26 (m, 3H, H-4, H-5, and H-6), 4.42 (d,
The reaction was carried out using 15b (35 mg, 0.082 mmol)
in a manner similar to the preparation of 5a, to give 6b
(34 mg, 99%). [a]D24 ꢁ169 (c 0.22, CH3OH). 1H NMR
(500 MHz, D2O): d 1.86 (s, 3H, NAc), 3.53–3.58 (m, 2H,
each 1H, Jgem¼16.6 Hz, OCH2C^), 6.17 (d, 1H, J3,4
¼
5.2 Hz, H-3), 6.92 (dd, 1H, J¼2.3, 5.2 Hz, Ar), 7.19 (d,

K. Sato et al. / Tetrahedron 63 (2007) 7571–7581
7581
Sialic Acids; Rosenberg, A., Ed.; Plenum: New York, NY,
1995.
H-7 and H-9a), 3.78 (dd, 1H, J8,9b¼2.3 Hz, Jgem¼12.0 Hz,
H-9b), 3.89 (ddd, 1H, J7,8¼8.6 Hz, H-8), 4.14 (d, 1H,
J5,6¼11.5 Hz, H-6), 4.18–4.21 (m, 2H, H-4 and H-5), 4.42
2. Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471.
3. (a) Ikeda, K.; Sato, M.; Torisawa, Y. Curr. Med. Chem. 2004, 3,
339; (b) Wilson, J. C.; Thomson, R. J.; Dyason, J. C.; Florio, P.;
Quelch, K. J.; Abo, S.; von Itzstein, M. Tetrahedron:
Asymmetry 2000, 11, 53; (c) Smith, P. W.; Starkey, I. D.;
Howes, P. D.; Sollis, I. L.; Keeling, S. P.; Cherry, P. C.; von
Itzstein, M.; Wu, W. Y.; Jin, B. Eur. J. Med. Chem. 1996,
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4. von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver,
S. W.; Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods,
J. M.; Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn,
C. R. Nature 1993, 363, 418.
(d, each 1H, Jgem¼17.2 Hz, OCH2C^), 5.92 (d, J3,4
¼
5.7 Hz, H-3), 7.08 (d, 1H, J¼3.5 Hz, Ar), 7.35 (m, 1H,
Ar), 7.55 (d, 1H, J¼2.3 Hz, Ar). Positive ion FABMS
(NBA): m/z 412 [M+H]+. FABHRMS calcd for
C18H22NO8S 412.1066, found 412.1012.
5.40. 5-Acetamido-2,6-anhydro-3,5-dideoxy-4-O-[3-(20-
thiazolyl)prop-2-ynyl]-D-glycero-D-talo-non-2-enonic
acid (6c)
The reaction was carried out using 15c (20 mg, 0.047 mmol)
in a manner similar to the preparation of 5a, to give 6c
(18 mg, 94%). [a]D24 ꢁ191 (c 0.15, CH3OH). 1H NMR
5. (a) Collins, P. L.; Chanock, R. M.; McIntosh, K.
Parainfluenza Viruses. In Fields Viology; Fields, B. N.,
Knipe, D. M., Howely, P. M., Eds.; Lippincott-Raven:
(500 MHz, D2O): d 1.86 (s, 3H, NAc), 3.55 (d, 1H, J7,8
¼
9.8 Hz, H-7), 3.58 (dd, 1H, J8,9a¼6.8 Hz, Jgem¼12.0 Hz,
H-9a), 3.81 (dd, 1H, J8,9b¼2.9 Hz, H-9b), 3.90 (ddd, 1H,
H-8), 4.18 (d, 1H, J5,6¼12.6 Hz, H-6), 4.24–4.27 (m, 2H,
H-4 and H-5), 4.56 (dd, each 1H, Jgem¼16.6 Hz,
OCH2C^), 5.96 (d, 1H, J3,4¼5.2 Hz, H-3), 7.60 (d, 1H,
J¼3.4 Hz, Ar), 7.77 (d, 1H, Ar). Positive ion FABMS
(NBA): m/z 413 [M+H]+. FABHRMS calcd for
C17H21N2O8S 413.1019, found 413.1005.
Philadelphia, PA, 1996;
p 1205; (b) Murphy, B. R.
Parainfluenza Viruses. In Infection Diseases; Gorbach,
S. L., Bartlett, J. G., Blacklow, N. R., Eds.; W.B. Saunders:
Philadelphia, PA, 1998; p 2125.
6. (a) Ikeda, K.; Sano, K.; Ito, M.; Saito, M.; Hidari, K.; Suzuki,
T.; Suzuki, Y.; Tanaka, K. Carbohydr. Res. 2001, 330, 31; (b)
Suzuki, T.; Ikeda, K.; Koyama, N.; Hosokawa, C.; Kogure,
T.; Takahashi, T.; Hidari, K.; Miyamoto, D.; Tanaka, K.;
Suzuki, Y. Glycoconjugate J. 2001, 18, 331.
7. Ikeda, K.; Sato, K.; Kitani, S.; Suzuki, T.; Maki, N.; Suzuki, Y.;
Sato, M. Bioorg. Med. Chem. 2006, 14, 7893.
Acknowledgements
8. (a) Bemics, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39,
2887; (b) De Laet, A.; Hehenkamp, J. J. J.; Wife, R. L.
J. Heterocycl. Chem. 2000, 37, 669.
9. Sonogashira, K. Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., De Meijere, A., Eds.; Wiley-
Interscience: New York, NY, 2002; Vol. 1, p 493.
This work was financially supported in part by the Grant-in
Aid for Scientific Research No. 19590103 from the Ministry
of Education, Science, Sports, and Culture of Japan. This
work was partly supported by the Japan Health Science
Foundation. The authors also thank Marukin Chuyu Co.,
Ltd (Kyoto, Japan) for the generous gift of Neu5Ac.
10. Siebeneicher, H.; Doya, S. Eur. J. Org. Chem. 2002, 1213.
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(b) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. Jpn.
1987, 60, 631; (c) Tomoo, T.; Kondo, T.; Abe, H.;
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284, 207.
References and notes
1. Schauer, R.; Kelm, S.; Reuter, G.; Roggentin, P.; Shaw, L.
Biochemistry and Role of Sialic Acids. In Biology of the