Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor

Article abstract of DOI:10.1016/j.bmc.2011.02.028

Synthesis and evaluation of four diastereomers (9a, 9b, 9c and 9d) of kotalanol, a potent α-glucosidase inhibitor isolated from an Ayurvedic medicinal plant Salacia species, are described. Stereo-inversion at C-3′ and C-4′ of kotalanol (2) caused signific

Full text of DOI:10.1016/j.bmc.2011.02.028

Bioorganic & Medicinal Chemistry 19 (2011) 2252–2262
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Role of the side chain stereochemistry in the
a-glucosidase inhibitory activity
of kotalanol, a potent natural
a-glucosidase inhibitor
Weijia Xie a,b, Genzoh Tanabe a, Kanjyun Matsuoka a, Mumen F. A. Amer a, Toshie Minematsu a,
Xiaoming Wu b, Masayuki Yoshikawa c, Osamu Muraoka a,
⇑
a School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China
c Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and evaluation of four diastereomers (9a, 9b, 9c and 9d) of kotalanol, a potent a-glucosidase
Received 28 December 2010
Revised 15 February 2011
Accepted 16 February 2011
Available online 24 February 2011
inhibitor isolated from an Ayurvedic medicinal plant Salacia species, are described. Stereo-inversion at
C-30 and C-40 of kotalanol (2) caused significant decrease of the inhibitory activities against maltase
and sucrase, whereas inhibitory activity against isomaltase sustained, thus resulted in exerting selectivity
against isomaltase.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Kotalanol
a-Glucosidase inhibitor
Salacia
SAR study
Selective inhibition
1. Introduction
reaction, and thus establish electrostatic interactions between
inhibitors and the active sites of the carboxylate residue.4
Glucosidases are enzymes that catalyze the cleavage of glyco-
sidic bonds in oligosaccharides or glycoconjugates. The activity of
glucosidases is fundamental to several important biochemical pro-
cesses, and glucosidase enzyme-catalyzed hydrolysis of complex
carbohydrates is a biologically widespread phenomenon in living
systems.1 Multi-function of glucosidase in organisms makes itself
an attractive target, and inhibition of the glucosidase has been used
as a potential therapeutic principle to treat diseases such as diabe-
tes, obesity, glycosphingolipid lysosomal storage disease, HIV infec-
tions, cancers and Gaucher’s disease.2 Thus, during the past few
decades, considerable attention has been paid on designing potent
glucosidase inhibitors in the chemical and medicinal research. One
special category of potent glucosidase inhibitor is naturally occur-
ring and synthesized azasugars such as deoxynojirimycin, acarbose,
voglibose and miglitol.3 The effective inhibition of azasugars
against glucosidase enzymes is attributed to bearing the positive
charge under physiological pH, which is postulated to bind in the
active sites of glucosidase enzymes. This evidence indicates that a
potent glucosidase inhibitor might include an atom that carries a
permanent positive charge at a suitable position that mimic the
oxacarbenium ion-like transition state of the enzyme-catalyzed
In late 1990’s, salacinol (1) was isolated by the authors as one of
the physiologically active components of an Ayurvedic medicinal
plant Salacia reticulata, which have traditionally been used for
the treatment of diabetes in Sri Lanka and the south region of In-
dia.5 Its
a-glucosidase inhibitory activities were revealed to be as
potent as those of voglibose and acarbose which are widely used
clinically these days. Besides, the structure of 1 was found quite
unique, bearing thiosugar sulfonium sulfate inner salt comprised
of 1-deoxy-4-thio-D
-arabinofranosyl cation and 30-sulfate anion
as shown in Figure 1.5 Since the discovery of 1, related sulfonium
sulfates, kotalanol6 (2), salaprinol7 (3) and ponkoranol7 (4) as well
as their de-O-sulfonated analogues, neosalacinol8 (5), neokotala-
nol9 (6), neosalaprinol10 (7), and neoponkoranol10 (8) have subse-
quently been isolated from the same Salacia genus plants. All
these sulfonium salts (2–8) showed potent
tory activities as 1, composing a new class of naturally occurring
-glycosidase inhibitors. Because of both their intriguing struc-
a-glucosidase inhibi-
a
tures and high a-glucosidase inhibitory activities, intensive struc-
ture–activity relationship (SAR) studies have been reported,11
and structural determinants of these sulfoniums for the
a-glucosidase inhibitory activities have been revealed to
a
considerable extent.
On the other hand, although the exact stereostructure of the
sulfonium sulfates 1, 3 and 4 had been determined soon after their
⇑
Corresponding author. Tel.: +81 6 6721 2332; fax: +81 6 6721 2505.
E-mail address: muraoka@phar.kindai.ac.jp (O. Muraoka).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.02.028

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
2253
OH OH OH
OH OH
OH
OH
OH OH OH
2'S
3'R
5'
OH
2'S
3'S
5'R
7'
6'
OH
4'S
6'S
4'R
OH
OH
S+
OH
-
S+
S+ OR
OH
S+ OR
S+
OH
OH
1
OSO3
HO
5
OR
OR
HO
HO
HO
HO
3
OH
HO
OH
HO
HO
OH
OH
HO
HO
-
-
-
: R = SO3
ponkoranol (4)
9a : 5'S,6'R; 9b : 5'R,6'S
9c : 5'S,6'S; 9d : 5'R,6'R
-
: R = SO
salaprinol (3)
neosalaprinol (7)
: R = SO3
3
kotalanol (2)
salacinol (1)
: R = SO3
neoponkoranol (8) : R = H
: R = H
neosalacinol (5) : R = H
neokotalanol (6) : R = H
Figure 1.
OH
OH
isolation, that of 2 had long been not clarified until recently when
it was elucidated through the total synthesis by Pinto and co work-
ers,12a and our degradation study of a natural kotalanol (2).12b In
their previous synthetic studies directed toward the stereochemi-
cal structure determination of 2, they synthesized few side chain
stereoisomers, and discussed on the role of the side chain stereo-
chemistry to the inhibitory activity against recombinant human
maltase glucoamylase (MGA).11d In the course of our synthetic
studies on 2, we also had synthesized several diastereomers of 2,
O
OR OR
D-xylose : R = H
4 steps
10 : R = Bn
a
t
OH OH
OH OH CO2 Bu
and evaluated their
a-glucosidase inhibitory activities against rat
+
+
t
small intestinal -glucosidases, maltase, sucrase and isomaltase,
a
CO2 Bu
as a part of SAR studies on this new class of inhibitors. In this paper
are described full details on the synthesis, evaluation and SAR
studies on four kotalanol diastereomers (9a, 9b, 9c and 9d), which
have reversed stereochemistries at both C-30 and C-40 positions to
kotalanol (2). Out of the four compounds examined, three (9a, 9b,
and 9d) considerably lost their activities against both maltase and
sucrase, while sustained the activity against isomaltase to a large
extent, thus resulted in exerting selectivity against isomaltase.
OBn OBn
OBn OBn
-11
Z
E
-11
b
b
O
R
O
O
O
R
t
OBn OBn
OBn OBn
t
2. Results and discussion
E
E
-12 : R = CO2 Bu
-13 : R = CH2OH
Z
Z
-12 : R = CO2 Bu
-13 : R = CH2OH
c
c
2.1. Preparation of cyclic sulfates
Scheme 1. Reagents and conditions: (a) Ph3P@CHCO2tBu, CH2Cl2, reflux; (b)
(CH3)2C(OCH3)2, p-TsOH, acetone, (c) 1 M soln of DIBAH in toluene, THF, ꢀ50 °C
to rt.
As a common synthon for the four target compounds with
30R,40S stereochemistries (9a, 9b, 9c and 9d), 3,5-di-O-
D
-xylofuranose (10),13 which was easily obtained via 4
(Scheme 2 and Table 1, run 5). Thus, it was found that by the
OsO4 dihydroxylation of E- and Z-13, no sufficient amounts of tri-
ols 14b and 14d for further steps could be obtained. Therefore, the
Sharpless asymmetric dihydroxylation15 was applied to the enitols
benzyl-
steps from a commercially available
D
-xylose, was selected. Thus,
the Wittig reaction of 10 with tert-butoxycarbonylmethylen-
etriphenylphosphorane gave tert-butyl (E)-5,7-di-O-benzyl-2,3-
E- and Z-13. It is interesting to note that AD-mix-
(DHQ)2PHAL] and AD-mix-b [ligand: (DHQD)2PHAL] showed quite
similar selectivity in the dihydroxylation, giving -facial syn-dihy-
a [ligand:
dideoxy-D-xylo-hept-2-enoate (E-11) and its Z-isomer (Z-11)
with a ratio of 6.5:1. The major enoate E-11 was then converted
to the corresponding acetal, tert-butyl (E)-5,7-di-O-benzyl-2,3-
a
droxylated products 14a or 14c predominantly in all the attempts
(Scheme 2 and Table 1, run 2, 3, 6, 7). After trial-and-error testing
on reagents of the asymmetric dihydroxylation, (DHQD)2PYR was
found most effective to increase the formation of 14b or 14d,
although the diastereoselectivity was still insufficient (Scheme 2
and Table 1, run 4 and 8). Finally, base catalyzed hydrolysis of an
epoxide (15) was employed as another approach for dihydroxyl-
ated product (14d). Thus E-13 was first converted to epoxide
(15) in good yield. Alkaline hydrolysis of 15 gave a mixture of
14c and 14d in a ratio of ca. 1.2:1, resulting in much more prefer-
able formation of 14d (Scheme 2).
dideoxy-4,6-O-isopropylidene-D-xylo-hept-2-enoate (E-12) by
treatment with 2,2-dimethoxypropane, and subsequent reduc-
tion of the product with diisobutyl aluminum hydride
(DIBAH) gave the corresponding E-enitol, (E)-5,7-di-O-benzyl-2,3-
dideoxy-4,6-O-isopropylidene-D-xylo-hept-2-enitol (E-13) in 89%
yield from enoate E-11. In a similar manner, the minor enoate
Z-11 was also converted to the corresponding Z-enitol (Z-13)
in good yield (Scheme 1).
With compounds E- and Z-13 in hand, osmium tetroxide (OsO4)
catalyzed dihydroxylation was performed in the presence of N-
methylmorphorine N-oxide (NMO) as a reoxidant. Upon reaction
The newly constructed stereochemistries of triols 14a and 14b
were confirmed to be in threo relationship after leading them to
with E-enitol (E-13),
proceeded to give a corresponding triol, 5,7-di-O-benzyl-4,6-O-iso-
propylidene- -glycero- -galacto-heptitol (14a), accompanied by
b-attack leading to its diastereomer, 5,7-di-O-benzyl-4,6-O-isopro-
a-facial syn-dihydroxylation predominantly
known heptitols,
D
-glycero-
L
-galacto-heptitol (16a)16 and
D-
D
L
glycero-
L
-ido-heptitol (16b),16 respectively, via acidic hydrogenoly-
sis. Owing to their too close polarity to be separated on TLC, stereo-
chemistry of 14c and 14d were determined at the next stage. Four
triols 14a, 14b, 14c and 14d, thus obtained were then converted to
corresponding tri-O-MOM ethers, 5,7-di-O-benzyl-4,6-O-isopro-
pylidene-D-glycero-L-ido-heptitol (14b) in a ratio of ca. 6:1
(Scheme 2 and Table 1, run 1).14 Dihydroxylation of Z-isomer (Z-
13) showed the same face-selectivity, giving a mixture of hardly
separable diastereomers 5,7-di-O-benzyl-4,6-O-isopropylidene-
pylidene-1,2,3-tri-O-methoxymethyl-
(17a), 5,7-di-O-benzyl-4,6-O-isopropylidene-1,2,3-tri-O-methoxy-
D-glycero-L-galacto-heptitol
D
-glycero-
L
-talo-heptitol (14c) and 5,7-di-O-benzyl-4,6-O-isopro-
-glycero- -gulo-heptitol (14d) in ratio of ca. 7:1
pylidene-
D
L
a

2254
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
5,7-cyclic sulfate (19c) and 4,6-O-isopropylidene-1,2,3-tri-
O-methoxymethyl- -glycero- -gulo-heptitol 5,7-cyclic sulfate (19d)
D
L
O
OH
O
OH
O
O
a, b or c
OH
OH
in 65–70% yield. Their FAB mass spectra showed peaks at m/z
447 corresponding to the protonated molecular-ion [M+H]+. In
the 1H NMR spectrum of 19a, characteristic downfield shift signals
due to methylene protons on C-7 and methine proton on C-5 were
observed at dH 4.90 (H-7 equiv), 4.55 (H-7 ax) and dH 4.98 (H-5),
respectively, supporting the cyclic sulfate formation. The signal
due to H-5 appeared as doublet of doublets (J5,6 = 1.5 and
J5,4 = 1.5 Hz) indicated the cis-decaline type bicyclic ring forma-
tion.(Scheme 3). The spectroscopic properties of these four cyclic
sulfates were very similar with each other.
+
E
-13
OBn OBn OH
OBn OBn OH
14b
14a
O
O
d
OH
O
OBn OBn
15
e
OH
OH
OH
O
O
2.2. Preparation of sulfonium salts
O
O
a, b or c
Z
-13
+
OH
The target sulfonium sulfates were prepared through ring open-
ing of cyclic sulfates (19a, 19b, 19c and 19d) by nucleophilic attack
of thiosugar (20).18 The reaction of cyclic sulfates (19a, 19b, 19c
and 19d) with thiosugar (20) proceeded slowly in 1,1,1,3,3,3-hexa-
fluoroisopropanol (HFIP) at 65 °C, giving corresponding coupled
products (21a, 21b, 21c and 21d) in around 70% yield. The relative
stereochemistry between the side chain and the methanol moiety
at C-4 of the coupled products (21a, 21b, 21c and 21d) were
determined to be in trans relationship on the basis of nuclear
Overhauser effect (NOE) experiments as shown in Scheme 4.
Finally, removal of both the MOM and isopropylidene groups
was carried out by using 30% aqueous TFA at 50 °C to give the de-
sired compounds (9a, 9b, 9c and 9d) in 76–85% yields. FAB mass
spectra of these four products showed peaks at m/z 425 due to
the protonated molecular-ion [M+H]+, corresponded to the depro-
tected structures.
OBn OBn OH
OBn OBn OH
14d
14c
O
O
OH
O
OH
O
OH
OH
OBn OBn OH
OBn OBn OH
Scheme 2. Reagents and conditions: (a) OsO4, NMO, acetone, H2O, reflux; (b) AD-
mix-
a
or AD-mix-b, tBuOH, H2O, rt; (c) (DHQD)2PYR, K2OsO2(OH)4, MeSO2NH2,
KFe(CN)6, K2CO3, tBuOH, H2O, 4 °C; (d) m-CPBA, NaHCO3, CH2Cl2; (e) 0.5 N aq NaOH,
1,4-dioxane, reflux, 4 h.
Table 1
Dihydroxylation of E- and Z-13
Run
Compd
Conditions
Product
Ratioa
Yield (%)
2.3. a-Glucosidase inhibitory activity
1
2
3
4
E-13
E-13
E-13
E-13
(a) OsO4, NMO
(b) AD-mix-b
(c) AD-mix-
(d) (DHQD)2PYR
14a/14b
14a/14b
14a/14b
14a/14b
ca. 6/1
82
75
79
83
ca. 10/1
ca. 10/1
ca. 1/1.2
Glucosidase inhibitory activities of four compounds (9a, 9b, 9c
and 9d) were tested for rat intestinal -glucosidases, that is, mal-
a
a
tase, sucrase and isomaltase in vitro, and the results are listed in
Table 2. Based on intensive SAR studies on salacinol (1) and related
sulfoniums,11 several important structural determinants for the
inhibitory activity against the maltase and sucrase, as well as those
for human intestinal N-terminal maltase-glucoamylase have al-
ready been disclosed. For example: (a) 2S, 3S, 4R configurations
5
6
7
8
Z-13
Z-13
Z-13
Z-13
(a) OsO4, NMO
(b) AD-mix-b
14c/14d
14c/14d
14c/14d
14c/14d
ca. 7/1
76
78
70
85
ca. 10/1
ca. 10/1
ca. 3.5/1
(c) AD-mix-
a
(d) (DHQD)2PYR
a
Determined by 500 MHz NMR spectrum.
methyl-
propylidene-1,2,3-tri-O-methoxymethyl-
(17c), and 5,7-di-O-benzyl-4,6-O-isopropylidene-1,2,3-tri-O-
methoxymethyl- -glycero- -gulo-heptitol (17d), respectively, by
D
-glycero-
L
-ido-heptitol (17b), 5,7-di-O-benzyl-4,6-O-iso-
D
-glycero- -talo-heptitol
L
OR1
1
OH OH
O
O
OH
OR1
1
3
5
3
b or c
5
OH
D
L
7
7
2
OR2
OH
treatment with chloromethyl methyl ether (MOMCl) in the pres-
ence of Hünig base (iPr2NEt). The tri-MOM ethers 17a, 17b, 17c
and 17d were then subjected to hydrogenolysis in the presence
of a small amount of sodium hydrogen carbonate,17 to give
corresponding diols, 4,6-O-isopropylidene-1,2,3-tri-O-methoxy-
OR2 OR1
OH OH
14 : R1 = H, R2 = Bn
16
a
d
17 : R1 = MOM, R2 = Bn
18 : R1 = MOM, R2 = H
a : 2α-OH, 3α-OH
b : 2β-OH, 3β-OH
c : 2β-OH, 3α-OH
d : 2α-OH, 3β-OH
methyl-
2,3-tri-O-methoxymethyl-
propylidene-1,2,3-tri-O-methoxymethyl-
(18c) and 4,6-O-isopropylidene-1,2,3-tri-O-methoxymethyl-
cero- -gulo-heptitol (18d) in good yields. The stereochemistries of
18c and 18d were confirmed after leading them to known hepti-
D
-glycero-
L
-galacto-heptitol (18a), 4,6-O-isopropylidene-1,
-glycero- -ido-heptitol (18b), 4,6-O-iso-
-glycero- -talo-heptitol
-gly-
e
D
L
O
S
D
L
D
O
O
O
4
OMOM
OMOM
O
O
L
6
5
5
O
O
6
O
H
O
R
O
tols, D-glycero-L D-glycero-L-gulo-heptitol
-talo-heptitol (16c)16 and
OMOM
4
H
S
H
(16d)16 by trifluoroacetic acid (TFA) catalyzed hydrolysis. Diols
18a, 18b, 18c and 18d were then subjected to the modified cyclic
sulfation11b to give desired cyclic sulfates, 4,6-O-isopropylidene-
O
19
R = CH(OMOM)CH(OMOM)CH2OMOM
1,2,3-tri-O-methoxymethyl-
sulfate (19a), 4,6-O-isopropylidene-1,2,3-tri-O-methoxymethyl-
-glycero- -ido-heptitol 5,7-cyclic sulfate (19b), 4,6-O-isopro-
pylidene-1,2,3-tri-O-methoxymethyl- -glycero- -talo-heptitol
D-glycero-L-galacto-heptitol 5,7-cyclic
i
Scheme 3. Reagents and conditions: (a) MOMCl, Pr2NEt, DMF, 60 °C; (b) H2, Pd-C,
80% aq AcOH, 60 °C; (c) 30% aq TFA 50 °C; (d) H2, Pd-C, NaHCO3, 1,4-dioxane, 60 °C;
(e) SOCl2, NEt3, CH2Cl2, 0 °C, then NaIO4, RuCl3ꢁnH2O, NaHCO3, CH3CN, CCl4, H2O,
0 °C to rt.
D
L
D
L

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
2255
S
OH OH OH
OH
O
O
OMOM
HO
OH
H
H
3'R
5'
OMOM
6'
NOE
HO
4'S
2'S
OH
HO
30% aq.TFA
50°C
S+
20
S+
-
H
OMOM
1 OSO3
OH
OSO3
HO
-
19
4
HFIP, K 2CO3, 65°C
OH
HO
HO
21
9
(
)
(
)
(
)
(
)
(
)
(
)
(
) (
, 6'R-OH
OH
)
OH
a : 5'S-OH
, 6'R-OH
; b: 5'R-OH
, 6'S-OH
; c : 5'S-OH
, 6'S-OH
; d : 5'R-OH
OH
OH
OH
OH
OH
OH
Scheme 4.
Table 2
Present findings will contribute the elucidation of the mode of
bindings of substrates to these three enzymes. Further SAR studies
IC50 Values (lM) of thiosugar sulfonium sulfate inner salts and two diabetics against
disaccharidases
on the series of thiosugar sulfoniums for the stronger
a-glucosi-
Entry
Compd
Sucrase
Maltase
Isomaltase
dase inhibitors and also for the elucidation of factors for selectivity
to the glucosidases are in progress.
1
2
3
4
5
6
7
8
9
10
1a
1.6
0.75
0.29
>100
>236 (8)
>236 (28)
23
>236 (34)
1.2
5.2
7.2
3.2
>100
>236 (25)
>236 (32)
57
>236 (45)
0.2
1.3
5.7
2.6
—
16
8.5
25
9
2a
3a
4a
3. Experimental
9a
9b
9c
9d
Mps were determined on a Yanagimoto MP-3S micromelting
point apparatus, and mps and bps are uncorrected. IR spectra were
measured on a Shimadzu FTIR-8600PC spectrophotometer. NMR
spectra were recorded on a JEOL JNM-ECA 500 (500 MHz 1H,
125 MHz 13C) or a JEOL JNM-ECA 600 (600 MHz 1H, 150 MHz 13C)
or a JEOL JNM-ECA 700 (170 MHz 1H, 175 MHz 13C) spectrometer.
Chemical shifts (d) and coupling constants (J) are given in ppm and
Hz, respectively. Low-resolution and high-resolution mass spectra
were recorded on a JEOL JMS-HX 100 spectrometer. Optical rota-
tions were determined with a JASCODIP-370 digital polarimeter.
Column chromatography was effected over Fuji Silysia silica gel
BW-200. All the organic extracts were dried over anhydrous so-
dium sulfate prior to evaporation.
Voglibosea
Acarbosea
2.1
155
2.0
1.7
a
Ref. 7. Values in parentheses indicate inhibition (%) at 100 lg/mL (236 lM).
of the thiosugar moiety are important as a common feature. (b) The
-orientation of the side chain is essential for the inhibitory activ-
a
ity. (c) Polyhydroxylated side chain longer than four carbons does
not enhance the inhibitory activity significantly. (d) Cooperative
role of 20S-OH and 40-OH is critical for onset of strong inhibitions.
Furthermore, it is of prime importance that R configuration of OH
at C40 is imperative to inhibitors bearing the side chain more than
four carbons. (e) For the compounds bearing six or seven carbon
side chain, 50S-OH is preferred for the activity.
All the four compounds prepared in the present study satisfied
the determinants (a) and (b), however had disadvantageous stereo-
chemical features with respect to the determinants (c) and (d).
Thus, out of these four sulfates, three compounds 9a, 9b and 9d
lost considerably their inhibitory activity against both maltase
and sucrase owing probably to their 40S configuration [against
determinant (d)]. It is interesting to note that compound 9c sus-
tained the inhibitory activities against maltase and sucrase to a
large extent, which could be attributed to its 50S configuration on
the side chain. However, compound 9a, the 60 epimer of 9c, was
found inactive against these enzymes, suggesting that the cooper-
ative role of 50S and 60S could trigger the revival of inhibition
against maltase and sucrase.
Against isomaltase, the four sulfoniums sustained their activi-
ties to a large extent. Especially compounds 9b and 9d showed
nearly equal activity to kotalanol 2, and among these four com-
pounds, 9b was found to be the most selective isomaltase inhibitor,
while compound 9c lost completely the selectivity against these
three enzymes, and was found to be a moderate inhibitor against
all enzymes.
Selectivity in inhibition against enzymes with similar function
is often so important as was exemplified by three clinically used
antidiabetics (voglibose, acarbose and miglitiol). Acarbose has
been proved to be inactive against isomaltase, but it has a much
3.1. tert-Butyl (E)- and (Z)- 5,7-di-O-benzyl-2,3-dideoxy-
hept-2-enoate (E-11 and Z-11)
D
-xylo-
A
mixture
of
1013
(36.1 g,
0.11 mol)
and
tert-
butoxycarbonylmethylenetriphenylphosphorane (60 g, 0.16 mol)
and CH2Cl2 (180 mL) was heated under reflux for 3 h. After removal
of the solvent, the oily residue was triturated with a 2:3 mixture of
n-hexane and diethyl ether (Et2O), and the deposited precipitates
were filtered off and washed with a 2:3 mixture of n-hexane and
Et2O. The combined filtrate and washings were concentrated to
give a pale yellow oil (62 g), which on column chromatography
(n-hexane/AcOEt, 5:1) gave a ca. 6.5:1 mixture of title compounds
E- and Z-11 (45.8 g, 98% from 10) as a colorless solid, which on
recrystallization from a mixture of n-hexane and AcOEt (8/1) gave
E-11 (21.4 g, 46%) as colorless needles. Condensation of the mother
liquid gave a ca. 3:1 mixture of E- and Z-11 (24.4 g, 52%), which
was used in the next step without purification. An analytical sam-
ple of Z-11 was obtained as a colorless oil by means of column
chromatography (n-hexane/Et2O = 5:1 ? 2:1 ? 1:1) of
amount of the crude mixture of E- and Z-11.
a small
Compound E-11: Mp 86–87 °C. ½a D24
ꢂ
ꢀ54.2 (c 1.07, CHCl3). IR
(nujol): 3364, 1709, 1655, 1281, 1153, 1138, 1130, 1103 cmꢀ1
.
1H
NMR (600 MHz, CDCl3) d: 1.49 [9H, s, (CH3)3C], 2.65 (1H, br d,
J = ca. 5.7, OH), 2.99 (1H, br d, J = ca. 6.0, OH), 3.53 (1H, dd,
J = 9.8, 5.7, H-7a), 3.594 (1H, dd, J = 9.8, 5.7, H-7b), 3.597 (1H, dd,
J = 5.7, 4.3, H-5), 3.95 (1H, dddd, J = 5.7, 5.7, 5.7, 4.3, H-6), 4.47
(1H, dddd, J = 6.0, 4.6, 4.3, 1.9, H-4), 4.50/4.52 (each 1H, d,
J = 11.9, PhCH2), 4.58/4.64 (each 1H, d, J = 11.2, PhCH2), 6.06 (1H,
dd, J = 15.7, 1.9, H-2), 6.90 (1H, dd, J = 15.7, 4.6, H-3), 7.25–7.37
(10H, m, arom.). 13C NMR (150 MHz, CDCl3) d: 28.1 [(CH3)3C],
70.81 (C-7), 70.83 (C-6), 71.2 (C-4), 73.5/74.8 (PhCH2), 80.4
[(CH3)3C], 80.9 (C-5), 123.6 (C-2), 127.9/128.1/128.2/128.48/
greater inhibitory activity on pancreatic
a-amylase, which cata-
lyzes the first step in the breakdown of polysaccharides, such as
starch, whereas voglibose has almost no effect on this enzyme.19
Miglitol also shows no inhibition against
selectively inhibit lactase and trehalase.20
a-amylase, but it can

2256
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
128.50 (d, arom.), 137.4/137.5 (s, arom.), 145.7 (C-3), 165.5 (C-1).
FABMS m/z: 429 [M+H]+ (pos.). FABHRMS m/z: 429.2278
(C25H33O6 requires 429.2277).
165.0 (C-1). FABMS m/z: 469 [M+H]+ (pos.). FABHRMS m/z:
469.2608 (C28H37O6 requires 469.2590).
Compound Z-11: ½a D24
ꢂ
ꢀ78.4 (c 1.78, CHCl3). IR (neat): 3418,
3.3. DIBAH reduction of acetonides E-12 and Z-12
1747, 1651, 1601, 1496, 1454, 1357, 1269, 1161, 1092,
1030 cmꢀ1
.
1H NMR (500 MHz, CDCl3) d: 1.47 [9H, s, (CH3)3C],
General procedure: To a solution of E-12 (5.0 g, 10.7 mmol) in
THF (120 mL) was added dropwise a 1 M solution of diisobutyl alu-
minium hydride (DIBAH) in toluene (32 mL, 32 mmol) at ꢀ50 °C.
The reaction mixture was allowed to reach rt, and was stirred for
4 h. After the reaction was quenched by addition of water
(300 mL), the deposited gel was filtered off through a celite, and
washed with THF. The combined filtrate and washings were con-
centrated, and the residual aqueous solution was extracted with
CH2Cl2. The extract was washed with brine and concentrated to
give a pale yellow oil (4.5 g), which on column chromatography
(n-hexane/AcOEt, 3:1) gave (E)-5,7-di-O-benzyl-2,3-dideoxy-4,6-
3.22 (1H, br s, OH), 3.58 (1H, dd, J = 9.7, 6.1, H-7a), 3.61 (1H, dd,
J = 9.7, 6.1, H-7b), 3.67 (1H, dd, J = 4.9, 3.2, H-5), 3.84 (1H, br s,
OH), 4.03 (1H, ddd, J = 6.1, 6.1, 3.2, H-6), 4.50/4.55 (each 1H, d,
J = 11.8, PhCH2), 4.64/4.67 (each 1H, d, J = 11.3, PhCH2), 5.18 (1H,
ddd, J = 7.2, 4.9, 1.5, H-4), 5.79 (1H, dd, J = 12.0, 1.5, H-2), 6.26
(1H, dd, J = 12.0, 7.2, H-3), 7.26–7.36 (10H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 28.0 [(CH3)3C], 69.2 (C-4), 70.7 (C-6), 71.0
(C-7), 73.4/74.8 (PhCH2), 80.7 (C-5), 81.5 [(CH3)3C], 122.9 (C-2),
127.7/127.87/127.92/128.2/128.38/ 128.42 (d, arom.), 137.89/
137.92 (s, arom.), 148.0 (C-3), 166.4 (C-1). FABMS m/z: 429
[M+H]+ (pos.). FABHRMS m/z: 429.2256 (C25H33O6 requires
429.2277).
O-isopropylidene-D-xylo-hept-2-enitol (E-13, 3.8 g, 89%) as a color-
less oil.
Compound E-13: ½a D24
ꢂ
ꢀ38.8 (c 1.24, CHCl3). IR (neat): 3418,
1H NMR
1497, 1381, 1265, 1204, 1169, 1103, 1069, 1026 cmꢀ1
.
3.2. Acetalization of enoates E-11 and Z-11
(600 MHz, CDCl3) d: 1.23 (1H, br s, OH), 1.47 [6H, s, (CH3)2C],
3.36 (1H, dd, J = 1.7, 1.7, H-5), 3.54 (1H, dd, J = 9.1, 5.3, H-7a),
3.66 (1H, dd, J = 9.1, 7.7, H-7b), 3.99 (1H, br dd, J = ca. 11.5, 5.3,
H-1a), 4.04 (1H, br dd, J = ca. 11.5, 5.3, H-1b), 4.14 (1H, ddd,
J = 7.7, 5.3, 1.7, H-6), 4.35 (1H, ddd, J = 6.5, 1.7, 1.0, H-4), 4.47/
4.53 (each 1H, d, J = 11.9, PhCH2), 4.54/4.63 (each 1H, d, J = 11.9,
PhCH2), 5.68 (1H, dddd, J = 15.6, 6.5, 1.6, 1.6, H-3), 5.85 (1H, dddd,
J = 15.6, 5.3, 5.3, 1.0, H-2), 7.26–7.36 (10H, m, arom.). 13C NMR
(150 MHz, CDCl3) d: 19.1/29.6 [(CH3)2C], 63.0 (C-1), 69.1 (C-7),
71.3 (C-6), 72.4 (C-5), 73.1 (C-4), 73.5/74.4 (PhCH2), 98.9
[(CH3)2C], 127.7/127.8/127.9/128.2/128.4/128.6 (d, arom.), 128.7
(C-3), 131.7 (C-2), 137.8/138.3 (s arom.). FABMS m/z: 399 [M+H]+
(pos.). FABHRMS m/z: 399.2163 (C24H31O5 requires 399.2171).
Following the method used for DIBAH reduction of acetonide E-
12, Z-12 (5.0 g, 10.7 mmol) was reduced with 1 M solution of DI-
BAH in toluene (32 mL, 32 mmol). Work-up and column chroma-
tography (n-hexane/AcOEt, 3:1) gave (Z)-5,7-di-O-benzyl-2,3-
A mixture of E-11 (12.0 g, 28 mmol), 2,2-dimethoxypropane
(34.3 mL, 280 mmol), p-toluenesulfonic acid (24 mg), and acetone
(120 mL) was stirred at rt for 1.5 h. After the reaction was
quenched by addition of aqueous sodium hydrogen carbonate
(30 mL), acetone was evaporated. The residual solution was diluted
with water (30 mL), and extracted with dichloromethane. The ex-
tract was washed with brine, and concentrated to give tert-butyl
(E)-5,7-di-O-benzyl-2,3-dideoxy-4,6-O-isopropylidene-D-xylo-hept-
2-enoate (E-12, 13.2 g) as a colorless waxy solid, which was used
for the next reaction without purification.
Following the method used for acetalization of E-11, a ca. 3:1
mixture of E- and Z-11 (24 g, 56 mmol) was converted to a mixture
of the corresponding acetonides E- and Z-12 (23.5 g, 90%), which
on column chromatography (n-hexane/AcOEt, 50:1) gave E-12
(14.8 g, 57%), Z-12 (4.6 g, 17.6%), and a ca. 2.3:1 mixture of E-12
and Z-12 (3.6 g, 14%).
dideoxy-4,6-O-isopropylidene-D-xylo-hept-2-enitol (Z-13, 3.62 g,
Compound E-12: Mp 69–70 °C. ½a D24
ꢀ31.6 (c 4.40, CHCl3). IR
ꢂ
85%) as a colorless oil.
Compound Z-13: ½a D24
ꢂ
ꢀ39.8 (c 1.03, CHCl3). IR (neat): 3445,
1H NMR
(KBr): 1703, 1653, 1456, 1377, 1369, 1307, 1202, 1155, 1094,
1067, 1047, 1028 cmꢀ1 1H NMR (600 MHz, CDCl3) d: 1.45/1.48
.
1454, 1381, 1265, 1203, 1169, 1146, 1096, 1030 cmꢀ1
.
[each 3H, s, (CH3)2C], 1.47 [9H, s, (CH3)3C], 3.44 (1H, dd, J = 1.7,
1.7, H-5), 3.53 (1H, dd, J = 9.1, 5.3, H-7a), 3.63 (1H, dd, J = 9.1, 7.5,
H-7b), 4.15 (1H, ddd, J = 7.5, 5.3, 1.7, H-6), 4.45/4.51 (each 1H, d,
J = 11.7, PhCH2), 4.50/4.56 (each 1H, d, J = 11.3, PhCH2), 4.52 (1H,
ddd, J = 4.6, 1.7, 1.7, H-4), 6.06 (1H, dd, J = 15.6, 1.7, H-2), 6.81
(1H, dd, J = 15.6, 4.6, H-3), 7.23–7.36 (10H, arom.). 13C NMR
(150 MHz, CDCl3) d: 19.0/29.5 [(CH3)2C], 28.1 [(CH3)3C], 69.2 (C-
7), 71.4 (C-6), 71.7 (C-5), 72.1 (C-4), 73.6/74.3 (PhCH2), 80.3
[(CH3)3C], 99.1 [(CH3)2C], 123.9 (C-2), 127.7/127.8/127.9/128.2/
128.4 (d, arom.), 137.78/137.82 (s, arom.), 143.1 (C-3), 165.5 (C-
1). FABMS m/z: 469 [M+H]+ (pos.). FABHRMS m/z: 469.2618
(C28H37O6 requires 469.2590).
(500 MHz, CDCl3) d:1.46/1.49 (each 3H, s, (CH3)2C), 1.76 (1H, br s,
OH), 3.34 (1H, dd, J = 1.7, 1.7, H-5), 3.52 (1H, dd, J = 9.2, 5.5, H-
7a), 3.62 (1H, dd, J = 9.2, 7.8, H-7b), 4.10 (br d, J = ca. 12.9, H-1a),
4.14 (1H, ddd, J = 7.8, 5.5, 1.7, H-6), 4.24 (1H, dd, J = ca. 12.9, 6.9,
H-1b), 4.45/4.50 (each 1H, d, J = 11.7, PhCH2), 4.59/4.63 (each 1H,
d, J = 10.6, PhCH2), 4.68 (1H, ddd, J = 6.6, 1.7, 1.2, H-4), 5.67 (1H,
dddd, J = 11.5, 6.6, 1.2, 1.2, H-3), 5.75 (1H, dddd, J = 11.5, 6.9, 5.7,
1.2, H-2), 7.25–7.36 (10H, m, arom.). 13C NMR (125 MHz, CDCl3)
d: 19.1/29.6 [(CH3)2C], 59.0 (C-1), 69.2 (C-7), 69.7 (C-4), 71.3 (C-
6), 72.1 (C-5), 73.6/74.6 (PhCH2), 99.0 [(CH3)2C], 127.7/127.8/
128.0/128.2/128.36/128.43 (d, arom.), 129.4 (C-3), 132.0 (C-2),
137.8/138.0 (s, arom.). FABMS m/z: 399 [M+H]+ (pos.). FABHRMS
m/z: 399.2189 (C24H31O5 requires 399.2171).
Compound Z-12: Mp 57–58 °C. ½a D24
ꢂ
+61.1 (c 1.04, CHCl3). IR
(KBr): 1707, 1647, 1456, 1373, 1368, 1235, 1199, 1159, 1134,
1093, 1026 cmꢀ1 1H NMR (500 MHz, CDCl3) d: 1.47/1.50 [each
.
3.4. Dihydroxylation of
3.4.1. Method A
D-xylo-hept-2-enitols E-13 and Z-13
3H, s, (CH3)2C], 1.48 [9H, s, (CH3)3C], 3.52 (1H, dd, J = 9.5, 6.0,
H-7a), 3.55 (1H, dd, J = 9.5, 6.6, H-7b), 3.68 (1H, dd, J = 1.5, 1.5,
H-5), 4.21 (1H, ddd, J = 6.6, 6.0, 1.5 Hz, H-6), 4.44/4.530 (each 1H,
d, J = 11.8, PhCH2), 4.50/4.531 (each 1H, d, J = 12.0, PhCH2), 5.45
(1H, ddd, J = 6.9, 1.5, 1.5, H-4), 5.63 (1H, dd, J = 11.8, 1.5, H-2),
6.21 (1H, dd, J = 11.8, 6.9, H-3), 7.22–7.36 (10H, m, arom.). 13C
NMR (125 MHz, CDCl3) d: 19.3/29.7 [(CH3)2C], 28.1 [(CH3)3C],
69.5 (C-7), 69.9 (C-4), 71.2 (C-6), 71.8 (C-5), 73.4/74.5 (PhCH2),
80.7 [(CH3)3C], 98.9 [(CH3)2C], 122.0 (C-2), 127.6/127.7/127.8/
128.2/128.3/128.4 (d, arom.), 138.0/138.1 (s, arom.), 146.2 (C-3),
A mixture of E-13 (270 mg, 0.68 mmol), 0.039 M aqueous os-
mium tetroxide (0.84 mL, 0.033 mmol), 4-methylmorpholine N-
oxide (170 mg, 1.45 mmol), acetone (2 mL) and water (0.5 mL)
was heated under reflux for 1 h. After the reaction was quenched
by addition of sodium sulfite (150 mg), the reaction mixture was
poured into water (10 mL) and extracted with Et2O. The extract
was washed with brine and concentrated to give a pale brown oil
(300 mg), which on column chromatography (n-hexane/AcOEt,

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
2257
1:1) gave a ca. 6:1 mixture of 5,7-di-O-benzyl-4,6-O-isopropyli-
dene- -glycero- -galacto-heptitol (14a) and 5,7-di-O-benzyl-4,
6-O-isopropylidene-D-glycero-L-ido-heptitol (14b) as a colorless
oil (241 mg, 82%).
Following the method A, Z-13 (1.8 g, 4.5 mmol) was dihy-
droxylated to give a ca. 7:1 hardly separable mixture of 5,7-di-
ddd, J = 8.9, 5.3, 1.2, H-6), 4.50/4.58 (each 1H, d, J = 11.7, PhCH2),
4.52/4.74 (each 1H, d, J = 11.7, PhCH2), 7.27–7.38 (10H, m, arom.).
13C NMR (150 MHz, CDCl3) d: 19.2/29.5 [(CH3)2C], 64.8 (C-1), 68.4
(C-7), 69.2 (C-2), 69.9 (C-5), 71.4 (C-6), 71.7 (C-4), 72.3 (C-3),
73.5/73.8 (PhCH2), 99.4 [(CH3)2C], 127.9/128.00/128.03/128.49/
128.54 (d, arom.), 137.5/137.7 (s, arom.). FABMS m/z: 433 [M+H]+
(pos.). FABHRMS m/z: 433.2247 (C24H33O7 requires 433.2226).
Following the method C, Z-13 (400 mg, 0.1 mmol) was dihy-
droxylated. Work-up gave a ca. 3.5:1 hardly separable mixture of
14c and 14d (367 mg, 85%) as a colorless oil.
D
L
O-benzyl-4,6-O-isopropylidene-
D
-glycero-
L
-talo-heptitol (14c) and
5,7-di-O-benzyl-4,6-O-isopropylidene-
(14d) as a colorless oil (1.5 g, 77%).
D
-glycero- -gulo-heptitol
L
3.4.2. Method B
Data for 14c extracted from the 1H and 13C NMR spectra of a
mixture of 14c and 14d: 1H NMR (700 MHz, pyridine-d5) d: 1.44/
1.51 [each 3 H, s, (CH3)2C], 3.79 (1H, dd, J = 9.2, 5.6, H-7a), 3.99
(1H, dd, J = 9.2, 7.4, H-7b), 4.19 (1H, br s, H-5), 4.40 (1H, dd,
J = 11.2, 3.7, H-1a), 4.43 (1H, br dd, J = ca. 7.4, 5.6, H-6), 4.44 (1H,
dd, J = 11.2, 7.0, H-1b), 4.51 (1H, br d, J = ca. 9.2, H-4), 4.54/4.57
(each 1H, d, J = 11.7, PhCH2), 4.64 (1H, ddd, J = 7.0, 3.7, 2.6, H-2),
4.83 (1H, dd, J = 9.2, 2.6, H-3), 4.88/5.17 (each 1H, d, J = 11.0,
PhCH2), 7.2–7.5 (10 H, m, arom.). 13C NMR (175 MHz, pyridine-
d5) d: 19.3/29.9 [(CH3)2C], 63.5 (C-1), 70.3 (C-7), 71.0 (C-5), 71.9
(C-3), 72.3 (C-6), 73.2 (C-2), 73.5/75.0 (PhCH2), 73.8 (C-4), 98.9
[(CH3)2C], 127.6/127.9/128.2/128.4/128.5/128.8 (d, arom.), 139.0/
139.8 (s, arom.).
A mixture of E-13 (50 mg, 0.125 mmol), AD-mix-
a (180 mg),
methanesulfonamide (12 mg, 0.125 mmol), tert-butanol (1 mL),
and water (1 mL) was stirred at rt for 2 days. After the reaction
was quenched by addition of sodium sulfite (190 mg), the resulting
mixture was diluted with water (2 mL) and extracted with AcOEt.
The organic layer was subsequently washed with 2 M aqueous
potassium hydroxide (1 mL) and brine, and concentrated to give
a pale yellow oil (56 mg), which on column chromatography (n-
hexane/AcOEt, 3:1) gave a ca. 10:1 mixture of 14a and 14b as a col-
orless oil (43 mg, 79%).
Following the method B, E-13 (50 mg, 0.125 mmol) was dihy-
droxylated with AD-mix-b (180 mg). Work-up gave a ca. 10:1 mix-
ture of 14a and 14b (41 mg, 76%).
Following the method B, Z-13 (50 mg, 0.125 mmol) was dihy-
droxylated with AD-mix-a (180 mg). Work-up gave a ca. 10:1 mix-
Data for 14d extracted from the 1H and 13C NMR spectra of a
mixture of 14c and 14d: 1H NMR (700 MHz, pyridine-d5) d: 1.47/
1.54 [each 3H, s, (CH3)2C], 3.78 (1H, dd, J = 8.8, 5.6, H-7a), 3.98
(1H, dd, J = 8.8, 7.6, H-7b), 4.05 (1H, br dd, J = ca. 1.4, 1.4, H-5),
4.35 (1H, dd, J = 10.9, 5.8, H-1a), 4.42–4.47 (2H, m, H-2 and H-6),
4.52 (1H, dd, J = 10.9, 5.8, H-1b), 4.53–4.56 (1H, m, H-3), 4.56/
4.59 (each 1H, d, J = ca. 11.5, PhCH2), 4.73 (1H, dd, J = 4.3, 1.4, H-
4), 4.80/5.04 (each 1H, d, J = ca. 11.5, PhCH2), 7.20–7.51 (10 H, m,
arom.). 13C NMR (175 MHz, pyridine-d5) d: 19.5/29.8 [(CH3)2C],
64.7 (C-1), 69.9 (C-7), 72.1 (C-4), 72.2 (C-6), 72.8 (C-2), 73.5/74.6
(PhCH2), 73.7 (C-3), 74.3 (C-5), 99.3 [(CH3)2C], 127.9/128.0/128.3/
128.6/128.7 (d, arom.), 138.9/139.2 (s, arom.).
ture of 14c and 14d (38 mg, 70%).
Following the method B, Z-13 (50 mg, 0.125 mmol) was dihy-
droxylated with AD-mix-b (180 mg). Work-up gave a ca. 10:1 mix-
ture of 14c and 14d (42 mg, 77%).
3.4.3. Method C
A mixture of E-13 (4.9 g, 12.3 mmol), (DHQD)2PYR (550 mg,
0.6 mmol), potassium osmate(VI) dihydrate (463 mg, 1.2 mmol),
methanesulfonamide (1.2 g, 12.6 mmol), potassium hexacyanofer-
rate(III) (12.3 g, 37.0 mmol), potassium carbonate (5.2 g,
37.0 mmol), tert-butanol (75 mL) and water (75 mL) was stirred
at 4 °C for 6.5 h. After the reaction was quenched by addition of so-
dium sulfite (2.7 g), the resulting mixture was diluted with water
(100 mL) and extracted with AcOEt. The organic layer was subse-
quently washed with 2 M aqueous potassium hydroxide (100 mL)
and brine, and concentrated to give a pale yellow oil (6.4 g), which
on column chromatography (n-hexane/AcOEt, 3:1) gave 14a (2.0 g,
38%) and 14b (2.46 g, 46%) both as a colorless oil.
3.5. Epoxidation of enitol E-13 and preparation of heptitols 14c
and 14d via hydrolysis of epoxides 15
Under Ar atmosphere, a solution of E-13 (7.2 g, 18 mmol) in
CH2Cl2 (230 mL) was added dropwise to a suspension of m-chloro-
perbenzoic acid (4.6 g, 33.3 mmol) and sodium hydrogen carbon-
ate (2.6 g, 31 mmol) in CH2Cl2 (360 mL), and the mixture was
stirred in dark for 12 h. After the reaction was quenched by addi-
tion of an aqueous mixture of sodium thiosulfate and sodium
hydrogen carbonate (300 mL), the resulting mixture was extracted
with CH2Cl2. The extract was washed with brine, and concentrated
to give a pale yellow oil (7.6 g), which on column chromatography
(n-hexane/AcOEt, 2:1) gave 15 (7.3 g, 97%) as a colorless oil. The oil
(6.0 g, 14.5 mmol) was then heated under reflux in a mixture of
0.5 M aqueous sodium hydroxide (30 mL) and 1,4-dioxane
(90 mL) for 4.5 h. After being cooled, the reaction mixture was ex-
tracted with AcOEt. The extract was washed with brine, and con-
centrated to give a pale yellow oil (6.2 g), which on column
chromatography (n-hexane/AcOEt, 1:1) gave a ca. 1.2:1 hardly sep-
arable mixture of 14c and 14d (5.3 g, 68%) as a colorless oil. The
NMR spectroscopic properties of the mixture were in good accord
with those of a mixture of 14c and 14d obtained by dihydroxyla-
tion of Z-13 (in Section 3.4.3).
Compound 14a: ½a D24
ꢂ
ꢀ47.8 (c 1.14, CHCl3). IR (neat): 3410,
1454, 1380, 1265, 1203, 1169, 1103 cmꢀ1
.
1H NMR (500 MHz,
CDCl3) d: 1.42/1.45 [each 3H, s, (CH3)2C], 2.31 (1H, d, J = 6.0, OH),
2.35/2.70 (each 1H, br s, OH), 3.53 (1H, dd, J = 9.2, 5.7, H-7a),
3.63 (1H, dd, J = 9.2, 7.8, H-7b), 3.64 (1H, dd, J = ca. 1.5, 1.5, H-5),
3.71 (2H, br d, J = ca. 4.6, H-1a and H-1b), 3.76 (1H, ddd, J = 8.9,
6.0, 2.0, H-3), 3.85 (1H, br m, H-2), 3.87 (1H, dd, J = 8.9, 1.5, H-4),
4.10 (1H, ddd, J = 7.8, 5.7, 1.5, H-6), 4.46/4.53 (each 1H, d,
J = 11.7, PhCH2), 4.69/4.71 (each 1H, d, J = 12.0, PhCH2), 7.26–7.37
(10 H, m, arom.) 13C NMR (125 MHz, CDCl3) d: 19.2/29.5
[(CH3)2C], 65.6 (C-1), 69.0 (C-5), 69.2 (C-7), 69.6 (C-2), 70.3 (C-3),
71.7 (C-6), 72.0 (C-4), 73.5/74.0 (PhCH2), 127.8/127.88/127.93/
128.3/128.41/128.43 (d, arom.), 137.8/138.5 (s, arom.). FABMS m/
z: 433 [M+H]+ (pos.). FABHRMS m/z: 433.2217 (C24H33O7 requires
433.2226).
Compound 14b: ½a D24
ꢂ
ꢀ35.6 (c 1.22, CHCl3). IR (neat): 3429,
1454, 1380, 1265, 1204, 1096, 1030 cmꢀ1
.
1H NMR (600 MHz,
3.6. Methoxymethylation of heptitols 14a, 14b, 14c and 14d
CDCl3) d: 1.46 [6H, s, (CH3)2C], 2.39/2.71/3.02 (each 1H, br s, OH),
3.14 (1H, br, H-2), 3.41 (1H, dd, J = 11.5, 4.1, H-1a), 3.56 (1H, dd,
J = 8.9, 5.3, H-7a), 3.57 (1H, dd, J = 11.5, 3.8, H-1b), 3.59
(1H, dd, J = ca. 1.5, 1.2, H-5), 3.72 (1H, dd, J = 8.9, 8.9, H-7b), 3.80
(1H, dd, J = 6.9, 2.4, H-3), 3.99 (1H, dd, J = 6.9, 1.5, H-4), 4.13 (1H,
General procedure: A mixture of 14a (1.8 g, 4.2 mmol), chloro-
methyl methyl ether (5 mL, 67.0 mmol), N-ethyldiisopropylamine
(23 mL, 113 mmol), and DMF (45 mL) was heated at 60 °C for
4.5 h. After the reaction was quenched by addition of aqueous

2258
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
sodium hydrogen carbonate (16 mL), the resulting mixture was di-
luted with water (16 mL), and extracted with a 2:1 mixture of n-
hexane/Et2O. The extract was washed with brine and concentrated
to give a pale yellow oil (2.6 g), which on column chromatography
(n-hexane/AcOEt, 5:1) gave 5,7-di-O-benzyl-4,6-O-isopropylidene-
arom.). 13C NMR (175 MHz, CDCl3) d: 18.8/29.5 [(CH3)2C], 55.1/
55.5/56.3 (OCH2OCH3), 67.5 (C-1), 69.5 (C-7), 69.7 (C-5), 72.0 (C-
4), 72.2 (C-6), 73.4/73.5 (PhCH2), 76.8 (C-2), 76.9 (C-3), 96.4/96.5/
97.8 (OCH2OCH3), 99.0 [(CH3)2C], 127.3/127.7/127.8/128.2/128.4
(d, arom.), 138.0/139.0 (s, arom.).
1,2,3-tri-O-methoxymethyl-
D
-glycero-
L
-galacto-heptitol (17a, 2.1 g,
Data for 17d extracted from the 1H and 13C NMR spectra of a ca.
1.1:1 mixture of 17c and 17d: 1H NMR (700 MHz, CDCl3) d:1.45/
1.46 [each 3H, s, (CH3)2C], 3.28/3.34/3.40 (each 3H, s, OCH2OCH3),
3.54 (1H, dd, J = 9.4, 5.6, H-7a), 3.55 (1H, br dd, J = ca. 1.6, 1.4, H-
5), 3.67 (1H, dd, J = 9.4, 7.6, H-7b), 3.72 (1H, dd, J = 10.4, 6.6, H-
1a), 3.79 (1H, dd, J = 10.4, 5.0, H-1b), 4.00 (1H, dd, J = 8.6, 1.6, H-
4), 4.01 (1H, ddd, J = 6.6, 5.0, 2.5, H-2), 4.09 (1H, ddd, J = 7.6, 5.6,
1.4, H-6), 4.16 (1H, dd, J = 8.6, 2.5, H-3), 4.46/4.51 (each 1H, d,
J = 11.8, PhCH2), 4.61/4.64 (each 1H, d, J = 6.8, OCH2OCH3), 4.62
(2H, br s, OCH2OCH3), 4.73/4.84 (each 1H, d, J = 11.6, PhCH2),
4.73/4.80 (each 1H, d, J = 6.4, OCH2OCH3), 7.25–7.37 (10H, m,
arom.). 13C NMR (175 MHz, CDCl3) d: 19.1/29.6 [(CH3)2C], 55.4/
55.5/55.6 (OCH2OCH3), 67.1 (C-1), 69.2 (C-7), 70.2 (C-5), 71.9 (C-
6), 73.1/73.5 (PhCH2), 73.9 (C-4), 74.7 (C-2), 76.5 (C-3), 95.2/96.8/
97.7 (OCH2OCH3), 98.9 [(CH3)2C], 127.2/127.8/127.9/128.2 (d,
arom.), 137.8/138.8 (s, arom.).
88%) as a colorless oil.
Compound 17a: ½a D24
ꢂ
-14.0 (c 1.34, CHCl3). IR (neat): 1454, 1381,
1H NMR (600 MHz, CDCl3)
1265, 1204, 1153, 1103, 1034 cmꢀ1
.
d:1.44/1.45 [each 3H, s, (CH3)2C], 3.32/3.38/3.40 (each 3H, s,
OCH2OCH3), 3.58 (1H, dd, J = 9.5, 5.8, H-7a), 3.68 (1H, dd, J = 9.6,
7.7, H-1a), 3.69 (1H, dd, J = 9.5, 7.2, H-7b), 3.71 (1H, dd, J = 1.4,
1.4, H-5), 3.75 (1H, dd, J = 9.6, 6.0, H-1b), 4.00 (1H, ddd, J = 7.7,
6.0, 1.5, H-2), 4.02 (1H, dd, J = 8.8, 1.4, H-4), 4.08 (1H, dd, J = 8.8,
1.5, H-3), 4.15 (1H, ddd, J = 7.2, 5.8, 1.4, H-6), 4.48/4.55 (each 1H,
d, J = 11.8, PhCH2), 4.60/4.62 (each 1H, d, J = 6.5, OCH2OCH3),
4.69/4.746 (each 1H, d, J = 6.5, OCH2OCH3), 4.71/4.750 (each 1H,
d, J = 6.5, OCH2OCH3), 4.742/4.82 (each 1H, d, J = 12.0, PhCH2),
7.22–7.35 (10H, m, arom.). 13C NMR (150 MHz, CDCl3) d: 19.0/
29.6 [(CH3)2C], 55.5/55.7/56.1 (OCH2OCH3), 67.5 (C-1), 69.5 (C-7),
69.6 (C-5), 71.6 (C-4), 72.4 (C-6), 73.1/73.4 (PhCH2), 76.2 (C-2),
77.2 (C-3), 96.9/98.3/98.6 (OCH2OCH3), 99.0 [(CH3)2C], 127.2/
127.7/127.8/128.2/128.4 (d, arom.), 138.0/139.1 (s, arom.). FABMS
m/z: 565 [M+H]+ (pos.). FABHRMS m/z: 565.3043 (C30H45O10 re-
quires 565.3013).
3.7. Hydrogenolysis of MOM ethers 17a, 17b, 17c and 17d
General procedure: A suspension of 10% palladium on carbon
(2.0 g) and sodium hydrogen carbonate (300 mg) in 1,4-dioxane
(35 mL) was pre-equilibrated with hydrogen. To the suspension
was added a solution of MOM ether 17a (2.0 g, 3.5 mmol) in 1,4-
dioxane (20 mL), and the mixture was hydrogenated at 60 °C under
atmospheric pressure for 3 h. The catalysts were filtered off,
washed with ethyl acetate. The combined filtrate and washings
were concentrated in vacuo to give practically pure 4,6-O-isopro-
In
a
similar manner, 5,7-di-O-benzyl-4,6-O-isopropylidene-
-glycero- -ido-heptitol (17b, 2.6 g,
1,2,3-tri-O-methoxymethyl-
D
L
85%) was obtained from triol 14b (2.3 g, 5.3 mmol) as a colorless
oil.
Compound 17b: ½a D24
ꢂ
+7.55 (c 1.13, CHCl3). IR (neat): 1454,
1H NMR (500 MHz,
1381, 1265, 1204, 1153, 1103, 1026 cmꢀ1
.
CDCl3) d: 1.45/1.46 [each 3H, s, (CH3)2C], 3.30/3.35/3.40 (each 3H,
s, OCH2OCH3), 3.57 (1H, dd, J = 9.2, 5.8, H-7a), 3.58 (1H, dd,
J = 10.1, 5.8, H-1a), 3.71 (1H, dd, J = 9.2, 7.5, H-7b), 3.73 (1H, dd,
J = 1.5, 1.5, H-5), 3.74 (1H, dd, J = 10.1, 6.3, H-1b), 3.82 (1H, ddd,
J = 6.3, 5.8, 1.4, H-2), 3.99 (1H, dd, J = 8.6, 1.4, H-3), 4.12 (1H, ddd,
J = 7.5, 5.8, 1.5, H-6), 4.22 (1H, dd, J = 8.6, 1.5, H-4), 4.51/4.56 (each
1H, d, J = 11.7, PhCH2), 4.54/4.56 (each 1H, d, J = 6.9, OCH2OCH3),
4.60/4.87 (each 1H, d, J = 7.0, OCH2OCH3), 4.66/4.76 (each 1H, d,
J = 11.8, PhCH2), 4.67/4.90 (each 1H, d, J = 6.6, OCH2OCH3), 7.23–
7.36 (10H, m, arom.). 13C NMR (125 MHz, CDCl3) d: 19.1/29.6
[(CH3)2C], 55.3/56.1/56.3 (OCH2OCH3), 68.2 (C-1), 69.1 (C-7), 69.6
(C-5), 72.0 (C-6), 73.5/73.7 (PhCH2), 74.0 (C-4), 74.6 (C-2), 76.5
(C-3), 96.67/96.72/98.7 (OCH2OCH3), 99.0 [(CH3)2C], 127.5/127.7/
127.75/127.82/128.2/128.4 (d, arom.), 137.9/138.6 (s, arom.). FAB-
MS m/z: 565 [M+H]+ (pos.). FABHRMS m/z: 565.2983 (C30H45O10 re-
quires 565.3013).
pylidene-1,2,3-tri-O-methoxymethyl-D-glycero-L-galacto-heptitol
(18a, 1.3 g, 97%) as a colorless oil, which was used in the next step
without further purification.
Compound 18a: ½a D24
ꢂ
ꢀ10.2 (c 1.16, CHCl3). IR (neat): 3460,
1458, 1384, 1265, 1203, 1158, 1108, 1061, 1029 cmꢀ1
.
1H NMR
(500 MHz, CDCl3) d: 1.456/1.463 [each 3H, s, (CH3)2C], 2.34 (1H,
dd, J = 8.0, 3.6, OH), 3.24 (1H, d, J = 8.6, OH), 3.38/3.39/3.45 (each
3H, s, OCH2OCH3), 3.68 (1H, dd, J = 9.7, 8.3, H-1a), 3.71 (1H, ddd,
J = 8.6, 1.4, 1.2, H-5), 3.76 (1H, dd, J = 9.7, 5.7, H-1b), 3.78 (1H,
ddd, J = 11.5, 8.0, 4.2, H-7a), 3.90, (1H, ddd, J = 11.5, 6.3, 3.6, H-
7b), 3.93 (1H, dd, J = 9.2, 1.8, H-3), 3.95 (1H, ddd, J = 8.3, 5.7, 1.8,
H-2), 3.98 (1H, ddd, J = 6.3, 4.2, 1.4, H-6), 4.01 (1H, dd, J = 9.2, 1.2,
H-4), 4.64/4.66 (each 1H, d, J = 6.6, OCH2OCH3), 4.71/4.72 (each
1H, d, J = 6.6, OCH2OCH3), 4.79/4.82 (each 1H, d, J = 6.3,
OCH2OCH3). 13C NMR (125 MHz, CDCl3) d: 19.1/29.6 [(CH3)2C],
55.6/55.8/56.5 (OCH2OCH3), 63.2 (C-5), 63.6 (C-7), 67.1 (C-1),
70.7 (C-4), 72.7 (C-6), 75.6 (C-2), 76.5 (C-3), 97.0/98.0/99.0
(OCH2OCH3), 99.4 [(CH3)2C]. FABMS m/z: 385 [M+H]+ (pos.). FAB-
HRMS m/z: 385.2063 (C16H33O10 requires 385.2074).
In
1,2,3-tri-O-methoxymethyl-
5,7-di-O-benzyl-4,6-O-isopropylidene-1,2,3-tri-O-methoxymethyl-
-glycero- -gulo-heptitol (17d) were obtained as a ca. 1.1:1 hardly
a
similar manner, 5,7-di-O-benzyl-4,6-O-isopropylidene-
D
-glycero- -talo-heptitol (17c) and
L
D
L
separable mixture (5.3 g, 81%) from a ca. 1.1:1 mixture of 14c
and 14d (5.0 g, 11.5 mmol). A ca. 7:1 mixture of 13c and 13d
(1.5 g, 3.5 mmol) was also converted to the corresponding tri-O-
MOM ethers 17c and 17d (1.7 g, 86%).
In a similar manner, 4,6-O-isopropylidene-1,2,3-tri-O-methoxy-
methyl-D-glycero-L-ido-heptitol (18b, 1.6 g, 95%) was obtained as a
colorless oil from 17b (2.5 g, 4.4 mmol).
Compound 18b: ½a D24
ꢂ
+59.3 (c 3.2, CHCl3). IR (neat): 3445, 1458,
Data for 17c extracted from the 1H and 13C NMR spectra of a ca.
7:1 mixture of 17c and 17d: 1H NMR (700 MHz, CDCl3) d:1.43/1.45
[each 3H, s, (CH3)2C], 3.35/3.36/3.39 (each 3H, s, OCH2OCH3), 3.55
(1H, dd, J = 9.4, 5.8, H-7a), 3.64 (1H, dd, J = 1.6, 1.6, H-5), 3.66
(1H, dd, J = 9.4, 7.4, H-7b), 3.67 (1H, dd, J = 10.8, 7.6, H-1a), 3.75
(1H, dd, J = 10.8, 4.0, H-1b), 3.93 (1H, dd, J = 9.0, 1.6, H-4), 4.06
(1H, dd, J = 9.0, 1.6, H-3), 4.12 (1H, ddd, J = 7.4, 5.8, 1.6, H-6), 4.16
(1H, ddd, J = 7.6, 4.0, 1.6, H-2), 4.47/4.54 (each 1H, d, J = 12.0,
PhCH2), 4.61/4.63 (each 1H, d, J = 6.6, OCH2OCH3), 4.70/4.74 (each
1H, d, J = 6.2, OCH2OCH3), 4.71/4.76 (each 1H, d, J = 11.6, PhCH2),
4.72/4.73 (each 1H, d, J = 6.6, OCH2OCH3), 7.25–7.35 (10H, m,
1385, 1265, 1204, 1153, 1107, 1018 cmꢀ1 1H NMR (700 MHz,
.
CDCl3) d: 1.47/1.48 [each 3H, s, (CH3)2C], 2.11 (1H, br s, OH), 2.72
(1H, d, J = 10.2, OH), 3.37/3.39/3.42 (each 3H, s, OCH2OCH3),
3.73–3.77 (1H, br m, H-7a), 3.75 (1H, dd, J = 10.2, 5.5, H-1a), 3.77
(1H, dd, J = 10.2, 6.2, H-1b), 3.79 (1H, br d, J = ca. 10.2, H-5), 3.82
(1H, br dd, J = ca. 11.0, 6.6, H-7b), 3.92 (1H, ddd, J = 6.6, 4.8, 1.4,
H-6), 3.94 (1H, dd, J = 8.0, 2.2, H-3), 4.05 (1H, ddd, J = 6.2, 5.5, 2.2,
H-2), 4.16 (1H, dd, J = 8.0, 1.2, H-4), 4.63/4.65 (each 1H, d, J = 6.4,
OCH2OCH3), 4.68/4.89 (each 1H, d, J = 6.4, OCH2OCH3), 4.68/4.86
(each 1H, d, J = 6.4, OCH2OCH3). 13C NMR (175 MHz, CDCl3) d:
19.1/29.7 [(CH3)2C], 55.4/56.0/56.2 (OCH2OCH3), 63.2 (C-7), 64.0

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
2259
(C-5), 67.9 (C-1), 72.9 (C-6), 74.2 (C-4), 75.3 (C-2), 76.5 (C-3), 96.8/
96.9/98.2 (OCH2OCH3), 99.6 [(CH3)2C]. FABMS m/z: 385 [M+H]+
(pos.). FABHRMS m/z: 385.2054 (C16H33O10 requires 385.2074).
In a similar manner, from a ca. 1.1:1 mixture of 17c and 17d
(5.2 g, 9.2 mmol) was obtained a mixture (3.3 g, 93%) of 4,6-O-iso-
properties of 16d extracted from the spectrum were in accord with
those reported.16
3.9. Preparation of cyclic sulfates 19a, 19b, 19c and 19d
propylidene-1,2,3-tri-O-methoxymethyl-
(18c) and 4,6-O-isopropylidene-1,2,3-tri-O-methoxymethyl-
cero- -gulo-heptitol (18d), which (500 mg) on column chromatog-
D
-glycero-
L
-talo-heptitol
General procedure: To a solution of diol 18a (1.0 g, 2.6 mmol)
and triethylamine (0.9 mL, 6.5 mmol) in CH2Cl2 (30 mL) was added
a solution of freshly distilled thionyl chloride (0.23 mL, 3.2 mmol)
in CH2Cl2 (30 mL) dropwise at 0 °C. The mixture was stirred at 0 °C
for 30 min, and then poured into ice-cooled and vigorously stirred
aqueous sodium hydrogen carbonate (2 mL), and extracted with
CH2Cl2. The extract was washed with brine and concentrated to
give the corresponding sulfite (1.0 g) as a pale yellow oil, which
was immediately used in the next step without purification.
To a well stirred mixture of the crude sulfite (1.0 g), sodium
hydrogen carbonate (800 mg, 9.5 mmol), carbon tetrachloride
(20 mL), acetonitrile (20 mL), and water (20 mL) was added drop-
wise a brown mixture of sodium metaperiodate (1.5 g, 7.0 mmol),
ruthenium chloride n-hydrate (90 mg) in water (20 mL) at 0 °C.
After being stirred at 0 °C for 3 h, the reaction was quenched by
addition of an aqueous mixture of sodium thiosulfate and sodium
hydrogen carbonate (85 mL). The resulting purple mixture was ex-
tracted with Et2O. The extract was washed with brine and concen-
D
-gly-
L
raphy (n-hexane/AcOEt, 100:1) gave an analytical sample of 18c
(80 mg) and a ca. 1:1.5 mixture of 18c and 18d (405 mg) both as
a colorless oil.
Compound 18c: ½a D24
ꢂ
+5.5 (c 1.03, CHCl3) IR (neat): 3468, 2943,
2893, 2824, 1466, 1443, 1385, 1265, 1153, 1103, 1026 cmꢀ1
.
1H
NMR (500 MHz, CDCl3) d: 1.45/1.46 [each 3H, s, (CH3)2C], 2.33
(1H, br s, OH), 3.08 (1H, d, J = 8.6, OH), 3.37/3.40/3.42 (each 3H,
s, OCH2OCH3), 3.65 (1H, dd, J = 10.7, 7.2, H-1a), 3.71 (1H, br d,
J = ca. 8.6, H-5), 3.73 (1H, dd, J = 10.7, 4.6, H-1b), 3.76 (1H, dd,
J = 11.6, 4.6, H-7a), 3.86 (1H, dd, J = 11.6, 6.3, H-7b), 3.94 (1H,
ddd, J = 6.3, 4.6, 1.5, H-6), 3.96 (1H, dd, J = ca. 9.0, 1.5, H-3), 3.98
(1H, br d, J = ca. 9.0, H-4), 4.08 (1H, ddd, J = 7.2, 4.6, 1.5, H-2),
4.63/4.75 (each 2H, s, OCH2OCH3), 4.75/4.80 (each 1H, d, J = 6.0,
OCH2OCH3). 13C NMR (125 MHz, CDCl3) d: 18.9/29.5 [(CH3)2C],
55.2/55.6/56.1 (OCH2OCH3), 63.39 (C-5), 63.45 (C-7), 67.2 (C-1),
71.3 (C-4), 72.9 (C-6), 75.99 (C-3), 76.04 (C-2), 96.2/96.5/97.6
(OCH2OCH3), 99.4 [(CH3)2C]. FABMS m/z: 385 [M+H]+ (pos.). FAB-
HRMS m/z: 385.2065 (C16H33O10 requires 385.2074).
trated to give
chromatography (n-hexane/AcOEt, 2:1) gave 4,6-O-isopropyli-
dene-1,2,3-tri-O-methoxymethyl- -glycero- -galacto-heptitol 5,7-
a pale yellow oil (0.9 g), which on column
D
L
Data for 18d extracted from the 1H and 13C NMR spectra of a
mixture of 18c and 18d: 1H NMR (500 MHz, CDCl3) d: 1.45 [6H, s,
(CH3)2C], 2.17 (1H, br s, OH), 2.85 (1H, d, J = 10.0, OH), 3.37 (3H,
s, OCH2OCH3), 3.40 (6H, s, OCH2OCH3), 3.61 (1H, br d, J = ca. 10.0,
H-5), 3.70 (1H, dd, J = 10.3, 6.3, H-1a), 3.73 (1H, br dm, J = ca.
11.2, H-7a), 3.78 (1H, dd, J = 10.3, 6.0, H-1b), 3.81 (1H, dd,
J = 11.2, 6.2, H-7b), 3.91 (1H, ddd, J = 6.2, 4.9, 1.5, H-6), 3.98 (1H,
dd, J = 7.5, 1.0, H-4), 4.01 (1H, dd, J = 7.5, 2.0, H-3), 4.04 (1H, ddd,
J = 6.3, 6.0, 2.0, H-2), 4.61/4.64 (each 1H, d, J = 6.4, OCH2OCH3),
4.70/4.76 (each 1H, d, J = 6.9, OCH2OCH3), 4.74/4.78 (each 1H, d,
J = 6.6, OCH2OCH3). 13C NMR (125 MHz, CDCl3) d: 19.1/29.7
[(CH3)2C] 55.4/55.7 (2C) (OCH2OCH3), 63.2 (C-7), 64.6 (C-5), 67.0
(C-1), 72.7 (C-6), 73.9 (C-4), 75.0 (C-2), 77.2 (C-3), 95.9/96.7/97.4
(OCH2OCH3), 99.6 [(CH3)2C].
cyclic sulfate (19a, 0.8 g, 69%) as a colorless solid. An analytical
sample of cyclic sulfate 19a was obtained by recrystallization from
a mixture of n-hexane and AcOEt (10/1) as colorless prisms.
Compound 19a: Mp: 102–103 °C. ½a D24
ꢂ
+9.06 (c 1.76, CHCl3). IR
(nujol): 1462, 1385, 1196, 1157, 1132, 1107, 1034 cmꢀ1
.
1H NMR
(500 MHz, CDCl3) d:1.47/1.50 [each 3H, s, (CH3)2C], 3.38/3.39/
3.44 (each 3H, s, OCH2OCH3), 3.69 (1H, dd, J = 9.8, 8.6, H-1a), 3.78
(1H, dd, J = 9.8, 5.8, H-1b), 3.93 (1H, ddd, J = 8.6, 5.8, 1.5, H-2),
3.95 (1H, ddd, J = 1.7, 1.5, 1.5, H-6), 4.00 (1H, dd, J = 9.2, 1.5, H-3),
4.21 (1H, dd, J = 9.2, 1.5, H-4), 4.55 (1H, dd, J = 12.3, 1.5, H-7a),
4.64/4.66/4.70/4.71 (each 1H, d, J = 6.6, OCH2OCH3), 4.75/4.77
(each 1H, d, J = 6.3, OCH2OCH3), 4.90 (1H, dd, J = 12.3, 1.7, H-7b),
4.98 (1H, dd, J = 1.5, 1.5, H-5). 13C NMR (125 MHz, CDCl3) d: 18.8/
29.1 [(CH3)2C], 55.6/55.9/56.6 (OCH2OCH3), 61.9 (C-6), 66.9 (C-1),
68.5 (C-4), 74.8 (C-3), 75.2 (C-7), 75.5 (C-2), 76.4 (C-5), 97.0/98.1/
99.0 (OCH2OCH3), 99.72 [(CH3)2C]. FABMS m/z: 445 [MꢀH]ꢀ
(neg.). FABHRMS m/z: 445.1387 (C16H29O12S requires 445.1380).
In a similar manner, 4,6-O-isopropylidene-1,2,3-tri-O-methoxy-
3.8. Elucidation of stereochemistries of heptitols
General procedure: A suspension of 10% palladium on carbon
(200 mg) in 80% acetic acid (3 mL) was pre-equilibrated with
hydrogen. To the suspension was added a solution of MOM ether
14a (112 mg, 0.26 mmol) in 80% acetic acid (2 mL), and the mix-
ture was hydrogenated at 60 °C under atmospheric pressure for
2 h. The catalysts were filtered off and washed with ethyl acetate.
The combined filtrate and washings were concentrated in vacuo to
give a colorless oil (93 mg), which on column chromatography
methyl-D-glycero-L-ido-heptitol 5,7-cyclic sulfate (19b, 0.75 g, 65%)
was obtained from 18b (1.0 g, 2.6 mmol) as a colorless oil.
Compound 19b: ½a D24
ꢂ
ꢀ9.66 (c 1.08, CHCl3). IR (neat): 1454,
1396, 1253, 1196, 1153, 1107, 1026 cmꢀ1
.
1H NMR (600 MHz,
CDCl3) d: 1.48/1.52 [each 3H, s, (CH3)2C], 3.39/3.40/3.41 (each 3H,
s, OCH2OCH3), 3.75 (1H, dd, J = 10.5, 4.8, H-1a), 3.82 (1H, dd,
J = 10.5, 5.8, H-1b), 3.90 (1H, ddd, J = 1.9, 1.5, 1.4, H-6), 3.94 (1H,
ddd, J = 5.8, 4.8, 2.8, H-2), 4.01 (1H, dd, J = 8.4, 2.8, H-3), 4.36 (1H,
dd, J = 8.4, 1.4, H-4), 4.53 (1H, dd, J = 12.4., 1.5, H-7a), 4.64 (2H, s,
OCH2OCH3), 4.67/4.82 (each 1H, d, J = 6.7, OCH2OCH3), 4.73/4.83
(each 1H, d, J = 6.5, OCH2OCH3), 4.87 (1H, dd, J = 12.4, 1.9, H-7b),
5.18 (1H, dd, J = 1.4, 1.4, H-5). 13C NMR (150 MHz, CDCl3) d: 18.9/
29.1 [(CH3)2C], 55.5/56.0/56.2 (OCH2OCH3), 61.5 (C-6), 67.5 (C-1),
71.4 (C-4), 74.4 (C-3), 74.9 (C-2), 75.3 (C-7), 76.9 (C-5), 96.6/96.9/
98.3 (OCH2OCH3), 99.7 [(CH3)2C]. FABMS m/z: 445 [MꢀH]ꢀ (neg.).
FABHRMS m/z: 445.1368 (C16H29O12S requires 445.1380).
(AcOEt/MeOH/H2O, 20:4:1) gave D-glycero-L-galacto-heptitol (16a,
54 mg, 98%) as a colorless oil. 13C NMR spectroscopic properties
of 16a were in accord with those reported.16
In a similar manner, diol 14b (112 mg, 0.26 mmol) was con-
verted to D-glycero-L
-ido-heptitol (16b, 41 mg, 74%). 13C NMR spec-
troscopic properties of 16b were in accord with those reported.16
A mixture of diol 18c (50 mg, 0.13 mmol) and 30% aqueous TFA
(5 mL) was heated at 50 °C for 2 h. After the reaction mixture was
concentrated at reduced pressure, the residue was subjected to col-
umn chromatography (AcOEt/MeOH/H2O, 20:4:1) to give
ro-
-talo-heptitol (16c, 24 mg, 87%). 13C NMR spectroscopic
properties of 16c were in accord with those reported.16
D
-glyce-
In a similar manner, 4,6-O-isopropylidene-1,2,3-tri-O-methoxy-
L
methyl-
D
-glycero-
L
-talo-heptitol 5,7-cyclic sulfate (19c, 1.29 g, 37%)
-glycero-L-
and 4,6-O-isopropylidene-1,2,3-tri-O-methoxymethyl-
D
In a similar manner, a ca. 1.2:1 mixture of diols 18c and 18d
gulo-heptitol 5,7-cyclic sulfate (19d, 1.08 g, 31%) were obtained
from a ca. 1.2:1 mixture of 18c and 18d (3.0 g, 7.8 mmol) both as
a colorless oil. 1H and 13C NMR spectroscopic properties of 19c
(50 mg, 0.13 mmol) was converted to a mixture (22 mg, 80%) of
16c and
D-glycero-L
-gulo-heptitol (16d). 13C NMR spectroscopic

2260
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
were in accord with those of a specimen prepared from the analyt-
methyl-3-(sulfooxy)heptyl]episulfoniumylidene}-D-arabinitol inner
ical sample of 18c obtained in the Section 3.7.
salt (21b, 350 mg, 79%) as a colorless oil.
Compound 19c: ½a D24
ꢂ
ꢀ17.7 (c 1.21, CHCl3). IR (neat): 1446,
Compound 21b: ½a D24
ꢂ
+6.38 (c 1.05, CH3OH). IR (neat): 3428,
1402, 1261, 1198, 1152, 1110, 1036 cmꢀ1
.
1H NMR (500 MHz,
1636, 1446, 1387, 1265, 1207, 1150, 1022 cmꢀ1 1H NMR
.
CDCl3) d: 1.47/1.50 [each 3H, s, (CH3)2C], 3.36/3.39/3.44 (each 3H,
s, OCH2OCH3), 3.63 (1H, dd, J = 10.5, 7.2, H-1a), 3.70 (1H, dd,
J = 10.5, 5.5, H-1b), 3.93 (1H, br ddd, J = ca. 2.0, 1.5, 1.5, H-6), 3.99
(1H, dd, J = 9.5, 1.2, H-3), 4.13 (1H, ddd, J = 7.2, 5.5, 1.2, H-2), 4.27
(1H, dd, J = 9.5, 1.5, H-4), 4.53 (1H, dd, J = 12.3, 1.5, H-7a), 4.61/
4.75 (each 2H, s, OCH2OCH3), 4.72/4.73 (each 1H, d, J = 6.3,
OCH2OCH3), 4.88 (1H, dd, J = 12.3, 2.0, H-7b), 4.95 (1H, br dd,
J = ca. 1.5, 1.5, H-5). 13C NMR (125 MH, CDCl3) d: 18.6/29.0
[(CH3)2C], 55.3/55.6/56.6 (OCH2OCH3), 61.9 (C-6), 67.4 (C-1), 68.8
(C-4), 73.7 (C-3), 75.3 (C-7), 75.6 (C-2), 76.4 (C-5), 96.3/96.5/97.1
(OCH2OCH3), 99.6 [(CH3)2C]. FABMS m/z: 469 [M+Na]+ (pos.). FAB-
HRMS m/z: 469.1359 (C16H30O12SNa requires 469.1356).
(700 MHz, CD3OD) d: 1.47/1.52 [each 3H, s, (CH3)2C] 3.34/3.38/
3.42 (each 3H, s, OCH2OCH3), 3.71 (1H, dd, J = 10.6, 3.2, H-70a),
3.765 (1H, dd, J = 12.6, 3.4, H-1a), 3.772 (1H, dd, J = 10.6, 8.4, H-
70b), 3.82 (1H, dd, J = 12.6, 1.8, H-1b), 3.91 (1H, dd, J = 13.2, 4.0,
H-10a), 3.90–3.92 (1H, m, H-4), 3.930 (1H, dd, J = 10.8, 1.6, H-5a),
3.932 (1H, dd, J = 13.2, 6.6, H-10b), 3.96 (1H, dd, J = 8.6, 1.6, H-50),
4.03 (1H, dd, J = 10.8, 5.5, H-5b), 4.35 (1H, dd, J = 8.6, 1.2, H-40),
4.36 (1H, ddd, J = 8.4, 3.2, 1.6, H-60), 4.40 (1H, m, H-3), 4.47 (1H,
dd, J = 1.4, 1.2, H-30), 4.52 (1H, ddd, J = 6.6, 4.0, 1.4, H-20), 4.58–
4.60 (1H, m, H-2), 4.60/4.61 (each 1H, d, J = 6.4, OCH2OCH3), 4.63/
4.80 (each 1H, d, J = 6.6, OCH2OCH3), 4.70/4.87 (each 1H, d,
J = 6.6, OCH2OCH3). 13C NMR (175 MHz, CD3OD) d: 19.5/29.6
[(CH3)2C], 50.3 (C-10), 51.4 (C-1), 55.5/56.4/56.8 (OCH2OCH3), 60.9
(C-5), 69.7 (C-20), 70.8 (C-70), 71.5 (C-30), 73.3 (C-40), 73.5 (C-4),
77.3 (C-50), 77.6 (C-60), 79.2 (C-2), 79.9 (C-3), 97.6/99.4/99.9
(OCH2OCH3), 101.6 [(CH3)2C]. FABMS m/z: 597 [M+H]+ (pos.). FAB-
HRMS m/z: 597.1867 (C21H41O15S2 requires 597.1887).
Compound 19d: ½a D22
ꢂ
ꢀ20.6 (c 0.3, CHCl3). IR (neat): 1442, 1404,
1257, 1196, 1153, 1107, 1026 cmꢀ1
.
1H NMR (700 MHz, CDCl3) d:
1.48/1.52 [each 3H, (CH3)2C], 3.38/3.40/3.41 (each 3H, s, CH2OCH3),
3.66 (1H, dd, J = 9.9, 5.3, H-1a), 3.80 (1H, dd, J = 9.9, 7.6, H-1b), 3.90
(1H, br ddd, J = ca. 1.6, 1.3, 1.3, H-6), 3.97 (1H, ddd, J = 7.6, 5.3, 1.6,
H-2), 4.10 (1H, dd, J = 8.2, 1.6, H-3), 4.23 (1H, dd, J = 8.2, 1.6, H-4),
4.53 (1H, dd, J = 12.4, 1.3, H-7a), 4.62/4.64 (each 1H, d, J = 6.4,
OCH2OCH3), 4.70/4.71 (each 1H, d, J = 6.8, OCH2OCH3), 4.75/4.77
(each 1H, d, J = 6.4, OCH2OCH3), 4.87 (1H, dd, J = 12.4, 1.6, H-7b),
4.90 (1H, br dd, J = ca. 1.6, 1.3, H-5). 13C NMR (175 MHz, CDCl3)
d: 18.8/29.2 [(CH3)2C], 55.6/55.7/55.8 (OCH2OCH3), 61.3 (C-6),
66.3 (C-1), 70.9 (C-4), 74.1 (C-2), 75.3 (C-7), 75.9 (C-3), 77.2 (C-
5), 95.9/96.9/97.6 (OCH2OCH3), 99.6 [(CH3)2C]. FABMS m/z: 469
[M+Na]+ (pos.). FABHRMS m/z: 469.1352 (C16H30O12SNa requires
469.1356).
In a similar manner, coupling reaction of 19c (1.0 g, 2.24 mmol)
with 20 (224 mg, 1.5 mmol) gave 1,4-dideoxy-1,4-{(S)-[(2S,3R,
4S,5S,6S)-2,4-O-isopropylidene-5,6,7-tri-O-methoxymethyl-3-(sul-
fooxy)heptyl]episulfoniumylidene}-D-arabinitol inner salt (21c,
550 mg, 62%) as a colorless oil.
Compound 21c: ½a D25
ꢂ
ꢀ22.3 (c 0.98, MeOH). IR (neat): 3422,
1H NMR
1645, 1447, 1387, 1258, 1206, 1149, 1103, 1028 cmꢀ1
.
(700 MHz, CD3OD) d: 1.44/1.51 [each 3H, s, (CH3)2C], 3.34/3.39/
3.41 (each 3H, s, OCH2OCH3), 3.66 (1H, dd, J = 10.7, 7.6, H-70a),
3.72 (1H, dd, J = 10.7, 4.2, H-70b), 3.77 (1H, dd, J = 12.7, 3.5, H-1a),
3.81 (1H, dd, J = 12.7, 2.0, H-1b), 3.88 (1H, dd, J = 13.3, 4.0, H-10a),
3.90–3.94 (1H, m, H-5a), 3.92–3.95, (1H, m, H-4), 3.97 (1H, dd,
J = 13.3, 7.4, H-10b), 4.02 (1H, dd, J = 9.0, 3.4, H-5b), 4.08–4.10
(2H, m, H-40 and H-50), 4.18 (1H, ddd, J = 7.6, 4.2, 0.6, H-60), 4.38
(1H, br d, J = ca. 1.6, H-3), 4.50 (1H, br dd, J = ca. 1.2, 1.2, H-30),
4.56 (1H, ddd, J = 7.4, 4.0, 1.2, H-20), 4.58–4.60 (1H, m, H-2), 4.59/
4.62 (each 1H, d, J = 6.4, OCH2OCH3), 4.71/4.77 (each 1H, d,
J = 6.6, OCH2OCH3), 4.75/4.96 (each 1H, d, J = 6.0, OCH2OCH3). 13C
NMR (175 MHz, CD3OD) d: 19.3/29.4 [(CH3)2C], 50.3 (C-10), 51.3
(C-1), 55.5/55.9/56.7 (OCH2OCH3), 60.9 (C-5), 69.0 (C-70), 70.0 (C-
20), 72.0 (C-30), 72.9 (C-40), 73.3 (C-4), 78.1 (C-60), 78.2 (C-50), 79.2
(C-2), 79.8 (C-3), 97.4/97.5/100.0 (OCH2OCH3), 101.5 [(CH3)2C].
FABMS m/z: 597 [M+H]+ (pos.). FABHRMS m/z: 597.1899
(C21H41O15S2 requires 597.1887).
3.10. Preparation of sulfonium sulfate inner salts 21a, 21b, 21c
and 21d
General procedure:
A solution of compound 19a (500 mg,
1.12 mmol), thiosugar (20, 112 mg, 0.75 mmol) and potassium car-
bonate (25 mg) in 1,1,1,3,3,3-hexafluoroisopropanol (2.5 mL) was
stirred in a sealed flask at 65 °C for one week. The mixture was con-
centrated to give a yellow oil (450 mg), which on column chroma-
tography (CHCl3/MeOH, 20:1) gave 1,4-dideoxy-1,4-{(S)-[(2S,3R,
4S,5S,6R)-2,4-O-isopropylidene-5,6,7-tri-O-methoxymethyl-3-(sul-
fooxy)heptyl]episulfoniumylidene}-D-arabinitol inner salt (21a,
320 mg, 72%) as a colorless amorphous.
Compound 21a: ½a D24
ꢂ
ꢀ25.0 (c 1.17, CH3OH). IR (nujol): 3364,
1262, 1207, 1153, 1107, 1026 cmꢀ1
.
1H NMR (600 MHz, CD3OD)
In a similar manner, coupling reaction of 19d (1.0 g, 2.24 mmol)
with 20 (224 mg, 1.5 mmol) gave 1,4-dideoxy-1,4-{(S)-[(2S,3R,4S,
5R,6R)-2,4-O-isopropylidene-5,6,7-tri-O-methoxymethyl-3-(sulfo-
d: 1.45/1.52 [each 3H, s, (CH3)2C], 3.35/3.37/3.39 (each 3H, s,
OCH2OCH3), 3.76 (1H, dd, J = 9.8, 6.7, H-70a), 3.79 (1H, br dd,
J = ca. 12.8, 3.5, H-1a), 3.81 (1H, dd, J = 9.8, 7.2, H-70b), 3.82 (1H,
br dd, J = ca. 12.8, 2.0, H-1b), 3.88 (1H, dd, J = 13.4, 3.6, H-10a),
3.91 (1H, dd, J = J = 11.0, 8.6, H-5a), 3.94 (1H, br dd, J = ca. 6.7,
6.7, H-60), 3.97–4.01 (1H, m, H-4), 4.01 (1H, dd, J = 13.4, 7.9, H-
10b), 4.03 (1H, dd, J = 11.0, 5.5, H-5b), 4.07 (2H, br s, H-40 and H-
50), 4.39 (1H, br dd, J = ca. 1.5, 1.5, H-3), 4.56 (1H, br s, H-30), 4.57
(1H, br dd, J = ca. 7.9, 3.6, H-20), 4.59–4.61 (1H, m, H-2), 4.61/4.63
(each 1H, d, J = 6.5, OCH2OCH3), 4.67/4.71 (each 1H, d, J = 6.5,
OCH2OCH3), 4.79/4.92 (each 1H, d, J = 6.7, OCH2OCH3). 13C NMR
(150 MHz, CD3OD) d: 19.5/29.5 [(CH3)2C], 50.2 (C-10), 51.2 (C-1),
55.8/56.1/56.2 (OCH2OCH3), 60.9 (C-5), 68.8 (C-70), 70.1 (C-20),
72.2 (C-30), 72.6 (C-40), 73.4 (C-4), 77.4 (C-60), 78.0 (C-50), 79.2 (C-
2), 79.8 (C-3), 97.9/99.1/100.4 (OCH2OCH3), 101.2 [(CH3)2C]. FAB-
MS m/z: 597 [M+H]+ (pos.). FABHRMS m/z: 597.1865
(C21H41O15S2 requires 597.1887).
oxy)heptyl]episulfoniumylidene}-D-arabinitol inner salt (21d,
670 mg, 75%) as a colorless oil.
Compound 21d: ½a D24
ꢂ
+33.6 (c 0.45, MeOH) IR (neat): 3447,
1H NMR
1636, 1456, 1385, 1258, 1215, 1155, 1107, 1020 cmꢀ1
.
(700 MHz, CD3OD) d: 1.47/1.50 [each 3H, s, (CH3)2C], 3.36/3.38/
3.40 (each 3H, s, OCH2OCH3), 3.66 (1H, dd, J = 10.2, 5.6, H-70a),
3.75 (1H, dd, J = 12.8, 3.6, H-1a), 3.81 (1H, dd, J = 12.8, 1.8, H-1b),
3.84 (1H, dd, J = 10.2, 6.9, H-70b), 3.90 (1H, dd, J = 13.5, 4.0, H-
10a), 3.90–3.93 (1H, m, H-4), 3.93, (1H, dd, J = 10.2, 8.3, H-5a),
3.98 (1H, dd, J = 13.5, 6.8, H-10b), 4.02 (1H, dd, J = 10.2, 5.0, H-5b),
4.14 (1H, dd, J = 8.8, 2.0, H-50), 4.24 (1H, dd, J = 8.8, 1.3, H-40),
4.32 (1H, ddd, J = 6.9, 5.6, 2.0, H-60), 4.38 (1H, dd, J = 1.4, 1.3, H-
30), 4.40 (1H, br d, J = ca. 1.8, H-3), 4.51 (1H, ddd, J = 6.8, 4.0, 1.4,
H-20), 4.58–4.60 (1H, m, H-2), 4.59/4.61 (each 1H, d, J = 6.3,
OCH2OCH3), 4.70/4.75 (each 1H, d, J = 6.3, OCH2OCH3), 4.79/4.96
(each 1H, d, J = 6.3, OCH2OCH3). 13C NMR (175 MHz, CD3OD) d:
19.5/29.6 [(CH3)2C], 50.5 (C-10), 51.4 (C-1), 55.8/56.0/56.2
(OCH2OCH3), 60.9 (C-5), 67.8 (C-70), 69.6 (C-20), 72.4 (C-30), 73.2
In
a similar manner, coupling reaction of 19b (500 mg,
1.12 mmol) with 20 (112 mg, 0.75 mmol) gave 1,4-dideoxy-1,
4-{(S)-[(2S,3R,4S,5R,6S)-2,4-O-isopropylidene-5,6,7-tri-O-methoxy-

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
2261
(C-4), 73.3 (C-40), 76.8 (C-60), 78.3 (C-50), 79.2 (C-2), 79.9 (C-3),
97.7/97.9/99.2 (OCH2OCH3), 101.6 [(CH3)2C]. FABMS m/z: 597
[M+H]+ (pos.). FABHRMS m/z: 597.1857 (C21H41O15S2 requires
597.1887).
[M+H]+ (pos.). FABHRMS m/z: 425.0798 (C12H25O12S2 requires
425.0787).
In
2,4,5,6,7-pentahydroxy-3-(sulfooxy)heptyl]episulfoniumylidene}-
-arabinitol inner salt (9d, 140 mg, 79%) was obtained from 21d
a similar manner, 1,4-dideoxy-1,4-{(S)-[(2S,3R,4S,5R,6R)-
D
(250 mg 0.42 mmol) as a colorless viscous oil.
3.11. Acidic hydrolysis of sulfonium sulfate inner salts 21a, 21b,
21c and 21d
Compound 9d: ½a 2D4
ꢂ
ꢀ15.2 (c 0.13, H2O). IR (neat): 3381, 1682,
1414, 1260, 1207, 1134, 1067, 1024 cmꢀ1
.
1H NMR (600 MHz,
D2O) d: 3.65 (1H, dd, J = 11.6, 5.8, H-70a), 3.72 (1H, dd, J = 8.2, 2.0,
H-50), 3.78 (1H, ddd, J = 8.2, 5.8, 3.0, H-60), 3.81 (1H, dd, J = 11.6,
3.0, H-70b), 3.87 (1H, dd, J = 13.2, 4.0, H-1a), 3.90 (1H, dd, J = 13.2,
3.6, H-1b), 3.90–3.93 (2H, m, H-10a and H-10b), 3.92 (1H, dd,
J = 12.3, 9.0, H-5a), 4.08 (1H, ddd, J = 9.0, 4.8, 2.8, H-4), 4.12 (1H,
dd, J = 12.3, 4.8, H-5b), 4.23 (1H, dd, J = 5.6, 2.0, H-40), 4.42 (1H,
dd, J = 3.6, 2.8, H-3), 4.49 (1H, dd, J = 5.6, 3.0, H-30), 4.50–4.53
(1H, m, H-20), 4.74 (1H, ddd, J = 4.0, 3.6, 3.6, H-2). 13C NMR
(175 MHz, D2O) d: 50.3 (C-1), 52.2 (C-10), 61.7 (C-5), 65.3 (C-70),
68.5 (C-20), 70.7 (C-40), 72.3 (C-4), 72.6 (C-50), 73.4 (C-60), 79.4 (C-
2), 80.1 (C-3), 83.4 (C-30). FABMS m/z: 425, [M+H]+ (pos.). FAB-
HRMS m/z: 425.0758 (C12H25O12S2 requires 425.0787).
General procedure: A mixture of 21a (250 mg 0.42 mmol) and
30% aqueous TFA (25 mL) was stirred at 50 °C for 3 h. The mixture
was then concentrated to give a residue (200 mg) which on column
chromatography (CHCl3/MeOH/H2O, 10:5:1) gave 1,4-dideoxy-1,4-
{(S)-[(2S,3R,4S,5S,6R)-2,4,5,6,7-pentahydroxy-3-(sulfooxy)heptyl]-
episulfoniumylidene}-D-arabinitol inner salt (9a, 150 mg, 84%) as a
colorless amorphous.
Compound 9a: ½a 2D4
ꢂ
ꢀ27.3 (c 1.06, H2O). IR (nujol): 3348, 1647,
1258, 1219, 1072 cmꢀ1. 1H NMR (600 MHz, CD3OD) d: 3.64 (1H, dd,
J = 10.3, 7.2, H-70a), 3.66 (1H, dd, J = 10.3, 4.6, H-70b), 3.73 (1H, dd,
J = 9.5, 1.4, H-50), 3.83 (1H, dd, J = 13.0, 3.2, H-1a), 3.85 (1H, dd,
J = 13.0, 2.2, H-1b), 3.89–3.93 (2H, m, H-5a and H-60), 3.94 (1H,
br dd, J = ca. 13.8, 1.2, H-10a), 3.97 (1H, br dd, J = ca. 13.8, 5.3, H-
10b), 4.00 (1H, br dd, J = ca. 8.9, 5.2, H-4), 4.04 (1H, dd, J = 10.8,
5.2, H-5b), 4.09 (1H, dd, J = 9.5, 1.2, H-40), 4.37 (1H, br dd, J = ca.
2.2, 1.2, H-3), 4.57–4.61 (1H, m H-20), 4.62 (1H, br ddd, J = ca. 3.2,
2.2, 2.2, H-2), 4.70 (1H, dd, J = 5.1, 1.2, H-30). 13C NMR (150 MHz,
CD3OD) d: 51.1 (C-10), 51.4 (C-1), 60.9 (C-5), 65.0 (C-70), 69.1 (C-
20), 70.1 (C-40), 70.7 (C-50), 71.4 (C-60), 73.4 (C-4), 78.7 (C-30), 79.4
(C-2), 79.6 (C-3). FABMS m/z: 423, [MꢀH]ꢀ (neg.). FABHRMS m/z:
423.0617 (C12H23O12S2 requires 423.0634).
3.12. a-Glucosidase inhibitory activity
Testing method already described5 was modified and used.
Briefly, rat small intestinal brush border membrane vesicles were
prepared21 and its suspension in 0.1 M maleate buffer (pH 6.0)
was used as small intestinal
a-glucosidases of maltase, sucrase,
and isomaltase. A test compound was dissolved in dimethylsulfox-
ide (DMSO), and the resulting solution was diluted with 0.1 M
maleate buffer to prepare the test compound solution (concentra-
tion of DMSO: 10%). The substrate solution in maleate buffer (malt-
In
2,4,5,6,7-pentahydroxy-3-(sulfooxy)heptyl]episulfoniumylidene}-
-arabinitol inner salt (9b, 135 mg, 76%) was obtained from 21b
a similar manner, 1,4-dideoxy-1,4-{(S)-[(2S,3R,4S,5R,6S)-
ose, 74 mM, sucrose, 74 mM, isomaltose, 7.4 mM, 50
lL), a test
D
compound solution (25 L), and the enzyme solution (25
l
l
L) were
(250 mg 0.42 mmol) as a colorless viscous oil.
Compound 9b: ½a 2D4
ꢂ
75.3 (c 1.05, H2O). IR (neat): 3421, 1684,
mixed and incubated at 37 °C for 30 min. After incubation, the
solution was immediately heated by boiling water for 2 min to stop
the reaction, and the solution was mixed with water (150 lL). Glu-
cose concentration was determined by the glucose-oxidase meth-
od. Final concentration of DMSO in the test solution was 2.5%
and no influence of DMSO was detected on the inhibitory activity.
The IC50 value was determined graphically by a plot of percent
inhibition versus log of the test compound.
1647, 1411, 1253, 1220, 1126, 1096, 1071, 1018 cmꢀ1
.
1H NMR
(700 MHz, D2O) d: 3.64 (1H, dd, J = 12.0, 7.2, H-70a), 3.70 (1H, dd,
J = 12.0, 4.0, H-70b), 3.79 (1H, dd, J = 5.1, 4.0, H-50), 3.900 (1H, dd,
J = 12.8, 4.0, H-1a), 3.906 (1H, ddd, J = 7.2, 4.0, 4.0, H-60), 3.912
(1H, dd, J = 12.8, 3.0, H-1b), 3.940 (1H, dd, J = 13.6, 4.0, H-10a),
3.944 (1H, dd, J = 12.4, 11.2, H-5a), 3.97 (1H, dd, J = 13.6, 9.2, H-
10b), 4.10 (1H, ddd, J = 11.2, 4.8, 3.0, H-4), 4.13 (1H, dd, J = 5.1,
4.0, H-40), 4.14 (1H, dd, J = 12.4, 4.8, H-5b), 4.45 (1H, br dd, J = ca.
3.0, 3.0, H-3), 4.53 (1H, dd, J = 4.0, 4.0, H-30), 4.58 (1H, ddd,
J = 9.2, 4.0, 4.0, H-20), 4.76 (1H, ddd, J = ca. 4.0, 3.0, 3.0, H-2). 13C
NMR (175 MHz, D2O) d: 50.3 (C-1), 51.9 (C-10), 61.7 (C-5), 65.5
(C-70), 68.9 (C-20), 72.0 (C-40), 72.4 (C-4), 72.9 (C-50), 74.2 (C-60),
79.5 (C-2), 80.1 (C-30), 81.9 (C-3). FABMS m/z: 425, [M+H]+ (pos.).
FABHRMS m/z: 425.0768, (C12H25O12S2 requires 425.0787).
Acknowledgment
This work was supported by ‘High-Tech Research Center’ Pro-
ject for Private Universities: matching fund subsidy from MEXT
(Ministry of Education, Culture, Sports, Science and Technology),
2007–2011.
In
2,4,5,6,7-pentahydroxy-3-(sulfooxy)heptyl]episulfoniumylidene}-
-arabinitol inner salt (9c, 149 mg, 84%) was obtained from 21c
a similar manner, 1,4-dideoxy-1,4-{(S)-[(2S,3R,4S,5S,6S)-
References and notes
D
1. (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750; (b)
Krasikov, V. V.; Karelov, D. V.; Firsov, L. M. Biochemistry (Moscow) 2001, 66, 267;
(c) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515;
(d) Herscovics, A. In Comprehensive Natural Products Chemistry; Pinto, B. M.,
Barton, D. H. R., Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier: UK, 1999; (e)
McCarter, J. D.; Withers, S. G. Curr. Opin. Struct. Biol. 1994, 4, 885; (f) Ly, H. D.;
Withers, S. G. Annu. Rev. Biochem. 1999, 68, 487.
2. (a) Hollander, P.; Pi-Sunyer, X.; Coniff, R. E. Diabetes Care 1997, 20, 248; (b)
Scott, L.; Spencer, C. M. Drugs 2000, 59, 521; (c) Cheng, A. Y. Y.; Josse, R. G. Drug
Discovery Today 2004, 201; (d) Mitrakou, A.; Tountas, N.; Raptis, A. E.; Bauer, R.
J.; Shulz, H.; Raptis, S. A. Diabet. Med. 1998, 15, 657; (e) Kordik, C. P.; Reitz, A. B.
J. Med. Chem. 1999, 42, 181; (f) Platt, F. M.; Butters, T. D. Exp. Rev. Mol. Med.
2000, 1; (g) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med. Chem. 2003, 3,
561; (h) Takeuchi, M.; Kamata, K.; Yoshida, M.; Kameda, Y.; Matsui, K. J.
Biochem. 1990, 108, 42; (i) Butters, T. D.; Dwek, R. A.; Platt, F. M. Glycobiology
2005, 15, 43.
(250 mg, 0.42 mmol) as a colorless viscous oil.
Compound 9c: ½a 2D3
ꢂ
+15.6 (c 1.04, H2O). IR (neat): 3418, 1684,
1418, 1258, 1206, 1136, 1067, 1024, 1001 cmꢀ1
.
1H NMR
(700 MHz, D2O) d: 3.68 (1H, dd, J = 11.8, 7.6, H-70a), 3.78 (1H, dd,
J = 11.8, 3.2, H-70b), 3.85 (1H, dd, J = 9.0, 4.0, H-50), 3.88 (1H, dd,
J = 13.2, 4.0, H-1a), 3.91 (1H, dd, J = 13.2, 3.2, H-1b), 3.91–3.94
(2H, m, H-10a and H-10b), 3.92 (1H, dd, J = 12.5, 9.7, H-5a), 3.96
(1H, ddd, J = 7.6, 4.0, 3.2, H-60), 4.01 (1H, dd, J = 9.0, 1.6, H-40),
4.07 (1H, ddd, J = 9.7, 4.8, 3.0, H-4), 4.13 (1H, dd, J = 12.5, 4.8, H-
5b), 4.44 (1H, dd, J = 3.2, 3.0, H-3), 4.61 (1H, ddd, J = 7.6, 5.0, 5.0,
H-20), 4.69 (1H, dd, J = J = 5.0, 1.6, H-30), 4.75 (1H, ddd, J = 4.0, 3.2,
13
3.2, H-2). C NMR (175 MHz, D2O) d: 50.3 (C-1), 51.4 (C-10), 61.8
3. (a) Iminosugars: Recent Insights into Their Bioactivity and Potential As
Therapeutic Agents In Martin, O. R., Compain, P., Eds.; Current Topics in
Medical Chemistry Bentham; Hilversum: Netherland, 2003; Vol. 3,. Issue 5 (b)
(C-5), 64.5 (C-70), 69.5 (C-20), 72.0 (C-40), 72.5 (C-4), 73.6 (C-50),
75.1 (C-60), 79.6 (C-2), 80.2 (C-3), 80.4 (C-30). FABMS m/z: 425,

2262
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2252–2262
Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto, B. M. J. Am. Chem.
Soc. 2004, 126, 12458.
10080; (f) Tanabe, G.; Hatanaka, T.; Minematsu, T.; Matsuda, H.; Yoshikawa,
M.; Muraoka, O. Heterocycles 2009, 79, 1093; (g) Sim, L.; Jayakanthan, K.;
Mohan, S.; Nasi, R.; Johnston, B. D.; Pinto, B. M.; Rose, D. R. Biochemistry 2010,
49, 443; (h) Mohan, S.; Jayakanthan, K.; Nasi, R.; Kuntz, D. A.; Rose, D. R.; Pinto,
B. M. Org. Lett. 2010, 12, 1088; (i) Eskandari, R.; Kuntz, D. A.; Rose, D. R.; Pinto,
B. M. Org. Lett. 2010, 12, 1632. and references cited therein.
12. (a) Jayakanthan, K.; Mohan, S.; Pinto, B. M. J. Am. Chem. Soc. 2009, 131, 5621; (b)
Muraoka, O.; Xie, W.; Osaki, S.; Kagawa, A.; Tanabe, G.; Amer, M. F. A.;
Minematsu, T.; Morikawa, T.; Yoshikawa, M. Tetrahedron 2010, 66, 3717.
13. Matsuda, F.; Terashima, S. Tetrahedron 1988, 44, 4721.
14. (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247; (b) Cha, J. K.;
Kim, N. S. Chem. Rev. 1995, 95, 1761.
15. (a) Sharpless, K. B.; Bmberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.;
Lubben, D.; Manoury, E.; Ogino, Y. J. Org. Chem. 1991, 56, 4585; (b) Wang, Z. M.;
Kakiuchi, K.; Sharpless, K. B. J. Org. Chem. 1994, 59, 6895; (c) Wang, L.;
Sharpless, K. B. J. Am. Chem. Soc. 1992, 19, 7569.
16. Angyal, S. J. Carbohydr. Res. 1984, 126, 15.
17. Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 2109. and references cited
therein.
4. Stutz, A. E. Iminosugars as Glycosidase Inhibitors; Wiley-VCH: New York, 1999.
5. (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara, J.;
Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367; (b) Yoshikawa, M.;
Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka, O. Bioorg. Med. Chem. 2002, 10,
1547.
6. Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem. Pharm. Bull. 1998,
46, 1339.
7. Yoshikawa, M.; Xu, F.; Nakamura, S.; Wang, T.; Matsuda, H.; Tanabe, G.;
Muraoka, O. Heterocycles 2008, 75, 1397.
8. (a) Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.; Takebayashi, K.; Adachi, I.;
Fleet, G. W. J.; Kettawan, A.; Okamoto, T.; Asano, N. Bioorg. Med. Chem. 2008, 16,
2734; (b) Tanabe, G.; Xie, W.; Ogawa, A.; Cao, C.; Minematsu, T.; Yoshikawa, M.;
Muraoka, O. Bioorg. Med. Chem. Lett. 2009, 19, 2195.
9. (a) Ozaki, S.; Oe, H.; Kitamura, S. J. Nat. Prod. 2008, 71, 981; (b) Oe, H.; Ozaki, S.
Biosci. Biotechnol. Biochem. 2008, 72, 1962; (c) Muraoka, O.; Xie, W.; Tanabe, G.;
Amer, F. A. M.; Minematsu, T.; Yoshikawa, M. Tetrahedron Lett. 2008, 49, 7315.
10. Xie, W.; Tanabe, G.; Akaki, J.; Morikawa, T.; Ninomiya, K.; Minematsu, T.;
Yoshikawa, M.; Wu, X.; Muraoka, O. Bioorg. Med. Chem. 2011, 19, 2014.
11. Recent review relevant to the present work: (a) Mohan, S.; Pinto, B. M.
Carbohydr. Res. 2007, 342, 1551; (b) Tanabe, G.; Yoshikai, K.; Hatanaka, T.;
Yamamoto, M.; Shao, Y.; Minematsu, T.; Muraoka, O.; Wang, T.; Matsuda, H.;
Yoshikawa, M. Bioorg. Med. Chem. 2007, 15, 3926; (c) Nasi, R.; Sim, L.; Rose, D.
R.; Pinto, B. M. J. Org. Chem. 2007, 72, 180; (d) Nasi, R.; Patrick, B. O.; Sim, L.;
Rose, D. R.; Pinto, B. M. J. Org. Chem. 2008, 73, 6172; (e) Tanabe, G.; Sakano, M.;
Minematsu, T.; Matusda, H.; Yoshikawa, M.; Muraoka, O. Tetrahedron 2008, 64,
18. (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7358; (b) Kim, B. M.;
Sharpless, K. B. Tetrahedron Lett. 1989, 30, 566; Lohray, B. B. Synthesis 1992,
1035.
19. Moritoh, Y.; Takeuchi, K.; Hazama, M. J. Pharmacol. Exp. Ther. 2009, 329, 669.
20. Samulitis, B. K.; Goda, T.; Lee, S. M.; Koldovsky, O. Drugs Exp. Clin. Res. 1987, 13,
517.
21. Kessler, M.; Acuto, O.; Storelli, C.; Murer, H.; Mueller, M.; Semenza, G. Biochim.
Biophys. Acta 1978, 506, 136.