Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2011.01.052

Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified.

Full text of DOI:10.1016/j.bmc.2011.01.052

Bioorganic & Medicinal Chemistry 19 (2011) 2015–2022
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Isolation, structure identification and SAR studies on thiosugar sulfonium salts,
neosalaprinol and neoponkoranol, as potent
a-glucosidase inhibitors
Weijia Xie a,c, Genzoh Tanabe a, Junji Akaki a, Toshio Morikawa b, Kiyofumi Ninomiya b, Toshie Minematsu a,
Masayuki Yoshikawa b, Xiaoming Wu c, Osamu Muraoka a,
⇑
a School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
b Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
c Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Jiang su 210009, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of a-glu-
cosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and
their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts,
Received 25 November 2010
Revised 24 January 2011
Accepted 25 January 2011
Available online 31 January 2011
several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal a-
glucosidases were evaluated. Among them, 30-epimer of 7 was found most potent in this class of mole-
cules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Neoponkoranol
Neosalaprinol
a-Glucosidase inhibitor
Salacia
SAR study
1. Introduction
proved to be the competitive inhibition against
Ki values against rat intestinal -glucosidases, that is, maltase, su-
crase, and isomaltase were revealed as 0.31, 0.32, and 0.47 g/mL,
a-glucosidase, and
a
Glucosidases are largely involved in the human metabolic sys-
tem. Thus, the inhibition of glucosidases is considered to be an effi-
cient way to treat diseases such as diabetes,1 cancers,2 viral
infections3 and Gaucher’s disease.4 Many naturally occurring and
synthesized azasugars, which are believed to carry a positive
charge at physiological pH and hence are postulated to bind in
the active sites of glucosidase enzymes, are effective inhibitors of
various glucosidases.5 These evidences indicated that a potent glu-
cosidase 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 reaction.6
l
respectively.7b Since the discovery of 1, related sulfonium sulfates,
kotalanol8 (2), ponkoranol9 (3) and salaprinol9 (4) were subse-
quently isolated, and the stereostructure of these sulfonium sul-
fates (2, 3, 4) were elucidated by the total synthesis or other
means10 (Fig. 1).
Other than 4, all these sulfonium sulfates showed potent
cosidase inhibitory activities, composing a new class of naturally
occurring -glycosidase inhibitors. Because of both the intriguing
structure and high -glucosidase inhibitory activities, much atten-
a-glu-
a
a
tion has been focused on 1, and intensive studies on the structure–
In late 1990s, salacinol (1) was isolated by us as a potent a-glu-
activity relationships (SAR) have been reported.11
cosidases inhibitor from an Ayurvedic medicinal plant Salacia retic-
ulata,7 which have been traditionally used for the treatment of
diabetes in Sri Lanka and south region of India. The structure of 1
was quite unique, bearing the permanent positive charge as the
thiosugar sulfonium sulfate inner salt comprised of 1-deoxy-4-
In 2008, another two compounds termed neosalacinol12 (50) and
13-membered cyclic sulfoxide13 (60) were reported, by Minami and
Ozaki, respectively, as the constituents responsible for the a-gluco-
sidase inhibitory activities of Salacia genus plants (Fig. 2). Shortly
thereafter, these two compounds were revised to be de-O-sulfo-
nates (514 and 615) of 1 and 2, respectively, as shown in Figure 1.
It was interesting to note that desulfonated kotalanol (6) showed
thio-
D
-arabinofranosyl cation and 30-sulfate anion as shown in Fig-
-glucosidase inhibitory activity was revealed to be as
ure 1.7 Its
a
potent as those of voglibose and acarbose which are widely used
higher a-glucosidase inhibitory activities than the original sulfate
clinically these days.7 The mode of action of salacinol (1) was also
(2).9 Ever since the discovery of the existence of 5 and 6 in Salacia
genus plants, intensive exploratory study on water extracts of
Salacia chinensis originated from Thailand have been conducted
by us in order to isolate other minor sulfoniums. In this paper, full
⇑
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.2011.01.052

2016
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
OH
OH OH
3'
OH OH OH
OH
2'
OH
1'
S+
5'
OH
OH
OH
S+
OR
R
S+
S+
OR
OH
OR
5
HO
1
HO
HO
HO
3
OH
OH
OH
HO
HO
ponkoranol (3)
neoponkoranol (7)
HO
kotalanol (2)
neokotalanol (6)
OH
HO
: R = 3'α-OSO3-, 5'α-OH
: R = 3'α-OH, 5'α-OH
5'-epi-7 : R = 3'α-OH, 5'β-OH
3'-epi-7 : R = 3'β-OH, 5'α-OH
-
-
salacinol (1)
neosalacinol (5)
salaprinol (4)
neosalaprinol (8)
2'-epi-8
: R = SO3
: R = SO3
: R = H
: R = SO3-, 2'β-OH
: R = H, 2'β-OH
: R = H, 2'α-OH
: R = H
Figure 1. Sulfonium salts isolated from Salacia species and related sulfonium salts as a new class of
a
OH
-
-glucosidase inhibitors.
OH
OBn
O
HO
HO
S
OH
OH
S
OH
HO
HO
HO
S+
O-
O
O
S
OH
+
HO
HO
OH
O
O
10
9
OH
HO
OH
a
5'
6'
OH
Figure 2. Proposed structures of neosalacinol (50) and neokotalanol (60).
S+
OSO3
-
S+
OSO3
HO
HO
+
details of isolation and identification of desulfonates of 3 and 4,
neoponkoranol (7) and neosalaprinol (8), respectively, the exis-
tence of which in the plants has been strongly expected, are de-
scribed. In addition, syntheses of their epimers (30-epi-7, 50-epi-7,
and 20-epi-8) and SAR studies on this neo-series of compounds
OH
HO
OH
2'-epi-4
HO
salaprinol (4)
b
b
OH
OH
against rat small intestinal a
-glucosidases are also presented.16
X-
X-
S+
OH
S+
OH
2. Results and discussion
HO
HO
2.1. Isolation and Identification of Neoponkolanol (7) and
Neosalaprinol (8)
OH
OH
HO
HO
neosalaprinol (8)
2'-epi-8
X = CH3OSO3
X = Cl
X = CH3OSO3
X = Cl
c
c
A water extract was prepared in 9.87% yield in a usual manner
from dried stems of S. chinensis originated from Thailand. The ex-
tract was then dissolved in water, and centrifuged. The superna-
tant was subjected to Diaion HP-20 column chromatography to
give a water-eluted fraction (4.00%) and a MeOH-eluted fraction
(1.95%). An aliquot of the H2O-eluted fraction was dissolved in
MeCN/H2O (50:50, v/v) and centrifuged one more time, then the
supernatant was subjected to column chromatography [Chromato-
rex NH, MeCN/H2O (50:50 ? 20:80, v/v) ? H2O] to give eight frac-
tions. The second fraction (Fr. 2) was purified by means of HPLC
[Daisopak-SP-120-5-ODS-BP (20 mm id ꢀ 250 mm), mobile phase:
0.1% (v/v) aqueous AcOH] to give neosalaprinol (8, 0.00096%) as a
colorless oil. According to the same procedure, neoponkoranol (7,
0.0016%) was isolated as a colorless solid from the fifth fraction
(Fr. 5). The 1H and 13C NMR spectral properties of 7 and 8 were
in good accord with those of authentic specimens synthesized
alternatively.
Scheme 1. Reagents and conditions: (a) K2CO3, HFIP, 65–70 °C; (b) 5% methanolic
HCl, 50 °C; (c) IRA 400J (Clꢁ form), CH3OH, rt.
of the anion from CH3OSOꢁ to Clꢁ could be unambiguously con-
3
firmed by the complete disappearance of the signals due to
CH3OSOꢁ in the 1H and 13C NMR spectra of 8 (X = Cl). Except for
3
proton and carbon signals corresponding to the CH3OSOꢁ moiety,
3
NMR spectral properties of these two sulfomium salts (X = CH3O-
SO3 and Cl) were in good accord with each other. Their FAB mass
spectra run in a positive ion mode showed a peak at m/z 225 due
to the sulfonium cation moiety corresponding to the desulfonated
structure.
Under similar conditions, 20-epi-4 was also converted to the
corresponding sulfonium chloride (20-epi-8) in 88% yield. The 1H
and 13C NMR spectral properties were quite similar with those of
8 (Scheme 1).
2.2. Synthesis of Neosalaprinol (8)
In the coupling reaction of thiosugar (9) and cyclic sulfate (10),
formation of a 1:1 mixture of 4 and 20-epi-4 is inevitable because of
the meso structure of 10, and each isomer (4 and 20-epi-4) could be
obtained only by exclusive recrystallization and subsequent careful
column chromatography.10c Therefore, an asymmetric synthetic
route to 8 has been developed in the present study by employing
the regioselective coupling reaction of an epoxide with a thiosugar.
Thus (S)-glycidol (11) was treated with thiosugar, 2,3,5-tri-O-ben-
Syntheses of salaprinol (4) and its 20-epimer (20-epi-4) had al-
ready been established by a coupling reaction of thiosugar, 1,4-
dideoxy-1,4-epithio-D
-arabinitol (9) with cyclic sulfate (10)10c
(Scheme 1). As the first attempt, acid catalyzed hydrolysis of 4–8
was conducted. Thus, a synthesized authentic sample of 4 was
treated with 5% methanolic hydrogen chloride at 50 °C to give
the desired degradation product (8, X = CH3OSO3). The 13C NMR
spectrum showed a peak at dc 55.1 corresponding to CH3OSOꢁ as
zyl-1,4-dideoxy-1,4-epithio-D-arabinitol (12) in the presence of
3
the counter anion, which was exchanged to the chloride (8,
tetrafluoroboric acid dimethyl ether complex. The crude product
X = Cl) by the treatment with IRA 400J (Clꢁ form). The exchange
was then treated with IRA 400J (Clꢁ form) to provide the sulfonium

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
2017
δ
C 49.0
δ
O
C 33.1
O
O
O
O
S
O
O
BnO
O
O
+
O
O
OH
b
δ
C 44.2
11
OBn
BnO
TfO-
BnO
OH
a
12
S
OR
BnO
δ
C 51.2
OH
OH
NOE
X-
OBn
14 : R = H
15 : R = Tf
a
Cl-
H2C
H
S+
OH
OH OH
S+
OH
16
c
HO
BnO
c,d,e
Cl-
δ
C 48.6
δ
C 65.0
S+
OH
HO
OBn
BnO
OH
OH
HO
13
neosalaprinol (8)
X = BF4
X = Cl
OH
3'-epi-7
HO
b
Scheme 2. Reagents and conditions: (a) HBF4ꢂ(CH3)2O, CH2Cl2, ꢁ45 °C–rt; K2CO3,
HFIP, 65–70 °C; (b) IRA 400J (Clꢁ form), CH3OH, rt; (c) H2, 10% Pd-C, 80% AcOH,
50 °C.
Scheme 3. Reagents and conditions: (a) Tf2O, 2,6-lutidine, ꢁ20–0 °C; (b) thiosugar
12, THF, 40 °C; (c) H2, 10% Pd-C, 30% aq TFA, 1,4-dioxane, 50 °C; (d) IRA 400J (Clꢁ
form), CH3OH, rt; (e) NaBH4, H2O, 0 °C.
chloride, 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-{(R)-[(2S)-2,3-dihydr-
oxypropyl]episulfoniumylidene}-D-arabinitol chloride (13) in 44%
yield. Its FAB mass spectrum run in a positive ion mode showed
a peak at m/z 495 corresponding to the desired sulfonium cation
moiety. As shown in Scheme 2, observed low field shift of 13C
flate of glucopyranoside, benzyl 2,3,4-tri-O-benzyl-6-O-trifluoro-
methanesulfonyl-b-
coupling partner with thiosugar (12).16 Thus, benzyl 2,3,4-tri-O-
benzyl-b- -glucose, was
-glucopyranoside17 (17), derived from
D-glucopyranoside (18) was employed as a
D
D
treated with Tf2O in dichloromethane in the presence of 2,6-luti-
dine to give 18 in 91% yield. The coupling reaction of triflate (18)
with thiosugar (12) completed in 7 h at 40 °C, to give the desired
sulfonium salt, 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-[(S)-(1,2,3,4-
NMR signals due to
a carbons to the sulfur supported the sulfo-
nium salt formation. The absolute stereochemistry at the stereo-
genic sulfur center was determined by means of nuclear
Overhauser effect (NOE) experiments, which showed H-4 to H-10
correlations, implying that these atoms are syn-facial with respect
to the sulfonium ring as shown in Scheme 2. Hydrogenolysis of sul-
fonium chloride (13) thus obtained was carried out over 10% Pd-C
at 60 °C in 80% acetic acid to give 8 in 85% yield (Scheme 2).
tetra-O-benzyl-6-deoxy-b-D-glucopyranos-6-yl)episulfoniumylid-
ene]- -arabinitol trifluoromethanesulfonate (19), in 64% yield. The
D
sulfonium salt 19 was then converted to 7 in 45% overall yields via
3 steps in a similar manner described above for the preparation of
30-epi-7 (Scheme 4).
2.3. Synthesis of 30-epi-Neoponkolanol (30-epi-7)
2.5. Characteristic cyclization of mannose derivative leading to
3,6-anhydromannopyranoside
Syntheses of 7 and its 50-epimer (50-epi-7) have been reported
very recently by Eskandari et al.11h They commented that 50-epi-
7 was more active than 7 itself, and that the compound (50-epi-7)
was the most active inhibitor to date in this class of molecules.
As 30-epimer of ponkoranol (7) had been found also active against
The protocol was also applied for the synthesis of 50-epimer (50-
epi-7) of 7. Thus, benzyl 2,3,4-tri-O-benzyl-
side18 (20) was converted to its triflate, benzyl 2,3,4-tri-O-ben-
zyl-6-O-trifluoromethanesulfonyl- -mannopyranoside (21), in
a-D-mannopyrano-
a-D
a
-glucosidases,10b 30-epimer of 7 (30-epi-7) was synthesized and
80% yield. The first trial of the coupling reaction performed at
40 °C resulted in a complex mixture, in which no formation of
the desired sulfonium salt, 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-
evaluated in the present study. Thus, commercially available
1,2:3,4-di-O-isopropylidene- -galactopyranose (14) was treated
a-D
with trifluoromethanesulfonic anhydride (Tf2O) in dichlorometh-
ane in the presence of 2,6-lutidine to give 1,2:3,4-di-O-isopropyli-
dene-6-O-trifluoromethanesulfonyl-a-D-galactopyranose (15) in
OBn
OBn
94% yield. The triflate (15) was then treated with thiosugar (12)
in THF at 40 °C for 15 h to give the desired coupled product,
2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-[(S)-(1,2:3,4-di-O-isopropyl-
OBn
O
OBn
OBn
b
TfO-
O
OBn
idene-6-deoxy-a-D-galactopyranos-6-yl)episulfoniumylidene]-D-
S+
OBn
arabinitol trifluoromethanesulfonate (16) in 76% yield. The FAB
mass spectrum run in a positive ion mode showed a peak at
m/z 663 due to the sulfonium cation moiety, while in a negative
ion mode, a peak due to the TfOꢁ ion was observed at m/z 149.
The sulfonium salt 16 was then converted to 30-epi-7 by hydrog-
enolysis over Pd-C, followed by the treatment with IRA 400J (Clꢁ
form) and finally by NaBH4 reduction in 50% overall yields from
16. The positive ion FAB mass spectrum showed a peak at m/z
315 corresponding to the desired sulfonium moiety of 30-epi-7
(Scheme 3).
BnO
OR OBn
BnO
OBn
19
17 : R = H
18 : R = Tf
a
OH OH
c,d,e
HO
Cl-
OH
S+
OH
OH
OH
HO
7
2.4. Synthesis of Neoponkoranol (7)
Scheme 4. Reagents and conditions: (a) Tf2O, 2,6-lutidine, ꢁ20–0 °C; (b) thiosugar
12, THF, 40 °C; (c) H2, 10% Pd-C, 80% aq AcOH, 60 °C; (d) IRA 400J (Clꢁ form), CH3OH,
rt; (e) NaBH4, H2O, 0 °C.
Neoponkoranol (7) was also synthesized in order to evaluate
simultaneously with other specimens. In the present study, a tri-

2018
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
OBn
OBn
H6a
OBn
OBn
H6b
Ph
O
TfO-
BnO
OBn
OBn
H1
O
O
S+
b
5
TfO-
BnO
+
1
+
BnO
OBn
OBn
O
S+
OBn
4
3
2
BnO
c,d,e
OR OBn
20 : R = H
OBn
OBn
a
23
24
OBn
22
21 : R = Tf
COSY
HMBC
NOE
OH OH
OH
Cl-
S+
OH
OH
HO
OH
5'-epi-7
HO
Scheme 5. Reagents and conditions: (a) Tf2O, 2,6-lutidine, ꢁ20–0 °C; (b) thiosugar 12, THF, 40 °C; (c) H2, Pd-C, 80% aq AcOH, 60 °C; (d) IRA 400J (Cl– form), CH3OH, rt; (e)
NaBH4, H2O, 0 °C.
Table 1
[(S)-(1,2,3,4-tetra-O-benzyl-6-deoxy-
a-D-mannopyranos-6-yl)-
IC50 Values (lM) of thiosugar sulfonium salts and related compounds against
disaccharidases
episulfoniumylidene]- -arabinitol trifluoromethanesulfonate (22)
was detected. At 0 °C, the desired sulfonium salt (22) was obtained
in 37% yield accompanied by two side products, benzyl 2,4-di-O-
D
Compound
Maltase
Sucrase
Isomaltase
benzyl-3,6-anhydro-
1,4-[(R)-benzylepisulfoniumylidene]-
a
-
D
-mannopyranoside (23) and 1,4-dideoxy-
-arabinitol trifluorometh-
Salacinol (1)
Neosalacinol (5)
Kotalanol (2)
Neokotalanol (6)
5.2a
1.6a /1.5b
1.3a
1.3a /1.5b
0.3a
D
8.0a
7.2a
0.75a
4.5a
5.7a
anesulfonate (24) in 40% and 48% yield, respectively. At ꢁ20 °C,
no progress of the reaction could be observed, and the starting
materials were recovered. The FAB mass spectrum of 23 showed
a peak at m/z 455 corresponding to the sodium adduct ion to the
molecule, which lost one benzyl moiety from the reactant (20).
Its NMR spectra showed signals at dc 100.9 and dH 5.06 character-
istic of the acetal moiety. A NOE correlation between H-6b and
H-1 as well as HMBC correlations between positions 3 and 6, and
also those between positions 5 and 1, well supported the depicted
structure 23. On the other hand, FAB mass spectrum of 24 in the
positive ion mode showed a peak at m/z 511, which indicated
the introduction of one more benzyl moiety to the reactant (12).
The negative-ion FAB mass spectrum showed a peak at m/z 149
corresponded to the triflate anion moiety (Scheme 5). The
formation of 23 and 24 was ascribable to an intramolecular cycli-
zation19 arising from an attack of 12 to the methylene carbon at
the C3-benzyloxy moiety as shown in Scheme 6. Finally, the sulfo-
nium salt 22 was transformed into the target compound (50-epi-7)
in a similar manner used for the preparation of 7 in 42% yield from
22.
4.8a
1.8a
15
6.5
Salaprinol (4)
>329(23)c
>329(42)c
90
c
Neosalaprinol (8)
20-epi-salaprinol (20-epi-4)
20-epi-neosalaprinol (20-epi-8)
Ponkoranol (3)
Neoponkoranol (7)
50-epi-neoponkoranol (50-epi-7)
30-epi-neoponkoranol (30-epi-7)
Voglibose
>384(35)
>329(12.6)
105
>329(0.5)c
>384(34.5)c
0.29a
1.0
>329(18.4)c
52.9
2.6a
c
3.2a
5.1
4.3
1.4
1.0
2.9
1.3
0.3
1.0
1.2a
0.2a
2.1a
Acarbose
2.0a
1.7a
155a
a
Lit. 9.
b
Inhibitory activities of 1 against sucrase and isomaltase were re-examined in
this study as references.
Values in parentheses indicate inhibition (%) at the corresponding concentra-
tions (lM).
c
salts (7) showed potent inhibitory activity against three enzymes
tested, while the other (8) inhibited both sucrase and isomaltase
more effectively than its sulfate (4). It is interesting to note that
upon de-O-sulfonation, all the resulting sulfonium salts (5, 6, 7,
8, and 20-epi-8) showed improved inhibitory activities against iso-
maltase. Even 20-episalaprinol (20-epi-4), which lost its characteris-
tic selectivity against isomaltase upon 20-epimerization, was
activated moderately against the enzyme.
2.6. a-Glucosidase inhibitory activities of sulfonium salts
Inhibitory activities of these six compounds synthesized (20-epi-
4, 7, 30-epi-7, 50-epi-7, 8 and 20-epi-8) were tested for rat small
Although 20-epimerization caused drastic decrease in its inhib-
itory activity against isomaltase, the configuration of the chiral
center at C03 and/or C05 positions showed no significant influence
intestinal
a-glucosidases in vitro, and compared with those of
other sulfoniums (1–6) or clinically used antidiabetics, voglibose
and acarbose (Table 1). One of the two newly isolated sulfonium
OBn
OBn
S
Ph
TfO
OTf
OBn
O
OBn
OBn
O
1
5
O
12
+
24
23
OBn
BnO
BnO
3
OBn
OBn
21
Scheme 6. Plausible mechanism for formation of 23 and 24.

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
2019
on the inhibitory activity. Thus, in ponkoranol series, all the four
compounds (3, 7, 30-epi-7, and 50-epi-7) showed potent inhibitory
activities irrespective of existence of the sulfate moiety at C30 and
also of stereochemistry at 30 and/or 50. Of the four, 30-epi-7 was
most potent, and showed almost the same inhibitory abilities as
voglibose against all enzymes. Thus, we comment 30-epi-7 is the
most potent inhibitor in this class of molecules to date.
which were in accord with those of an authentic specimen synthe-
sized alternatively. The fraction 5 (0.28 g) was purified by HPLC
[detection: RI, column: Daisopak-SP-120-5-ODS-BP (20 mm
id ꢀ 250 mm), mobile phase: H2O and 0.1% (v/v) aqueous AcOH]
to give neoponkoranol (7, 10.1 mg), the 1H and 13C NMR spectral
properties of which were in accord with those of an authentic spec-
imen synthesized alternatively.
4.3. Synthesis of 1,4-dideoxy-1,4-{(R)-[(2S)-2,3-dihydro- xypro-
3. Conclusions
pyl]episulfoniumylidene}-D-arabinitol Chloride (Neosalaprinol
8) and its 20-epimer (20-epi-8)
In conclusion, by intensive exploratory studies on Salacia ex-
tracts, two prognosticated constituents, neoponkoranol (7) and
neosalaprinol (8), have been isolated. The structures of 7 and 8
were unambiguously identified by comparison of their physical
and spectral data with those reported or with authentic specimens
alternatively synthesized. Thus, all the predicted or speculated
neo-type members of the sulfonium salt so far were finally ex-
tracted out successively. One of the two newly isolated sulfonium
salts (7) showed potent inhibitory activity against three enzymes,
and its 30-epimer (30-epi-7) was found to be the most potent inhib-
4.3.1. Acidic methanolysis of salaprinol (4) and 20-epimer of
salaprinol (20-epi-4)
A mixture of salaprinol10c (4, 2 mg, 0.0066 mmol) and 5% meth-
anolic hydrogen chloride (1 mL) was stirred at 50 °C for 2 h. The
mixture was condensed to give a colorless oil (2.1 mg), which
was then treated with ion exchange resin IRA 400J (Clꢁ form,
20 mg) in methanol (1 mL) at room temperature for 1 h. The resins
were filtered off and washed with methanol. The combined filtrate
and the washings were condensed to give neosalaprinol (8) as a
colorless oil (1.5 mg, 87%), ½a D25
ꢃ
+18.0 (c 0.1, CH3OH). IR (neat):
itor against rat small intestinal a-glucosidases so far in this class of
molecules. Epimerization at C02-position resulted in losing com-
pletely the activity even against isomaltase. Further SAR studies
3302, 1072, 1063, 1020 cmꢁ1
.
1H NMR (700 MHz, CD3OD) d: 3.57
(1H, dd, J = 11.4, 5.8, H-30a), 3.64 (1H, dd, J = 11.4, 4.6, H-30b),
3.65 (1H, dd, J = 13.0, 8.9, H-10a), 3.75 (1H, dd, J = 13.0, 3.2, H-
10b), 3.84 (1H, dd, J = 12.8, 3.4, H-1a), 3.87 (1H, dd, J = 12.8, 1.8,
H-1b), 3.93 (1H, dd, J = 11.1, 9.2, H-5a), 4.01 (1H, br s dd, J = ca.
9.2, 5.4, H-4), 4.04 (1H, dd, J = 11.1, 5.4, H-5b), 4.11 (1H, dddd,
J = 8.9, 5.8, 4.6, 3.2, H-20), 4.37 (1H, dd, J = ca. 1.5, 1.5, H-3), 4.62
(1H, ddd, J = ca. 3.4, 1.8, 1.5, H-2), 13C NMR (175 MHz, CD3OD) d:
51.5 (C-10), 52.0 (C-1), 61.0 (C-5), 65.6 (C-30), 69.6 (C-20), 73.7(C-
4), 79.5(C-2), 79.6 (C-3). FABMS m/z: 225 [MꢁClꢁ]+ (pos). FAB-
HRMS m/z: 225.0758 (C8H17O5S requires 225.0796).
on this series of compounds for the stronger a-glucosidase inhibi-
tory activity and selectivity to glucosidases are in progress.
4. Experimental
4.1. General experimental procedures
IR spectra were measured on either a Shimadzu IR-435 grating
spectrophotometer or a Shimadzu FTIR-8600PC spectrophotome-
In a similar manner, 20-epimer of salaprinol10c (20-epi-4, 2 mg,
0.0066 mmol) was derived to the corresponding sulfonium chlo-
ter. 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 (700 MHz 1H, 175 MHz 13C)
spectrometers. Chemical shifts (d) and coupling constants (J) are
given in ppm and Hz, respectively. DSS was used as an internal
standard in the measurement of NMR spectra in D2O, and TMS
was used otherwise mentioned. Low-resolution and high-resolu-
tion mass spectra were recorded on a JEOL JMS-HX 100 spectrom-
eter. Optical rotations 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 sodium sulfate prior to evaporation.
ride (20-epi-8, 1.6 mg, 88%) as a colorless oil, ½a 2D3
ꢁ11.4 (c 0.83,
ꢃ
CH3OH). IR (neat): 3385, 1641, 1456, 1417, 1258, 1067, 1047
cmꢁ1 1H NMR (700 MHz, CD3OD) d: 3.58 (1H, dd, J = 11.4, 5.8,
.
H-30a), 3.64 (1H, dd, J = 11.4, 4.6, H-30b), 3.70 (1H, dd, J = 13.0,
7.4, H-10a), 3.72 (1H, dd, J = 13.0, 4.4, H-10b), 3.82 (1H, dd, J = ca.
12.8, 2.5, H-1a), 3.85 (1H, dd, J = ca. 12.8, 3.0, H-1b), 3.95 (1H, dd,
J = 11.6, 9.0, H-5a), 4.04 (1H, dd, J = 11.6, 5.8, H-5b), 4.07–4.10
(1H, m, H-4), 4.08–4.13 (1H, m, H-20), 4.40 (1H, dd, J = ca. 2.5, 1.5,
H-3), 4.62 (1H, ddd, J = ca. 3.0, 2.5, 2.5, H-2). 13C NMR (175 MHz,
CD3OD) d: 50.8 (C-1), 50.9 (C-10), 61.1 (C-5), 65.5 (C-30), 69.4
(C-20), 73.5 (C-4), 79.4 (C-2), 79.8 (C-3). FABMS m/z: 225 [M–Cl-]+
(pos). FAB-HRMS m/z: 225.0759 (C8H17O5S requires 225.0796).
4.2. Isolation of Neoponkoranol (7) and Neosalaprinol (8)
Dried stems of S. chinensis (15.0 kg) originated from Thailand
were extracted twice with water (150 L) under reflux for 2 h. Evap-
oration of the water under reduced pressure provided a extract
(1.48 kg), which (1.00 kg) was then dissolved in water (10 L) and
centrifuged at 3000 rpm for 10 min. The supernatant was sub-
jected to Diaion HP-20 column chromatography (4.0 kg,
H2O ? MeOH, twice) to give a water-eluted fraction (405.6 g)
and a methanol-eluted fraction (197.8 g). An aliquot of the H2O-
eluted fraction (25.0 g) was dissolved in MeCN/H2O (50:50, v/v,
500 mL) and centrifuged at 3000 rpm for 10 min, then the superna-
tant was subjected to column chromatography [Chromatorex NH,
2.0 kg, MeCN/H2O (50:50 ? 20:80, v/v) ? H2O] to give eight frac-
tions [Fr. 1 (5.91 g), Fr. 2 (2.84 g), Fr. 3 (0.88 g), Fr. 4 (0.90 g), Fr.
5 (0.29 g), Fr. 6 (1.22 g), Fr. 7 (0.68 g), and Fr. 8 (6.28 g)]. The frac-
tion 2 (0.80 g) was purified by HPLC [detection: RI, column: Dais-
opak-SP-120–5-ODS-BP (20 mm id ꢀ 250 mm), mobile phase:
H2O and 0.1% (v/v) aqueous AcOH] to give neosalaprinol (8,
1.7 mg, 0.00096%), the 1H and 13C NMR spectral properties of
4.3.2. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-{(R)-[(2S)-2,3-dihy-
droxypropyl]episulfoniumylidene}-D-arabinitol chloride (13)
To a solution of (S)-glycidol (11, 35 mg, 0.47 mmol) and thio-
sugar (12, 100 mg, 0.24 mmol) in dichloromethane (2 mL) was
added tetrafluoroboric acid dimethyl ether complex (64 lL,
0.53 mmol), and the mixture was stirred at ꢁ45 °C for 2 h, and then
at room temperature for another 14 h. The reaction mixture was
condensed under reduced pressure to give
a colorless oil
(195 mg), which was used in the next step without purification.
The oil (190 mg) was treated with IRA 400J (Clꢁ form, 2.10 g) in
methanol (7 mL) at room temperature for 1 h. The resins were fil-
tered off and washed with methanol. The combined filtrate and the
washings were condensed to give a colorless oil (170 mg), which
on column chromatography (CHCl3 ? CHCl3/MeOH, 50/1 ? 20/
1 ? 10/1) gave title compound (13) as a colorless oil (56.0 mg,
44%), ½a 2D3
ꢃ
+14.8 (c 0.65, CHCl3). IR (neat): 3312, 1497, 1456,
1398, 1364, 1094, 1072 cmꢁ1
.
1H NMR (700 MHz, CDCl3) d: 1.98
(1H, br s, OH), 3.73 (1H, dd, J = 12.0, 3.2, H-30a), 3.78 (1H, dd,

2020
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
J = 10.0, 7.2, H-5a), 3.83 (1H, dd, J = 10.0, 6.4, H-5b), 3.84 (1H, dd,
J = 12.0, 5.2, H-30b), 3.90 (1H, br d, J = ca. 12.4, H-10a), 3.97 (1H,
br dd, J = ca. 13.2, 2.0, H-1a), 4.11 (1H, br d, J = ca. 12.4, H-10b),
4.23 (1H, br d, J = ca. 13.2, H-1b), 4.27 (1H, br s, H-3), 4.27–4.31
(1H, br m, H-20), 4.31–4.36 (1H, br m, H-4), 4.40/4.50 (each 1H, d,
J = 11.6, PhCH2), 4.45–4.47 (1H, br m, H-2), 4.48/4.57 (each 1H, d,
J = 12.0, PhCH2), 4.57/4.62 (each 1H, d, J = 12.0, PhCH2), 5.97 (1H,
br, OH), 7.13–7.35 (15H, m, arom.). 13C NMR (175 MHz, CDCl3) d:
48.6 (C-1), 51.2 (C-10), 64.2 (C-30), 65.0 (C-4), 67.0 (C-5), 68.7 (C-
20), 71.9/72.3/73.6 (PhCH2), 82.4 (C-2), 82.6 (C-3), 127.96/127.98/
128.1/128.3/128.4/128.5/128.6/128.7/128.8 (d, arom.), 135.9/
136.1/136.9 (s, arom.). FABMS m/z: 495 [MꢁClꢁ]+ (pos.).
3.78 (1H, dd, J = 13.4, 9.0, H-60a), 3.82 (1H, dd, J = 13.4, 2.6, H-1b),
3.86 (1H, dd, J = 10.0, 8.3, H-5a), 3.94 (1H, dd, J = 10.0, 6.6, H-5b),
4.14 (1H, dd, J = 13.4, 3.0, H-60b), 4.31 (1H, dd, J = 5.0, 2.6, H-20),
4.32–4.35 (1H, m, H-4), 4.34 (1H, dd, J = 7.8, 1.8, H-40), 4.38 (1H,
ddd, J = 9.0, 3.0, 1.8, H-50), 4.43/4.45 (each 1H, d, J = 11.8, PhCH2),
4.44 (1H, m, H-3), 4.50–4.52 (1H, m, H-2), 4.51/4.63 (each 1H, d,
J = 11.8, PhCH2), 4.62 (1H, dd, J = 7.8, 2.6, H-30), 4.55/4.58 (each
1H, d, J = 11.8, PhCH2), 5.42 (1H, d, J = 5.0, H-10), 7.16–7.34 (15H,
m, arom.). 13C NMR (175 MHz, CDCl3) d: 24.1/24.8/25.77/25.83
[CH3]2C], 47.4 (C-60), 48.6 (C-1), 64.7 (C-4), 65.3 (C-50), 66.9 (C-5),
70.3 (C-20), 70.6 (C-30), 71.1 (C-40), 72.2/72.3/73.6 (PhCH2), 82.4
(C-3), 83.3 (C-2), 96.1 (C-10), 109.6/109.8 [(CH3)2C], 120.7 (q,
J = 319,
CF3SOꢁ),
127.96/128.06/128.3/128.45/128.49/128.52/
3
4.3.3. Hydrogenolysis of 13 (Neosalaprinol 8)
128.7(2xC)/128.72 (d, arom.), 135.9/136.1/137.0 (s, arom.). FABMS
A suspension of 10% Pd-C (50 mg) in 80% aqueous acetic acid
(1.0 mL) was pre-equilibrated with hydrogen. To the suspension
was added a solution of sulfonium salt (13, 35.0 mg, 0.066 mmol)
in 80% aqueous acetic acid (1.0 mL), and the mixture was hydroge-
nated at 60 °C under atmospheric pressure for 6 h until uptake of
hydrogen ceased. The catalysts were filtered off and washed with
methanol. The combined filtrate and the washings were evapo-
rated, and co-evaporated with benzene to give a colorless oil
(16.5 mg), which on column chromatography (AcOEt/MeOH,
10:1 ? AcOEt/MeOH/H2O, 20:4:1 ? 10:4:1) gave title compound
(8) as a colorless oil (14.6 mg, 85%), the 1H and 13C NMR spectro-
scopic properties of which were in accord with those of a specimen
synthesized by acidic methanolysis of 4.
m/z: 663 [M–CF3SO3ꢁ]+ (pos.), 149 [CF3SO3]ꢁ (neg.)
4.4.3. 1,4-Dideoxy-1,4-{(R)-[(2S,3R,4R,5S)-2,3,4,5,6-pentahydroxy-
hexyl]episulfoniumylidene}-D
-arabinitol chloride (30-epi-7)
A suspension of 10% Pd-C (600 mg) in 30% aqueous TFA solution
(15 mL) was pre-equilibrated with hydrogen. To the suspension
was added a mixture of compound 16 (340 mg, 0.42 mmol), TFA
(5 mL) and 1,4-dioxane (10 mL). The resulted mixture was hydro-
genated at 50 °C under atmospheric pressure until uptake of
hydrogen ceased. The catalyst was filtered off and washed with a
mixture of methanol and water. After the combined filtrate and
the washings were condensed under reduced pressure, the residue
(245 mg) was washed with dichloromethane to give a colorless oil
(230 mg), which was treated with IRA 400J (Clꢁ form, 2.5 g) in
methanol (3 mL) at room temperature for 3 h. The resins were fil-
tered off and washed with methanol. The filtrate and the washings
were combined and condensed under reduced pressure to give a
colorless oil (200 mg), which was treated with NaBH4 (130 mg,
3.4 mmol) in water (15 mL) at 0 °C for 20 min. The mixture was
acidified with 2 M hydrochloric acid to pH ca. 4, and condensed un-
der reduced pressure to give a white solid (320 mg), which on col-
umn chromatography (CHCl3/MeOH, 10:1 ? 4:1) gave title
compound (30-epi-7) as colorless amorphous (74.0 mg, 50% yield
4.4. Syntheses of Neoponkoranol (7) and its 30- and 50-epimers
4.4.1. 1,2:3,4-Di-O-isopropylidene-6-O-trifluoromethane-
sulfonyl-a-D-galactopyranose (15)
Under argon atmosphere, to a solution of 2,6-lutidine (1.1 mL,
4.5 mmol) in dry dichloromethane (35 mL) was added trifluoro-
methanesulfonic anhydride (Tf2O, 1.8 mL, 4.5 mmol) at ꢁ20 °C.
After 5 min, a solution of 1,2:3,4-di-O-isopropylidene-a-D-galacto-
pyranose (14, 780 mg, 3.0 mmol) in dichloromethane (40 mL) was
added dropwise to the solution at ꢁ20 °C. The resulting solution
was stirred at ꢁ20 °C for 5 min, and then at 0 °C for another
30 min. The mixture was poured into ice-cooled water and ex-
tracted with dichloromethane. The extract was condensed under
reduced pressure to give a pale yellow oil (1.9 g), which on column
chromatography (n-hexane/AcOEt, 20:1) gave title compound (15)
from 16), ½a 2D5
ꢁ38.6 (c 1.13, CH3OH). IR (neat): 3383, 1669,
ꢃ
1418, 1317, 1204, 1140, 1074, 1046, 1030, 843, 802, 723, 666 cmꢁ1
.
1H NMR (700 MHz, D2O) d: 3.66–3.70 (2H, m, H-30 and H-40),
3.69 (2H, d, J = ca. 6.4, H-60a and H-60b), 3.79 (1H, dd, J = 13.5,
3.0, H-10a), 3.89 (1H, dd, J = 13.5, 9.4, H-10b), 3.90 (1H, dd,
J = 13.3, 4.0, H-1a), 3.92 (1H, dd, J = 13.3, 3.2, H-1b), 3.960 (1H,
td, J = 6.4, 0.8, H-50), 3.962 (1H, dd, J = 12.5, 9.4, H-5a), 4.09 (1H,
ddd, J = 9.4, 5.0, 3.2, H-4), 4.15 (1H, dd, J = 12.5, 5.0, H-5b), 4.45
(1H, dd, J = 3.2, 3.2, H-3), 4.48 (1H, ddd, J = 9.4, 3.0, 1.0, H-20),
4.76 (1H, ddd, J = ca. 4.0, 3.2, 3.2, H-2). 13C NMR (175 MHz, D2O)
d: 50.7 (C-1), 53.2 (C-10), 61.9 (C-5), 65.7 (C-60), 68.8 (C-20), 72.0
(C-40), 72.3 (C-4), 72.5 (C-50), 73.6 (C-30), 79.5 (C-2), 80.1 (C-3). FAB-
MS m/z: 315 [MꢁClꢁ]+ (pos). FAB-HRMS m/z: 315.1129 (C11H23O8S
requires 315.1114).
as a colorless oil (1.10 g, 94%), ½a D25
ꢃ
ꢁ44.6 (c 1.8, CHCl3). IR (neat):
1416, 1385, 1250, 1211, 1150, 1119, 1073, 1015 cmꢁ1
.
1H NMR
(500 MHz, CDCl3) d: 1.337/1.343/1.45/1.53 [each 3H, s, (CH3)2C],
4.11 (1H, ddd, J = 7.2, 4.7, 2.0, H-5), 4.25 (1H, dd, J = 8.0, 2.0, H-4),
4.36 (1H, dd, J = 5.0, 2.6, H-2), 4.58 (1H, dd, J = 10.5, 7.2, H-6a),
4.64 (1H, dd, J = 10.5, 4.7, H-6b), 4.66 (1H, dd, J = 8.0, 2.6, H-3),
5.54 (1H, d, J = 5.0, H-1). 13C NMR (125 MHz, CDCl3) d: 24.4/24.8/
25.8/25.9 [(CH3)2C], 66.0 (C-5), 70.2 (C-2), 70.4 (C-4), 70.6 (C-3),
74.6 (C-6), 96.1 (C-1), 109.1/110.1 [(CH3)2C], 118.6 (q, J = 318,
CF3SO3-). FABMS m/z: 393 [M+H]+ (pos).
4.4.4. Benzyl 2,3,4-tri-O-benzyl-6-O-trifluoromethanesulfonyl-
b-D
-glucopyranoside (18)
4.4.2. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-[(S)-(1,2:3,4-di-O-iso-
In a manner similar to that used for the synthesis of triflate (15:
propylidene-6-deoxy-
a-
D-galactopyranos-6-yl)episulfoniumyl-
4.4.1.), benzyl 2,3,4-tri-O-benzyl-b-D
-glucopyranoside17 (17,
idene]- -arabinitol trifluoromethanesulfonate (16)
D
250 mg, 0.46 mmol) was derived to the corresponding triflate
Under argon atmosphere, a mixture of triflate (15, 1.0 g,
2.55 mmol), thiosugar (12, 710 mg, 1.69 mmol), and THF (10 mL)
was stirred at 40 °C for 15 h. The reaction mixture was condensed
under reduced pressure to give a pale yellow oil (1.7 g), which on
column chromatography (CHCl3/MeOH, 200:1) gave title com-
(18, 282 mg, 91%) as a colorless oil, ½a D24
ꢃ
+11.0 (c 1.13, CHCl3). IR
(neat): 1456, 1377, 1308, 1213, 1148, 1073, 963 cmꢁ1
.
1H NMR
(700 MHz, CDCl3) d: 3.44 (1H, dd, J = 10.0, 9.0, H-4), 3.52 (1H, dd,
J = 9.0, 7.6, H-2), 3.56 (1H, ddd, J = 10.0, 6.2, 2.0, H-5), 3.67 (1H,
dd, J = 9.0, 9.0, H-3), 4.41 (1H, dd, J = 10.6, 6.2, H-6a), 4.52 (1H, d,
J = 7.6, H-1), 4.56/4.71 (each 1H, d, J = 11.0, PhCH2), 4.58 (1H, dd,
J = 10.6, 2.0, H-6b), 4.66/4.92 (each 1H, d, J = 11.7, PhCH2), 4.77/
4.952 (each 1H, d, J = 11.0, PhCH2), 4.89/4.956 (each 1H, d,
J = 11.0, PhCH2), 7.23–7.37 (20H, m, arom.). 13C NMR (175 MHz,
pound (16) as a colorless oil (1.05 g, 76%), ½a D25
ꢁ71.2 (c 1.96,
ꢃ
CHCl3). IR (neat): 1454, 1385, 1262, 1215, 1157, 1069, 1030,
.
1003 cmꢁ1 1H NMR (700 MHz, CDCl3) d: 1.31 [6H, s, (CH3)2C],
1.35/1.56 [each 3H, s, (CH3)2C], 3.77 (1H, dd, J = 13.4, 4.2, H-1a),

W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
2021
CDCl3) d: 71.1 (PhCH2), 72.3 (C-5), 74.7 (C-6), 74.9/75.0/75.7
(PhCH2), 76.3 (C-4), 82.0 (C-2), 84.4 (C-3), 102.0 (C-1), 118.6 (q,
J = 317, CF3SO3), 127.8/127.9/128.0/128.1/128.16/128.23/128.3/
128.39(2xC)/ 128.44/128.5/128.7 (d, arom.), 136.9/137.2/138.12/
138.16 (s, arom.). FABMS m/z: 695 [M+Na]+ (pos.).
11.6, PhCH2), 4.58/4.97 (each 1H, d, J = 11.0, PhCH2), 4.60 (1H, d,
J = ca. 11.6, H-6a), 4.62 (1H, d, J = ca. 11.6, H-6b), 4.648/4.70 (each
1H, d, J = 12.4, PhCH2), 4.91, (1H, d, J = 1.8, H-1), 7.37–7.24 (20H, m,
arom.). 13C NMR (175 MHz, CDCl3) d: 69.4/72.7/75.2/75.4 (PhCH2),
70.0 (C-5), 72.1 (C-6), 73.6 (C-4), 74.3 (C-2), 80.0 (C-3), 97.0 (C-1),
118.6 (q, J = 319, CF3SOꢁ), 127.6/127.7(3xC)/127.8/127.9/128.0/
3
4.4.5. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-[(S)-(1,2,3,4-tetra-O-
128.1/128.36/128.41/128.5/128.6 (d, arom.) 136.8/137.7/137.9/
benzyl-6-deoxy-b-
-arabinitol trifluoromethanesulfonate (19)
Under argon atmosphere, a mixture of triflate (18, 230 mg,
D
-glucopyranos-6-yl)episulfoniumylidene]-
138.0 (s, arom.). FABMS m/z: 695 [M + Na]+ (pos.).
D
4.4.8. 2,3,5-Tri-O-benzyl-1,4-dideoxy-1,4-[(S)-(1,2,3,4-tetra-O-
0.34 mmol), thiosugar (12, 95 mg, 0.23 mmol) and THF (0.5 mL)
was stirred at 40 °C for 7 h. The reaction mixture was condensed
under reduced pressure to give a pale yellow oil (325 mg), which
on column chromatography (CHCl3/MeOH, 200:1) gave title com-
benzyl-6-deoxy-a-D-mannopyranos-6-yl)episulfoniumyli-
dene]- -arabinitol Trifluoromethanesulfonate (22)
D
Under argon atmosphere, a mixture of triflate (21, 900 mg,
1.34 mmol), thiosugar (12, 370 mg, 0.88 mmol) and THF (2 mL)
was stirred at 0 °C for 17 h. The reaction mixture was condensed
under reduced pressure to give a pale yellow oil (1.25 g), which
on column chromatography (CHCl3/MeOH, 200:1) gave title com-
pound (22, 364 mg, 37% from 12), benzyl 2,4-di-O-benzyl-3,6-
pound (19) as a colorless oil (161 mg, 64%), ½a D24
ꢃ
+9.9 (c 1.63,
CHCl3). IR (neat): 1589, 1497, 1454, 1362, 1250, 1223, 1153,
1100, 1030 cmꢁ1 1H NMR (700 MHz, CDCl3) d: 3.364 (1H, dd,
.
J = 8.8, 8.8, H-40), 3.366 (1H, dd, J = 8.8, 7.8, H-20), 3.43 (1H, dd,
J = 13.0, 7.2, H-60a), 3.61–3.64 (1H, m, H-1a), 3.636 (1H, dd,
J = 8.8, 8.8, H-30), 3.642 (1H, dd, J = 10.4, 8.8, H-5a), 3.69–3.73
(1H, m, H-1b), 3.70 (1H, dd, J = 10.4, 6.0, H-5b), 3.75 (1H, dd,
J = 13.0, 2.8, H-60b), 3.76 (1H, ddd, J = 8.8, 7.2, 2.8, H-50), 4.04 (1H,
br dd, J = ca. 8.8, 6.0, H-4), 4.18 (1H, dd, J = ca. 1.8, 1.8, H-3), 4.42/
4.43/4.47 (each 1H, d, J = ca. 12.0, PhCH2), 4.48 (1H, d, J = 7.8, H-
10), 4.49–4.51 (1H, m, H-2), 4.49/4.50/4.56/4.58/4.63/4.64/4.772/
4.776/4.83/4.86/4.93 (each 1H, d, J = ca. 12.0, PhCH2), 7.16–7.35
anhydro-a-
D-mannopyranoside (23, 230 mg, 40% from 21), and
1,4-dideoxy-1,4-[(R)-benzylepisulfoniumylidene]-
D-arabinitol tri-
fluoromethanesulfonate (24, 283 mg, 48% from 12).
Compound 22: Colorless oil, ½a D25
ꢃ
+31.1 (c 2.04, CHCl3). IR (neat):
1454, 1366, 1262, 1154, 1111, 1073, 1030 cmꢁ1
.
1H NMR
(700 MHz, CDCl3) d: 3.50 (1H, dd, J = 13.2, 6.0, H-60a), 3.57 (1H,
dd, J = 10.2, 7.6, H-5a), 3.59 (1H, dd, J = 10.2, 7.4, H-5b), 3.62 (1H,
dd, J = 13.2, 3.4, H-60b), 3.69 (1H, dd, J = 13.2, 2.8, H-1a), 3.70 (1H,
dd, J = 13.2, 3.5, H-1b), 3.78 (1H, dd, J = 2.6, 2.1, H-20), 3.80 (1H,
dd, J = 9.4, 9.2, H-40), 3.95 (1H, ddd, J = 9.2, 6.0, 3.4, H-50), 3.96
(1H, dd, J = 9.4, 2.6, H-30), 3.98 (1H, br dd, J = ca. 7.6, 7.4, H-4),
4.23–4.25 (1H, m, H-3), 4.46–4.88 (13H, m, PhCH2), 4.58–4.60
(1H, m, H-2), 4.81 (1H, d, J = 2.1, H-10), 4.87 (1H, d, J = 11.4, PhCH2),
7.10–7.36 (35H, m, arom.). 13C-NMR (175 MHz, CDCl3) d: 47.5 (C-
60), 47.6 (C-1), 66.37 (C-5), 66.41 (C-4), 68.8 (C-50), 70.5/
72.3(2xC)/72.4/73.1/73.3 (PhCH2), 74.2 (C-40), 74.5 (C-20/PhCH2),
79.6 (C-30), 82.2 (C-3), 82.5 (C-2), 98.2 (C-10), 120.8 (q,
13
(35H, m, arom.). C NMR (175 MHz, CDCl3) d: 47.2 (C-60), 47.5
(C-1), 66.5 (C-5), 66.9 (C-4), 70.7 (C-50), 72.0/72.2/72.4/73.6/74.3/
74.8/75.7 (PhCH2), 77.5 (C-40), 81.7 (C-20), 82.3 (C-2), 82.5 (C-3),
83.9 (C-30), 103.1 (C-10), 120.8 (q, J = 318, CF3SOꢁ3 ), 127.6/127.76/
127.82/127.9/128.0/128.1/128.3(2xC)/128.37/128.44/128.49(2xC)/
128.51(2xC)/128.59(2xC)/128.68/128.73/128.79/128.82/129.1 (d,
arom.), 135.95/135.99/136.ꢁ6/137.1/137.4/ 138.0(2xC) (s, arom.).
FABMS m/z: 943 [MꢁCF3SO3 ]+ (pos).
4.4.6. 1,4-Dideoxy-1,4-{(R)-[(2S,3S,4R,5S)-2,3,4,5,6-pentahydro-
J = 318, CF3SOꢁ), 127.7/127.8(2xC)/127.92/128.04(2xC)/128.1/
xyhexyl]episulfoniumylidene}-D-arabinitol chloride (Neopon-
3
128.2/128.3(2xC)/128.4(2xC)/128.49/128.53(2xC)/128.6(2xC)/
128.7(2xC)/ 128.8/129.2 (d, arom.), 136.2/136.3/136.79/136.82/
137.6/137.8- (2xC) (s, arom.). FABMS m/z: 943 [M–CF3SOꢁ3 ]+ (pos.).
koranol 7)
Hydrogenolysis of 19 (96 mg, 0.088 mmol) was conducted by
employing 80% aqueous acetic acid (10 mL) as the solvent to give
the de-benzylated intermediate, which was derived to title com-
pound (7, 14 mg, 45% from 19) by a similar manner used for the
Compound 23: Colorless oil, ½a D25
ꢃ
+ 46.8 (c = 1.12, CHCl3). IR
(neat): 1497, 1454, 1361, 1331, 1273, 1150, 1111, 1087, 1026
cmꢁ1 1H-NMR (500 MHz, CDCl3) d: 3.76 (1H, dd, J = 6.6, 1.6, H-2),
.
synthesis of 30-epi-7 (4.4.3.) as a colorless solid, ½a 2D3
ꢃ
+4.3 (c 0.60,
H2O), lit.11h
½
a 2D3 +4.0 (c 0.50, H2O). 1H NMR (700 MHz, D2O) d:
ꢃ
3.89 (1H, dd, J = 10.6, 2.9, H-6a), 3.91 (1H, dd, J = 6.0, 2.9, H-4),
4.04 (1H, d, J = 10.6, H-6b), 4.20 (1H, dd, J = 6.0, 1.6, H-3), 4.41
(1H, dd, J = 2.9, 2.9, H-5), 4.49/4.64 (each 1H, d, J = 12.0, PhCH2),
4.57/4.72 (each 1H, d, J = 12.0, PhCH2), 4.69/4.95 (each 1H, d,
J = 12.0, PhCH2), 5.06 (1H, d, J = 6.6, H-1), 7.24–7.41 (15H, m,
arom.). 13C-NMR (125 MHz, CDCl3) d: 69.5 (C-6), 70.9/72.0/72.7
(PhCH2), 73.2 (C-5), 75.4 (C-3), 76.1 (C-2), 77.3 (C-4), 100.9 (C-1),
127.5/127.6/127.86/127.9/ 127.95/127.99/128.2/128.3/128.5 (d,
arom.), 137.3/137.7/138.3 (s, arom.). FABMS m/z: 455 [M + Na]+
(pos.).
3.51 (1H, dd, J = 11.7, 5.6, H-60a), 3.62 (1H, dd, J = 11.7, 3.6, H-
60b), 3.63 (1H, dd, J = 7.8, 1.8, H-30), 3.68 (1H, dd, J = 13.2, 9.2, H-
10a), 3.71 (1H, ddd, J = ca. 5.6, 5.6, 3.6, H-50), 3.73 (1H, dd, J = ca.
5.6, 1.8, H-40), 3.79 (1H, dd, J = 13.0, 4.0, H-1a), 3.83 (1H, dd,
J = 13.0, 3.0, H-1b), 3.850 (1H, dd, J = 11.0, 8.2, H-5a), 3.854 (1H,
dd, J = 13.2, 3.2, H-10b), 4.02 (1H, ddd, J = ca. 8.2, 4.8, 3.0, H-4),
4.04 (1H, dd, J = 11.0, 4.8, H-5b), 4.15 (1H, ddd, J = 9.2, 7.8, 3.2, H-
20), 4.36 (1H, dd, J = ca. 3.0, 3.0, H-3), 4.66 (1H, ddd, J = ca. 4.0,
13
3.0, 3.0, H-2). C NMR (175 MHz, D2O) d: 50.9 (C-1), 52.7 (C-10),
Compound 24: Colorless oil, ½a D25
ꢃ
= –1.6 (c = 1.26, CHCl3). IR
(neat): 1497, 1454, 1366, 1339, 1273, 1215, 1154, 1088, 1026
61.9 (C-5), 65.0 (C-60), 70.2 (C-20), 72.0 (C-40), 72.7 (C-4), 75.4 (C-
50), 75.8 (C-30), 79.7 (C-2), 80.3 (C-3).
cmꢁ1 1H NMR (700 MHz, CDCl3) d: 3.58 (1H, dd, J = 10.2, 10.2, H-
.
5a), 3.66 (1H, dd, J = 13.4, 3.8, H-1a), 3.67 (1H, dd, J = 10.2, 5.8, H-
5b), 3.89 (1H, br dd, J = ca. 10.2, 5.8, H-4), 4.17 (1H, dd, J = ca. 1.5,
1.5, H-3), 4.28 (1H, dd, J = 13.4, 1.4, H-1b), 4.30/4.34 (each 1H, d,
J = 11.8, PhCH2), 4.41/4.58 (each 1H, d, J = 11.8, PhCH2), 4.48–4.50
(1H, m, H-2), 4.49/4.55 (each 1H, d, J = 11.8, PhCH2), 4.63 (1H, d,
J = 12.7, H-10a), 5.04 (1H, d, J = 12.7, H-10b), 7.04–7.39 (20H, m,
4.4.7. Benzyl 2,3,4-tri-O-benzyl-6-O-trifluoromethanesulfonyl-
a
-
D
-mannopyranoside (21)
In a manner similar to that used for the synthesis of triflate (15:
4.4.1.), benzyl 2,3,4-tri-O-benzyl-
-mannopyranoside18 (20,
a-D
1.0 g, 1.8 mmol) was derived to the corresponding triflate (21,
967 mg, 80%) as a colorless oil, ½a D24
ꢃ
+43.6 (c 1.40, CHCl3). IR (neat):
13
arom.). C-NMR (175 MHz, CDCl3) d: 46.0 (C-1), 49.3 (C-10), 63.2
1454, 1416, 1246, 1208, 1146, 1115, 1030 cmꢁ1
.
1H NMR
(C-4), 66.8 (C-5), 72.0/72.6/73.4 (PhCH2), 82.1 (C-2), 83.2 (C-3),
120.7 (q, J = 320, CF3SO3-), 127.6/127.7/128.1/128.50/128.54/
128.7/128.8(2xC)/ 128.9/129.7/130.3/130.7 (d, arom.), 135.7/
(700 MHz, CDCl3) d: 3.80 (1H, dd, J = 3.1, 1.8, H-2), 3.85–3.90
(2H, m, H-4 and H-5), 3.97 (1H, dd, J = ca. 9.2, 3.1, H-3), 4.46/
4.648 (each 1H, d, J = 12.0, PhCH2), 4.57/4.59 (each 1H, d, J = ca.

2022
W. Xie et al. / Bioorg. Med. Chem. 19 (2011) 2015–2022
- +
6. (a) Koshland, D. E. Biol. Rev. 1953, 28, 416; (b) McCarter, J. D.; Withers, S. G.
Curr. Opin. Struct. Biol. 1994, 4, 885; (c) Dwek, R. A. Chem. Rev. 1996, 96, 683; (d)
Yuasa, H.; Izumi, M.; Hashimoto, H. Yuki Gosei Kagaku Kyokaishi 2002, 60, 774.
7. (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.
8. Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem. Pharm. Bull. 1998,
46, 1339.
9. Yoshikawa, M.; Xu, F.; Nakamura, S.; Wang, T.; Matsuda, H.; Tanabe, G.;
Muraoka, O. Heterocycles 2008, 75, 1397.
10. (a) Jayakanthan, K.; Sankar, M. S.; Pinto, B. M. J. Am. Chem. Soc. 2009, 131, 5621;
(b) Johnston, B. D.; Jensen, H. H.; Pinto, B. M. J. Org. Chem. 2006, 71, 1111; (c)
Tanabe, G.; Sakano, M.; Minematsu, T.; Matusda, H.; Yoshikawa, M.; Muraoka,
O. Tetrahedron 2008, 64, 10080; (d) Muraoka, O.; Xie, W.; Osaki, S.; Kagawa, A.;
Tanabe, G.; Amer, M. F. A.; Minematsu, T.; Morikawa, T.; Yoshikawa, M.
Tetrahedron 2010, 66, 3717.
11. Recent review relevant to the work: (a) Mohan, S.; Pinto, B. M. Carbohydr. Res.
2007, 342, 1551; (b) Tanabe, G.; Matsuoka, K.; Minematsu, T.; Morikawa, T.;
Ninomiya, K.; Matsuda, H.; Yoshikawa, M.; Murata, H.; Muraoka, O. J. Pharm.
Soc. Jpn. 2007, 127, 129; (c) Nasi, R.; Patrick, B. O.; Sim, L.; Rose, D. R.; Pinto, B.
M. J. Org. Chem. 2008, 73, 6172; (d) Tanabe, G.; Hatanaka, T.; Minematsu, T.;
Matsuda, H.; Yoshikawa, M.; Muraoka, O. Heterocycles 2009, 79, 1093; (e)
Mohan, S.; Jayakanthan, K.; Nasi, R.; Kuntz, D. A.; Rose, D. R.; Pinto, B. M. Org.
Lett. 2010, 12, 1088; (f) Sim, L.; Jayakanthan, K.; Mohan, S.; Nasi, R.; Johnston, B.
D.; Pinto, B. M.; Rose, D. R. Biochemistry 2010, 49, 443; (g) Nakamura, S.;
Takahira, K.; Tanabe, G.; Morikawa, T.; Sakano, M.; Ninomiya, K.; Yoshikawa,
M.; Muraoka, O.; Nakanishi, I. Bioorg. Med. Chem. Lett. 2010, 20, 4420; (h)
Eskandari, R.; Kuntz, D. A.; Rose, D. R.; Pinto, B. M. Org. Lett. 2010, 12, 1632; (i)
Eskandari, R.; Jayakanthan, K.; Kuntz, D. A.; Rose, D. R.; Pinto, B. M. Bioorg. Med.
Chem. 2010, 18, 2829; (j) Eskandari, R.; Jones, K.; Rose, D. R.; Pinto, B. M. Bioorg.
Med. Chem. Lett. 2010, 20, 5686. and references cited therein.
135.9/136.5(2xC) (s, arom.). FABMS m/z: 511 [M–CF3SO3 ] (pos.),
149 [CF3SO3]- (neg.).
4.4.9. 1,4-Dideoxy-1,4-{(R)-[(2S,3S,4R,5R)-2,3,4,5,6-pentahydroxy-
hexyl]episulfoniumylidene}-D-arabinitol Chloride (50-epi-7)
In a manner similar to that used for the synthesis of neoponkor-
anol (7: 4.4.3.), sulfonium salt (22, 200 mg, 0.19 mmol) was de-
rived to title compound (50-epi-7, 27.0 mg, 42% from 22) as a
colorless solid,
[
a]
D
24 + 9.7 (c = 0.30, H2O), lit11h
½
a 2D3
+ 11.0
ꢃ
(c = 0.3, H2O). 1H-NMR (700 MHz, D2O) d: 3.68 (1H, dd, J = 12.0,
6.0, H-60a), 3.75 (1H, ddd, J = 9.0, 6.0, 2.8, H-50), 3.78 (1H, dd,
J = 9.0, 1.2, H-40), 3.82 (1H, dd, J = 13.4, 9.0, H-10a), 3.86 (1H, dd,
J = 12.0, 2.8, H-60b), 3.89 (1H, dd, J = 8.2, 1.2, H-30), 3.91 (1H, dd,
J = 13.0, 4.0, H-1a), 3.95 (1H, dd, J = 13.0, 3.0, H-1b), 3.97 (1H, dd,
J = 11.2, 8.2, H-5a), 4.00 (1H, dd, J = 13.4, 3.2, H-10b), 4.14 (1H,
ddd, J = ca. 8.2, 5.0, 2.6, H-4), 4.16 (1H, dd, J = 11.2, 5.0, H-5b),
4.24 (1H, ddd, J = 9.0, 8.2, 3.2, H-20), 4.47 (1H, dd, J = ca. 3.0, 2.6,
H-3), 4.78 (1H, ddd, J = ca. 4.0, 3.0, 3.0, H-2). 13C NMR (175 MHz,
D2O) d: 50.8 (C-1), 53.1 (C-10), 61.9 (C-5), 65.7 (C-60), 70.0
(C-20), 71.6 (C-40), 72.7 (C-4), 73.3 (C-50), 74.3 (C-30), 79.7 (C-2),
80.2 (C-3).
Acknowledgment
12. Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.; Takebayashi, K.; Adachi, I.; Fleet,
W. J. G.; Kettawan, A.; Okamoto, T.; Asano, N. Bioorg. Med. Chem. 2008, 16, 2734.
13. (a) Ozaki, S.; Oe, H.; Kitamura, S. J. Nat. Prod. 2008, 71, 981; (b) Oe, H.; Ozaki, S.
Biosci. Biotechnol. Biochem. 2008, 72, 1962.
14. Tanabe, G.; Xie, W.; Ogawa, A.; Cao, C.; Minematsu, T.; Yoshikawa, M.;
Muraoka, O. Bioorg. Med. Chem. Lett. 2009, 19, 2195.
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.
15. Muraoka, O.; Xie, W.; Tanabe, G.; Amer, F. A. M.; Minematsu, T.; Yoshikawa, M.
Tetrahedron Lett. 2008, 49, 7315.
References and notes
16. During this exploratory study, syntheses and evaluation of neoponkoranol (7)
and its 50-epimer (50-epi-7) have been reported by Eskandari and coworkers.11h
In the present study the reaction time (4 days) and yield (7: revised to be 41%)
of the coupling reaction reported have been improved by substituting the
reactant from the tosylate to the triflate.
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17. Wallach, L.; Latifeh, N.; Scott, D. T. Carbohydr. Res. 2005, 340, 1213.
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19. A similar mode of intramolecular cyclization leading to anhydro-sugars has
been reported: (a) Foster, A. B.; Overend, W. G.; Stacey, M.; Vaughan, G. J. Chem.
Soc. 1954, 3367; (b) Peter, K.; Herbert, K. Liebigs Ann. Chem. 1981, 11, 1960; (c)
Valentin, F. Collect. Czech. Chem. Commun. 1934, 6, 354; (d) Wolfrom, M. L.;
Chakravarty, P.; Horton, D. J. Org. Chem. 1966, 31, 2502.