Hydrophobic substituents increase the potency of salacinol, a potent α-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’

Article abstract of DOI:10.1016/j.bmc.2016.06.013

Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 3′-O-position in salacinol (1), a highly potent natural α-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’, were designed and synthesized. In order to verify the computational SAR assessments, their α-glucosidase inhibitory activities were evaluated in vitro. All analogs (8a–8g) exhibited an equal or considerably higher level of inhibitory activity against rat small intestinal α-glucosidases compared with the original sulfonate (1), and were as potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol. Their activities against human maltase exhibited good relationships to the results obtained with enzymes of rat origin. Among the designed compounds, the one with a 3′-O-neopentyl moiety (8g) was most potent, with an approximately ten fold increase in activity against human maltase compared to 1.

Full text of DOI:10.1016/j.bmc.2016.06.013

Bioorganic & Medicinal Chemistry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Hydrophobic substituents increase the potency of salacinol, a potent
a-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’
Genzoh Tanabe a, Weijia Xie b, Gorre Balakishan c, Mumen F. A. Amer d, Nozomi Tsutsui a,
Haruka Takemura a, Shinya Nakamura a, Junji Akaki e, Kiyofumi Ninomiya e, Toshio Morikawa e,
Isao Nakanishi a, Osamu Muraoka a,e,
⇑
a Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
b Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, Jiang su 210009, PR China
c Department of Organic Chemistry, Telangana University, Nizamabad 503322, Telangana State, India
d Faculty of Pharmacy, Applied Science Private University, Al Arab St 21, Amman 11931, Jordan
e Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Using an in silico method, seven analogs bearing hydrophobic substituents (8a: Me, 8b: Et, 8c: n-Pent, 8d:
n-Hept, 8e: n-Tridec, 8f: isoBu and 8g: neoPent) at the 30-O-position in salacinol (1), a highly potent nat-
Received 21 April 2016
Revised 6 June 2016
Accepted 6 June 2016
Available online xxxx
ural
sized. In order to verify the computational SAR assessments, their
were evaluated in vitro. All analogs (8a–8g) exhibited an equal or considerably higher level of inhibitory
activity against rat small intestinal -glucosidases compared with the original sulfonate (1), and were as
a
-glucosidase inhibitor from Ayurvedic traditional medicine ‘Salacia’, were designed and synthe-
a-glucosidase inhibitory activities
a
Keywords:
potent as or higher in potency than the clinically used anti-diabetics, voglibose, acarbose or miglitol.
Their activities against human maltase exhibited good relationships to the results obtained with enzymes
of rat origin. Among the designed compounds, the one with a 30-O-neopentyl moiety (8g) was most
potent, with an approximately ten fold increase in activity against human maltase compared to 1.
Ó 2016 Elsevier Ltd. All rights reserved.
a-Glucosidase inhibitor
In silico docking study
Salacinol
Salacia
SAR study
1. Introduction
as its desulfonated analogs, neosalacinol5 (4) neokotalanol6 (5) and
neoponkoranol7 (6), was subsequently isolated (Fig. 1), and was
The roots and stems of plants belonging to the genus Salacia,
including, Salacia reticulata, S. oblonga, S. chinensis have tradition-
ally been used in the Ayurvedic system for treating diabetes. In
1997, a novel thiosugar sulfonate, salacinol (1), was isolated from
a methanol extract of S. reticulata as a constituent responsible for
the antidiabetic property of the extract. The structure of 1 is quite
revealed to exhibit the same level of inhibitory activity. On this
basis, human clinical trials on patients with type-2 diabetes were
conducted with extracts of Salacia reticulata, which demonstrated
effective treatment of type-2 diabetes with minimal side effects.8
Because of their intriguing structure and the potent glucosidase
inhibitory activity, much attention has been focused on these nat-
ural inhibitors 1–6, and intensive structure–activity relationship
(SAR) studies including the total syntheses of these inhibitors have
been reported.9 Following detailed X-ray crystallographic studies
on salacinol (1) in a complex with human N-terminal catalytic
domain of maltase-glucoamylase (hNtMGAM), Pinto and co-work-
ers concluded that the 30-O-sulfonate anion of 1 was constrained
by the surrounding hydrophobic residues (Phe575, Tyr299 and
Trp406) of the enzyme, which possibly caused the negative binding
interactions of 1 with the residues (Fig. 2-A).9g Based on these
findings, several 30-O-benzylated analogs (7), in which the
sulfonate anion of 1 was substituted by a hydrophobic benzyl
moiety, were designed. These analogs exhibited activities
unique that comprises of 1,4-anhydro-4-thio-D-arabinitol cation
and deoxyalditol side chain. The crystal structure revealed by X-
ray crystallographic analysis showed that the sulfonate anion and
the sulfonium cation established an internal bond, forming a spiro-
bicyclic structure as shown in Figure 1. The mechanism of action of
1 was revealed to be
a-glucosidase inhibition, with its inhibitory
activity as effective as those of voglibose and acarbose, which are
widely used clinically.1,2 Two years later, a side chain-extended
analog kotalanol (2) was isolated from the same genus of plants
as a constituent with an even greater inhibitory activity.3 There-
after, a related sulfonium sulfonate such as ponkoranol4 (3) as well
(IC50 = 0.13–0.98
lM) superior to the original compound 1
⇑
Corresponding author. Tel.: +81 6 4307 4015; fax +81 6 6721 2505.
E-mail address: muraoka@phar.kindai.ac.jp (O. Muraoka).
(IC50 = 5.2
l
M).9e,9f
http://dx.doi.org/10.1016/j.bmc.2016.06.013
0968-0896/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

2
G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
OH OH
3'
OH OH
3'
4'
HO
OH OH OH
OH OH OH
OH OH
Cl-
Cl-
3'
2'
O
S+
O
R
O
S+
O
X
HO
3'
4'
S
1'
2'
HO
O
S+ OR OH
S+
OR OH OH
HO
-O
S+ OH
1'
S+
HO
HO
HO
OH
HO
OH
1
HO
5
HO
8
7
OH
HO OH
HO
kotalanol (2) : R = SO3
neokotalanol (5) : R = H
3
HO
OH
e: C13H27
f: CH2CH(CH3)2
g: CH2C(CH3)3
a: CH3
R=
HO
OH
-
-
ponkoranol (3) : R = SO3
neoponkoranol (6) : R = H
b: C2H5
c: C5H11
d: C7H15
X = H, CH3, Cl, CF3, NO2
salacinol (1)
neosalacinol (4)
Figure 1. Cyclic sulfonium salts as a new class of a-glucosidase inhibitors.
candidates (8a–8g), all compounds except 8a were supposed to
be superior inhibitors according to the calculation. Thus, these 30-
O-alkylated analogs (8a, 8b, 8c, 8d, 8e, 8f and 8g) were synthesized
and their inhibitory activities were examined to evaluate the com-
putational assessment. Their inhibitory activities were measured
against not only rat intestinal maltase but also human intestinal
maltase.
2. Results and discussion
2.1. Chemistry
Syntheses of 8a–8g were carried out by applying a regioselec-
tive ring-opening reaction between appropriate epoxides (10a–
10g) and thiosugar, 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epithio-D-
arabinitol (9), which was prepared by the method described in
our earlier work.9m First, epoxides 10a–10g were prepared in the
following manner. 3,4-O-Isopropylidene-D
-erythritol11 (11), read-
ily obtained via 4 steps starting from
D-isoascorbic acid, was
subjected to selective benzylation of the primary hydroxyl to give
1-O-benzyl-3,4-O-isopropylidene-
-erythritol12 (12) and 2-O-ben-
zyl-3,4-O-isopropylidene-
-erythritol13 (13) in 91% and 7% yields,
D
D
respectively. Alkylation of the major alcohol 12 with seven kinds
of alkyl halides, MeI, EtI, n-PentBr, n-HeptBr, n-TridecBr, isoBuBr
or neoPentBr in DMF in the presence of NaH, and subsequent
deacetonization of the resulting 2-O-alkylated 1-O-benzyl-3,4-O-
isopropylidene-
acid gave 2-O-alkyl-1-O-benzyl-
D
-erythritols (14a–14g) by action of hydrochloric
-erythritols (15a–15g), respec-
D
tively, in good yields. Glycols 15a, 15b, 15c, 15d, 15e, 15f and
15g were then subjected to the Mitsunobu reaction by treatment
with DEAD and Ph3P in refluxing toluene to give 2-O-alkylated
3,4-anhydro-1-O-benzyl-2-O-(pent-1-yl)-D-erythritols (10a, 10b,
10c, 10d, 10e, 10f and 10g), in 77%, 76%, 82%, 85%, 81%, 82% and
89% yields, respectively (Scheme 1).
With epoxides 10a–10g in hand, the coupling reaction of these
epoxides with thiosugar 9 was carried out in the presence of either
tetrafluoroboric acid dimethyl ether complex or diethyl ether com-
plex (HBF4ꢀMe2O or HBF4ꢀEt2O) at ꢁ60 °C in CH2Cl2. In every case,
the reaction proceeded regiospecifically and stereoselectively, giv-
ing predominantly corresponding
a-sulfonates (a-16a–a-16g,
X = BF4) along with a small amount of its b-isomer (b-16a–b-16g,
a
/b = ca. ꢂ9/1) in good yields. After the BF–4 anion of the coupled
products was exchanged with a Clꢁ anion,9d,9f by treatment with
ion exchange resins IRA-400 J (Clꢁ form), the mixture of chlorides
(16a–16g, X = Cl) were subjected to silica gel column
Figure 2. Superpositions of salacinol (1) (A) and 8g (B) in the hNtMGAM active site.
Dotted lines show hydrogen bonding (gray) and salt bridge (red). Orange arrows (a),
(b), (c) in salacinol (1) (A) and double-headed pink dotted arrows (a), (b), (c) in 8g
(B) show the distances between the alkyl group and amino acid residues. (A:
salacinol (1), (a): 3.6 Å, (b): 3.7 Å, (c): 4.0 Å, B: 8g, (a): 3.9 Å, (b): 4.5 Å, (c): 4.7 Å).
chromatography to give pure
approximately 70% isolated yield. In the FAB mass spectra run in
a positive mode, the products -16a, -16b, -16c, -16d, -16e,
-16f and -16g showed peaks due to the sulfonium ions at m/z
a-isomers (a-16a–a-16g, X = Cl) in
a
a
a
a
a
a
a
In this paper, as another attempt to reduce the hydrophilicity at
the 30-O-position in 1, several derivatives bearing simple alkyl .
groups (8a: Me, 8b: Et, 8c: n-Pent, 8d: n-Hept, 8e: n-Tridec, 8f:
isoBu and 8g: neoPent) at the position were designed using an in
silico method. The binding affinities of these compounds calculated
by the MM/GBVI method10 are provided in Table 1. Among the 7
629, 643, 685, 713, 797, 671 and 685, respectively, which
represented the corresponding cation structure. The 13C NMR
spectral properties of the products (a-16a–a-16g) were similar
with each other except for signals due to C-30-O-alkyl moieties,
and chemical shifts due to the core nine carbons (C1–C5 and
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G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
3
Table 1
Ebind (kcal/mol) of 8a–8g, 7 (o-NO2), 1, and 4 to hNtMGAM, and their IC50
(l
M) values against rat and human intestinal disaccharidases
a
a
Entry
Compound
Ebind
Rat
Human
Maltase
Entry
Compound
Ebind
Rat
Human
Maltase
Maltase
Sucrase
Isomaltase
Maltase
Sucrase
Isomaltase
1
2
3
4
5
6
7
8a (CH3)
8b (C2H5)
ꢁ35.4
ꢁ38.2
ꢁ38.0
ꢁ41.3
ꢁ41.9
ꢁ36.6
ꢁ38.6
5.3c
1.7c
1.5
0.80
1.04c
0.79
0.30
0.46c
0.12c
0.50
0.24
1.3c
0.39c
0.27c
0.47
0.25
0.95c
0.34
0.28
2.0
0.96
1.5
0.64
1.1
0.69
0.47
8
9
10
11
12
13
7 (o-NO2)
1
4
Voglibose
Acarbose
Miglitol
ꢁ38.9b
ꢁ37.0b
ꢁ36.4b
0.13b
5.2d
8.0d
1.2c
1.7e
8.2
0.042b
1.6d
0.21b
1.3d
0.15
4.9f
8c (C5H11
8d (C7H15
8e (C13H27
8f [CH2CH(CH3)2]
8g [CH2C(CH3)3]
)
)
1.3d
0.3d
9.0f
0.2c
2.1c
1.3f
)
1.5e
646e
4.6
15.2f
3.7f
0.09
0.09
0.43
a
b
c
d
e
f
Calculation has been performed using the reported scheme.9h
Lit.9e
Lit.9f
Lit.4
Lit.18
Lit.19
OH
isomers (b-16a–b-16g), characteristic upfield shift, induced by
the cis-oriented b-substituent effect,14 was observed with respect
to the signals due to carbons C-1 (dC: 45) and C-4 (dC: 61) when
OH
OH
OBn
i
O
O
O
+
OBn
OH
O
O
O
11
12
15
13
compared with those of
C-4 (dC: 66)], supporting the b-orientation of the side chain.
Attempted hydrogenolysis of -isomers -16a– -16g with pal-
a-isomer [a-16a–a-16g: C-1 (dC: 48) and
ii
OBn
OR
OBn
OR
a
a
a
OBn
iii
iv
O
HO
HO
O
ladium on carbon in 80% aqueous acetic acid at 50–60 °C gave the
corresponding debenzylated products with a concomitant forma-
tion of partially acetylated products. Then, the crude products were
subjected to acidic methanolysis to give the target compounds 8a–
8g in around 70% yields. MS spectra of 8a, 8b, 8c, 8d, 8e, 8f and 8g
run in a positive mode showed peaks at m/z 269, 283, 325, 353, 311
and 325, respectively, due to corresponding sulfonium cations.
Downfield shifted signals due to C-30 carbons (around dC 84) of
OR
O
14
10
a : R = CH3, b : R = C2H5, c : R = C5H11, d : R = C7H15
e : R = C13H27, , f : R = CH2CH(CH3)2, g : R = CH2C(CH3)3
Scheme 1. Synthesis of epoxides 10a–10g. Reagents and conditions: (i) Bu2SnO,
toluene, reflux, then BnBr, CsF, DMF, 60 °C; (ii) alkyl halides, NaH, DMF, 0 °C–rt; (iii)
0.5% aq HCl, EtOH, reflux; (iv) Ph3P, DEAD, toluene, reflux.
0
the products compared with that of neosalacinol (4: dC-3 75.3) sup-
ported the 30-O-alkylated neosalacinol-type structure (Table 3).
Finally, the anti-relationship between the side chain and the
hydroxymethyl moiety on C-4 of 8a–8g was confirmed by means
of NOE experiments as shown in Scheme 2.
C10–C40) were in good accord with each other as shown in Table 2.
The relative stereochemistry of the side chain of the major isomers
was confirmed to be in anti-relationship to the benzyloxymethyl
moiety at C-4 on the basis of observed nuclear Overhauser effect
(NOE) as shown in Scheme 2. In the 13C NMR spectra of minor
2.2
a-Glucosidase inhibitory activity
a
-Glucosidase catalytic domains in maltose digestion in rats are
Table 2
known to be homologous to those in humans. For instance, the N-
terminal catalytic domain of maltase-glucoamylase (rNtMGAM)
and that of human (hNtMGAM) were reported to share 60% amino
acid sequence similarity.15 In this study inhibitory activities of the
synthesized compounds 8a, 8b, 8c, 8d, 8f, 8e, 8g were evaluated
using both enzymes from rat and human origin, and the activities
compared (Table 1).
13C NMR data for nine carbons (C1–C5 and C10–C40) of sulfonium salts 16a–16g
a
-16aa
a
-16ba
a
-16cb
a
-16db
a
-16ea
a
-16fa
a
-16ga
C1
C2
C3
C4
C5
48.4
82.4
82.3
66.1
66.9
48.3
82.5
82.4
65.8
67.0
51.8
68.0
80.4
68.5
48.2
82.4
82.5
65.9
67.0
51.9
68.1
80.7
68.4
48.2
82.51
82.45
65.9
67.0
51.9
68.1
80.7
68.5
48.2
82.5
82.4
65.8
67.0
51.9
68.1
80.7
68.4
48.2
82.4
82.4
66.0
67.0
51.9
68.1
80.9
68.3
48.0
82.3
82.5
66.2
67.1
51.8
68.1
81.3
68.5
First, inhibitory activities against rat a-glucosidases were eval-
C10 51.9
C20 68.1
C30 82.0
C40 67.4
uated. The inhibitory activities against maltase significantly varied
according to the alkyl species. The potency of 8a was almost equal
to that of 1, indicating that replacement of the sulfonate moiety
with a methyl group caused no significant effect on the inhibitory
activity. Analogs 8b, 8c, 8d, and 8e bearing linear alkyl chains and
an isobutyl group exhibited slightly higher activities than 1,
although 8d and 8e were predicted to have superior inhibitory
action according to the analysis. Among the seven derivatives eval-
uated in this study, 8g was found to be the most potent, approxi-
mately 20–25-times more active than 1. It is interesting to note
that the analog bearing the most bulky side chain (8g) exhibited
the strongest activity. Against sucrase, compounds bearing the
bulky substituents [8f: CH2CH(CH3)2 and 8g: CH2C(CH3)3] also
showed a high inhibitory activity of approximately 20 times
greater than that of 1. Isomaltase inhibitory activities of all the
analogs were either the same or very similar to that of 1 regardless
of the alkyl species. The results indicated that simple alkylation at
b-16aa,d b-16ba,d b-16ca,d b-16dc,d b-16eb b-16fa,d b-16gb,d
C1
C2
C3
C4
C5
45.1
82.5
84.6
60.7
65.3
45.3
82.5
84.6
60.8
65.3
42.9
66.1
80.2
69.6
45.1
82.5
84.6
60.6
65.2
42.9
66.2
80.6
69.6
45.2
82.5
84.6
60.7
65.3
42.9
66.3
80.6
69.6
45.3
82.5
84.6
60.8
65.3
42.9
66.3
80.6
69.6
45.2
82.5
84.6
60.8
65.3
42.9
66.3
80.9
69.5
44.9
82.5
84.5
60.7
65.1
42.9
66.1
81.5
69.6
C10 42.8
C20 66.1
C30 81.9
C40 68.8
a
b
c
All spectra were measured in CDCl3 125 MHz.
All spectra were measured in CDCl3 175 MHz.
All spectra were measured in CDCl3 200 MHz.
d
Chemical shift values extracted from the spectrum of a mixture of
a- and b-
isomer. Other signals due to the alkyl moieties at 30-O-position are provided in
Section 4.
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4
G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
iii
OH
3'
OH
OH
4'
H21C'
3'
NOE
HO
2'
OH
NOE
BnO
H21C'
Cl-
OBn
+
OBn
O
X-
S
X-
OR
OR
S+
+
OR
H
S+
i, ii
H
S
BnO
OBn
1
+
1
4
4
3
BnO
OR
10
2
5
OBn
BnO
HO
BnO
BnO
OBn
OH
OBn
9
X = BF4 or Cl
8
a: CH3, b: C2H5, c: C5H11, d: C7H15
e: C13H27, f: CH2CH(CH3)2, g: CH2C(CH3)3
R=
α-16
β-16
Scheme 2. Synthesis of sulfonium salts 8a–8g. Reagents and conditions: (i) HBF4ꢀ(CH3)2O or HBF4ꢀ(C2H5)2O, CH2Cl2, ꢁ60 °C; (ii) IRA-400J (Clꢁ form), MeOH–H2O, rt; (iii) H2,
Pd–C, 80% AcOH, 50–60 °C, then 10% aq HCl–CH3OH, rt.
Table 3
be attributable to the entropic disadvantage caused by the loss of
rotational flexibility of the long straight alkyl chain through pro-
13C NMR data of neosalacinol4b (4) and compounds 8a-8g
4
8aa
8bb
8ca
8da
8eb
8fa
8ga
tein binding. Furthermore, the contribution of other catalytic
domains including a C-terminal maltase-glucoamylase (CtMGAM)
and/or sucrase-isomaltase (CtSI) has been shown to affect the
hydrolysis of maltose, which could be another reason for the dis-
crepancy mentioned above.16
C1
C2
C3
C4
C5
C10
C20
C30
C40
52.1
79.4
79.5
73.7
61.0
51.8
69.6
75.3
64.0
52.1
79.4
79.5
73.7
61.0
51.8
68.6
85.1
60.0
52.1
79.4
79.5
73.7
61.1
51.8
68.7
83.5
60.8
52.2
79.46
79.52
73.8
61.0
51.8
68.7
83.7
60.7
52.2
79.48
79.52
73.8
61.1
51.8
68.7
83.7
60.7
52.2
79.5
79.6
73.8
61.1
51.8
68.8
83.7
60.8
52.2
79.47
79.52
73.8
61.0
51.9
68.8
83.9
60.7
52.3
79.5
79.5
73.8
61.0
51.9
68.9
84.2
60.8
3. Conclusions
Thus, using an in silico method,
a-glucosidase inhibitors (8c–
Signals due to the alkyl moieties at the 30-O-position were described in Section 4.
8g) with higher activities than the seed compound salacinol (1)
were effectively designed and developed. The activity of 8g, the
most active compound, is approximately 10 times as potent as 1,
but less potent than the previously developed ortho-nitrobenzyl
derivative (7: X = o-nitro).9e As a nitro group is reported to
occasionally cause toxicity during the metabolism of some drug
candidates,17 an alkylated analog 8g would overcome this disad-
vantage, and will be a promising candidate as a new type of a-glu-
cosidase inhibitor. Further SAR studies using in silico methods are
currently in progress.
a
All spectra were measured in CD3OD 125 MHz.
All spectra were measured in CD3OD 175 MHz.
b
the 30-O-position of the side chain caused a beneficial effect,
enhancing the inhibitory activity against
origin.
Next, inhibitory activities against human intestinal maltase
were examined and compared with those against rat intestinal
maltase. All analogs showed satisfactory potent inhibitory activi-
a-glucosidases of rat
ties with IC50 values ranging from 2.0 to 0.47 lM. The relative inhi-
bitory potencies were equivalent to those against rat intestinal
maltase. It is of interest that against human maltase, compound
4. Experimental section
4.1. General method
bearing a CH3 group (8a, entry 1, 2.0
than the parent sulfonium salts 1 and 4 (4.9 and 9.0
l
M) exhibited more potency
M, respec-
l
Mps were determined on an AS ONE ATM-02 melting point
apparatus and are uncorrected. IR spectra were measured on a Shi-
madzu IRAffinity-1 spectrophotometer. NMR spectra were
recorded on a JEOL JNM-ECA 500 (500 MHz 1H, 125 MHz 13C), JEOL
JNM-ECA 700 (700 MHz 1H, 175 MHz 13C), or a JEOL JNM-ECA 800
(800 MHz 1H, 200 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-700T spectrometer. Optical rotations were deter-
mined with a JASCO P-2200 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.
tively), which was not forecasted by in silico docking studies. As
a result, all analogs were shown to be more potent inhibitors than
either 1 or 4 as well as the three anti-diabetics. Among them, 8g
(entry 7, IC50 value of 0.47 lM) was the most potent compound
also against human intestinal maltase.
The superposition of the most potent analogue 8g in the
hNtMGAM is provided in Figure 2-B. As the binding pocket of
hNtMGAM was rigid, their inhibitory activities were affected by
physicochemical properties of the substituents. Instead of the neg-
ative binding effects between aromatic residues and the sulfonate
oxygens of salacinol (weak CHAO interaction: orange arrows a, b,
and c in Fig. 2-A, but penalized by desolvation of polar groups),
intermolecular van der Waals interactions were detected between
the neopentyl moiety and the surrounding hydrophobic parts,
Phe575, Tyr299, and Trp406 (double-headed pink dotted arrows
a, b, c in Fig. 2-B). The distances between the terminal methyl
groups of the neopentyl moiety and the residues, Phe575,
Tyr299, and Trp406, were calculated to be approximately 3.9, 4.5,
and 4.7 Å, respectively. These distances induced effective van der
Waals interactions. This interaction and less desolvation penalty
of the nonpolar group might contribute to the enhanced inhibitory
activity.
4.2. Chemistry
4.2.1. 1-O-Benzyl-3,4-O-isopropylidene-
D-erythritol (12) and 2-
O-benzyl-3,4-O-isopropylidene- -erythritol (13)
D
In a egg-plant flask equipped with Dean Stark condenser, a mix-
ture of diol11 (11, 6 g, 37.0 mmol), dibutyltinoxide(IV) (Bu2SnO,
11.1 g, 44.6 mmol) and toluene (60 mL) was heated under reflux
for 1 h, and the reaction mixture was condensed at reduced pres-
sure. To the residue were subsequently added DMF (60 mL),
cesium fluoride (8.5 g, 55.9 mmol), and benzyl bromide (6.6 mL,
55.2 mmol), and the resulting suspension was heated at 60 °C for
1 h. After being cooled, the reaction mixture was diluted with
As shown in Table 1, compounds bearing long alkyl chains (8d
and 8e) were calculated to bind to hNtMGAM more effectively than
8g whereas, the observed inhibitory potency of 8d and 8e against
enzymes was less when compared with 8g. This discrepancy could
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
5
diethyl ether (200 mL), and diethyl ether-insoluble materials were
filtered off and washed with diethyl ether. The combined filtrate
and washings were made alkaline (pH >11) by addition of 10%
aqueous sodium hydroxide. The deposited gel was filtered off
through celite and washed with diethyl ether. The organic layer
was washed with brine and condensed to give a pale yellow oil
(11.3 g), which on column chromatography (n-hexane–AcOEt,
10:1?5:1?1:1) gave title compounds 1212 (8.5 g, 91%) and 1313
(651 mg, 7%).
66.7 (C-4), 70.0 (C-1), 71.2 [OCH2(CH2)3CH3], 73.4 (OCH2Ph), 75.4
(C-3), 79.5 (C-2), 109.0 [C(CH3)2], 127.5/128.3 (d, arom.), 138.3 (s,
arom.). LRMS (FAB, pos.) m/z: 345 [M+Na]+. HRMS (FAB, pos.): calcd
for C19H30O4Na 345.2042, found 345.2035.
4.2.2.4. With heptyl bromide.
zyl-2-O-(hept-1-yl)-3,4-O-isopropylidene-
673 mg, 97%) was obtained from 12 (500 mg, 1.98 mmol) as color-
In a similar manner, 1-O-ben-
D-erythritol (14d,
23
less oil, [
a]
D
+13.3 (c 0.97, CHCl3). IR (neat): 1454, 1369, 1346,
1273, 1253, 1215, 1099, 1076 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d:
4.2.2. Alkylation of 1-O-benzyl-3,4-O-isopropylidene-
erythritol (12)
D
-
0.88 [3H, t, J = 7.0, O(CH2)6CH3], 1.22–1.34 [8H, m O(CH2)2(CH2)4CH3],
1.35/1.40 [each 3H, s, C(CH3)2], 1.52–1.59 [2H, m OCH2CH2(CH2)4
CH3], 3.46 (1H, ddd, J = 6.6, 5.2, 3.1, H-2), 3.47/3.68 [each 1H, dt,
J = 9.2, 7.0, OCH2(CH2)5CH3], 3.54 (1H, dd, J = 10.3, 5.2, H-1a), 3.69
(1H, dd J = 10.6, 3.1, H-1b), 3.93 (1H, dd, J = 8.3, 6.0, H-4a), 4.05
(1H, dd, J = 8.3, 6.3, H-4b), 4.14 (1H, ddd, J = 6.6, 6.3, 6.0, H-3),
4.58/4.54 (each 1H, d, J = 12.0, OCH2Ph), 7.25–7.35 (5H, m, arom.).
13C NMR (125 MHz, CDCl3) d: 14.1 [O(CH2)6CH3], 22.6 [O(CH2)5
CH2CH3], 25.4/26.6 [C(CH3)2], 26.1 [O(CH2)2CH2(CH2)3CH3], 29.1
[O(CH2)3CH2CH2CH3], 30.1 [OCH2CH2(CH2)4CH3], 31.8 [O(CH2)4
CH2CH2CH3], 66.7 (C-4), 70.0 (C-1), 71.3 [OCH2(CH2)5CH3], 73.4
(OCH2Ph), 75.4 (C-3), 79.5 (C-2), 109.0 [C(CH3)2], 127.5/128.3 (d,
arom.), 138.3 (s, arom). LRMS (FAB, pos.) m/z: 373 [M+Na]+. HRMS
(FAB, pos.): calcd for C21H34O4Na 373.2355, found 373.2365.
4.2.2.1. With methyl iodide.
A solution of compound (12,
1.9 g, 7.54 mmol) in DMF (10 mL) was added dropwise to a mixture
of sodium hydride (452 mg, 11.3 mmol, 60% in liquid paraffin),
methyl iodide (1 mL, 16 mmol), and DMF (10 mL) at 0 °C. After
being stirred at 0 °C for 1 h, the mixture was poured into ice-water
(100 mL) and extracted with a mixture of n-hexane and diethyl
ether (v/v, 1:1). The extract was washed with brine and condensed
to give a pale yellow oil (2.31 g), which on column chromatography
(n-hexane–AcOEt, 100:1?10:1) gave 1-O-benzyl-2-O-methyl-3,4-
O-isopropylidene-
D
-erythritol (14a, 1.96 g, 98%) as colorless oil,
+13.5 (c 1.10, CHCl3). IR (neat): 1454, 1370, 1253, 1211,
1153, 1100, 1053 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 1.35/1.41
20
[a]
D
.
[each 3H, s, C(CH3)2], 3.38 (1H, ddd, J = 6.6, 4.9, 2.9, H-2), 3.48
(3H, s, OCH3), 3.55 (1H, dd, J = 10.6, 4.9, H-1a), 3.71 (1H, dd,
J = 10.6, 2.9, H-1b), 3.93 (1H, dd, J = 8.3, 6.1, H-4a), 4.05 (1H, dd,
J = 8.3, 6.3, H-4b), 4.14 (1H, ddd, J = 6.6, 6.3, 6.1, H-3), 4.56/4.58
(each 1H, d, J = 12.1, OCH2Ph), 7.26–7.36 (5H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 25.3/26.6 [C(CH3)2], 58.7 (OCH3), 66.5 (C-4),
69.3 (C-1), 73.5 (OCH2Ph), 75.3 (C-3), 81.0 (C-2), 109.1 [C(CH3)2],
127.6/128.3 (d, arom.), 138.2 (s, arom.). LRMS (FAB, pos.) m/z:
289 [M+Na]+. HRMS (FAB, pos.): calcd for C15H22O4Na, 289.1416,
found 289.1444.
4.2.2.5. With tridecyl bromide.
benzyl-2-O-(tridec-1-yl)-3,4-O-isopropylidene-
1.2 g, 87%) was obtained from 12 (800 mg, 3.17 mmol) as colorless
In a similar manner, 1-O-
D
-erythritol (14e,
24
oil, [
a]
+10.7 (c 1.03, CHCl3). IR (neat): 1456, 1377, 1369, 1256,
D
1213, 1099, 1076 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d: 0.88 [3H, t,
J = 6.9, O(CH2)12CH3], 1.22–1.33 [20H, O(CH2)2(CH2)10CH3],
1.35/1.40 [each 3H, s, C(CH3)2], 1.51–1.59 [2H, m, OCH2CH2(CH2)10
CH3], 3.45 (1H, ddd, J = 6.6, 5.2, 3.2, H-2), 3.48/3.68 [each 1H, dd,
J = 9.2, 6.9, OCH2(CH2)11CH3], 3.54 (1H, dd, J = 10.3, 5.2, H-1a),
3.69 (1H, dd, J = 10.3, 3.2, H-1b), 3.93 (1H, dd, J = 8.3, 6.3, H-4a),
4.05 (1H, dd, J = 8.3, 6.6, H-4b), 4.15 (1H, ddd, J = 6.6, 6.6, 6.3, H-
3), 4.55/4.58 (each 1H, d, J = 12.1, OCH2Ph), 7.25–7.36 (5H, m,
arom.). 13C NMR (125 MHz, CDCl3) d: 14.1 [O(CH2)12CH3], 22.7 [O
(CH2)11CH2CH3], 25.4/26.6 [C(CH3)2], 26.1 [O(CH2)10CH2CH2CH3],
29.3/29.5/29.61/29.64/29.7 [O(CH2)3(CH2)7(CH2)2CH3], 30.1 [OCH2
CH2(CH2)10CH3], 31.9 [O(CH2)2CH2(CH2)9CH3], 66.7 (C-4), 70.0 (C-1),
71.3 [OCH2(CH2)11CH3], 73.4 (OCH2Ph), 75.4 (C-3), 79.5 (C-2),
109.0 [C(CH3)2], 127.5/128.3 (d, arom.), 138.3 (s, arom.). LRMS
(FAB, pos.) m/z: 457 [M+Na]+. HRMS (FAB, pos.): calcd for C27H46
O4Na 457.3294, found 457.3279.
4.2.2.2. With ethyl iodide.
2-O-ethyl-3,4-O-isopropylidene-
In a similar manner, 1-O-benzyl-
D-erythritol (14b, 2.13 g, 96%)
24
was obtained from 12 (2.0 g, 7.94 mmol) as colorless oil, [
+10.4 (c 0.85, CHCl3). IR (neat): 1456, 1371, 1260, 1213, 1099,
1074 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 1.19 (3H, t, J = 7.2, OCH2
a]
D
.
CH3), 1.35/1.40 [each 3H, s, C(CH3)2], 3.48 (1H, ddd, J = 6.6, 5.2,
3.2, H-2), 3.54 (1H, dd, J = 10.3, 5.2, H-1a), 3.57/3.75 (each 1H, dq,
J = 9.5, 7.2, OCH2CH3), 3.68 (1H, dd, J = 10.3, 3.2, H-1b), 3.93 (1H,
dd, J = 8.3, 6.1, H-4a), 4.05 (1H, dd, J = 8.3, 6.3, H-4b), 4.14 (1H,
ddd, J = 6.6, 6.3, 6.1, H-3), 4.55/4.57 (each 1H, d, J = 12.3 Hz, OCH2Ph),
7.26–7.36 (5H, m, arom.). 13C NMR (125 MHz, CDCl3) d: 15.6
(OCH2CH3), 25.4/26.6 [C(CH3)2], 66.5 (OCH2CH3), 66.6 (C-4), 70.1
(C-1), 73.4 (OCH2Ph), 75.5 (C-3), 79.3 (C-2), 109.1 [C(CH3)2],
127.5/1278.3 (d, arom.), 138.3 (s, arom.). LRMS (FAB, pos.) m/z:
303 [M+Na]+. HRMS (FAB, pos.): calcd for C16H24O4Na 303.1572,
found 303.1593.
4.2.2.6. With isobutyl bromide.
benzyl-2-O-isobutyl-3,4-O-isopropylidene-
In a similar manner, 1-O-
-erythritol (14f,
D
503 mg, 82%) was obtained from 12 (500 mg, 1.98 mmol). In this
reaction, a excess amount of isobutyl bromide (5 equiv) and
sodium hydride (2 equiv) were added thrice to the reaction mix-
ture, because the E2 elimination of isobutyl bromide competed
23
4.2.2.3. With pentyl bromide.
zyl-2-O-(pent-1-yl)-3,4-O-isopropylidene-
96%) was obtained from 12 (900 mg, 3.57 mmol) as colorless oil,
In a similar manner, 1-O-ben-
with the O-alkylation of 12. Colorless oil, [
a]
+14.4 (c 1.02,
D
D
-erythritol (14c, 1.1 g,
CHCl3). IR (neat): 1454, 1369, 1254, 1215, 1084, 1080,
1057 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 0.89/0.90 [each 3H, d,
.
23
[
a]
D
+16.0 (c 0.91, CHCl3). IR (neat): 1454, 1370, 1258, 1211,
J = 6.6, OCH2CH(CH3)2], 1.35/1.40 [each 3H, s, C(CH3)2], 1.83 [1H,
triple hept., J = 6.6, 6.6, OCH2CH(CH3)2], 3.23/3.47 [each 1H, dd,
J = 8.9, 6.6, OCH2CH(CH3)3], 3.45 (1H, ddd, J = 6.3, 5.2, 3.2, H-2),
3.55 (1H, dd, J = 10.3, 5.2, H-1a), 3.69 (1H, dd, J = 10.3, 3.2, H-1b),
3.94 (1H, dd, J = 8.3, 6.3, H-4a), 4.06 (1H, dd, J = 8.3, 6.3, H-4b),
4.16 (1H, ddd, J = 6.3, 6.3, 6.3, H-3), 4.55/4.58 (each 1H, d,
J = 12.3, OCH2Ph), 7.26–7.35 (5H, m, arom.). 13C NMR (125 MHz,
CDCl3) d: 19.3/19.4 [OCH2CH(CH3)2], 25.4/26.6 [C(CH3)2], 28.8
[OCH2CH(CH3)2], 66.7 (C-4), 69.9 (C-1), 73.4 (OCH2Ph), 75.5 (C-3),
1099, 1072 cmꢁ1 1H NMR (500 Hz, CDCl3) d: 0.89 [3H, t, J = 7.1, O
.
(CH2)4CH3], 1.28–1.34 [4H, m, OCH2CH2(CH2)2CH3], 1.35/1.40 [each
3H, s, C(CH3)2], 1.52–1.59 [2H, m, OCH2CH2(CH2)2CH3], 3.46 (1H,
ddd, J = 6.6, 5.2, 3.1, H-2), 3.48/3.68 [each 1H, dt, J = 9.0, 6.9, OCH2
(CH2)3CH3], 3.54 (1H, dd, J = 10.3, 5.2, H-1a), 3.69 (1H, dd, J = 10.3,
3.1, H-1b), 3.93 (1H, dd, J = 8.3, 6.0, H-4a), 4.05 (1H, dd, J = 8.3, 6.6,
H-4b), 4.15 (1H, ddd, J = 6.6, 6.6, 6.0, H-3), 4.55/4.57 (each 1H, d,
J = 12.3, OCH2Ph), 7.26–7.36 (5H, m, arom). 13C NMR (125 Hz,
CDCl3) d: 14.0 [O(CH2)4CH3], 22.5 [O(CH2)3CH2CH3], 25.4/26.6 [C
(CH3)2], 28.3 [O(CH2)2CH2CH2CH3], 29.8 [OCH2CH2(CH2)2CH3],
78.0
[OCH2CH(CH3)2],
79.7
(C-2),
109.0
[C(CH3)2],
127.51/127.54/128.3 (d, arom.), 138.4 (s, arom.). LRMS (FAB, pos.)
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

6
G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
m/z: 331 [M+Na]+. HRMS (FAB, pos.): calcd for C18H28O4Na
331.1885, found 331.1900.
1.35 [4H, m, OCH2CH2(CH2)2CH3], 1.52–1.59 [2H, m, OCH2CH2
(CH2)2CH3], 2.42 (1H, t, J = 6.0, OH), 2.93 (1H, d, J = 5.2, OH),
3.47/3.62 (each 1H, dt, J = 9.2, 6.9, OCH2(CH2)5CH3], 3.54 (1H,
ddd, J = 5.5, 5.2, 5.2, H-2), 3.64 (1H, dd, J = 10.0, 5.5, H-1a), 3.66
(1H, dd, J = 10.0, 5.2, H-1b), 3.72 (2H, dd-like, J = ca. 6.0, 4.5, H-4a
and H-4b), 3.81 (1H, ddt, J = 5.2, 5.2, 4.5, H-3), 4.55/4.57 (each
1H, d, J = 11.8, OCH2Ph), 7.28–7.38 (5H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 14.0 [O(CH2)4CH3], 22.5 [O(CH2)3CH2CH3],
28.2 [O(CH2)2CH2CH2CH3], 29.7 [OCH2CH2(CH2)2CH3], 63.5 (C-4),
69.6 (C-1), 71.1 [OCH2(CH2)5CH3], 72.1 (C-3), 73.6 (OCH2Ph), 79.1
(C-2), 127.7/127.9/128.5 (d, arom.), 137.6 (s, arom.).
4.2.2.7. With neopentyl bromide.
In the presence of tetra-
butylammonium iodide (738 mg, 2.0 mmol), 12 (800 mg,
3.71 mmol) was alkylated with neopentyl bromide (2.4 mL,
19 mmol) at 50 °C in DMF to give 1-O-benzyl-2-O-neopentyl-3,4-
O-isopropylidene-
[a]
D
D
-erythritol (14g, 409 mg, 40%) as colorless oil,
+15.0 (c 1.05, CHCl3). IR (neat): 1477, 1454, 1369, 1253,
1215, 1084, 1061, 1030 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 0.90
23
.
[9H, s, OCH2C(CH3)3], 1.35/1.41 [each 3H, s, C(CH3)2], 3.13/3.35
[each 1H, d, J = 8.3, OCH2C(CH3)3], 3.46 (1H, ddd, J = 6.3, 4.9, 3.2,
H-2), 3.55 (1H, dd, J = 10.6, 4.9, H-1a), 3.68 (1H, dd, J = 10.6, 3.2,
H-1b), 3.95 (1H, dd, J = 8.3, 6.3, H-4a), 4.05 (1H, dd, J = 8.3, 6.3, H-
4b), 4.16 (1H, ddd, J = 6.3, 6.3, 6.3, H-3), 4.56 (2H, s, OCH2Ph),
7.25–7.36 (5H, m, arom.). 13C NMR (125 MHz, CDCl3) d: 25.4/26.7
[C(CH3)2], 26.7 [OCH2C(CH3)3], 32.2 [OCH2C(CH3)3], 66.7 (C-4),
70.0 (C-1), 73.4 (OCH2Ph), 75.6 (C-3), 79.9 (C-2), 81.5 [OCH2C
(CH3)3], 108.9 [C(CH3)2], 127.5/128.3 (d, arom.), 138.4 (s, arom.).
LRMS (FAB, pos.) m/z: 345 [M+Na]+. HRMS (FAB, pos.): calcd for
4.2.3.4. 1-O-Benzyl-2-O-(hept-1-yl)-
D
-erythritol (15d).
In a
similar manner, 14d (637 mg, 1.82 mmol) was hydrolyzed in a
mixture of 1% hydrochloric acid (2 mL) and ethanol (3 mL). A sim-
ilar work-up used for the preparation of 15c gave a practically pure
title compound (15d, 553 mg, 98%) as colorless oil, 1H NMR
(700 MHz, CDCl3) d: 0.88 (3H, t, J = 7.0, O(CH2)6CH3], 1.22–1.34
[8H m O(CH2)2(CH2)4CH3], 1.51–1.58 [2H, m OCH2CH2(CH2)4CH3],
2.38 (1H, t, J = 6.2, OH), 2.90 (1H, d, J = 5.4, OH), 3.46/3.62 (each
1H, dt, J = 9.2, 7.0, OCH2(CH2)5CH3], 3.54 (1H, ddd, J = 5.4, 5.3, 4.8,
H-2), 3.64 (1H, dd, J = 10.0, 5.4, H-1a), 3.66 (1H, dd, J = 10.0, 4.8,
H-1b), 3.72 (2H, dd-like, J = ca. 6.2, 4.5, H-4a and H-4b), 3.81 (1H,
ddt, J = 5.4, 5.4, 4.5, H-3), 4.55/4.57 (each 1H, d, J = 12.0, OCH2Ph),
7.28–7.37 (5H, m, arom.). 13C NMR (175 MHz, CDCl3) d: 14.1 [O
(CH2)6CH3], 22.6 [O(CH2)5CH2CH3], 26.0 [O(CH2)2CH2(CH2)3CH3],
29.1 [O(CH2)3CH2(CH2)2CH3], 30.0 [OCH2CH2(CH2)4CH3], 31.8 [O
(CH2)4CH2CH2CH3], 63.5 (C-4), 69.7 (C-1), 71.1 [OCH2(CH2)5CH3],
72.2 (C-3), 73.7 (OCH2Ph), 79.2 (C-2), 127.7/127.9/128.5 (d, arom.),
137.6 (s, arom.).
C19H30O4Na 345.2042, found 345.2052.
4.2.3. Hydrolysis of 2-O-alkylated 1-O-benzyl-3,4-O-isopropy-
lidene- -erythritols (14a–14g)
4.2.3.1. 1-O-Benzyl-2-O-methyl- A mix-
D
D
-erythritol (15a).
ture of 14a (2.0 g, 7.5 mmol), 1% hydrochloric acid (4 mL), and
ethanol (6 mL) was heated under reflux for 30 min. After removal
of the solvent, the residue was dissolved in ethanol (20 mL), and
the resulting mixture was neutralized with ion exchange resin
(IRA67). The resin was filtered off, and the filtrate was condensed
to give an oil (2.0 g), which was triturated with n-hexane to give
a practically pure title compound (15a, 1.63 g, 96%) as colorless
oil, which was used in the next step without further purification.
1H NMR (500 MHz, CDCl3) d: 2.27 (2H, br s, OH), 3.446 (3H, s,
OCH3), 3.448 (1H, ddd, J = 5.2, 5.2, 4.6, H-2), 3.66 (1H, dd, J = 10.3,
4.6, H-1a), 3.69 (1H, dd, J = 10.3, 5.2, H-1b), 3.71 (2H, d-like,
J = ca. 4.6, H-4a and H-4b), 3.83 (1H, dt, J = 5.2, 4.6, H-3),
4.55/4.58 (each 1H, d, J = 12.0, OCH2Ph), 7.28–7.38 (5H, m, arom.).
13C NMR (125 MHz, CDCl3) d: 58.4 (OCH3), 63.5 (C-4), 69.0 (C-1),
71.9 (C-3), 73.7 (OCH2Ph), 80.6 (C-2), 127.8/127.9/128.6 (d, arom.),
137.5 (s, arom.).
4.2.3.5. 1-O-Benzyl-2-O-(tridec-1-yl)-
D
-erythritol (15e).
In a
similar manner, 14e (950 mg, 2.19 mmol) was hydrolyzed in a
mixture of 1% hydrochloric acid (3 mL) and ethanol (9 mL). A sim-
ilar work-up used for the preparation of 15c gave a practically pure
title compound (15e, 818 mg, 95%) as colorless oil, 1H NMR
(500 MHz, CDCl3) d: 0.88 (3H, t, J = 7.0, O(CH2)12CH3], 1.22–1.34
[20H m O(CH2)2(CH2)10CH3], 1.50–1.59 [2H, m OCH2CH2(CH2)10
CH3], 2.37 (1H, br t, J = ca. 5.2, OH), 2.89 (1H, d, J = 5.2, OH),
3.46/3.62 (each 1H, dt, J = 9.2, 7.0, OCH2(CH2)11CH3], 3.54 (1H,
ddd, J = 5.5, 5.2, 5.2, H-2), 3.64 (1H, dd, J = 10.0, 5.5, H-1a), 3.66
(1H, dd, J = 10.0, 5.2, H-1b), 3.72 (2H, dd-like, J = ca. 5.2, 5.2, H-4a
and H-4b), 3.81 (1H, ddt, J = 5.2, 5.2, 5.2, H-3), 4.54/4.57 (each
1H, d, J = 12.0, OCH2Ph), 7.28–7.37 (5H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 14.1 [O(CH2)12CH3], 22.6 [O(CH2)11CH2CH3],
26.1 [O(CH2)2CH2(CH2)9CH3], 29.3/29.4/29.57/29.59/29.64/29.67
[O(CH2)3(CH2)7(CH2)2CH3], 30.0 [OCH2CH2(CH2)10CH3], 31.9 [O
(CH2)10CH2CH2CH3], 63.5 (C-4), 69.7 (C-1), 71.1 [OCH2(CH2)11CH3],
72.1 (C-3), 73.7 (OCH2Ph), 79.1 (C-2), 127.7/127.9/128.5 (d, arom.),
137.6 (s, arom.).
4.2.3.2. 1-O-Benzyl-2-O-ethyl-D-erythritol (15b).
In a similar
manner, 14b (2.1 g, 7.5 mmol) was hydrolyzed in a mixture of 1%
hydrochloric acid (3 mL) and ethanol (6 mL). A similar work-up
used for the preparation of 15a gave a practically pure title com-
pound (15b, 1.72 g, 96%) as colorless oil. 1H NMR (500 MHz, CDCl3)
d: 1.19 (3H, t, J = 7.2, OCH2CH3), 2.37/2.90 (each 1H, br s, OH),
3.55/3.70 (each 1H, dq, J = 9.5, 7.2, OCH2CH3), 3.56 (1H, ddd-like,
J = ca. 5.2, 5.2, 5.2, H-2), 3.64 (1H, dd, J = 10.0, 5.2, H-1a), 3.67
(1H, dd, J = 10.0, 5.2, H-1b), 3.72 (2H, d-like, J = ca. 4.3, H-4a and
H-4b), 3.83 (1H, dt-like, J = ca. 5.2, 4.3, H-3), 4.55/4.58 (each 1H,
d, J = 12.0, OCH2Ph), 7.28–7.38 (5H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 15.5 (OCH2CH3), 63.5 (C-4), 66.3 (OCH2CH3),
69.7 (C-1), 72.1 (C-3), 73.7 (OCH2Ph), 78.9 (C-2),
127.7/127.9/128.5 (d, arom.), 137.6 (s, arom.).
4.2.3.6. 1-O-Benzyl-2-O-isobutyl-
D
-erythritol (15f).
In a sim-
ilar manner, 14f (352 mg, 1.14 mmol) was hydrolyzed in a mixture
of 1% hydrochloric acid (1.3 mL) and ethanol (2 mL). A similar
work-up used for the preparation of 15c gave a practically pure
title compound (15f, 294 mg, 96%) as colorless oil, 1H NMR
(800 MHz, CDCl3) d: 0.89/0.90 [each 3H, d, J = 6.4, OCH2CH
(CH3)2], 1.83 [1H, triple hept, J = 6.4, 6.4, OCH2CH(CH3)2], 2.41
(1H, t, J = 5.6, OH), 2.93 (1H, d, J = 5.6, OH), 3.24/3.40 [each 1H,
dd, J = 8.8, 6.4, OCH2CH(CH3)2], 3.53 (1H, ddd, J = 6.4, 5.6, 4.8,
H-2), 3.65 (1H, dd, J = 10.4, 5.6 H-1a), 3.67 (1H, dd, J = 10.4, 4.8,
H-1b), 3.73 (2H, dd-like, J = 5.6, 4.8, H-4a and H-4b), 3.82 (1H,
ddt, J = 6.4, 5.6, 4.8, H-3), 4.55/4.57 (each 1H, d, J = 12.0, OCH2Ph),
7.30–7.37 (5H, m, arom.). 13C NMR (200 MHz, CDCl3) d:
19.27/19.29 [OCH2CH(CH3)2], 28.8 [OCH2CH(CH3)2], 63.5 (C-4),
4.2.3.3. 1-O-Benzyl-2-O-(pent-1-yl)-
D-erythritol (15c).
In a
similar manner, 14c (798 mg, 2.5 mmol) was hydrolyzed in a mix-
ture of 1% hydrochloric acid (2 mL) and ethanol (3 mL). After being
cooled, the reaction mixture was poured into water (25 mL), and
the resulting mixture was neutralized by addition of sodium
hydrogen carbonate and extracted with diethyl ether. The extract
was washed with brine and condensed to give a practically pure
title compound (15c, 610 mg, 87%) as colorless oil, 1H NMR
(500 MHz, CDCl3) d: 0.89 (3H, t, J = 6.9 Hz, O(CH2)4CH3], 1.27–
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
7
69.6 (C-1), 72.2 (C-3), 73.6 (OCH2Ph), 77.8 [OCH2CH(CH3)2], 79.3
(C-2), 127.7/127.9/128.5 (d, arom.), 137.6 (s, arom).
2.77 (1H, dd, J = 5.4, 2.6, H-4a), 2.80 (1H dd, J = 5.4, 3.7, H-4b), 3.05
(1H,ddd, J = 5.2, 3.7, 2.6, H-3), 3.36 (1H, ddd, J = 5.5, 5.2, 4.3, H-2),
3.51/3.58 [each 1H, dt, J = 9.2, 6.9, OCH2(CH2)3CH3], 3.61 (1H dd
J = 10.3, 5.5, H-1a), 3.64 (1H, dd, J = 10.3, 4.3, H-1b), 4.59 (2H, s,
OCH2Ph), 7.25–7.36 (5H, m, arom.). 13C NMR (125 MHz, CDCl3) d:
14.0 [O(CH2)4CH3], 22.5 [O(CH2)3CH2CH3], 28.2 [O(CH2)2CH2CH2
CH3], 29.7 [OCH2CH2(CH2)2CH3], 45.4 (C-4), 51.3 (C-3), 70.6 (C-1),
71.0 [OCH2(CH2)3CH3], 73.4 (OCH2Ph), 78.1 (C-2), 127.6/128.3 (d,
arom.), 138.2 (s, arom). LRMS (FAB, pos.) m/z: 287 [M+Na]+. HRMS
(FAB, pos.): calcd for C16H24O3Na 287.1623, found 287.1628.
4.2.3.7. 1-O-Benzyl-2-O-neopentyl-D-erythritol (15g).
In a
similar manner, 14g (161 mg, 0.5 mmol) was hydrolyzed in a mix-
ture of 1% hydrochloric acid (0.5 mL) and ethanol (1 mL). A similar
work-up used for the preparation of 15c gave a practically pure
title compound (15g, 121 mg, 86%) as colorless oil, 1H NMR
(500 MHz, CDCl3) d: 0.90 [9H, s, OCH2C(CH3)3], 3.13/3.30 [each
1H, d, J = 8.6, OCH2C(CH3)3], 3.54 (1H, ddd, J = 5.8, 5.8, 4.6, H-2),
3.64 (1H, dd, J = 10.1, 5.8 H-1a), 3.67 (1H, dd, J = 10.1, 4.6, H-1b),
3.74 (2H, d-like, J = ca. 4.6, H-4a and H-4b), 3.83 (1H, dt, J = 5.8,
4.6, H-3), 4.56 (2H, s-like, OCH2Ph), 7.28–7.38 (5H, m, arom.). 13C
NMR (125 MHz, CDCl3) d: 26.6 [OCH2C(CH3)3], 32.1 [OCH2C
(CH3)3], 63.5 (C-4), 69.6 (C-1), 72.3 (C-3), 73.7 (OCH2Ph), 79.6 (C-
2), 81.4 [OCH2C(CH3)3], 127.7/127.9/128.5 (d, arom.), 137.6 (s,
arom).
4.2.4.4.
(10d).
3,4-Anhydro-1-O-benzyl-2-O-(hept-1-yl)-
In a similar manner, 15d (544 mg, 1.75 mmol) was
D-erythritol
subjected to the epoxidation. Work-up and column chromatogra-
phy (n-hexane–AcOEt, 50:1?25:1) gave the title compound (10d,
435 mg, 85%) as a colorless oil, [
a]
25 +4.7 (c 0.93, CHCl3). IR (neat):
.
D
1454, 1366, 1254, 1099, 1030 cmꢁ1
1H NMR (700 MHz, CDCl3) d:
0.88 (3H, t, J = 6.9, O(CH2)6CH3], 1.22–1.35 [8H, m O(CH2)2(CH2)4-
CH3], 1.53–1.59 [2H, m OCH2CH2(CH2)4CH3], 2.77 (1H, dd J = 5.4,
2.6 H-4a), 2.81 (1H, dd, J = 5.4, 4.0, H-4b), 3.05 (1H, ddd, J = 5.2,
4.0, 2.6, H-3), 3.36 (1H, ddd, J = 5.4, 5.2, 4.2, H-2), 3.51/3.57 [each
1H, dt, J = 9.2, 6.9, OCH2(CH2)5CH3], 3.61 (1H, dd J = 10.2, 5.4, H-
1a), 3.64 (1H, dd, J = 10.2, 4.2, H-1b), 4.58 (2H, s-like, OCH2Ph),
7.26–7.36 (5H, m, arom.). 13C NMR (175 MHz, CDCl3) d: 14.1 [O
(CH2)6CH3], 22.6 [O(CH2)5CH2CH3], 26.0 [O(CH2)2CH2(CH2)3CH3],
29.1 [O(CH2)3CH2CH2CH3], 30.0 [OCH2CH2(CH2)4CH3], 31.8 [O
(CH2)4CH2CH2CH3], 45.4 (C-4), 51.4 (C-3), 70.6 (C-1), 71.0 [OCH2
(CH2)5CH3], 73.5 (OCH2Ph), 78.1 (C-2), 127.6/128.4 (d, arom.),
138.2 (s, arom.). LRMS (FAB, pos.) m/z: 315 [M+Na]+. HRMS (FAB,
pos.): calcd for C18H28O3Na 315.1936, found 315.1924.
4.2.4. Epoxydation of diols (15a–15g)
4.2.4.1.
(10a).
3,4-Anhydro-1-O-benzyl-2-O-methyl-
To a mixture of 15a (1.51 g, 6.7 mmol), triphenylphos-
D-erythritol
phine (2.1 g, 8.0 mmol), and toluene (10 mL) was added dropwise
40% solution of diethyl azodicarboxylate (DEAD) in toluene
(3.9 mL, 8.6 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 30 min and heated under reflux for further
4 h. After removal of the solvent, the residue was triturated with
a 1:1 mixture of diethyl ether and n-hexane. The deposited solid
was filtered off, and the filtrate was condensed to give an orange
oil (2.61 g), which on column chromatography (petroleum ether–
AcOEt, 20:1?10:1) gave the title compound (10a, 1.07 g, 77%), as
24
colorless oil, [
a]
+11.2 (c 1.08, CHCl3). IR (neat): 1454, 1366,
D
1335, 1249, 1200, 1099 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d: 2.77
4.2.4.5. 3,4-Anhydro-1-O-benzyl-2-O-(tridec-1-yl)-
D-erythritol
(1H, dd, J = 5.2, 2.9, H-4a), 2.83 (1H, dd, J = 5.2, 4.0, H-4b), 3.05
(1H, ddd, J = 5.5, 4.0, 2.9, H-3), 3.26 (1H, ddd, J = 5.5, 5.5, 4.0, H-
2), 3.45 (3H, s, OCH3), 3.61 (1H, dd, J = 10.4, 5.5, H-1a), 3.66 (1H,
dd, J = 10.4, 4.0, H-1b), 4.59 (2H, s-like, OCH2Ph), 7.26–7.36 (5H,
m, arom.). 13C NMR (125 MHz, CDCl3) d: 45.5 (C-4), 50.9 (C-3),
58.4 (OCH3), 70.2 (C-1), 73.5 (OCH2Ph), 79.7 (C-2), 127.6/128.4 (d,
arom.), 138.0 (s, arom.). LRMS (FAB, pos.) m/z: 231 [M+Na]+. HRMS
(FAB, pos.): calcd for C12H16O3Na 231.0997, found 231.0969.
(10e). In a similar manner, 15e (1.0 g, 2.5 mmol) was sub-
jected to epoxidation. Work-up and column chromatography (n-
hexane–AcOEt, 50:1?30:1) gave the title compound (10e
24
772 mg, 81%) as colorless oil, [
a]
D
+11.4 (c 0.94 CHCl3). IR (neat):
1466, 1456, 1364, 1250, 1101, 1028 cmꢁ1 1H NMR (700 MHz,
.
CDCl3) d: 0.88 (3H, t, J = 7.0, O(CH2)12CH3], 1.22–1.34 [20H m O
(CH2)2(CH2)10CH3], 1.53–1.59 [2H, m OCH2CH2(CH2)10CH3], 2.76
(1H, dd, J = 5.4, 2.8, H-4a), 2.80 (1H, dd, J = 5.4, 4.0, H-4b), 3.05
(1H, ddd, J = 5.2, 4.0, 2.8, H-3), 3.36 (1H, ddd, J = 5.4, 5.2, 4.2, H-
2), 3.50/3.57 [each 1H, dt, J = 9.2, 7.0, OCH2(CH2)11CH3], 3.61 (1H,
dd, J = 10.2, 5.4, H-1a), 3.64 (1H, dd, J = 10.2, 4.2, H-1b), 4.59 (2H,
s-like, OCH2Ph), 7.26–7.36 (5H, m, arom.). 13C NMR (175 MHz,
CDCl3) d: 14.1 [O(CH2)12CH3], 22.7 [O(CH2)11CH2CH3], 26.0 [O
4.2.4.2.
(10b).
3,4-Anhydro-1-O-benzyl-2-O-ethyl-
In a similar manner, 15b (1.36 g, 5.7 mmol) was sub-
D-erythritol
jected to the epoxidation. Work-up and column chromatography
(petroleum ether–AcOEt, 20:1?10:1) gave the title compound
24
(10b, 956 mg, 76%) as colorless oil, [
a]
+6.0 (c 1.20, CHCl3). IR
.
(CH2)2CH2(CH2)9CH3],
29.3/29.5/29.61/29.63/29.65/29.67
[O
D
(neat): 1456, 1364, 1325, 1252, 1101 cmꢁ1
1H NMR (700 MHz,
(CH2)3(CH2)7(CH2)2CH3], 30.0 [OCH2CH2(CH2)10CH3], 31.9 [O
(CH2)10CH2CH2CH3], 45.4 (C-4), 51.4 (C-3), 70.6 (C-1), 71.0 [OCH2
(CH2)11CH3], 73.5 (OCH2Ph), 78.1 (C-2), 127.6/128.4 (d, arom.),
138.2 (s, arom.). LRMS (FAB, pos.) m/z: 399 [M+Na]+. HRMS (FAB,
pos.): calcd for C24H40O3Na 399.2875, found 399.2896.
CDCl3) d: 1.20 (3H, t, J = 7.0, OCH2CH3), 2.77 (1H, dd, J = 5.5, 2.8,
H-4a), 2.81 (1H, dd, J = 5.5, 4.0, H-4b), 3.06 (1H, ddd, J = 5.4, 4.0,
2.8, H-3), 3.37 (1H, ddd, J = 5.4, 5.4, 4.2, H-2), 3.59/3.65 (each 1H,
dt, J = 9.2, 7.0, OCH2CH3), 3.61 (1H, dd, J = 10.2, 5.4, H-1a), 3.64
(1H, dd, J = 10.2, 4.2, H-1b), 4.59 (2H, s-like, OCH2Ph), 7.27–7.35
(5H, m, arom.). 13C NMR (175 MHz, CDCl3) d: 15.5 (OCH2CH3),
45.5 (C-4), 51.3 (C-3), 66.2 (OCH2CH3), 70.6 (C-1), 73.5 (OCH2Ph),
78.0 (C-2), 127.6/128.3 (d, arom.), 138.2 (s, arom.). LRMS (FAB,
pos.) m/z: 245 [M+Na]+. HRMS (FAB, pos.): calcd for C13H18O3Na
245.1154, found 245.1173.
4.2.4.6.
(10f).
3,4-Anhydro-1-O-benzyl-2-O-isobutyl-
In a similar manner, 15f (150 mg, 0.56 mmol) was sub-
D-erythritol
jected to the epoxidation. Work-up and column chromatography
(n-hexane–AcOEt, 100:1?25:1) gave the title compound (10f,
23
115 mg, 82%) as colorless oil, [
a]
+9.0 (c 0.66, CHCl3). IR (neat):
D
1470, 1454, 1366, 1096, 1030 cmꢁ1 1H NMR (500 MHz, CDCl3) d:
.
4.2.4.3.
(10c).
3,4-Anhydro-1-O-benzyl-2-O-(pent-1-yl)-
In a similar manner, 15c (600 mg, 2.12 mmol) was sub-
D
-erythritol
0.89/0.90 [each 3H, d, J = 6.6, OCH2CH(CH3)2], 1.84 [1H, triple hept.,
J = 6.6, 6.6, OCH2CH(CH3)2], 2.77 (1H, dd, J = 5.4, 2.6, H-4a), 2.80
(1H, dd, J = 5.4, 4.0, H-4b), 3.06 (1H, ddd, J = 5.2, 4.0, 2.6, H-3),
3.28/3.34 [each 1H, d, J = 8.9, 6.6, OCH2CH(CH3)2], 3.37 (1H, ddd,
J = 5.2, 5.2, 4.3, H-2), 3.61 (1H, dd, J = 10.3, 5.2, H-1a), 3.64 (1H,
dd, J = 10.3, 4.3, H-1b), 4.59 [2H, s-like, OCH2Ph], 7.26–7.36 (5H,
m, arom.). 13C NMR (125 MHz, CDCl3) d: 19.3 [OCH2CH(CH3)2],
28.8 [OCH2CH(CH3)2], 45.3 (C-4), 51.4 (C-3), 70.6 (C-1), 73.5
jected to the epoxidation. Work-up and column chromatography
(n-hexane–AcOEt, 50:1?25:1) gave the title compound (10c
22
460 mg, 82%) as colorless oil, [
a
]
+6.4 (c 1.02, CHCl3). IR (neat):
D
1454, 1366, 1342, 1254, 1207, 1099, 1030 cmꢁ1
.
1H NMR
(500 MHz, CDCl3) d: 0.89 [3H, t, J = 6.9, O(CH2)4CH3), 1.27–1.36
[4H, m, O(CH2)2(CH2)2CH3], 1.52–1.61 [2H, m, OCH2CH2(CH2)2CH3],
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

8
G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
(OCH2Ph), 77.8 [OCH2CH(CH3)2] 78.2 (C-2), 127.6/128.4 (d, arom.),
138.2 (s, arom.). LRMS (FAB, pos.) m/z: 273 [M+Na]+. HRMS (FAB,
pos.): calcd for C15H22O3Na 273.1467, found 273.1445.
J = ca. 13.0, 7.8, H-10b), 4.19 (1H, br s-like, H-3), 4.31 (1H, dd-like,
J = ca. 13.2, 3.2, H-1b), 4.33–4.37 (1H, m, H-20), 4.39 (1H, d,
J = 11.8, OCH2Ph), 4.37–4.41 (1H, m, H-2), 4.43–4.62 (7H, m, OCH2
Ph), 6.57 (1H, br s, OH), 7.12–7.36 (20H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 15.5 (OCH2CH3), 48.3 (C-1), 51.8 (C-10), 65.8
(C-4), 66.0 (OCH2CH3), 67.0 (C-5), 68.0 (C-20), 68.5 (C-40),
71.9/72.2/73.5/73.6 (OCH2Ph), 80.4 (C-30), 82.4 (C-3), 82.5 (C-2),
127.6/127.8/127.9/128.1/128.2/128.3/128.4/128.47/128.54/128.68/
128.72/128.83 (d, arom.), 135.9/136.0/136.7/137.9 (s, arom.). LRMS
(FAB, pos.) (pos.) m/z: 643 [MꢁCl]+.
4.2.4.7.
(10g).
3,4-Anhydro-1-O-benzyl-2-O-neopentyl-
In a similar manner, 15g (110 mg, 0.39 mmol) was sub-
D-erythritol
jected to the epoxidation. Work-up and column chromatography
(n-hexane–AcOEt, 100:1?20:1) gave the title compound (10g,
23
92 mg, 89%) as colorless oil, [
a
]
D
+11.2 (c 0.99, CHCl3). IR (neat):
2955, 2866, 1454, 1362, 1258, 1099, 1026 cmꢁ1
.
1H NMR
(500 MHz, CDCl3) d: 0.90 [9H, s, OCH2C(CH3)3], 2.79 (2H, d-like,
J = 3.4, H-4a and H-4b), 3.06 (1H, dt, J = 4.9, 3.4 H-3), 3.16 [each
1H, d, J = 8.6, OCH2C(CH3)3], 3.40 (1H, ddd, J = 4.9, 4.9, 4.9, H-2),
3.61 (1H, dd, J = 10.8, 4.9, H-1a), 3.64 (1H, dd, J = 10.8, 4.9, H-1b),
4.59 [2H, s-like, OCH2Ph], 7.25–7.36 (5H, m, arom.). 13C NMR
(125 MHz, CDCl3) d: 26.7 [OCH2C(CH3)3], 32.2 [OCH2C(CH3)3],
45.0 (C-4), 51.7 (C-3), 70.7 (C-1), 73.4 (OCH2Ph), 78.4 (C-2), 81.5
[OCH2C(CH3)3], 127.5/127.6/128.4 (d, arom.), 138.3 (s, arom.).
LRMS (FAB, pos.) m/z: 287 [M+Na]+. HRMS (FAB, pos.): calcd for
4.2.5.3.
(pent-1-yl)-
dideoxy- -arabinitol chloride (
title compound ( -16c, 242 mg, 71%) was obtained by the S-alky-
lation of thiosugar 9 (200 mg, 0.48 mmol) with epoxide 10c
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
-erythritol-4-yl]episulfoniumylidene}-1,4-
-16c). In a similar manner,
D
D
a
a
23
(150 mg, 0.57 mmol) as colorless oil, [
a]
ꢁ6.4 (c 0.96, CHCl3). IR
D
(neat): 3167, 1497, 1454, 1400, 1362, 1207, 1096, 1030 cmꢁ1
.
1H
NMR (700 MHz, CDCl3) d: 0.87 [3H, t, J = 7.0, O(CH2)4CH3], 1.23–
1.32 [4H m O(CH2)2(CH2)2CH3], 1.48–1.56 [2H, m, OCH2CH2(CH2)2
CH3], 3.48/3.61 [each 1H, dt, J = 9.2, 7.0, OCH2(CH2)3CH3], 3.67
(1H dd, J = 11.4, 3.9, H-40a), 3.74 (1H, br dd-like, J = ca. 6.0, 3.9, H-
30), 3.75 (1H, br d-like, J = ca. 11.4, H-40b), 3.77 (2H, d-like, J = 7.4,
H-5a and H-5b), 4.07 (1H, br d, J = 13.2, H-1a), 4.13 (1H, dd,,
J = 13.0, 4.0, H-10a), 4.14–4.18 (1H, m, H-4), 4.17 (1H, dd-like,
J = ca, 13.0, 7.8, H-10b), 4.19 (1H, br s-like, H-3), 4.31 (1H, dd,
J = 13.2, 3.4, H-1b), 4.34–4.38 (1H, m, H-20), 4.38–4.40 (1H, br m,
H-2), 4.38–4.61 (8H, m, OCH2Ph), 6.60 (1H, br s, OH), 7.23–7.36
(20H, m, arom.). 13C NMR (175 MHz, CDCl3) d: 14.0 [O(CH2)4CH3],
22.4 [O(CH2)3CH2CH3], 28.1 [O(CH2)2CH2CH2CH3], 29.6 [OCH2CH2
(CH2)2CH3], 48.2 (C-1), 51.9 (C-10), 65.9 (C-4), 67.0 (C-5), 68.1 (C-20),
68.4 (C-40), 70.8 [OCH2(CH2)3CH3], 71.9/72.3/73.6/73.6 (OCH2Ph),
80.7 (C-30), 82.4 (C-3), 82.5 (C-2), 127.7/127.8/127.9/128.0/12
8.2/128.3/128.4/128.49/128.54/128.6/128.7/128.8 (d, arom.), 135.9/
136.0/136.7/138.0 (s, arom). LRMS (FAB, pos.) m/z: 685 [M–Cl]+.
C16H24O3Na 287.1623, found 287.1635.
4.2.5. S-Alkylation of reaction of thiosugar (9) with epoxides
(10a–10g)
4.2.5.1.
methyl-
arabinitol chloride (
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
-erythritol-4-yl]episulfoniumylidene}-1,4-dideoxy-
-16a). To a mixture of epoxide 10a
D
D-
a
(100 mg, 0.48 mmol), thiosugar 9 (168 mg, 0.4 mmol), and CH2Cl2
(2 mL) was added tetrafluoroboric acid dimethyl ether complex
(HBF4ꢀ(CH3)2O, 63 L, 0.52 mmol) at ꢁ60 °C. The reaction mixture
l
was stirred for 3 h and concentrated in vacuo. The residue was
treated with ion exchange resin IRA-400J (Clꢁ form) in methanol
(3 mL) at room temperature. The resin was filtered off, and the fil-
trate was concentrated to give a colorless oil (290 mg), which on
column chromatography (CHCl3 ? CHCl3–MeOH, 100:1?50:1)
gave the title compound (
a-16a, 191 mg, 72%) and a mixture of a
and b-isomers (77 mg). Re-purification of the mixture by column
24
chromatography gave
ꢁ7.3 (c 0.65, CHCl3). IR (neat): 3174, 1454, 1404, 1365, 1261,
1095, 1072, 1030 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 3.41 (3H, s,
a
-16a (43 mg, 16%). Colorless oil. [
a
]
4.2.5.4.
(hept-1-yl)-
dideoxy- -arabinitol chloride (
title compound ( -16d, 192 mg, 69%) was obtained by the S-alkyla-
tion of thiosugar 9 (156 mg, 0.37 mmol) with epoxide 10d (130 mg,
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
-erythritol-4-yl]episulfoniumylidene}-1,4-
-16d). In a similar manner,
D
D
.
D
a
OCH3), 3.67 (1H, dd-like, J = ca. 11.5, 2.5, H-40a), 3.68 (1H, ddd-like,
J = ca. 6.0, 3.8, 2.5, H-30), 3.76 (2H, d-like, J = ca. 8.0, H-5a and H-5b),
3.80 (1H, dd, J = 11.5, 3.8, H-40b), 4.10 (1H, dd, J = 12.6, 3.7, H-10a),
4.11–4.15 (2H, m, H-1a and H-4), 4.15 (1H, dd-like, J = ca. 12.6, 7.4,
H-10b), 4.17 (1H, m, H-3), 4.31 (1H, dd, J = 13.2, 3.8, H-1b), 4.34–
4.39 (1H, m, H-20), 4.39–4.41 (1H, m, H-2), 4.39 (1H, d, J = 11.7,
OCH2Ph), 4.47–4.61 (7H, m, OCH2Ph), 6.65 (1H, br s, OH), 7.13–
7.37 (20H, m, arom.). 13C NMR (125 MHz, CDCl3) d: 48.4 (C-1),
51.9 (C-10), 57.9 (OCH3), 66.1 (C-4), 66.9 (C-5), 67.4 (C-40), 68.1
(C-20), 71.9/72.3/73.6(2xC) (OCH2Ph), 82.0 (C-30), 82.3 (C-3), 82.4
(C-2), 127.7/127.8/127.96/127.99/128.2/128.3/128.4/128.5/128.56/
128.6/128.7/128.8 (d, arom), 135.8/136.0/136.7/ 137.9 (arom).
LRMS (FAB, pos.) m/z: 629 [M–Cl]+ (pos.).
a
23
0.45 mmol) as colorless oil, [
a
]
D
ꢁ15.0 (c 1.32, CHCl3). IR (neat):
3167, 1454, 1404, 1362, 1207, 1096, 1030 cmꢁ1. H NMR (700 MHz,
CDCl3) d: 0.87 (3H, t, J = 7.0, O(CH2)6CH3], 1.21–1.31 [8H, m O
(CH2)2(CH2)4CH3], 1.47–1.55 [2H,
m
OCH2CH2(CH2)4CH3],
3.49/3.60 [each 1H, dt, J = 9.2, 7.0, OCH2(CH2)5CH3], 3.67 (1H, dd-
like, J = ca. 11.0, 3.8, H-40a), 3.72–3.76 (1H, m, H-30), 3.75 (1H dd-like,
J = ca. 11.0, 3.5, H-40b), 3.77 (2H, d-like, J = 7.4, H-5a and H-5b), 4.07
(1H, br d, J = ca. 13.2, H-1a), 4.13 (1H, dd-like, J = ca. 13.5, 3.8, H-10a),
4.15–4.18 (1H, m, H-4), 4.16 (1H, dd, J = 13.5, 7.5, H-10b), 4.19 (1H, br
s-like, H-3), 4.30 (1H, dd, J = 13.2, 3.2, H-1b), 4.34–4.37 (1H, m, H-20),
4.38 (1H, m. H-2), 4.38/4.47 (each 1H, d, J = 11.6, OCH2Ph), 4.48–4.61
(6H, m, OCH2Ph), 6.58 (1H, d, J = 7.2, OH), 7.13–7.36 (20H, m, arom.).
13C NMR (175 MHz, CDCl3) d: 14.1 [O(CH2)6CH3], 22.6 [O(CH2)5CH2
CH3], 26.0 [O(CH2)2CH2(CH2)3CH3], 29.1 [O(CH2)3CH2CH2CH3], 30.0
[OCH2CH2(CH2)4CH3], 31.8 [O(CH2)4CH2CH2CH3], 48.2 (C-1), 52.0
(C-10), 65.9 (C-4), 67.0 (C-5), 68.1 (C-20), 68.5 (C-40), 70.9 [OCH2
(CH2)5CH3], 71.9/72.3/73.58/73.63 (OCH2Ph), 80.7 (C-30), 82.45 (C-
3), 82.51 (C-2), 127.7/127.8/127.9/128.0/128.2/128.3/128.4/12
8.50/128.54/128.6/128.7/128.8 (d, arom.), 135.9/136.0/136.7/13
8.0 (s, arom). LRMS (FAB, pos.) m/z:713 [MꢁCl]+.
4.2.5.2.
ethyl- -erythritol-4-yl]episulfoniumylidene}-1,4-dideoxy-
arabinitol chloride ( -16b). In a similar manner, title com-
pound ( -16b, 186 mg, 73%) was obtained by the S-alkylation of
thiosugar 9 (158 mg, 0.38 mmol) with epoxide 10b (100 mg,
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
D
D-
a
a
24
0.45 mmol) as colorless oil, [
3186, 1497, 1454, 1400, 1366, 1327, 1257, 1207, 1099, 1072,
1026 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 1.15 (3H, t, J = 7.0, OCH2
a
]
ꢁ8.8 (c 1.02, CHCl3). IR (neat):
D
.
CH3), 3.56/3.70 (each 1H, dq-like, J = 9.2, 7.0, OCH2CH3), 3.67 (1H,
dd-like, J = ca. 10.6, 2.0, H-40a), 3.74 (1H, dd-like, J = ca. 10.6, 2.6,
H-40b), 3.72–3.76 (1H, m, H-30), 3.78 (2H, d-like, J = 7.5, H-5a and
H-5b), 4.07 (1H, br d-like, J = ca. 13.2, H-1a), 4.13 (1H, br dd-like,
J = ca. 13.0, 3.5, H-10a), 4.13–4.17 (1H, m, H-4), 4.17 (1H, dd-like,
4.2.5.5.
(tridec-1-yl)-
dideoxy- -arabinitol chloride (16e).
title compound (
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
D
-erythritol-4-yl]episulfoniumylidene}-1,4-
D
In a similar manner,
a
-16e, 135 mg, 73%) was obtained by the S-alky-
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
9
lation of thiosugar
(100 mg, 0.27 mmol) as colorless oil. Small amount of a sample
of minor b-isomer b-16e suitable for NMR analysis was obtained
with a purity of >ca. 90% from the later chromatographic fractions.
9
(93 mg, 0.22 mmol) with epoxide 10e
71.9/72.4/73.5/73.6 (OCH2Ph), 77.4 [OCH2C(CH3)3], 80.9 (C-30),
82.4 (C-2 and C-3), 127.6/127.8/128.0/128.2/128.26/128.34/12
8.49/128.53/128.6/128.7/128.8 (d, arom.), 135.8/136.0/136.7/13
8.0 (s, arom). LRMS (FAB, pos.) m/z: 671 [M–Cl]+ (pos.).
24
The major isomer
a
-16e: [
a
]
ꢁ3.9 (c 0.96 CHCl3). IR (neat):
D
3333, 1456, 1361, 1096, 1074, 1028 cmꢁ1
.
1H NMR (500 MHz,
4.2.5.7.
neopentyl-D
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
-erythritol-4-yl]episulfoniumylidene}-1,4-dideoxy-
-16g). In a similar manner, title com-
-16g, 79 mg, 67%) was obtained by the S-alkylation of
(69 mg, 0.16 mmol) with epoxide 10g (60 mg,
CDCl3) d: 0.88 [3H, t, J = 7.0, O(CH2)12CH3], 1.21–1.31 [20H, m, O
(CH2)2(CH2)10CH3], 1.46–1.58 [2H, m, OCH2CH2(CH2)10CH3],
3.48/3.60 [each 1H, dt, J = 9.2, 7.0, OCH2CH2(CH2)10CH3], 3.67 (1H,
dd-like, J = 11.4, 4.0, H-40a), 3.72–3.76 (1H, m, H-30), 3.74 (1H, dd,
J = 11.4, 3.6, H-40b), 3.77 (2H, d-like, J = 7.4, H-5a and H-5b), 4.07
(1H, dd, J = 13.4, 2.0, H-1a), 4.13 (1H, dd-like, J = ca. 13.0, 4.0,
H-10a), 4.13–4.18 (1H, m, H-4), 4.17 (1H, dd-like, J = ca. 13.0, 7.0, H-
10b), 4.19 (1H, br m, H-3), 4.31 (1H, dd, J = 13.4, 3.8, H-1b), 4.33–
4.37 (1H, m, H-20), 4.37–4.41 (1H, m, H-2), 4.39 (1H, d, J = 11.8,
OCH2Ph), 4.44–4.60 (8H, m, OCH2Ph), 6.60 (1H, d, J = 7.2, OH),
7.14–7.35 (20H, m, arom). 13C NMR (125 MHz, CDCl3) d: 14.1 [O
(CH2)12CH3], 22.7 [O(CH2)11CH2CH3], 26.1 [O(CH2)2CH2(CH2)9CH3],
29.3/29.5/29.6/29.7 [O(CH2)3(CH2)7(CH2)2CH3], 30.0 [OCH2CH2
(CH2)10CH3], 31.9 [O(CH2)10CH2CH2CH3], 48.2 (C-1), 51.9 (C-10),
65.9 (C-4), 67.0 (C-5), 68.1 (C-20), 68.4 (C-40), 70.9 [OCH2(CH2)11
CH3], 71.9/72.3/73.56/73.60 (OCH2Ph), 80.7 (C-30), 82.4 (C-3),
82.5 (C-2), 127.6/127.8/127.9/128.0/128.2/1283/128.4/128.50/
128.54/128.6/128.7/128.8 (d, arom), 135.8/136.0/136.7/138.0 (4C,
s, arom). LRMS (FAB, pos.) m/z: 797 [M–Cl]+.
D-arabinitol chloride (a
pound (
a
thiosugar
0.23 mmol) as colorless oil, [
3167, 1454, 1404, 1361, 1327, 1254, 1211, 1095, 1061,
1026 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 0.85 [9H, s, OCH2C
9
20
a]
ꢁ11.8 (c 1.05, CHCl3). IR (neat):
D
.
(CH3)3], 3.13/3.31 [each 1H, d, J = 8.9, OCH2C(CH3)3], 3.68 (1H, dd,
J = 10.4, 3.5, H-40a), 3.69–3.73 (1H, m, H-30), 3.73 (1H dd J = 10.8,
8.9, H-5a), 3.77 (1H, dd, J = 10.8, 7.2, H-5b), 3.78 (1H, dd, J = 10.4,
2.3, H-40b), 4.08 (1H, dd, J = 12.3, 3.4, H-10a), 4.148 (1H, dd-like,
J = ca. 12.3, 8.0, H-10b), 4.152 (1H, br s-like, H-3), 4.16 (1H, dd-like,
J = 13.2, 2.3, H-1a), 4.14–4.18 (1H, m, H-4), 4.30 (1H, dd, J = 13.2,
3.7, H-1b), 4.34–4.40 (1H, m, H-20), 4.40 (1H, m, H-2), 4.44 (1H,
d, J = 11.8, OCH2Ph), 4.47–4.61 (7H, m, OCH2Ph), 7.14–7.36 (20H,
m, arom.). 13C NMR (125 MHz, CDCl3) d: 26.7 [OCH2C(CH3)3], 32.1
[OCH2C(CH3)3], 48.0 (C-1), 51.8 (C-10), 66.2 (C-4), 67.1 (C-5), 68.1
(C-20), 68.5 (C-40), 71.9/72.4/73.5/73.7 (OCH2Ph), 81.0 [OCH2C
(CH3)3], 81.3 (C-30), 82.3 (C-2), 82.5 (C-3), 127.6/127.7/127.97/12
The minor isomer b-16e: 1H NMR (700 MHz, CDCl3) d: 0.88 (3H,
t, J = 7.0, O(CH2)12CH3], 1.22–1.34 [20H m O(CH2)2(CH2)10CH3],
1.45–1.50 [2H, m OCH2CH2(CH2)10CH3], 3.47/3.61 [each 1H, dt,
J = 9.4, 7.0, OCH2CH(CH3)2], 3.57 (1H, dd, J = 10.6, 4.2, H-40a), 3.66
(1H, ddd-like, J = ca. 5.6, 4.2, 3.2, H-30), 3.71 (1H, dd, J = 10.6, 3.2,
H-40b), 3.72–3.76 (1H, m, H-1a), 3.75 (1H, dd, J = 10.4, 5.8, H-5a),
3.85 (1H, dd, J = 10.4, 8.6, H-5b), 3.88 (1H, dd, J = 12.4, 5.8, H-10a),
4.06 (1H, dd, J = 12.4, 3.8, H-10b), 4.13 (1H ddd-like, J = ca. 8.6,
5.8, 2.0, H-4), 4.22 (1H, br s-like, H-3), 4.34/4.43 (each 1H, d,
J = 11.8, OCH2Ph), 4.38 (1H, br s-like, H-2), 4.44/4.48 (each 1H, d,
J = 12.0, OCH2Ph), 4.43–4.46 (1H, m, H-20), 4.44 (2H, s, OCH2Ph),
4.52/4.80 (each 1H, d, J = 12.0, OCH2Ph), 4.75 (1H, d, J = 14.6, H-
1b), 7.13–7.36 (20H, m, arom.). 13C NMR (175 MHz, CDCl3) d:
14.1 [O(CH2)12CH3], 22.7 [O(CH2)11CH2CH3], 26.1 [O(CH2)2CH2
(CH2)9CH3], 29.3/29.5/29.6/29.7, [O(CH2)3(CH2)7(CH2)2CH3], 30.1
[OCH2CH2(CH2)10CH3], 31.9 [O(CH2)10CH2CH2CH3], 42.9 (C-10),
45.3 (C-1), 60.8 (C-4), 65.3 (C-5), 66.3 (C-20), 69.6 (C-40), 71.0
[OCH2(CH2)11CH3], 72.2/72.3/73.4/73.5 (OCH2Ph), 80.6 (C-30), 82.5
(C-2), 84.6 (C-3), 127.6/127.7/127.97/128.01/128.3/12 8.39/12
7.99/128.2/128.3/128.4/128.5/128.6/128.76/128.81(d,
arom.),
135.8/136.0/136.2/138.2 (s, arom). LRMS (FAB, pos.) m/z: 685
[MꢁCl]+.
4.2.6. Hydrogenolysis of sulfonium salts (
4.2.6.1. 1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-methyl-
4-yl]episulfoniumylidene}- -arabinitol chloride (8a).
a-16a–
a
-16g)
D
-erythritol-
D
A
suspension of 10% Pd–C (100 mg) in 80% aqueous acetic acid
(2 mL) was pre-equilibrated with hydrogen. To the suspension
was added a solution of
a-16a (160 mg, 0.24 mmol) in 80% aque-
ous acetic acid (3 mL), and the mixture was hydrogenated at
50 °C for 12 h. The catalysts were filtered off, and the filtrate was
condensed to give colorless oil (78 mg), in which a partially acety-
lated product was contaminated. The oil was then treated with a
mixture of 10% hydrochloric acid (0.1 mL) and methanol (1 mL)
at room temperature for 3 h. Removal of the solvent at reduced
pressure left a colorless oil (74 mg), which on column chromatog-
raphy (CHCl3–MeOH, 10:1 ? CHCl3–MeOH–H2O, 6:4:1) gave title
26
compound (8a, 53 mg, 72%) as colorless oil, [
a]
+2.1 (c 1.97, CH3
D
8.42/128.6/128.65/128.71128.8
(d,
arom.),
135.9/136.1/13
OH). IR (neat): 3333, 1651, 1408, 1261, 1084, 1053, 1026 cmꢁ1 1H
.
6.3/138.1 (s, arom.). LRMS (FAB, pos.) m/z: 797 [MꢁCl]+.
NMR (500 MHz, CD3OD) d: 3.29 (1H, ddd-like, J = ca. 6.0, 4.0, 4.0, H-
30), 3.47 (3H, s, OCH3), 3.66 (1H, dd, J = 12.3, 4.0, H-40a), 3.73 (1H,
dd, J = 12.9, 9.2, H-10a), 3.80 (1H, dd, J = 12.3, 4.0, H-40b), 3.82
(1H, dd, J = 12.9, 3.4, H-10b), 3.85 (2H, d-like, J = ca. 2.3, H-1a and
H-1b), 3.92 (1H, dd, J = 10.9, 9.5, H-5a), 3.99 (1H, br dd-like,
J = ca. 9.5, 4.9, H-4), 4.05 (1H, dd, J = 10.9, 4.9, H-5b), 4.20 (1H,
ddd, J = 9.2, 6.0, 3.4, H-20), 4.36 (1H, dd, J = 2.3, 1.1, H-3), 4.62
(1H, dt, J = 2.3, 2.3, H-2). 13C NMR (125 MHz, CD3OD) d: 51.8 (C-
10), 52.1 (C-1), 58.5 (OCH3), 60.0 (C-40), 61.0 (C-5), 68.6 (C-20),
73.7 (C-4), 79.4 (C-2), 79.5 (C-3), 85.1 (C-30). LRMS (FAB, pos.)
m/z: 269 [M–Cl]+. HRMS (FAB, pos.): calcd for C10H21O6S 269.1059,
found 269.1059.
4.2.5.6.
isobutyl-
2,3,5-Tri-O-benzyl-1,4-{(R)-[1-O-benzyl-4-deoxy-3-O-
-erythritol-4-yl]episulfoniumylidene}-1,4-dideoxy-
-16f). In a similar manner, title com-
-16f, 135 mg, 73%) was obtained by the S-alkylation of
(110 mg, 0.26 mmol) with epoxide 10f (78 mg,
D
D-
arabinitol chloride (
pound (
thiosugar
0.31 mmol) as a colorless oil, [
3152, 1497, 1454, 1400, 1366, 1327, 1254, 1207, 1177, 1092,
1030 cmꢁ1 1H NMR (500 MHz, CDCl3) d: 0.84/0.85 [each 3H, d,
a
a
9
20
a]
D
ꢁ9.3 (c 0.98, CHCl3). IR (neat):
.
J = 6.6, OCH2CH(CH3)2], 1.78 [1H, triple hept., J = 6.6, 6.6, OCH2CH
(CH3)2], 3.23/3.39 [each 1H, dd, J = 9.2, 6.6, OCH2C(CH3)3], 3.67
(1H, dd-like, J = ca. 10.5, 2.0, H-40a), 3.70–3.75 (1H, m, H-30),
3.73–3.77 (1H, m, H-40b), 3.77 (2H, d-like, J = ca. 7.2, H-5a and H-
5b), 4.10 (1H, br d-like, J = ca. 13.0, H-1a), 4.09–4.17 (3H, m, H-
10a, H-10b and H-4), 4.18 (1H, br s-like, H-3), 4.31 (1H, br d-like,
J = ca. 13.0, H-1b), 4.34–4.40 (1H, m, H-20), 4.40/4.49 (each 1H, d,
J = 12.1, OCH2Ph), 4.41 (1H, m, H-2), 4.52–4.60 (6H, m, OCH2Ph),
7.14–7.36 (20H, m, arom.). 13C NMR (125 MHz, CDCl3) d:
19.3/19.4 [OCH2CH(CH3)2], 28.6 [OCH2CH(CH3)2], 48.2 (C-1), 51.9
(C-10), 66.0 (C-4), 67.0 (C-5), 68.1 (C-20), 68.3 (C-40),
4.2.6.2. 1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-ethyl-
yl]episulfoniumylidene}- -arabinitol chloride (8b).
similar manner, sulfonium salt -16b (110 mg, 0.16 mmol) was
subjected to the hydrogenolysis. Work-up and column chromatog-
D-erythritol-4-
D
In
a
a
24
raphy gave title compound (8b, 39 mg, 75%) as a colorless oil, [
+3.3 (c 0.68, CH3OH). IR (neat): 3333, 1647, 1408, 1261, 1173,
1084, 1030 cmꢁ1 1H NMR (700 MHz, CD3OD) d: 1.21 (3H, t,
J = 7.0, OCH2CH3), 3.39 (1H, dd, J = 5.8, 4.2, 4.0, H-30), 3.59/3.75
a]
D
.
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

10
G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
26
(each 1H, dq, J = 9.4, 7.0, OCH2CH3), 3.65 (1H, dd, J = 12.1, 4.0, H-
40a), 3.74 (1H, dd, J = 13.2, 9.0, H-10a), 3.76 (1H, dd, J = 12.1, 4.2,
H-40b), 3.83 (1H, dd, J = 13.2, 3.4, H-10b), 3.86 (2H, d-like, J = ca.
2.6, H-1a and H-1b), 3.92 (1H, dd, J = 11.4, 9.6, H-5a), 3.99 (1H,
br dd-like, J = ca. 9.6, 5.2, H-4), 4.05 (1H, dd, J = 11.4, 5.2, H-5b),
4.19 (1H, ddd, J = 9.0, 5.8, 3.4, H-20), 4.37 (1H, dd, J = 2.4, 1.2, H-
3), 4.62 (1H, td, J = 2.6, 2.4, H-2). 13C NMR (175 MHz, CD3OD) d:
15.8 (OCH2CH3), 51.8 (C-10), 52.1 (C-1), 60.8 (C-40), 61.1 (C-5),
67.2 (OCH2CH3), 68.7 (C-20), 73.7 (C-4), 79.4 (C-2), 79.5 (C-3),
83.5 (C-30). LRMS (FAB, pos.) m/z: 283 [M–Cl]+. HRMS (FAB, pos.):
calcd for C11H23O6S 283.1215, found 283.1212.
a colorless oil, [
1645, 1506, 1408, 1262, 1086, 1053, 1026 cmꢁ1
(700 MHz, CDCl3) d: 0.89 [3H, t, J = 7.0, O(CH2)12CH3], 1.25–1.34
[20H, m, O(CH2)2(CH2)10CH3], 1.54–1.63 [2H, m, OCH2CH2(CH2)10
a
]
+11.0 (c 0.51, CH3OH). IR (neat): 3433,
D
.
1H NMR
-
CH3], 3.37 (1H, ddd, J = 5.6, 4.4, 4.0, H-30), 3.52/3.68 [each 1H, dt,
J = 9.2, 7.0, OCH2(CH2)11CH3], 3.66 (1H, dd, J = 12.0, 4.0, H-40a),
3.74 (1H, dd, J = 13.2, 9.0, H-10a), 3.76 (1H, dd, J = 12.0, 4.4, H-
40b), 3.82 (1H, dd, J = 13.2, 3.4, H-10b), 3.85 (2H, d-like, J = ca.
2.8, H-1a and H-1b), 3.92 (1H, dd, J = 11.0, 9.8, H-5a), 3.97 (1H,
dd-like, J = ca. 9.8, 4.8, H-4), 4.04 (1H, dd, J = 11.0, 4.8, H-5b),
4.20 (1H, ddd, J = 9.0, 5.6, 3.4, H-20), 4.37 (1H, dd, J = 2.2, 1.2, H-
3), 4.62 (1H, td-like, J = 2.8, 2.2, H-2). 13C NMR (175 MHz, CDCl3)
d: 14.4 [O(CH2)12CH3], 23.7 [O(CH2)11CH2CH3], 27.2 [O(CH2)2CH2
(CH2)9CH3], 30.4/30.6/3 0.7 [O(CH2)3(CH2)7(CH2)2CH3], 31.1 [OCH2-
CH2(CH2)10CH3], 33.0 [O(CH2)10CH2CH2CH3], 51.8 (C-10), 52.2 (C-1),
60.8 (C-40), 61.1 (C-5), 68.8 (C-20), 72.0 [OCH2(CH2)12CH3], 73.8
(C-4), 79.5 (C-2), 79.6 (C-3), 83.7 (C-30). LRMS (FAB, pos.) m/z:
437 [M–Cl]+. HRMS (FAB, pos.): calcd for C22H45O6S requires
437.2937, found 437.2949.
4.2.6.3.
thritol-4-yl]episulfoniumylidene}-
(8c). In a similar manner, sulfonium salt
1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-(pent-1-yl)-D-ery-
D
-arabinitol
chloride
a
-16c (80 mg,
0.11 mmol) was subjected to hydrogenolysis. Work-up and column
chromatography gave title compound (8c, 31 mg, 73%) as a color-
23
less oil, [
a
]
D
+10.2 (c 1.27, CH3OH). IR (neat): 3032, 1454, 1404,
1373, 1254, 1215, 1157, 1072 cmꢁ1 1H NMR (500 MHz, CD3OD)
.
d: 0.92 [3H, t, J = 6.9, O(CH2)4CH3], 1.31–1.38 [4H m O(CH2)2(CH2)2
CH3], 1.54–1.64 [2H, m, OCH2CH2(CH2)2CH3], 3.38 (1H, ddd, J = 5.7,
4.3, 4.1, H-30), 3.52/3.69 [each 1H, dt, J = 9.2, 6.9, OCH2(CH2)3CH3],
3.66 (1H, dd, J = 12.0, 4.1, H-40a), 3.74 (1H, dd, J = 13.2, 9.2, H-10a),
3.76 (1H, dd, J = 12.0, 4.3, H-40b), 3.83 (1H, dd, J = 13.2, 3.5, H-10b),
3.85 (1H, d-like, J = 2.6, H-1a and H-1b), 3.92 (1H, dd, J = 10.6, 9.8,
H-5a), 3.98 (1H, br dd-like, J = ca. 9.8, 4.3, H-4), 4.05 (1H, dd,
J = 10.6, 4.3, H-5b), 4.20 (1H, ddd, J = 9.2, 5.7, 3.5, H-20), 4.37 (1H,
dd, J = 2.6, 1.1, H-3), 4.62 (1H, dt, J = 2.6, 2.6, H-2). 13C NMR
(125 MHz, CD3OD) d: 14.3 [O(CH2)4CH3], 23.6 [O(CH2)3CH2CH3],
29.4 [O(CH2)2CH2CH2CH3], 30.8 [OCH2CH2(CH2)2CH3], 51.8 (C-10),
52.2 (C-1), 60.7 (C-40), 61.0 (C-5), 68.7 (C-20), 71.9 [OCH2(CH2)3
CH3], 73.8 (C-4), 79.46 (C-2), 79.52 (C-3), 83.7 (C-30). LRMS (FAB,
pos.) m/z: 325 [M–Cl]+. HRMS (FAB, pos.): calcd for C14H29O6S
325.1685, found 325.1639.
4.2.6.6. 1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-isobutyl-
tol-4-yl]episulfoniumylidene}- -arabinitol
(8f). In similar manner, sulfonium salt a-16f (79 mg,
D
-erythri-
chloride
D
a
0.11 mmol) was subjected to hydrogenolysis. Work-up and column
chromatography gave title compound (8f, 29 mg, 75%) as a color-
23
less oil, [
a]
+9.3 (c 0.66, CH3OH). IR (neat): 3306, 1470, 1404,
D
1369, 1327, 1250, 1172, 1084, 1022 cmꢁ1 1H NMR (500Mz,
.
CD3OD) d: 0.91/0.93 [each 3H, d, J = 6.6, OCH2CH(CH3)2], 1.85
[1H, triple hept., J = 6.6, 6.6, OCH2CH(CH3)2], 3.29/3.46 [each 1H,
dd, J = 8.9, 6.6, OCH2C(CH3)3], 3.36 (1H, ddd, J = 5.8, 4.0, 4.0, H-30),
3.67 (1H, dd, J = 12.1, 4.0, H-40a), 3.75 (1H, dd, J = 12.9, 9.2, H-
10a), 3.76 (1H, dd, J = 12.1, 4.0, H-40b), 3.84 (1H, dd, J = 12.9, 3.2,
H-10b), 3.85 (1H, dd-like, J = 12.5, 3.5, H-1a), 3.87 (1H, dd-like,
J = 12.5, 1.8, H-1b), 3.92 (1H, dd, J = 10.9, 9.8, H-5a), 3.98 (1H, br
dd-like, J = ca. 9.8, 4.6, H-4), 4.05 (1H, dd, J = 10.9, 4.6, H-5b), 4.22
(1H, ddd, J = 9.2, 5.8, 3.2, H-20), 4.38 (1H, dd, J = 2.0, 1.2, H-3),
4.62 (1H, ddd, J = 3.5, 2.0, 1.8, H-2). 13C NMR (125 MHz, CD3OD)
d: 19.7/19.8 [CH(CH3)2], 30.0 [CH(CH3)2], 51.9 (C-10), 52.2 (C-1),
60.7 (C-40), 61.0 (C-5), 68.8 (C-20), 73.8 (C-4), 78.7 [OCH2CH
(CH3)2], 79.47 (C-2), 79.52 (C-3), 83.9 (C-30). LRMS (FAB, pos.)
m/z: 311 [M]+. HRMS (FAB, pos): calcd for C13H27O6S 311.1529,
found 311.1550.
4.2.6.4.
thritol-4-yl]episulfoniumylidene}-
(8d). In a similar manner, sulfonium salt
1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-(hept-1-yl)-D-ery-
D
-arabinitol
chloride
a
-16d (50 mg,
0.07 mmol) was subjected to hydrogenolysis. Work-up and column
chromatography gave title compound (8d, 18.5 mg, 71%) as a col-
23
orless oil, [
a]
+10.0 (c 0.96, CH3OH). IR (neat): 3287, 1454,
D
1404, 1315, 1261, 1215, 1173, 1088, 1022 cmꢁ1
.
1H NMR
(500 MHz, CD3OD) d: 0.90 (3H, t, J = 6.9, O(CH2)6CH3], 1.26–1.40
[8H, m O(CH2)2(CH2)4CH3], 1.55–1.63 [2H, m OCH2CH2(CH2)4CH3],
3.38 (1H, ddd, J = 5.7, 4.6, 4.0, H-30), 3.53/3.69 [each 1H, dt, J = 9.2,
6.9, OCH2(CH2)5CH3], 3.66 (1H, dd, J = 12.0, 4.0, H-40a), 3.74 (1H, dd,
J = 13.2, 8.9, H-10a), 3.76 (1H, dd, J = 12.0, 4.6, H-40b), 3.83 (1H, dd,
J = 13.2, 3.4, H-10b), 3.85 (2H, d-like, J = 2.6, H-1a and H-1b), 3.93
(1H, dd, J = 10.3, 9.5, H-5a), 3.97 (1H, br dd-like, J = ca. 9.5, 4.3, H-
4), 4.05 (1H, dd, J = 10.3, 4.3, H-5b), 4.20 (1H, ddd, J = 8.9, 5.7, 3.4,
H-20), 4.37 (1H, dd, J = 2.3, 1.2, H-3), 4.62 (1H, td, J = 2.6, 2.3, H-
2). 13C NMR (125 MHz, CD3OD) d: 14.4 [O(CH2)6CH3], 23.7 [O
(CH2)5CH2CH3], 27.2 [O(CH2)2CH2(CH2)3CH3], 30.3 [O(CH2)3CH2-
CH2CH3], 31.1 [OCH2CH2(CH2)4CH3], 33.0 [O(CH2)4CH2CH2CH3],
51.8 (C-10), 52.2 (C-1), 60.7 (C-40), 61.1 (C-5), 68.7 (C-20), 72.0
[OCH2(CH2)5CH3], 73.8 (C-4), 79.48 (C-2), 79.52 (C-3), 83.7 (C-30).
LRMS (FAB, pos.) m/z: 353 [MꢁCl]+. HRMS (FAB, pos.): calcd for
4.2.6.7. 1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-neopentyl-
tol-4-yl]episulfoniumylidene}- -arabinitol chloride (8g).
a similar manner, sulfonium salt -16g (60 mg, 0.08 mmol) was
subjected to hydrogenolysis. Work-up and column chromatogra-
D
-erythri-
D
In
a
24
phy gave title compound (8g, 21 mg, 70%) as a colorless oil, [
+12.7 (c 0.66, CH3OH). IR (neat): 3267, 1632, 1408, 1361, 1323,
1265, 1219, 1172, 1087, 1023 cmꢁ1 1H NMR (500 MHz, CD3OD)
a]
D
.
d: 0.92 [9H, s, C(CH3)3], 3.20/3.37 [each 1H, d, J = 8.6, OCH2C
(CH3)3], 3.35 (1H, ddd, J = 6.0, 4.3, 4.0, H-30), 3.68 (1H, dd,
J = 12.0, 4.0, H-40a), 3.75 (1H, dd, J = 13.0, 9.5, H-10a), 3.76 (1H,
dd, J = 12.0, 4.3, H-40b), 3.83 (1H, dd, J = 12.6, 3.5, H-1a), 3.86 (1H,
dd, J = 13.0, 3.5, H-10b), 3.87 (1H, dd, J = 12.6, 1.7, H-1b), 3.93 (1H,
dd, J = 10.6, 9.8, H-5a), 3.97 (1H, br dd-like, J = ca. 9.8, 4.3, H-4),
4.05 (1H, dd, J = 10.6, 4.3, H-5b), 4.23 (1H, ddd, J = 9.5, 6.0, 3.5, H-
20), 4.38 (1H, br d-like, J = ca. 1.5, H-3), 4.62 (1H, ddd, J = 3.5, 1.7,
1.5, H-2). 13C NMR (125 MHz, CD3OD) d: 27.1 [C(CH3)3], 33.1 [C
(CH3)3], 51.9 (C-10), 52.3 (C-1), 60.8 (C-40), 61.0 (C-5), 68.9 (C-20),
73.8 (C-4), 79.5 (C-2 and C-3), 82.2 [OCH2C(CH3)3], 84.2 (C-30).
LRMS (FAB, pos.) m/z: 325 [MꢁCl]+. HRMS (FAB, pos.) calcd for
C16H33O6S 353.1998, found 353.2024.
4.2.6.5. 1,4-Dideoxy-1,4-{(R)-[4-deoxy-3-O-(tridec-1-yl)-
D
-ery-
thritol-4-yl]episulfoniumylidene}-
D
-arabinitol
chloride
(8e). In a similar manner, sulfonium salt
a-16e (83 mg,
0.10 mmol) was subjected to hydrogenolysis. Work-up and col-
umn chromatography gave title compound (8e, 37 mg, 78%) as
C14H29O6S 325.1685, found 325.1678.
Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013

G. Tanabe et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
11
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4.3.1. Inhibitory effects on rat intestinal a-glucosidases
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reported.19,20 Thus, rat small intestinal brush border membrane
vesicles were prepared and their suspensions in 0.1 M maleate buf-
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fer (pH 6.0) were used as small intestinal
a-glucosidases of mal-
tase, sucrose, and isomaltase.21 A test sample was dissolved in
dimethyl sulfoxide (DMSO), and the resulting solution was diluted
with 0.1 M maleate buffer to prepare the test sample solution
(concentration of DMSO 10 %). A substrate solution in the maleate
buffer (maltose 74 mM, sucrose 74 mM, isomaltase 7.4 mM, 50
the test sample solution (25 L), and the enzyme solution (25
l
l
L),
L)
l
were mixed at 37 °C for 30 min, and then immediately heated by
boiling water for 2 min to stop the reaction. The glucose concentra-
tions were determined by a glucose-oxidase method. The final con-
centration of DMSO in the test solution was 2.5% and no influence
of DMSO on the inhibitory activity was detected.
4.3.2. Inhibitory effects on human intestinal maltase
A human small intestinal microsome (batch MIC318017, pur-
chased from BIOPREDIC International, Rennes, France) in 0.1 M
maleate buffer (pH 6.0) was used to determine the small intestinal
a-glucosidase activity of maltase. Through a similar procedure, the
effect of maltase inhibitory activity was measured as described
above.
Acknowledgments
This work was supported by ‘High-Tech Research Center’
Project for Private Universities: matching fund subsidy from MEXT
(Ministry of Education, Culture, Sports. Science and Technology),
2007–2011 (O.M.) and also supported by a grant-in aid for scien-
tific research by JSPS (the Japan Society for the Promotion of
Science) (G.T. and T.M.). Thanks are due to the Takano Science
Foundation for the financial support.
10. Labute, P. J. Comput. Chem. 2008, 29, 1693.
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12. Marco, J. A.; Carda, M.; González, F.; Rodrígues, S.; Murga, J. Liebigs Ann. 1996,
1801. Mirror image was reported..
13. Rao, G. S.; Sudhakar, N.; Rao, B. V.; Basha, S. J. Tetrahedron: Asymmetry 2010, 21,
1963.
Supplementary data
14. (a) Schneider, H.-J.; Nguyen-Ba, N.; Thomas, F. Tetrahedron 1982, 38, 2327; (b)
Christl, M.; Reich, H. J.; Roberts, J. D. J. Am. Chem. Soc. 1971, 93, 3463.
15. Maltase-glucoamylase Gene ID: (a) Entrez Gene 312272 [Rattus norvegicus
(Norway rat)]; (b) Entrez Gene 8972 [Homo sapiens (human)].
16. (a) Sim, L.; Willemsma, C.; Mohan, S.; Naim, H. Y.; Pinto, B. M.; Rose, D. R. J. Biol.
Chem. 2010, 285, 17763; (b) Jones, K.; Sim, L.; Mohan, S.; Kumarasamy, J.; Liu,
H.; Avery, S.; Naim, H. Y.; Quezada-Calvillo, R.; Nichols, B. L.; Pinto, B. M.; Rose,
D. R. Bioorg. Med. Chem. 2011, 19, 3929; (c) Ren, L.; Cao, X.; Geng, P.; Bai, F.; Bai,
G. Carbohydr. Res. 2011, 346, 2688; (d) Nakamura, S.; Takahira, K.; Tanabe, G.;
Muraoka, O.; Open, J. Med. Chem. 2012, 2, 50.
Supplementary data (1H and 13C NMR spectra of new com-
pounds) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.bmc.2016.06.013.
References and notes
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Please cite this article in press as: Tanabe, G.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.06.013