Discovery of potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment

Article abstract of DOI:10.1016/j.bmc.2018.12.015

A new series of C-phenyl D-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes.

Full text of DOI:10.1016/j.bmc.2018.12.015

Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of potent, low-absorbable sodium-dependent glucose
cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment
⁎
Shoichi Kurodaa, , Yohei Kobashia, Takahiro Oib, Kenichi Kawabea, Fumiyasu Shiozawab,
Lisa Okumura-Kitajimac, Mami Sugisaki-Kitanoc, Fusayo Iod, Koji Yamamotoc,
⁎
Hiroyuki Kakinumaa,
a Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
b Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
c Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan
d Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1 Takada, Toshima-ku, Tokyo 170-8635, Japan
A B S T R A C T
A new series of C-phenyl D-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also
investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low
absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the
appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent
residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a
clinical candidate for the treatment of type 2 diabetes.
1. Introduction
Several glucose derivatives have been reported to act as SGLT1 in-
hibitors.12,13,14 In a previous paper, we reported a low-absorbable
SGLT1 inhibitor 1 that exerted a blood glucose-lowering effect at doses
of 0.1, 0.3 and 1 mg/kg during an oral glucose tolerance test (OGTT) in
Sprague-Dawley (SD) rats.15 However, as will be described later, small
amounts of compound 1 were absorbed from the small intestine and
accumulated in the kidney. The elimination half-life in the kidney was
160 h, as evaluated using14 C-labeled 1. Since toxicity, such as hy-
poglycemia, is an important consideration, we believed that creating a
low-absorbable SGLT1 inhibitor that does not accumulate in the kid-
neys would result in a safer compound. Since the main excretion route
of compound 1 was urinary, we presumed that drug retention in the
kidney could potentially be avoided by creating a compound that would
be excreted via a biliary pathway. We established a synthesis protocol
for promoting biliary excretion by imparting greater lipophilicity,
compared with compound 1, while maintaining the activity and low
absorbability of compound 1 in Fig. 1. When the side chain direction
was fixed to the benzene ring by placing a double bond in the side chain
of compound 1, there was a tendency that the inhibition against SGLT 1
was stronger. Therefore, we adopted a dimethylbutene skeleton in
which lipophilicity increases and there is no concern for isomerization.
First, compound 2, which has a novel side chain with a higher lipo-
philicity than compound 1, was converted to optimize the SGLT1 in-
hibitory activity, ClogP, and topological polar surface area (TPSA).16
The number of people with type 2 diabetes (T2DM) is increasing.
The International Diabetes Federation estimates that about 415 million
adults suffer from diabetes, and this total is expected to increase to 642
million by the year 2040. T2DM causes serious health problems such as
cardiovascular disease, blindness, renal failure, and lower limb ampu-
tation. Recently, the risk of developing diabetes has been correlated
with sugar intake, especially from sugary drinks. In 2014 the World
Health Organization (WHO) published a new recommendation for
limiting sugar intake. Maintaining blood glucose levels is important for
the prevention of T2DM.1
Sodium-dependent glucose cotransporter (SGLT) has attracted
considerable attention as a new therapeutic target for T2DM. SGLT2 is
mainly expressed in the initial renal proximal tubule and is responsible
for > 90% of the renal reabsorption of filtered glucose (160–180 g/
day).2,3,4 Indeed, some SGLT2 inhibitors including dapagliflozin,5 ca-
nagliflozin,6 empagliflozin,7 ipragliflozin,8 luseogliflozin9 and tofogli-
flozin10 have been approved. On the other hand, SGLT1 has an im-
portant role in glucose absorption from the intestinal lumen into the
epithelial cells of the small intestine. In fact, small intestinal SGLT1
mRNA expression and intestinal glucose uptake were found to be ele-
vated in patients with T2DM. Therefore, an SGLT1 inhibitor is an at-
tractive solution for the treatment of T2DM.11
⁎ Corresponding authors.
https://doi.org/10.1016/j.bmc.2018.12.015
Received 6 November 2018; Received in revised form 7 December 2018; Accepted 10 December 2018
0968-0896/©2018ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:Kuroda,S.,Bioorganic&MedicinalChemistry,https://doi.org/10.1016/j.bmc.2018.12.015

S. Kuroda et al.
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Fig. 1. Synthesis of a low-absorbable SGLT1 inhibitor with biliary excretion.
Scheme 1. (a) n-BuLi, THF, −78 °C, then 5; (b) MsOH, MeOH, rt, 64% in 2steps; (c) TMSCl, Et3N, DMF, rt, 96%; (d) n-BuLi, THF, −78 °C, then 8a–8f; (e) MsOH,
MeOH, rt; (f) Ac2O, pyridine, rt; (g) Et3SiH, BF3·OEt2, CH3CN/CHCl3, 37–85% in 4steps; (h) WSCI·HCl, HOBt·H2O, CHCl3, rt, 51%; (i) Pd(OAc)2, (o-tolyl)3P, Et3N, 14,
DMF or MeCN, 120 °C, 36–87%; (j) NaOMe, MeOH, rt, 59–78%.
Scheme 2. (a) Pd(OAc)2, (o-tolyl)3P, Et3N, MeCN, 120 °C, 72%; (b) EtSH, BF3·OEt2, CHCl3, rt, 4%.
Next, we searched for R4 at a linear site and found a low-absorbable
compound (3). These compounds were confirmed to have a biliary
excretion route, as expected, and accumulation in the kidney was found
to be greatly reduced.
conditions, yielding crude intermediates 10a–10f. The reduction of
methyl glucoside and the acetoxy group at the benzyl position of
compounds 10a–10f was performed using triethylsilane and boron
trifluoride diethyletherate to yield aryl β-C-glucoside 11a–11f in a
Herein, we describe the synthesis and structure–activity relation-
ships (SARs) of this new series of C-phenyl D-glucitol derivatives, fo-
cusing on finding a good balance between ClogP and TPSA.
stereoselective manner. A subsequent Mizoroki-Heck reaction of
11a–11f under microwave irradiation with compound 14, obtained by
condensing 12 and 13 using water soluble carbodiimide hydrochloride
(WSCI·HCl), yielded 15a–15f. Finally, the acetyl groups of 15a–15f
were removed using Zemplén deacetylation to yield 16a–16f.
The synthesis of C-phenyl D-glucitol derivative19 in Table 1 is shown
in Scheme 2. A Mizoroki–Heck reaction of (1S)-1,5-anhydro-2,3,4,6-
tetra-O-benzyl-1-{2-(benzyloxy)-5-[(4-bromophenyl)methyl]-4-methyl-
phenyl}-D-glucitol (17), synthesized under microwave irradiation with
compound 14 (as described in our previous paper), yielded 18. The
benzyl group of 18 was then removed using ethanethiol and boron
trifluoride diethyletherate to yield 19.
2. Chemistry
The synthesis of C-phenyl D-glucitol derivatives 16a–16f in Table 1
is shown in Scheme 1. For the synthesis of compounds 16a–16f, com-
pound 6 was obtained by adding lactone 59 to lithium reagents pre-
pared from commercially available 1,5-dibromo-2,4-dimethylbenzene
(4) and n-BuLi, followed by methyl glucosylation under acidic condi-
tions. The hydroxyl groups of 6 were re-protected by trimethylsilyl
groups to yield 7. The crude intermediates 9a–9f were obtained by
adding commercially available aldehydes 8a–8f to lithium reagents
prepared from 7 and n-BuLi and then removing the trimethylsilyl
groups under acidic conditions. The resulting hydroxyl groups of 9a–9f
were protected by acetyl groups using acetic anhydride under base
The synthesis of C-phenyl D-glucitol derivatives 28e–28h in Table 1
is shown in Scheme 3. For the synthesis of compounds 28e–28h,
commercially available 3-isopropylphenol (20) was iodinated with
potassium iodide and iodide under acid conditions to yield 21. Com-
pound 21 was protected by a benzyl group or a methyl group using
2

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Scheme 3. (a) KI, I2, H2O, AcOH, rt, 57%; (b) BnBr or MeI, K2CO3, MeCN, rt, 85%; (c) n-BuLi, THF, −78 °C, then 5; (d) MsOH, MeOH, rt; (e) Ac2O, pyridine, 4-
dimethylaminopyridine, rt; (f) Et3SiH, BF3·OEt2, CH3CN/CHCl3, 4 °C, 40–59% in 4steps; (g) 10%Pd–C, H2, MeOH, rt; (h) Br2, AcOH, rt, 52% in 2steps; (i) Br2, AcOH,
rt, 96%; (j) Et3N, MeOH/H2O, 50 °C or NaOMe, MeOH, rt; (k) TMSCl, Et3N, DMF, 4 °C; (l) n-BuLi, THF, −78 °C, then 8a or 8c; (m) MsOH, MeOH, rt; (n) Ac2O,
pyridine, rt; (o) Et3SiH, BF3·OEt2, CH3CN/CHCl3, 4 °C, 34–56% in 4steps; (p) 14, Pd(OAc)2, (o-tolyl)3P, Et3N, CH3CN, 120 °C; (q) NaOMe, MeOH, rt, 38–54% in
2steps.
alkyl halide under basic conditions to yield 22a and 22b. Next, lactone
5 was added to lithium reagents prepared from 22a or 22b and n-BuLi
and the trimethylsilyl groups were removed under acidic conditions to
protect the hydroxyl group at the anomeric position; then, the hydroxyl
groups thus obtained were protected with acetyl groups using acetic
anhydride under base conditions, followed by the reduction of methyl
glucoside using triethylsilane and boron trifluoride diethyletherate to
yield aryl β-C-glucoside 23a or 23b in a stereoselective manner. The
reduction of the benzyl group and the bromination of the aromatic ring
of 23a yielded 24a. Also, the bromination of 23b yielded 24b. The
acetyl groups of 24a and 24b were removed using trimethylamine in
methanol–water, and the hydroxyl groups were protected using tri-
methylsilylchloride under base conditions to yield 25a, 25b. The
compounds26e–26h were obtained by adding aldehydes 8a or 8c to
lithium reagents prepared from 25a or 25b and n-BuLi; the TMS groups
were then removed under acidic conditions. The resulting hydroxyl
groups of 26e–26h were protected by acetyl groups using acetic an-
hydride under base conditions and the acetoxy group at the benzyl
position was reduced using triethylsilane and boron trifluoride die-
thyletherate, yielding 27e–27h. Finally, the conversions from 27e–27h
to 28e–28h were performed in the same manner as that described in
Scheme 1.
methoxide to yield the desired products (34d–34n).
3. Results and discussion
To avoid the accumulation of compounds in the kidney, we aimed to
create chemical classes with different excretion pathways from that of
compound 1 (ClogP = 1.57, TPSA = 212), while maintaining a low
absorption and SGLT1 inhibitory activity. Generally, to convert the
excretion pathway from urinary to biliary, an increase in lipophilicity is
necessary.17 However, since an increase in lipophilicity leads to an
improvement in membrane permeability, a low-absorbable compound
with a TPSA > 160 Å2 was deemed to be necessary.18
Initially, we designed and synthesized compounds bearing various
substituents at R1, R2, and R3 to investigate the effects on SGLT1 in-
hibitory activity and lipophilicity (Table 1). When R1 and R2 were fixed
to a methyl group, the SGLT1 inhibitory activity arising from conver-
sion at the R3 site was investigated. Compound 16a exerted a more
potent SGLT1 inhibition activity than 16b, 16d with halogen groups
and 16c, 16e with alkyl groups, or 16f with an alkoxy group. The in-
troduction of a hydroxyl group at R1 caused the TPSA of 19 to increase,
compared with that of 16a. Fortunately, compound 19 had the same
SGLT1 inhibitory activity as 16a. To increase the ClogP of 19, deriva-
tives 28e–28h, in which substituents to increase lipophilicity were in-
troduced at R1, R2 and R,3 were synthesized. Derivatives 28e–28h with
isopropyl groups introduced at R2 had higher ClogP values, compared
with that of 19, while exhibiting the same SGLT1 inhibitory activity
(21 nM–74 nM). However, SGLT2 inhibitory activity was difficult to
separate from SGLT1 inhibitory activity for this chemical class. Also
from the results of a parallel artificial membrane permeability assay
(PAMPA) of 28f and 28g, it was considered low absorption is in-
sufficient. When these compounds are absorbed, there is a risk of
The synthesis of C-phenyl D-glucitol derivatives 34d–34n in Table 2
is shown in Scheme 4.
Compound 30 was obtained by condensing commercially available
12 and 29 using an acid chloride of 12. Methyl ester 30 was hydrolyzed
to obtain carboxylic acid 31. A subsequent Mizoroki-Heck reaction of
27f–27h with carboxylic acid 31 under microwave irradiation yielded
32a–32c. 33d–33n were obtained by condensing 32a–32c and the
corresponding amines using WSCI·HCl or carbonyldiimidazole (CDI).
Finally, the acetyl groups of 33d–33n were removed using sodium
3

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Scheme 4. (a) (COCl)2, DMF(cat.), CHCl3, rt, then Et3N, 29, 93%; (b) aq. NaOH, MeOH, rt, 94%; (c) Pd(OAc)2, (tolyl)3P, Et3N, CH3CN, 120 °C, 60–87%; (d)
WSCI·HCl, HOBt·H2O, amines, CHCl3, rt or CDI, CHCl3, rt, 21–95%; (e) NaOMe, MeOH, rt or Et3N, H2O, MeOH, rt, 47–98%.
hypothesized that the TPSA value should be more than > 160 Å.2 To
Table 1
Structure-activity/ClogP value/TPSA relationships of C-phenyl D-glucitol deri-
achieve a bioavailability of almost 0%, the TPSA value should be even
higher. We next hypothesized that the TPSA could be increased by in-
troducing various amines at R4 and were able to synthesize compounds
with the expected physical properties. Compounds 34d–34n, in which
three or four kinds of amines were introduced to 32a, 32b, or 32c, had
higher TPSA values while maintaining the same SGLT1 inhibitory ac-
tivity. Compounds 34d–34j had SGLT2 inhibitory activity levels that
were comparable to their SGLT1 inhibitory activities. On the other
hand, the SGLT2 inhibitory potency of compounds 34l–34n was lower
than the SGLT1 inhibitory activity by about 6-fold. Based on these re-
sults, although the SGLT1 inhibitory activity was unaffected by any of
the substituents, the introduction of a methyl substituent at R3 was
thought to weaken the SGLT2 inhibitory activity. Considering the in
vitro data profiles, shown in Table 2, since compound 34j had a higher
TPSA value (195 Å2) than 34d–34n, this compound should have been
selected for further pharmacokinetic (PK) evaluation. Compound 34j
and the salts (hydrochloric acid, sulfuric acid, citric acid, tartaric acid,
phosphoric acid andacetic acid), however, did not crystallize under
various solvents and temperature conditions. Thus, 34j was expected to
be difficult to develop from the viewpoint of manufacturability. When
the crystallinity of the compounds was examined, 34d was the only
compound that crystalized in an ethanol solution.
vatives.
Cpd. R1
R2 R3
hSGLT1a
hSGLT2a
PAMPA
ClogPb TPSAc (Å2)
IC50 (nM) IC50 (nM) at pH7.4
(×10−6
cm/s)
16a Me
16b Me
Me
Me
H
F
22
10
NTd
NTd
7.5
3.35
3.49
3.80
4.06
4.72
3.27
2.18
2.96
3.35
3.41
3.79
139
139
139
139
139
149
160
160
149
160
149
34
17
16c
Me
Me Me
Me Cl
Me iPr
111
176
12,531
84
16d Me
16e Me
NTd
2126
798
NTd
19
NTd
NTd
NTd
NTd
NTd
1.8
16f
19
Me
OH
Me OMe 1166
Me
iPr
H
H
H
21
23
36
55
74
28e OH
28f
OMe iPr
34
28g OH
iPr Me
69
0.5
28h OMe iPr Me
354
NTd
Given the promising potency data obtained in vitro, we evaluated
the PK profiles of compounds 34d and 34j in SD rats and the membrane
permeability of compounds 34d and 34j using PAMPA. The resulting
PK parameters and permeability of 34d and 34j are shown in Table 3.
As expected, compounds 34d and 34j exhibited low membrane per-
meabilities. Also, the bioavailability of compounds 34d and 34j was
very low in vivo. These data indicated that compounds 34d and 34j had
a low absorbability.
a
The IC50 values for the hSGLT1 and hSGLT2 activities represent the mean
values of at least two experiments.
b
The ClogP value was calculated using software from Daylight Chemical
Information Systems, Inc.
c
The TPSA value was calculated using software from ACD/Percepta, version
2015, Advanced Chemistry Development, Inc.
d
Not tested.
Next, to investigate the excretion pathways of 34d and 34j, the
compounds were administered intravenously to bile duct-cannulated
(BDC) SD rats. The resulting accumulative excretion results for 34d and
34j are shown in Table 4. Fortunately, compounds 34d and 34j were
confirmed to be mainly excreted via a biliary excretion pathway, sug-
gesting that the PK profiles of 34d and 34j differed from that of 1.
hypoglycemia because of the inhibition of glucose absorption in the
small intestine and glucose excretion in the kidneys. Therefore, we
thought that the creation of gastrointestinal-specific SGLT1 inhibitors
was needed.
Next, we conducted an optimization study of 28e–28h focusing on
the conversion of the side chain (R4). To impart a low absorbability, we
4

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Table 2
Table 4
Structure-activity/ClogP value/TPSA relationships of R1, R3, R4.
Accumulative excretion of 1, 34d, and 34j after intravenous administration to
BDC SD rats.
Compound
Dose
Urine
Bile
(mg/kg)
(% of dose)
(% of dose)
1
2
36.2
18.1
5.3
11.0
9.3
0.4
30.2
65.1
89.8
10.4
34d
34j
0.3
0.3
17.7
5.7
Cpd. R1
R3
R4
hSGLT1a
hSGLT2a
ClogPb TPSAc (Å2)
Dosing vehicle: saline.
Collection period: 24 h.
IC50 (nM) IC50 (nM)
Each data represents the mean
SD of three animals.
34d
34e
34f
OMe
H
29
38
42
35
30
35
20
17
26
74
28
81
3.66
3.55
4.01
3.72
3.61
4.07
161
161
152
172
172
163
Table 5
OMe
OMe
OH
H
Concentrations of 1, 34d, and 34j in the kidneys after intravenous adminis-
tration to SD rats.
H
Compound
Dose (mg/kg)
Kidney concentration (ng/g tissue)
34g
34h
34i
Me
Me
Me
Me
2 h
24 h
72 h
OH
1
0.3
0.3
0.3
1900
1090
1060
90.7
55.7
28.9
1110
104
72.3
16.7
12.9
803
64.8
9.43
10.9
34d
34j
29.2
12.5
OH
83.8
34j
OH
27
46
64
3.53
4.11
195
161
Dosing vehicle: saline.
Each data point represents the mean
NTd
SD of three animals.
34k
OMe Me
OMe Me
34l
34
55
54
200
281
322
4.00
4.46
3.92
161
152
184
1.2%, respectively. In this chemical class, a ClogP value of 3.5 or more
was found to lead to biliary excretion, thereby enabling renal residue to
be avoided. This result suggests that the risk of adverse effects, such as
hypoglycemia, could be reduced. Considering the difficulty of the
synthesis and preparation of 34j, however, an in vivo drug efficacy test
was only performed for 34d, as described below.
34m OMe Me
34n
OMe Me
a
The IC50 values for the hSGLT1 and hSGLT2 activities represent the mean
values of at least two experiments.
Finally, the glucose-lowering effect of 34d was evaluated using an
oral sucrose tolerance test in SD rats, which is a model of impaired
glucose tolerance. Compound 34d was orally administered just prior to
sucrose loading, and the plasma glucose concentration was then mea-
sured over 2 h. The reductions in glucose excursion (ΔAUC from 0 to
2 h) were 27.5%, 50.8% and 45.7% at 0.3, 1.0, and 3.0 mg/kg, re-
spectively (Fig. 2). The glucose-lowering effect was significantly effec-
tive at 0.3 mg/kg, and a maximum efficacy was obtained at 1 mg/kg. In
addition, no gastrointestinal symptoms such as diarrhea were observed
in this study. Together, these results suggest that compound 34d could
potentially be useful as a therapeutic agent for patients with T2DM.
b
The ClogP value was calculated using software from Daylight Chemical
Information Systems, Inc.
c
The TPSA value was calculated using software from ACD/Percepta, version
2015, Advanced Chemistry Development, Inc.
d
Not tested.
Because of this difference in the excretion pathway, further research
was performed with the expectation that the accumulation of the
compounds in the kidneys would be reduced.
Subsequently, to investigate the kidney residue properties of com-
pounds 1, 34d, and 34j, the time course of the drug concentration in
the kidney after intravenous administration to SD rats was evaluated.
The resulting concentrations in the kidneys of 1, 34d, and 34j are
shown in Table 5. Compounds 34d and 34j were confirmed to have
rapidly reduced accumulations in the kidneys, compared with com-
pound 1. Specifically, 42% of the unchanged compound 1 remained in
the kidney after 72 h, compared with the value at 2 h after adminis-
tration, while the accumulations of 34d and 34j decreased to 2.7% and
4. Conclusion
In summary, a new series of C-phenyl D-glucitol derivatives was
designed and synthesized, and their SGLT1 inhibitory potency and
absorbability were evaluated. We also investigated whether kidney
drug retention could be avoided by creating molecules with different
excretion pathways. To achieve a class of molecules with low absorp-
tion and that were excreted in bile, optimized synthesis was performed
Table 3
Pharmacokinetic parameters in SD rats and permeability of 34d and 34j.
Cpd.
Pharmacokinetic parameters
Permeability
IVa
POb
PAMPA at pH7.4
Dose
CLtotal
Vdss
t1/2
(h)
Dose
Cmax
Tmax
(h)
F
(mg/kg)
(mL/h/kg)
(mL/kg)
(mg/kg)
(ng/mL)
(%)
(×10−6 cm/s)
34d
34j
0.4
0.4
4020
3760
1640
964
2.39
30
30
1.88
5.34
2.83
0.17
0.09
0.0
0.0
0.578
0.250
Each data point represents the mean value of three animals.
a
b
Dosing vehicle: saline.
Dosing vehicle: 0.5% CMC Na.
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Fig. 2. Effects of the oral administration of 34d (0.3 or 1 or 3 mg/kg) on plasma glucose during an oral sucrose tolerance test in SD rats. Each point represents the
mean
SE. *p < 0.05, **p < 0.01, ***p < 0.001 vs. Vehicle group, Dunnett’s test (n = 5).
to bring the ClogP value and the TPSA to within the appropriate ranges.
Optimization studies led to the identification of compounds 34d and
34j, which possessed the targeted PK properties (low bioavailability) in
SD rats and were confirmed to be excreted via a biliary pathway,
thereby greatly reducing accumulation in the kidneys. Compound 34d,
which had a glucose-lowering effect at 0.3 mg/kg (p.o.) in SD rats, was
identified, suggesting its possible effectiveness for the treatment of
T2DM. The further research and development of compound 34d
(SGL5213) is planned.
5.2. Pharmacokinetic evaluation
The permeability measurement and the data analysis of the test
compound were performed using PAMPA Evolution™ (pION Inc.). A 96-
well PAMPA sandwich plate (pION Inc.) was used for the permeability
measurement. The “sandwich” filters were coated with 4 μL of GIT-0
Lipid (pION Inc.). The donor plate was filled with 200 μL of the test
compound dissolved in the PRISMA HT Universal Buffer (pION Inc.).
The concentrations of the test compound in the donor solution were
25 μM (compound 35d) and 5 μM (compound 35d).
The plasma and kidney concentration–time profiles of the test
compounds were investigated in fasted male SD rats. After a single
intravenous administration of the test compounds, blood was obtained
from the tail vein at each sampling time point and then centrifuged to
prepare the plasma samples. After a single intravenous administration
of the test compounds, the animal were euthanized at each sampling
time point and the kidneys were harvested and homogenized in purified
water. The cumulative excretion of unaltered drug in the urine and bile
was investigated in bile duct-cannulated SD rats. After a single in-
travenous administration of the test compounds, urine and bile samples
were collected for a 24-hour time period. The quantitative analysis of
the target analyte in each sample was performed using liquid chroma-
tography-tandem mass spectrometry. The pharmacokinetic parameters
were calculated using a non-compartmental analysis with Phoenix
WinNonlin (version 6.2, Certara).
5. Experimental section
5.1. Glucose uptake inhibition assay
Chinese hamster ovary-K1 cells stably expressing human SGLT2
(NM_003041) or human SGLT1 (NM_000343) were used for the so-
dium-dependent glucose transport inhibition test. Cells were incubated
in 200 μL of pretreatment buffer solution (140 mM choline chloride,
2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES/5 mM Tris, pH7.4)
for 20 min. The pretreatment buffer was removed, and 75 μL of uptake
buffer containing the test compound (methyl-α-D-glucopyranoside
containing 14C] methyl-α-D-glucopyranoside [0.1 mM for SGLT1 in-
hibition, 1 mM for SGLT2 inhibition], 140 mM NaCl, 2 mM KCl, 1 mM
CaCl2, 1 mM MgCl2, 10 mM HEPES/5mM Tris, pH7.4) were added. The
uptake reaction was performed at 37 °C for 30 min (SGLT1) or 1 h
(SGLT2). After the reaction, the cells were washed twice with 200 μL of
washing buffer (10 mM methyl-α -D-glucopyranoside, 140 mM choline
chloride, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES/5 mM
Tris, pH7.4) and dissolved in 75 μL of 0.25 M NaOH. Opti phase Super
Mix (Perkin-Elmer Corporation) was added and mixed well with the
sample; the radioactivity was then measured using a Micro Beta Trilux
counter (Perkin-Elmer Corporation). An uptake buffer that did not
contain the test compound was used as a control. Another uptake buffer
containing choline chloride instead of NaCl was also prepared as a
background control. To determine the IC50 values, each test compound
was tested at six suitable concentrations. The concentration at which
glucose uptake was inhibited by 50% (IC50 value) compared with the
glucose uptake in the control (100%) was then calculated.
5.3. Plasma glucose level after sucrose administration in normal rats
After overnight fasting, SD rats were orally administered the vehicle
(water for injection) or a 34d (SGL5213) solution and a sucrose (2.5 g/
kg) solution. Blood was collected from the tail vein. The plasma glucose
concentration was measured using the Glucose CII test Wako kit (Wako
Pure Chemical Industries Ltd., Osaka Japan). The difference from the
baseline plasma glucose level throughout the study period was calcu-
lated as the delta area under the curve (ΔGlucose AUC).
5.4. Chemistry
All the solvents and reagents were obtained from commercial
6

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
suppliers and were used without further purification or were prepared
according to published procedures. The 1H NMR and 13C NMR spectra
liquid was neutralized with triethylamine (1.1 mL), and the reaction
mixture was concentrated to obtain compound 9a (4.17 g). Compound
9a was used in the next reaction without purification. Compound 9a
(4.17 g, 7.8 mmol) was dissolved in pyridine (24 mL). Acetic anhydride
(20 mL) was added to the resulting solution, and the mixture was stirred
for 16 h at room temperature. Ice water was added, and the mixture was
extracted twice with toluene. The combined organic layer was washed
with 2-N hydrochloric acid and a saturated sodium hydrogen carbonate
solution and then dried over anhydrous magnesium sulfate. The de-
siccant was filtered out, and the solvent was distilled off under reduced
pressure to obtain crude compound 10a (4.43 g). Et3SiH (4.2 mL,
25.4 mmol) was added to a solution of crude compound 10a (4.43 g) in
chloroform (22 mL) and acetonitrile (22 mL), and the mixture was
cooled with ice in a nitrogen atmosphere. Under ice cooling, BF3·OEt2
(2.4 mL, 19.0 mmol) was added dropwise over 10 min, and the mixture
was stirred for 2 h at the same temperature. A saturated aqueous so-
lution of sodium hydrogen carbonate was added to the reaction liquid,
and the mixture was extracted with ethyl acetate. Then, the organic
layer was dried over anhydrous magnesium sulfate. The desiccant was
filtered out, and the solvent was distilled off under reduced pressure.
The resulting residue was purified using acidic silica gel column chro-
matography (hexane:ethyl acetate ratio = 40:1) to obtain the title
compound as a colorless powder (1.74 g, 37% in 4 steps). 1H NMR
(300 MHz, CDCl3) δ ppm 1.76 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 2.07 (s,
3H), 2.11 (s, 3H), 2.35 (s, 3H), 3.79–3.90 (m, 3H), 4.10–4.27 (m, 2H),
4.58–4.67 (m, 1H), 5.18–5.36 (m, 3H), 6.92–6.97 (m, 3H), 7.11 (s, 1H),
7.33–7.36 (m, 1H), 7.37–7.40 (m, 1H).
were recorded using
a JOEL JNM-ECA600, Varian Inova300, or
Gemini2000, and all the chemical shifts were reported in parts per
million (ppm) relative to tetramethylsilane (TMS) as an internal stan-
dard. Mass spectra were recorded using a Shimadzu LCMS 2010 EV
spectrometer. High-resolution mass spectral data were acquired using a
Shimadzu LCMS-IT-TOF equipped with an ESI/APCI dual ion source.
5.4.1. Methyl 1-C-(5-bromo-2,4-dimethylphenyl)-D-glucopyranoside (6)
A 2.8-M n-butyllithium solution in hexane (26.8 mL, 74.2 mmol)
was added dropwise to a THF (100 mL) solution of 1,5-dibromo-2,4-
dimethylbenzene (4) (17.6 g, 74.2 mmol) at −78 °C in a nitrogen at-
mosphere, and the mixture was stirred for 15 min at the same tem-
perature. Then,
a THF (60 mL) solution of 2,3,4,6-tetra-O-tri-
methylsilyl-D-glucono-1,5-lactone (5) (38.1 g, 81.7 mmol) was added
dropwise over 25 min, and the mixture was stirred for 15 min at the
same temperature. Ice water was added to the reaction solution, and the
resulting mixture was warmed to room temperature and then extracted
with ethyl acetate. The combined organic layer was washed with a
saturated saline solution and dried over anhydrous magnesium sulfate.
The desiccant was filtered out, and the solvent was distilled off under
reduced pressure. The resulting residue was dissolved in a methanol
(370 mL) solution containing methanesulfonic acid (0.48 mL,
7.42 mmol), and the solution was stirred for 16 h at room temperature.
Then, the solution was neutralized with triethylamine (1.4 mL,
10.3 mmol), and the reaction mixture was concentrated. The resulting
residue was purified using neutral silica gel column chromatography
(chloroform:methanol ratio = 9:1 to 8:1) to obtain the title compound
as a light-yellow gummy substance (17.8 g, 64% in 2 steps). 1H NMR
(300 MHz, CDCl3) δ ppm 2.32 (s, 3H), 2.33 (s, 3H), 2.93 (s, 1H), 3.08 (s,
3H), 3.26–3.38 (m, 1H), 3.55–3.62 (m, 2H), 3.82–3.92 (m, 4H),
4.83–4.91 (m, 1H), 4.97–5.08 (m, 1H), 7.00 (s, 1H), 7.57 (s, 1H).
MS ESI/APCI Dual m/z 627 [M+Na]+
.
5.4.4. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromo-2-
fluorophenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (11b)
Compound 11b (69% in 4 steps) was obtained from 7 in a manner
similar to that described for 11a. 1H NMR (300 MHz, CDCl3) δ ppm
1.77 (s, 3H), 2.01 (s, 3H), 2.05 (s, 4H), 2.07 (s, 3H), 2.13 (s, 3H), 2.36
(s, 3H), 3.78–3.96 (m, 3H), 4.11–4.28 (m, 2H), 4.60 (d, J = 9.5 Hz, 1H),
5.17–5.37 (m, 3H), 6.74 (t, J = 8.1 Hz, 1H), 6.95 (s, 1H), 7.08 (s, 1H),
7.12–7.17 (m, 2H), 7.21 (dd, J = 9.3, 1.9 Hz, 1H). MS ESI/APCI Dual
5.4.2. Methyl
1-C-(5-bromo-2,4-dimethylphenyl)-2,3,4,6-tetrakis-O-
(trimethylsilyl)-D-glucopyranoside (7)
Triethylamine (24.1 mL, 172.5 mmol) and chlorotrimethylsilane
(18.8 mL, 147.9 mmol) were added to
a
N,N-dimethylformamide
m/z 645 [M+Na]+
.
(102 mL) solution of compound 6 (9.3 g, 24.7 mmol) under ice cooling.
The reaction mixture was stirred for 16 h at room temperature, and ice
water was added. The mixture was extracted twice with toluene, and
the combined organic layer was washed with water and then dried over
anhydrous magnesium sulfate. The desiccant was filtered out, and the
solvent was distilled off under reduced pressure to obtain the title
compound (15.8 g, 96%). This compound was used in the next reaction
without purification. 1H NMR (300 MHz, CDCl3) δ ppm −0.32 (s, 9H),
0.13 (s, 9H), 0.19 (s, 9H), 0.20 (s, 9H), 2.33 (s, 3H), 2.43 (s, 3H), 3.10
(s, 3H), 3.38 (d, J = 9.0 Hz, 1H), 3.49–3.62 (m, 2H), 3.77 (d,
J = 2.9 Hz, 2H), 3.97–4.07 (m, 1H), 6.99 (s, 1H), 7.67 (s, 1H).
5.4.5. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromo-2-
methylphenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (11c)
Compound 11c (85% in 4 steps) was obtained from 7 in a manner
similar to that described for 11a. 1H NMR (300 MHz, CDCl3) δ ppm
1.76 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 2.27
(s, 3H), 2.37 (s, 3H), 3.76–3.86 (m, 3H), 4.08–4.28 (m, 2H), 4.58 (d,
J = 9.6 Hz, 1H), 5.14–5.36 (m, 3H), 6.61 (d, J = 8.2 Hz, 1H), 6.95 (d,
J = 9.2 Hz, 2H), 7.19 (dd, J = 8.16, 1.79 Hz, 1H), 7.33 (d, J = 1.9 Hz,
1H). MS ESI/APCI Dual m/z 641 [M+Na]+
.
5.4.6. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromo-2-
chlorophenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (11d)
5.4.3. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromophenyl)
methyl]-2,4-dimethylphenyl}-D-glucitol (11a)
Compound 11d (52% in 4 steps) was obtained from 7 in a manner
similar to that described for 11a. 1H NMR (300 MHz, CDCl3) δ ppm
1.78 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.10 (s, 3H), 2.37
(s, 3H), 3.78–3.87 (m, 3H), 4.08–4.29 (m, 2H), 4.60 (d, J = 9.3 Hz, 1H),
5.16–5.38 (m, 3H), 6.65 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 7.03 (s, 1H),
7.23 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H). MS ESI/APCI Dual
A 2.77 M n-butyllithium hexane solution (2.8 mL, 7.8 mmol) was
added dropwise to a THF (40 mL) solution of compound 7 (5.2 g,
7.8 mmol) at −78 °C in an argon atmosphere, and the mixture was
stirred for 30 min at the same temperature. Then, a THF (10 mL) so-
lution of 4-bromobenzaldehyde (8a) (1.4 g, 8.6 mmol) was added
dropwise over 15 min, and the mixture was stirred for 2 h at the same
temperature. Water was added to the reaction liquid; after the mixture
was warmed to room temperature, the warmed mixture was extracted
twice with ethyl acetate. The combined organic layer was washed with
a saturated saline solution and dried over anhydrous magnesium sul-
fate. The desiccant was filtered out, and the solvent was distilled off
under reduced pressure. The resulting residue was dissolved in a me-
thanol (39 mL) solution containing methanesulfonic acid (0.051 mL),
and the solution was stirred for 2 h at room temperature. The reaction
m/z 661 [M+Na]+
.
5.4.7. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(5-{[4-bromo-2-
(propan-2-yl)phenyl]methyl}-2,4-dimethylphenyl)-D-glucitol (11e)
Compound 11e (56% in 4 steps) was obtained from 7 in a manner
similar to that described for 11a. 1H NMR (300 MHz, CDCl3) δ ppm
1.21 (d, J = 3.6 Hz, 3H), 1.23 (d, J = 3.6 Hz, 3H), 1.76 (s, 3H), 1.99 (s,
3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.13 (s, 3H), 2.36 (s, 3H), 3.06–3.18 (m,
1H), 3.73–3.84 (m, 1H), 3.87 (s, 2H), 4.07–4.14 (m, 1H), 4.18–4.27 (m,
7

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1H), 4.58 (d, J = 9.8 Hz, 1H), 5.10–5.34 (m, 3H), 6.60 (d, J = 8.2 Hz,
1H), 6.92 (s, 1H), 6.96 (s, 1H), 7.17 (dd, J = 8.2, 2.2 Hz, 1H), 7.40 (d,
5.4.12. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-
hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-
methylphenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (15c)
J = 2.2 Hz, 1H). MS ESI/APCI Dual m/z 647 [M+Na]+
.
Compound 15c (36%) was obtained from 11c in a manner similar to
that described for 15a. 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (s, 6H),
1.37 (s, 6H), 1.77 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H), 2.14 (s, 3H), 2.31
(s, 3H), 2.37 (s, 3H), 3.55 (d, J = 5.28 Hz, 2H), 3.78–3.87 (m, 3H),
4.07–4.25 (m, 2H), 4.58 (d, J = 9.6 Hz, 1H), 4.85 (s, 1H), 5.13–5.35
(m, 3H), 6.22–6.32 (m, 1H), 6.46–6.54 (m, 1H), 6.72 (d, J = 7.8 Hz,
1H), 6.97 (s, 2H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 7.23 (s, 1H).
5.4.8. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromo-2-
methoxyphenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (11f)
Compound 11f (84% in 4 steps) was obtained from 7 in a manner
similar to that described for 11a. 1H NMR (300 MHz, CDCl3) δ ppm
1.75 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 2.36
(s, 3H), 3.79–3.86 (m, 6H), 4.11–4.17 (m, 1H), 4.20–4.27 (m, 1H), 4.59
(d, J = 9.5 Hz, 1H), 5.17–5.36 (m, 3H), 6.58 (d, J = 7.9 Hz, 1H),
6.92–6.98 (m, 3H), 7.05 (s, 1H).
5.4.13. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(2-chloro-4-{(1E)-
4-[(1-hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-
yl}phenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (15d)
5.4.9. N-(1-hydroxy-2-methylpropan-2-yl)-2,2-dimethylbut-3-enamide
(14)
Compound 15d was obtained as a mixture with 14 from 11d in a
manner similar to that described for 15a. 1H NMR (300 MHz, CDCl3) δ
ppm 1.23 (s, 6H), 1.37 (s, 6H), 1.79 (s, 3H), 1.99 (s, 3H), 2.05 (s, 3H),
2.06 (s, 3H), 2.13 (s, 3H), 2.38 (s, 3H), 2.49 (s, 3H), 3.55 (s, 2H),
3.77–3.87 (m, 1H), 3.91–4.08 (m, 2H), 4.11–4.27 (m, 2H), 4.61 (d,
J = 9.48 Hz, 1H), 5.28–5.38 (m, 3H), 6.26–6.33 (m, 1H), 6.42–6.50 (m,
1H), 6.76 (d, J = 8.08 Hz, 1H), 6.97 (s, 1H), 7.04–7.19 (m, 2H),
7.29–7.36 (m, 1H), 7.40–7.46 (m, 1H).
2-Amino-2-methylpropan-1-ol (13) (1.0 g, 11.2 mol), WSCI HCl
(2.15 g, 11.2 mmol) and HOBt H2O (1.51 g, 11.2 mmol) were added to a
chloroform (37 mL) solution of 2,2-dimethyl-3-butenoic acid (12)
(1.11 g, 7.48 mmol) in a nitrogen atmosphere, and the mixture was
stirred for 16 h at room temperature. Water was added to the reaction
liquid, and the mixture was extracted with chloroform. Then, the or-
ganic layer was washed with 2-M hydrochloric acid, a saturated aqu-
eous solution of sodium hydrogen carbonate, and a saturated saline
solution and then dried over anhydrous magnesium sulfate. The de-
siccant was filtered out, and the solvent was distilled off under reduced
pressure. The resulting residue was purified using silica gel column
chromatography (hexane:ethyl acetate ratio = 9:1 to 1:1) to obtain the
title compound as a colorless powder (0.70 g, 51%). 1H NMR (300 MHz,
CDCl3) δ ppm 1.24 (s, 6H), 1.28 (s, 6H), 3.55 (s, 2H), 5.19–5.30 (m,
2H), 5.74 (br s, 1H), 5.99 (dd, J = 17.49, 10.65 Hz, 1H).
5.4.14. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(5-{[4-{(1E)-4-[(1-
hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-
(propan-2-yl)phenyl]methyl}-2,4-dimethylphenyl)-D-glucitol (15e)
Compound 15e was obtained as a mixture with 14 from 11e in a
manner similar to that described for 15a. 1H NMR (300 MHz, CDCl3) δ
ppm 1.24–1.28 (m, 12H), 1.38 (s, 6H), 1.77 (s, 3H), 1.98 (s, 3H), 2.04
(s, 6H), 2.16 (s, 3H), 2.37 (s, 3H), 3.12–3.22 (m, 1H), 3.55 (d,
J = 5.9 Hz, 2H), 3.77–3.83 (m, 1H), 3.93 (s, 2H), 4.07–4.14 (m, 1H),
4.16–4.25 (m, 1H), 4.59 (d, J = 9.9 Hz, 1H), 4.82–4.89 (m, 2H),
5.12–5.35 (m, 3H), 5.96 (d, J = 10.7 Hz, 1H), 6.02 (d, J = 10.6 Hz,
1H), 6.27 (d, J = 16.2 Hz, 1H), 6.50–6.58 (m, 1H), 6.73 (d, J = 8.1 Hz,
1H), 6.96 (d, J = 4.4 Hz, 2H), 7.13 (dd, J = 7.9, 1.4 Hz, 1H), 7.29 (s,
5.4.10. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-
hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}
phenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (15a)
1H). MS ESI/APCI Dual m/z 752 [M+Na]+
.
In an argon atmosphere, an acetonitrile (36 mL) suspension of
compound 11a (0.5 g, 0.83 mmol), compound 14 (0.37 g, 1.98 mmol),
palladium (II) acetate (37 mg, 0.17 mmol), tri-o-tolylphosphine
(101 mg, 0.33 mmol), and triethylamine (0.58 mL, 4.15 mmol) was
stirred for 30 min at 120 °C under microwave irradiation. The reaction
mixture was filtered using Celite (registered trademark) and washed
with ethyl acetate. The filtrate was concentrated under reduced pres-
sure, and the resulting residue was purified using neutral silica gel
column chromatography (hexane:ethyl acetate ratio = 1:2) to obtain
the title compound as a partially purified product (1.5 g). The title
compound (1.5 g) was further purified using neutral silica gel column
chromatography (hexane:ethyl acetate ratio = 7:3 → 2:8) to obtain the
title compound as a light-yellow amorphous substance (514 mg, 87%).
1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 6H), 1.36 (s, 6H), 1.78 (s,
3H), 2.01 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.14 (s, 3H), 2.36 (s, 3H),
3.79–3.87 (m, 1H), 3.93 (s, 2H), 4.09–4.27 (m, 3H), 4.59–4.67 (m, 1H),
4.83 (br s, 1H), 5.18–5.37 (m, 3H), 6.22–6.29 (m, 1H), 6.47–6.54 (m,
1H), 6.94 (s, 1H), 7.06 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 7.29 (d,
5.4.15. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-
hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-
methoxyphenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (15f)
Compound 15f was obtained as a mixture with 14 from 11f in a
manner similar to that described for 15a. 1H NMR (300 MHz, CDCl3) δ
ppm 1.22–1.29 (m, 56H), 1.37 (s, 6H), 1.77 (s, 3H), 2.00 (s, 3H),
2.03–2.07 (m, 9H), 2.15 (s, 3H), 2.36 (s, 3H), 2.49 (s, 2H), 3.77–3.87
(m, 3H), 3.89 (s, 3H), 4.12 (q, J = 7.2 Hz, 1H), 4.21 (d, J = 4.7 Hz, 1H),
4.60 (d, J = 9.3 Hz, 1H), 5.16–5.37 (m, 3H), 6.22–6.31 (m, 1H),
6.47–6.55 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.82–6.90 (m, 2H), 6.95
(s, 1H), 7.08 (s, 1H). MS ESI/APCI Dual m/z 740 [M+Na]+
.
5.4.16. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)methyl]-2,4-
dimethylphenyl}-D-glucitol (16a)
Sodium methoxide (4.88 M) in methanol solution (0.593 mL,
2.90 mmol) was added to a methanol (4.8 mL) solution of compound
15a (0.514 g, 0.724 mmol), and the mixture was stirred for 2 h at room
temperature. Dry ice was added to the reaction liquid, and the solvent
was distilled off under reduced pressure. The resulting residue was
purified using neutral silica gel column chromatography (ethyl acet-
ate:ethanol:water ratio = 30:2:1) to obtain the title compound as col-
orless amorphous substance (306 mg, 78%). 1H NMR (300 MHz,
CD3OD) δ ppm 1.26 (s, 6H) 1.33 (s, 6H) 2.13 (s, 3H) 2.36 (s, 3H) 3.34
(s, 1H) 3.31–3.71 (m, 7H) 3.82–3.91 (m, 1H) 3.94 (s, 2H) 4.42 (d
J = 9.1 Hz, 1H) 6.29–6.38 (m, 1H) 6.39–6.46 (m, 1H) 6.47–6.59 (m,
1H) 6.95 (s, 1H) 7.07 (d, J = 8.2 Hz, 2H) 7.21–7.34 (m, 3H); 13C NMR
(126 MHz, CD3OD) δ ppm 19.4, 19.5, 23.8, 25.9, 40.1, 46.5, 55.9, 63.4,
69.8, 72.3, 76.1, 79.8, 80.3, 82.5, 127.5, 130.0, 130.4, 130.5, 133.4,
J = 8.2 Hz, 2H). MS ESI/APCI Dual m/z 710 [M+H]+, 723 [M+Na]+
.
5.4.11. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(2-fluoro-4-{(1E)-
4-[(1-hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-
yl}phenyl)methyl]-2,4-dimethylphenyl}-D-glucitol (15b)
Compound 15b (70%) was obtained from 11b in a manner similar
to that described for 15a. 1H NMR (300 MHz, CDCl3) δ ppm 1.24 (s,
5H), 1.37 (s, 4H), 1.78 (s, 2H), 2.00 (s, 2H), 2.06 (s, 2H), 2.06 (s, 2H),
2.16 (s, 2H), 2.36 (s, 3H), 3.55 (s, 2H), 3.79–4.00 (m, 1H), 3.80–4.00
(m, 2H), 4.12–4.27 (m, 2H), 4.61 (d, J = 9.5 Hz, 1H), 5.19–5.37 (m,
3H), 6.24–6.32 (m, 1H), 6.43–6.51 (m, 1H), 6.84 (t, J = 7.9 Hz, 1H),
6.95 (s, 1H), 7.01–7.12 (m, 3H). MS ESI/APCI Dual m/z 728 [M+H]+
,
750 [M+Na]+
.
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135.0, 136.2, 136.3, 136.8, 137.3, 137.5, 141.9, 179.0; HRMS ESI/
3.83–3.89 (m, 5H) 4.40 (d, J = 9.0 Hz, 1H) 6.29–6.60 (m, 3H)
6.71–6.79 (m, 1H) 6.82–6.91 (m, 1H) 6.92–7.03 (m, 2H) 7.18 (s, 1H);
13C NMR (126 MHz, CD3OD) δ ppm 19.3, 19.4, 23.8, 25.9, 33.8, 46.5,
55.9, 56.0, 63.5, 69.8, 72.3, 76.1, 79.9, 80.3, 82.5, 109.2, 119.9, 130.1,
130.4, 130.8, 130.9, 133.2, 135.1, 136.2, 136.5, 137.3, 137.3, 137.8,
159.0, 179.0; HRMS ESI/APCI Dual m/z calcd for C32H45NO8 572.3218
[M+H]+, found 572.3198.
APCI Dual m/z calcd for
C
31H43NO7 542.3112 [M+H]+
, found
542.3105.
5.4.17. (1S)-1,5-anhydro-1-{5-[(2-fluoro-4-{(1E)-4-[(1-hydroxy-2-
methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)
methyl]-2,4-dimethylphenyl}-D-glucitol (16b)
Compound 16b (59%) was obtained from 15b in a manner similar
to that described for 16a. 1H NMR (300 MHz, CD3OD) δ ppm 1.27 (s,
6H) 1.34 (s, 6H) 2.15 (s, 3H) 2.36 (s, 3H) 3.37–3.40 (m, 1H) 3.44–3.54
(m, 4H) 3.60–3.72 (m, 1H) 3.82–3.97 (m, 4H) 4.38–4.42 (m, 1H)
6.36–6.56 (m, 2H) 6.85–7.27 (m, 5H); 13C NMR (126 MHz, CD3OD) δ
ppm 19.3, 19.4, 23.8, 25.8, 32.4, 46.6, 56.0, 63.4, 69.8, 72.3, 76.1,
79.8, 80.3, 82.5, 113.4, 113.6, 123.5 (d, J = 2.5 Hz), 128.2, 128.3,
129.5, 130.3, 131.9 (d, J = 5.0 Hz), 133.4, 136.1, 136.5, 136.7, 137.0,
137.2, 138.9 (d, J = 7.5 Hz), 161.6, 163.5, 178.7; HRMS ESI/APCI Dual
m/z calcd for C31H42FNO7 560.3018 [M+H]+, found 560.3004.
5.4.22. (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-{2-(benzyloxy)-5-[(4-
{(1E)-4-[(1-hydroxy-2-methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-
1-en-1-yl}phenyl)methyl]-4-methylphenyl}-D-glucitol (18)
In an argon atmosphere, an acetonitrile (36 mL) suspension of (1S)-
1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-{2-(benzyloxy)-5-[(4-bromo-
phenyl)methyl]-4-methylphenyl}-D-glucitol (17) (518 mg, 0.58 mmol),
compound 14 (162 mg, 0.87 mmol), palladium (II) acetate (13.1 mg,
0.058 mmol), tri-o-tolylphosphine (35.4 mg, 0.116 mmol), and triethy-
lamine (0.406 mL, 2.91 mmol) was stirred for 20 min at 120 °C under
microwave irradiation. The reaction mixture was filtered using Celite
(registered trademark) and washed with ethyl acetate. The filtrate was
concentrated under reduced pressure, and the resulting residue was
purified using neutral silica gel column chromatography (hexane:ethyl
acetate ratio = 1:1) to obtain the title compound as pale-yellow oil
(416 mg, 72%). 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (s, 6H), 1.36 (s,
6H), 2.20 (s, 3H), 3.55 (s, 3H), 3.72–3.79 (m, 4H), 3.92 (s, 2H), 4.00
(m, 1H), 4.41–4.52 (m, 2H), 4.57–4.65 (m, 2H), 4.83–4.92 (m, 3H),
5.00 (s, 2H), 5.21–5.29 (m, 2H), 5.73 (s, 2H), 6.21 (d, J = 16.3 Hz, 1H),
6.46 (d, J = 16.3 Hz, 1H), 6.75 (s, 1H), 6.93 (m, 2H), 7.05 (d,
J = 8.1 Hz, 2H), 7.11–7.46 (m, 26H); MS ESI/APCI Dual m/z 994 [M
5.4.18. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-methylphenyl)methyl]-
2,4-dimethylphenyl}-D-glucitol (16c)
Compound 16c (77%) was obtained from 15c in a manner similar to
that described for 16a. 1H NMR (300 MHz, CD3OD) δ ppm 1.27 (s, 6H)
1.34 (s, 6H) 2.14 (s, 3H) 2.30 (s, 3H) 2.37 (s, 3H) 3.34–3.49 (m, 6H)
3.61 (dd, J = 11.8, 5.6 Hz, 1H) 3.80–3.91 (m, 3H) 4.34–4.41 (m, 1H)
6.29–6.39 (m, 1H) 6.43 (s, 1H) 6.46–6.57 (m, 1H) 6.76 (d, J = 7.9 Hz,
1H) 6.99 (s, 1H) 7.04–7.13 (m, 2H) 7.24 (s, 1H); 13C NMR (126 MHz,
CD3OD) δ ppm 19.4, 19.4, 19.9, 23.9, 25.9, 37.3, 46.5, 55.9, 63.5, 69.8,
72.3, 75.9, 79.9, 80.3, 82.5, 125.1, 129.2, 130.0, 130.2, 130.7, 133.3,
134.8, 136.3, 136.4, 136.7, 137.0, 137.3, 137.9, 139.8, 179.0; HRMS
ESI/APCI Dual m/z calcd for C32H45NO7 556.3269 [M+H]+, found
556.3252.
+H]+
.
5.4.23. (1S)-1,5-anhydro-1-{2-hydroxy-5-[(4-{(1E)-4-[(1-hydroxy-2-
methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)
methyl]-4-methylphenyl}-D-glucitol (19)
5.4.19. (1S)-1,5-anhydro-1-{5-[(2-chloro-4-{(1E)-4-[(1-hydroxy-2-
methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)
methyl]-2,4-dimethylphenyl}-D-glucitol (16d)
EtSH (4.1 mL, 26.5 mmol) was added to a solution of compound 18
(410 mg, 0.412 mmol) in chloroform (4.1 mL), and the mixture was
cooled with ice in a nitrogen atmosphere. Under ice cooling, BF3·OEt2
(0.82 mL, 6.5 mmol) was added, and the mixture was stirred for 2 h at
room temperature. Methanol was added to the reaction liquid, and the
mixture was distilled off under reduced pressure. The resulting residue
was purified using acidic silica gel column chromatography (ethyl
acetate:ethanol:water ratio = 20:2:1) to obtain the title compound as a
partially purified product (72 mg). The title compound (72 mg) was
further purified using acidic silica gel column chromatography
(chloroform → chloroform:methanol ratio = 4:1) to obtain the title
compound as colorless amorphous substance (8.7 mg, 4%). 1H NMR
(300 MHz, CDCl3) δ ppm 1.26 (s, 6H) 1.35 (s, 6H) 2.10 (s, 3H)
3.34–3.71 (m, 7H) 3.84–3.91 (m, 2H) 4.07 (s, 1H) 4.52 (d, J = 9.5 Hz,
1H) 6.29–6.58 (m, 2H) 6.64 (s, 1H) 7.04–7.14 (m, 3H) 7.30 (d,
Compound 16d (5% in 2 steps) was obtained from 15d in a manner
similar to that described for 16a. 1H NMR (300 MHz, CD3OD) δ ppm
1.27 (s, 6H) 1.34 (s, 6H) 2.11 (s, 3H) 2.37 (s, 3H) 3.33–3.69 (m, 7H)
3.81–3.92 (m, 1H) 4.02 (s, 2H) 4.41 (d, J = 9.17 Hz, 1H) 6.35–6.56 (m,
3H) 6.83 (d, J = 7.9 Hz, 1H) 7.00 (s, 1H) 7.14–7.25 (m, 2H) 7.45–7.47
(m, 1H); MS ESI/APCI Dual m/z 576 [M+H]+, 574 [M−H]-.
5.4.20. (1S)-1,5-anhydro-1-(5-{[4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-(propan-2-yl)phenyl]
methyl}-2,4-dimethylphenyl)-D-glucitol (16e)
Compound 16e (51% in 2 steps) was obtained from 15e in a manner
similar to that described for 16a. 1H NMR (300 MHz, CD3OD) δ ppm
1.23 (d, J = 2.3 Hz, 3H) 1.26 (d, J = 2.3 Hz, 3H) 1.28 (s, 6H) 1.36 (s,
6H) 2.17 (s, 3H) 2.37 (s, 3H) 3.14–3.23 (m, 1H) 3.34–3.50 (m, 6H)
3.55–3.64 (m, 2H) 3.84 (dd, J = 12.0, 2.0 Hz, 1H) 3.96 (s, 2H)
4.33–4.40 (m, 1H) 6.31–6.39 (m, 1H) 6.45 (s, 1H) 6.51–6.60 (m, 1H)
6.79 (d, J = 8.1 Hz, 1H) 7.00 (d, J = 5.9 Hz, 2H) 7.12 (dd, J = 7.9,
1.6 Hz, 1H) 7.34 (d, J = 1.6 Hz, 1H); 13C NMR (126 MHz, CD3OD) δ
ppm 19.4, 19.5, 23.9, 24.1, 24.2, 26.0, 30.2, 36.6, 46.5, 55.9, 63.5,
69.8, 72.3, 76.0, 79.9, 80.3, 82.5, 124.6, 124.7, 129.8, 130.9, 131.0,
133.3, 134.7, 136.3, 136.6, 136.8, 137.1, 137.5, 138.1, 148.6, 179.0;
J = 8.2 Hz, 1H); MS ESI/APCI Dual m/z 544 [M+H]+, 542 [M−H]−
5.4.24. 2-Iodo-5-(propan-2-yl)phenol (21)
.
An aqueous suspended solution (75 mL) of potassium iodate (7.88 g,
0.0368 mol) and iodine (18.7 g, 0.0736 mol) was added to an acetic
acid (200 mL) solution of 3-isopropylphenol (25 g, 0.184 mol), and the
resulting reaction solution was stirred for 20 h at room temperature.
After the addition of diethyl ether (400 mL) and water (300 mL), the
organic layer was separated. The organic layer was washed with water,
a saturated aqueous solution of sodium hydrogen carbonate, and a sa-
turated saline solution and then dried over anhydrous magnesium sul-
fate. The desiccant was filtered out, and the solvent was distilled off
under reduced pressure. The resulting residue was purified using neu-
tral silica gel column chromatography (hexane:ethyl acetate
ratio = 95:5) to obtain a colorless oily title compound (27.6 g, 57%). 1H
NMR (300 MHz, CDCl3) δ ppm 1.16–1.25 (m, 6H) 2.64–2.98 (m, 1H)
5.21 (s, 1H) 6.57 (dd, J = 8.1, 2.2 Hz, 1H) 6.88 (d, J = 2.2 Hz, 1H) 7.54
(d, J = 8.1 Hz, 1H).
HRMS ESI/APCI Dual m/z calcd for C34H49NO7 584.3582 [M+H]+
,
found 584.3569.
5.4.21. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-methoxyphenyl)methyl]-
2,4-dimethylphenyl}-D-glucitol (16f)
Compound 16f (33% in 2 steps) was obtained from 15f in a manner
similar to that described for 16a. 1H NMR (300 MHz, CD3OD) δ ppm
1.27 (s, 6H) 1.35 (s, 6H) 2.13 (s, 3H) 2.35 (s, 3H) 3.36–3.67 (m, 7H)
9

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5.4.25. 2-(Benzyloxy)-1-iodo-4-(propan-2-yl)benzene (22a)
resulting residue was purified using silica gel column chromatography
(hexane:ethyl acetate ratio = 5:1 → 2:1) to obtain the title compound
as a light-yellow amorphous substance (19.1 g, 40% in 4 steps). 1H
NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J = 6.99 Hz, 6H) 1.78 (s, 3H)
2.01 (s, 6H) 2.05 (s, 3H) 2.86 (m, 1H) 3.80 (m, 1H) 4.06–4.13 (m, 1H)
4.19–4.27 (m, 1H) 4.96 (d, J = 9.9 Hz, 1H) 5.10 (s, 2H) 5.16–5.25 (m,
1H) 5.33 (t, J = 9.2 Hz, 1H) 5.40–5.49 (m, 1H) 6.79 (d, J = 1.4 Hz, 1H)
6.85 (dd, J = 7.9, 1.4 Hz, 1H) 7.26–7.52 (m, 6H); MS ESI/APCI Dual m/
Benzyl bromide (14.4 mL, 0.121 mol) was added to an acetonitrile
suspension of compound 21 (26.5 g, 0.101 mol) and potassium carbo-
nate (20.9 g, 0.152 mol), and the mixture was stirred at room tem-
perature for 2 h, followed by the addition of methanol (1.0 mL) and
stirring for an additional 30 min. The insoluble materials were filtered
off, and the filtrate was concentrated. The resulting residue was purified
using silica gel column chromatography (hexane:ethyl acetate
ratio = 95:5) to obtain the title compound as a colorless oil (30.2 g,
85%). 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J = 7.0 Hz, 6H) 2.84
(m, 1H) 5.14 (s, 2H) 6.62 (dd, J = 8.4, 2.2 Hz, 1H) 6.74 (d, J = 2.2 Hz,
1H) 7.23–7.58 (m, 5H) 7.68 (d, J = 8.4 Hz, 1H).
z 579 [M+Na]+
.
5.4.28. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[2-methoxy-4-(propan-
2-yl)phenyl]-D-glucitol (23b)
A 2.6-M n-butyllithium solution in hexane (34 mL, 88.6 mmol) was
added dropwise to a THF (100 mL) solution of compound 22b (24.5 g,
88.6 mmol) at −78 °C in a nitrogen atmosphere, and the mixture was
stirred for 5 min at the same temperature. Then, a THF (60 mL) solution
of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (5) (37.6 g,
80.5 mmol) was added dropwise over 25 min, and the mixture was
stirred for 10 min at the same temperature. Ice water was added to the
reaction solution, and the resulting mixture was warmed to room
temperature and then extracted twice with ethyl acetate. The combined
organic layer was washed with a saturated saline solution and dried
over anhydrous magnesium sulfate. The desiccant was filtered out, and
the solvent was distilled off under reduced pressure. The resulting re-
sidue was dissolved in a methanol (380 mL) solution containing me-
thanesulfonic acid (1.55 g, 16.1 mmol), and the solution was stirred for
2 h at room temperature. Then, the solution was neutralized with
triethylamine (11.2 mL, 80.5 mmol), and the reaction mixture was
concentrated. The resulting residue (30.2 g) was dissolved in pyridine
(100 mL), and acetic anhydride (100 mL) was then added; the mixture
was then stirred for 14 h at room temperature. Ice water (400 mL) was
added, and the mixture was extracted twice with ethyl acetate
(200 mL). The combined organic layer was washed with 1-M hydro-
chloric acid, a saturated aqueous solution of sodium hydrogen carbo-
nate, and a saturated saline solution and then dried over anhydrous
magnesium sulfate. The desiccant was filtered out, and the solvent was
distilled off under reduced pressure. The resulting residue was purified
using neutral silica gel column chromatography (hexane → hex-
ane:ethyl acetate ratio = 6:4). The obtained organic layer was distilled
off under reduced pressure. Et3SiH (21 mL, 128 mmol) and BF3·OEt2
(49 mL, 385 mmol) were added to a solution of the resulting residue
(32.8 g) in chloroform (150 mL) and acetonitrile (150 mL) at 4 °C in a
nitrogen atmosphere, and the mixture was stirred for 1 h at the same
temperature. A saturated aqueous solution of sodium hydrogen carbo-
nate was added to the reaction solution, and the mixture was extracted
with chloroform. Then, the organic layer was washed with a saturated
saline solution and dried over anhydrous magnesium sulfate. The de-
siccant was filtered out, and the solvent was distilled off under reduced
pressure. The resulting residue was purified using neutral silica gel
column chromatography (hexane:ethyl acetate ratio = 2:1) to obtain
the title compound as light-yellow gummy substance (22.9 g, 59% in 4
steps). 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (d, J = 7.0 Hz, 6H) 1.77
(s, 3H) 2.01 (s, 3H) 2.05 (s, 3H) 2.07 (s, 3H) 2.87 (dt, J = 13.8, 7.0 Hz,
1H) 3.80–3.87 (m, 1H) 3.84 (s, 3H) 4.09–4.16 (m, 1H) 4.22–4.29 (m,
1H) 4.88–4.95 (m, 1H) 5.18–5.27 (m, 1H) 5.32–5.38 (m, 2H) 6.71 (d,
J = 1.6 Hz, 1H) 6.83 (dd, J = 7.9, 1.6 Hz, 1H) 7.23–7.30 (m, 1H); MS
5.4.26. 1-Iodo-2-methoxy-4-(propan-2-yl)benzene (22b)
Methyl iodide (9.8 mL, 0.156 mol) was added to an acetonitrile
suspension (200 mL) of compound 21 (27.4 g, 0.104 mol) and po-
tassium carbonate (21.7 g, 0.156 mol), and the mixture was stirred for
2.5 h at 40 °C. Methyl iodide (3.5 mL, 0.052 mol) was further added,
and the mixture was stirred for 1 h at the same temperature. The in-
soluble materials were filtered off, and the filtrate was diluted with
ethyl acetate. The organic layer was washed with water, a 10% aqueous
solution of sodium thiosulfate, and a saturated saline solution and then
dried over anhydrous magnesium sulfate. The desiccant was filtered
out, and the solvent was distilled off under reduced pressure. The re-
sulting residue was purified using neutral silica gel column chromato-
graphy (hexane → hexane:ethyl acetate ratio = 95:5) to obtain a light-
yellow oily compound (24.5 g, 85%). 1H NMR (300 MHz, CDCl3) δ ppm
1.24 (d, J = 6.8 Hz, 6H) 2.87 (m, 1H) 3.88 (s, 3H) 6.58–6.65 (m, 1H)
6.70 (d, J = 1.9 Hz, 1H) 7.65 (d, J = 8.1 Hz, 1H); MS ESI/APCI Dual m/
z 277 [M+H]+
.
5.4.27. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[2-(benzyloxy)-4-
(propan-2-yl)phenyl]-D-glucitol (23a)
n-Butyllithium (2.6 M) in hexane (33 mL, 85.7 mmol) was added
dropwise to a solution of compound 22a (30.2 g, 85.7 mmol) in THF
(450 mL) at −78 °C under a nitrogen atmosphere, and the mixture was
stirred at the same temperature for 15 min. Next, a solution of 2,3,4,6-
tetra-O-trimethylsilyl-D-glucono-1,5-lactone (40.0 g, 85.7 mmol) in THF
(230 mL) was added dropwise over 15 min, and the mixture was stirred
at the same temperature for 20 min. Saturated aqueous ammonium
chloride (150 mL) and water (100 mL) were added to the reaction
mixture, and the mixture was warmed to room temperature and then
extracted twice with ethyl acetate. The combined organic layers were
washed with brine and dried over anhydrous magnesium sulfate. After
filtering off the desiccant, the solvent was distilled off under reduced
pressure. The resulting residue was dissolved in a solution containing
methanesulfonic acid (2.9 g) in methanol (840 mL), and the mixture
was stirred at room temperature for 14.5 h. After neutralization with
triethylamine (2.5 mL), the reaction mixture was concentrated. The
resulting residue (46.4 g) was dissolved in pyridine (125 mL) and
cooled to 4 °C. Acetic anhydride (75 mL) and 4-dimethylaminopyridine
(102 mg, 0.835 mmol) were added to the solution, and the mixture was
stirred at room temperature for 19 h. After the addition of ice water
(500 mL), the mixture was extracted twice with ethyl acetate (500 mL).
The combined organic layers were washed with saturated aqueous so-
dium bicarbonate and brine and then dried over anhydrous magnesium
sulfate. After filtering off the desiccant, the solvent was distilled off
under reduced pressure to yield a crude compound (53 g). Et3SiH
(13.7 mL, 85.7 mmol) and BF3.Et2O (10.9 mL, 85.7 mmol) were added
to a solution of the crude compound in chloroform (250 mL) and
acetonitrile (250 mL) at 4 °C under a nitrogen atmosphere, and the
mixture was stirred at the same temperature for 1.5 h. The reaction
mixture was diluted with saturated aqueous sodium bicarbonate and
extracted with chloroform. The organic layer was washed with brine
and dried over anhydrous magnesium sulfate. After filtering off the
desiccant, the solvent was distilled off under reduced pressure and the
ESI/APCI Dual m/z 503 [M+Na]+
.
5.4.29. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-bromo-2-hydroxy-4-
(propan-2-yl)phenyl]-D-glucitol (24a)
Ten-percent palladium on activated carbon (1.8 g) was added to a
solution of compound 23a (19.1 g, 34.3 mmol) in methanol (200 mL),
and the mixture was stirred under a hydrogen atmosphere at room
temperature for 2 h. After the reaction mixture was filtered through
celite, the solvent was distilled off under reduced pressure and the re-
sulting residue was purified using silica gel column chromatography
10

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
(hexane:ethyl acetate ratio = 2:1 → 1:1) to yield (1S)-2,3,4,6-tetra-O-
acetyl-1,5-anhydro-1-[2-hydroxy-4-(propan-2-yl)phenyl]-D-glucitol as a
colorless amorphous substance (12.3 g). Bromine (4.2 g, 26.3 mmol)
was then added dropwise to a solution of (1S)-2,3,4,6-tetra-O-acetyl-
was added to a methanol (250 mL) suspension of compound 24b
(25.5 g, 45.6 mmol), and the mixture was stirred for 2 h at room tem-
perature. Dry ice was placed in the reaction solution, and the solvent
was distilled off under reduced pressure. The resulting residue was
dissolved in N,N-dimethylformamide (135 mL); triethylamine (45 mL)
and chlorotrimethylsilane (35 mL) were then added under ice cooling.
The reaction mixture was stirred for 2 h at room temperature, and ice
water was added. The mixture was extracted twice with toluene, and
the combined organic layer was washed with a saturated saline solu-
tion; the system was then dried over anhydrous magnesium sulfate. The
desiccant was filtered out, and the solvent was distilled off under re-
duced pressure to obtain the title compound as a brown oily substance
(30.3 g). This compound was used in the next reaction without pur-
ification. 1H NMR (300 MHz, CDCl3) δ ppm −0.32 (s, 9H) 0.09 (s, 9H)
0.18 (s, 9H) 0.20 (s, 9H) 1.19 (d, J = 6.8 Hz, 3H) 1.23 (d, J = 6.8 Hz,
3H) 3.26–3.44 (m, 3H) 3.52–3.58 (m, 2H) 3.65–3.75 (m, 3H) 3.76–3.83
(m, 1H) 3.80 (s, 3H) 4.60 (d, J = 8.6 Hz, 1H) 6.72 (s, 1H) 7.51 (s, 1H);
1,5-anhydro-1-[2-hydroxy-4-(propan-2-yl)phenyl]-D-glucitol
(12.3 g,
26.3 mmol) in acetic acid (120 mL) at room temperature. The reaction
mixture was stirred for 1.5 h, and ice water (150 mL) was added. This
mixture was extracted twice with ethyl acetate, and the combined or-
ganic layers were washed with saturated aqueous sodium bicarbonate
and 10% aqueous sodium thiosulfate and brine and then dried over
anhydrous magnesium sulfate. After filtering off the desiccant, the
solvent was distilled off under reduced pressure. The resulting residue
was dissolved in 2-propanol (20 mL), to which hexane (50 mL) was then
added dropwise. The mixture was stirred at 4 °C for 1 h, and the re-
sulting precipitate was filtered to obtain the title compound (9.8 g, 52%
in 2 steps) as a colorless powder. 1H NMR (300 MHz, CDCl3) δ ppm
1.12–1.26 (m, 6H) 1.89 (s, 3H) 2.01 (s, 3H) 2.07 (s, 3H) 2.13 (s, 3H)
3.22 (sept, J = 6.74 Hz, 1H) 3.87 (ddd, J = 9.5, 3.7, 2.2 Hz, 1H)
4.14–4.22 (m, 1H) 4.28–4.36 (m, 1H) 4.53 (d, J = 9.3 Hz, 1H)
5.16–5.39 (m, 3H) 6.82 (s, 1H) 7.14 (s, 1H); MS ESI/APCI Dual m/z 567
MS ESI/APCI Dual m/z 701 [M+Na]+
.
5.4.33. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromophenyl)
methyl]-2-methoxy-4-(propan-2-yl)phenyl}-D-glucitol (27f)
[M+Na]+
.
A 2.7-M n-butyllithium hexane solution (4.7 mL, 12.9 mmol) was
added dropwise to a THF (40 mL) solution of compound 25b (8.7 g,
12.9 mmol) at −78 °C in an argon atmosphere, and the mixture was
stirred for 10 min at the same temperature. Then, a THF (25 mL) so-
lution of 4-bromobenzaldehyde (8a) (2.6 g, 14.2 mmol) was added
dropwise over 15 min, and the mixture was stirred for 30 min at the
same temperature. A saturated aqueous solution of ammonium chloride
was added to the reaction liquid; after the mixture was warmed to room
temperature, the warmed mixture was extracted twice with ethyl
acetate. The combined organic layer was washed with a saturated saline
solution and dried over anhydrous magnesium sulfate. The desiccant
was filtered out, and the solvent was distilled off under reduced pres-
sure. The resulting residue was dissolved in a methanol (65 mL) solu-
tion containing methanesulfonic acid (0.2 g), and the solution was
stirred for 14 h at room temperature. The reaction liquid was neu-
tralized with triethylamine (1.8 mL), and the reaction mixture was
concentrated. The resulting residue was purified using acidic silica gel
5.4.30. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-bromo-2-methoxy-
4-(propan-2-yl)phenyl]-D-glucitol (24b)
Bromine (2.4 mL, 47.6 mmol) was added dropwise to an acetic acid
(90 mL) solution of compound 23b (22.9 g, 47.7 mmol) at room tem-
perature. The reaction mixture was stirred for 1 h, and the resulting
reaction liquid was added to a saturated aqueous solution of sodium
hydrogen carbonate (400 mL). The mixture was extracted twice with
ethyl acetate, and the combined organic layer was washed with a 10%
saline solution; the system was then dried over anhydrous magnesium
sulfate. The desiccant was filtered out, and the solvent was distilled off
under reduced pressure. The resulting residue was purified using neu-
tral silica gel column chromatography (hexane:ethyl acetate
ratio = 3:2) to obtain the title compound as a light-yellow amorphous
substance (25.5 g, 96%). 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (d,
J = 6.8 Hz, 3H) 1.23 (d, J = 6.8 Hz, 3H) 1.80 (s, 3H) 2.01 (s, 3H) 2.05
(s, 3H) 2.09 (s, 3H) 3.31 (quin, J = 6.8 Hz, 1H) 3.77–3.82 (m, 1H) 3.83
(s, 3H) 4.10–4.17 (m, 1H) 4.22–4.30 (m, 1H) 4.83 (d, J = 9.5 Hz, 1H)
5.17–5.38 (m, 3H) 6.75 (s, 1H) 7.49 (s, 1H); MS ESI/APCI Dual m/z 581
column
chromatography
(chloroform → chloroform:methanol
ratio = 9:1) to obtain an intermediate compound (26f) as a colorless
amorphous substance (2.9 g). Compound 26f (2.9 g, 5.8 mmol) was
dissolved in pyridine (18 mL). Acetic anhydride (9 mL) was added to
the resulting solution, and the mixture was stirred for 5 h at room
temperature. Ice water was added, and the mixture was extracted twice
with ethyl acetate. The combined organic layer was washed with 3-N
hydrochloric acid and a saturated saline solution and then dried over
anhydrous magnesium sulfate. The desiccant was filtered out, and the
solvent was distilled off under reduced pressure to obtain a crude
product (3.3 g). Et3SiH (1.1 mL, 7.1 mmol) was added to a solution of
the crude product (3.3 g) in chloroform (25 mL) and acetonitrile
(25 mL), and the mixture was cooled with ice in a nitrogen atmosphere.
Under ice cooling, BF3·OEt2 (0.9 mL, 7.1 mmol) was added dropwise
over 10 min, and the mixture was stirred for 30 min at the same tem-
perature. A saturated aqueous solution of sodium hydrogen carbonate
was added to the reaction liquid, and the mixture was extracted with
chloroform. Then, the organic layer was washed with a saturated saline
solution and dried over anhydrous magnesium sulfate. The desiccant
was filtered out, and the solvent was distilled off under reduced pres-
sure. The resulting residue was purified using acidic silica gel column
chromatography (hexane:ethyl acetate ratio = 9:1 → 6:4) to obtain the
title compound as a colorless oil (2.9 g, 34% in 4 steps). 1H NMR
(300 MHz, CDCl3) δ ppm 1.04 (d, J = 6.8 Hz, 3H) 1.09 (d, J = 6.8 Hz,
3H) 1.76 (s, 3H) 2.01 (s, 3H) 2.05 (s, 3H) 2.06 (s, 3H) 2.91–3.06 (m,
1H) 3.80–3.88 (m, 4H) 3.91 (d, J = 5.1 Hz, 2H) 4.06–4.18 (m, 1H)
4.20–4.31 (m, 1H) 4.82–4.93 (m, 1H) 5.15–5.43 (m, 3H) 6.77 (s, 1H)
6.92 (d, J = 8.6 Hz, 2H) 7.11 (s, 1H) 7.36 (d, J = 8.6 Hz, 2H); MS ESI/
[M+Na]+
.
5.4.31. (1S)-1,5-Anhydro-1-{5-bromo-4-(propan-2-yl)-2-[(trimethylsilyl)
oxy]phenyl}-2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucitol (25a)
Triethylamine (24 mL) and water (24 mL) were added to a solution
of compound 24a (12.2 g, 22.3 mmol) in methanol (120 mL). The re-
action mixture was stirred at room temperature for 15 h and then fur-
ther stirred at 50 °C for 10 h; the solvent was distilled off under reduced
pressure. The resulting residue was dissolved in N,N-dimethylforma-
mide (106 mL), to which triethylamine (18.6 mL, 134 mmol) and
chlorotrimethylsilane (14.3 mL, 112 mmol) were added at 4 °C under a
nitrogen atmosphere. The reaction mixture was stirred at 4 °C for 1 h,
followed by the addition of ice water (150 mL). The mixture was ex-
tracted three times with toluene, and the combined organic layers were
washed with water and saturated aqueous sodium bicarbonate and
brine and then dried over anhydrous magnesium sulfate. After filtering
off the desiccant, the solvent was distilled off under reduced pressure to
obtain the title compound (17.4 g) as an oil. 1H NMR (300 MHz, CDCl3)
δ ppm −0.28 (s, 9H) 0.08 (s, 9H) 0.19 (s, 9H) 0.20 (s, 9H) 0.29 (s, 9H)
1.16 (d, J = 6.8 Hz, 3H) 1.21 (d, J = 6.8 Hz, 3H) 3.17–3.37 (m, 1H)
3.41–3.56 (m, 3H) 3.62–3.72 (m, 1H) 3.76–3.86 (m, 1H) 4.46 (d,
J = 8.2 Hz, 1H) 6.64 (s, 1H) 7.47 (s, 1H).
5.4.32. (1S)-1,5-anhydro-1-[5-bromo-2-methoxy-4-(propan-2-yl)phenyl]-
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucitol (25b)
A 25 wt% sodium methoxide-methanol solution (1 mL, 4.9 mmol)
11

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
39.2, 46.5, 55.9, 56.5, 63.4, 69.8, 72.3, 75.9, 76.8, 80.3, 82.5, 109.8,
126.2, 127.5, 129.9, 130.5, 130.8, 132.1, 135.0, 136.2, 142.9, 149.8,
158.7, 179.0; HRMS ESI/APCI Dual m/z calcd for C33H47NO8 586.3374
[M+H]+, found 586.3347.
APCI Dual m/z 671 [M+Na]+
.
5.4.34. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-[(4-bromophenyl)
methyl]-4-(propan-2-yl)phenyl]-1,5-anhydro-D-glucitol (27e)
Compound 27e (56% in 4 steps) was obtained from 25a and 8a in a
manner similar to that described for 27f. 1H NMR (300 MHz, CDCl3) δ
ppm 1.06 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 1.77 (s, 3H),
2.01 (s, 3H), 2.04 (s, 3H), 2.07 (s, 3H), 2.36 (s, 3H), 2.95–3.05 (m, 1H),
3.75–3.83 (m, 1H), 3.96 (s, 2H), 4.08 (dd, J = 12.5, 2.2 Hz, 1H), 4.29
(dd, J = 12.5, 4.7 Hz, 1H), 4.51–4.58 (m, 1H), 5.15–5.24 (m, 1H),
5.28–5.34 (m, 2H), 6.91–6.98 (m, 3H), 7.15 (s, 1H), 7.38 (d,
5.4.39. (1S)-1,5-anhydro-1-{2-hydroxy-5-[(4-{(1E)-4-[(1-hydroxy-2-
methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-
methylphenyl)methyl]-4-(propan-2-yl)phenyl}-D-glucitol (28g)
Compound 28g (48% in 2 steps) was obtained from 27g and 14 in a
manner similar to that described for 16a. 1H NMR (600 MHz, CD3OD) δ
ppm 1.10 (d, J = 6.9 Hz, 6H) 1.27 (s, 7H) 1.34 (s, 6H) 2.31 (s, 3H)
2.89–2.96 (m, 1H) 3.34 (s, 1H) 3.37–3.39 (m, 2H) 3.43–3.49 (m, 2H)
3.52–3.56 (m, 1H) 3.66–3.70 (m, 1H) 3.81–3.90 (m, 3H) 4.46 (d,
J = 9.6 Hz, 1H) 6.32–6.36 (m, 1H) 6.42 (s, 1H) 6.50 (d, J = 16.1 Hz,
1H) 6.75 (d, J = 7.8 Hz, 1H) 6.80 (s, 1H) 6.96 (s, 1H) 7.07–7.12 (m,
1H) 7.23 (s, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 23.9, 24.1,
24.2, 26.0, 30.3, 36.3, 46.5, 55.9, 63.1, 69.8, 71.9, 75.5, 79.2, 80.2,
82.4, 114.3, 124.0, 125.0, 129.1, 129.2, 130.2, 130.7, 131.8, 134.7,
136.2, 137.6, 140.8, 149.6, 155.7, 179.0; HRMS ESI/APCI Dual m/z
calcd for C33H47NO8 586.3374 [M+H]+, found 586.3354.
J = 8.2 Hz, 2H); MS ESI/APCI Dual m/z 699 [M+Na]+
.
5.4.35. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-[(4-bromo-2-
methylphenyl)methyl]-4-(propan-2-yl)phenyl]-1,5-anhydro-D-glucitol
(27g)
Compound 27g (50% in 4 steps) was obtained from 25a and 8c in a
manner similar to that described for 27f. 1H NMR (300 MHz, CDCl3) δ
ppm 1.12 (d, J = 6.7 Hz, 3H) 1.14 (d, J = 6.7 Hz, 3H) 1.76 (s, 3H) 1.99
(s, 3H) 2.03 (s, 3H) 2.06 (s, 3H) 2.27 (s, 3H) 2.37 (s, 3 H) 2.93 (sept,
J = 6.7 Hz, 1H) 3.76 (ddd, J = 9.9, 4.5, 2.2 Hz, 1H) 3.87 (s, 2H) 4.06
(dd, J = 12.5, 2.2 Hz, 1H) 4.27 (dd, J = 12.5, 4.5 Hz, 1H) 4.49 (d,
J = 9.6 Hz, 1H) 5.10–5.33 (m, 3H) 6.59 (d, J = 8.4 Hz, 1H) 6.97 (s, 1H)
7.00 (s, 1H) 7.20 (dd, J = 8.4, 2.5 Hz, 1H) 7.34 (d, J = 2.5 Hz, 1H); MS
5.4.40. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}-2-methylphenyl)methyl]-2-
methoxy-4-(propan-2-yl)phenyl}-D-glucitol (28h)
ESI/APCI Dual m/z 713 [M+Na]+
.
Compound 28h (38% in 2 steps) was obtained from 27h and 14 in a
manner similar to that described for 16a. 1H NMR (600 MHz, CD3OD) δ
ppm 1.12–1.17 (m, 6H) 1.27 (s, 5H) 1.34 (s, 5H) 2.32 (s, 3H) 2.96–3.02
(m, 1H) 3.34–3.37 (m, 2H) 3.43–3.53 (m, 3H) 3.59–3.65 (m, 1H)
3.80–3.85 (m, 3H) 3.92 (s, 1H) 4.61 (d, J = 9.6 Hz, 1H) 6.34 (d,
J = 16.5 Hz, 1H) 6.42 (s, 1H) 6.50 (d, J = 16.5 Hz, 1H) 6.74 (d,
J = 7.8 Hz, 1H) 6.92 (s, 1H) 7.04–7.11 (m, 2H) 7.23 (s, 1H); MS ESI/
5.4.36. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-bromo-2-
methylphenyl)methyl]-2-methoxy-4-(propan-2-yl)phenyl}-D-glucitol (27h)
Compound 27h (53% in 4 steps) was obtained from 25b and 8c in a
manner similar to that described for 27f. 1H NMR (300 MHz, CDCl3) δ
ppm 1.11 (d, J = 6.7 Hz, 3H) 1.14 (d, J = 6.7 Hz, 3H) 1.75 (s, 3H) 1.99
(s, 3H) 2.04 (s, 3H) 2.05 (s, 3H) 2.28 (s, 3H) 2.90 (sept, J = 6.7 Hz, 1H)
3.71–3.90 (m, 3H) 3.86 (s, 3H) 3.85–3.87 (m, 1H) 4.05–4.15 (m, 1H)
4.19–4.28 (m, 1H) 4.77–4.85 (m, 1H) 5.11–5.23 (m, 1H) 5.26–5.37 (m,
2H) 6.54 (d, J = 8.2 Hz, 1H) 6.81 (s, 1H) 6.96 (s, 1H) 7.17 (dd, J = 8.2,
2.6 Hz, 1H) 7.32 (d, J = 2.6 Hz, 1H); MS ESI/APCI Dual m/z 685 [M
APCI Dual m/z 600 [M+H]+, 598 [M−H]−
.
5.4.41. Methyl N-(2,2-dimethylbut-3-enoyl)-2-methylalaninate (30)
Oxalyl chloride (4.43 mL, 49.9 mmol) and N,N-dimethylformamide
(3 drops) were added to a chloroform (250 mL) solution of 2,2-di-
+Na]+
.
methyl-3-butenoic acid (12)
(5.42 g, 47.5 mmol) in a nitrogen at-
19
mosphere, and the mixture was stirred for 1.5 h at room temperature.
The reaction mixture was cooled with ice, and triethylamine (19.9 mL,
143 mmol) and α-aminoisobutyric acid methyl ester hydrochloride (29)
(10.9 g, 71.2 mmol) were added; the mixture was then stirred for 1 h at
room temperature. Water was added to the reaction liquid, and the
mixture was extracted with chloroform. Then, the organic layer was
washed with 3-M hydrochloric acid, a saturated aqueous solution of
sodium hydrogen carbonate, and a saturated saline solution and dried
over anhydrous magnesium sulfate. The desiccant was filtered out, and
the solvent was distilled off under reduced pressure. The resulting re-
sidue was purified using silica gel column chromatography (hexane →
hexane:ethyl acetate ratio = 4:1) to obtain the title compound as a
colorless powder (9.38 g, 93%). 1H NMR (300 MHz, CDCl3) δ ppm 1.27
(s, 6H) 1.51 (s, 6H) 3.73 (s, 3H) 5.17–5.32 (m, 2H) 6.02 (dd, J = 17.6,
5.4.37. (1S)-1,5-anhydro-1-{2-hydroxy-5-[(4-{(1E)-4-[(1-hydroxy-2-
methylpropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)
methyl]-4-(propan-2-yl)phenyl}-D-glucitol (28e)
Compound 28e (49% in 2 steps) was obtained from 27e and 14 in a
manner similar to that described for 16a. 1H NMR (600 MHz, CD3OD) δ
ppm 1.03 (d, J = 6.9 Hz, 6H) 1.26 (s, 6H) 1.33 (s, 6H) 3.02 (dt,
J = 13.6, 6.7 Hz, 1H) 3.34 (s, 2H) 3.39–3.45 (m, 2H) 3.46–3.51 (m, 3H)
3.58 (t, J = 9.2 Hz, 1H) 3.71 (dd, J = 12.2, 5.3 Hz, 1H) 3.87 (dd,
J = 11.9, 1.8 Hz, 1H) 3.95 (s, 2H) 4.52 (d, J = 9.6 Hz, 1H) 6.34 (d,
J = 16.5 Hz, 1H) 6.42 (s, 1H) 6.51 (d, J = 16.5 Hz, 1H) 6.76 (s, 1H)
7.06 (d, J = 8.3 Hz, 2H) 7.14 (s, 1H) 7.29 (d, J = 8.3 Hz, 2H); 13C NMR
(126 MHz, CD3OD) δ ppm 23.9, 24.1, 24.2, 25.9, 30.3, 39.2, 46.5, 55.9,
63.1, 69.8, 71.9, 75.7, 78.9, 80.2, 82.5, 114.4, 124.0, 127.5, 129.8,
129.9, 130.5, 132.1, 135.0, 136.1, 143.1, 149.6, 155.8, 179.0; HRMS
ESI/APCI Dual m/z calcd for C32H45NO8 572.3218 [M+H]+, found
572.3206.
10.6 Hz, 1H) 6.25 (s, 1H); MS ESI/APCI Dual m/z 214 [M+H]+
5.4.42. N-(2,2-dimethylbut-3-enoyl)-2-methylalanine (31)
.
A 4-M aqueous solution of sodium hydroxide (16.5 mL, 66.0 mmol)
was added to a methanol (20 mL) solution of compound 30 (9.38 g.
43.9 mmol), and the mixture was stirred for 1 h at room temperature.
Then, the reaction mixture was concentrated. The resulting residue was
dissolved in water, and the solution was neutralized by the addition of
3-M hydrochloric acid. The mixture was extracted twice with ethyl
acetate, and the combined organic layer was washed with a saturated
saline solution and dried over anhydrous magnesium sulfate. The de-
siccant was filtered out, and the solvent was distilled off under reduced
pressure to obtain the title compound as a colorless powder (8.19 g,
94%). 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (s, 6H) 1.54 (s, 6H)
5.16–5.36 (m, 2H) 6.01 (dd, J = 17.5, 10.7 Hz, 1H) 6.14 (s, 1H); MS
5.4.38. (1S)-1,5-Anhydro-1-{5-[(4-{(1E)-4-[(1-hydroxy-2-methylpropan-
2-yl)amino]-3,3-dimethyl-4-oxobut-1-en-1-yl}phenyl)methyl]-2-methoxy-
4-(propan-2-yl)phenyl}-D-glucitol (28f)
Compound 28f (54% in 2 steps) was obtained from 27f and 14 in a
manner similar to that described for 16a. 1H NMR (600 MHz, CD3OD) δ
ppm 1.08 (t, J = 6.0 Hz, 6H) 1.26 (s, 6H) 1.34 (s, 7H) 3.06–3.15 (m,
1H) 3.38 (d, J = 4.6 Hz, 1H) 3.47 (s, 2H) 3.56 (t, J = 9.2 Hz, 1H) 3.65
(d, J = 10.6 Hz, 1H) 3.81–3.88 (m, 3H) 3.98 (s, 2H) 4.65 (d, J = 9.6 Hz,
1H) 6.34 (d, J = 16.1 Hz, 1H) 6.42 (s, 1H) 6.52 (d, J = 15.6 Hz, 1H)
6.88 (s, 1H) 7.07 (d, J = 7.8 Hz, 2H) 7.23 (s, 1H) 7.30 (d, J = 6.4 Hz,
2H); 13C NMR (126 MHz, CD3OD) δ ppm 23.9, 24.1, 24.2, 25.9, 30.7,
12

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
ESI/APCI Dual m/z 200 [M+H]+, 222 [M+Na]+
.
into water, and the mixture was extracted twice with ethyl acetate. The
combined organic layer was washed with a saturated saline solution
and dried over anhydrous magnesium sulfate. The desiccant was fil-
tered out, and the solvent was distilled off under reduced pressure. The
resulting residue was purified using neutral silica gel column chroma-
tography (hexane:ethyl acetate = 7:3 → 2:8) to obtain the title com-
pound as a colorless amorphous substance (103 mg, 94%). 1H NMR
(300 MHz, CDCl3) δ ppm 1.05 (d, J = 6.8 Hz, 3H) 1.10 (d, J = 6.8 Hz,
3H) 1.38 (s, 6H) 1.49 (s, 6H) 1.77 (s, 3H) 2.00 (s, 3H) 2.05 (s, 3H) 2.06
(s, 3H) 2.46 (s, 6H) 2.64–2.78 (m, 2H) 3.04 (sept, J = 6.8 Hz, 1H)
3.38–3.49 (m, 2H) 3.783.83 (m, 1H) 3.85 (s, 3H) 3.87–4.04 (m, 2H)
4.08–4.18 (m, 1H) 4.18–4.30 (m, 1H) 4.87 (d, J = 9.5 Hz, 1H)
5.16–5.27 (m, 1H) 5.28–5.44 (m, 2H) 6.35 (s, 1H) 6.40–6.57 (m, 2H)
6.77 (s, 1H) 7.01 (d, J = 8.2 Hz, 2H) 7.13 (s, 1H) 7.32 (d, J = 8.2 Hz,
5.4.43. 2-{[(3E)-4-(4-{[4-methoxy-2-(propan-2-yl)-5-
{(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]oxan-2-yl}
phenyl]methyl}phenyl)-2,2-dimethylbut-3-enoyl]amino}-2-
methylpropanoic acid (32a)
In an argon atmosphere, an acetonitrile (36 mL) suspension of
compound 31 (1.2 g, 1.85 mmol), compound 27f (2.59 g, 13.0 mmol),
palladium (II) acetate (44 mg, 0.19 mmol), tri-o-tolylphosphine
(112 mg, 0.37 mmol), and triethylamine (1.3 mL, 9.25 mmol) was
stirred for 30 min at 120 °C under microwave irradiation. The reaction
mixture was filtered using Celite (registered trademark) and washed
with ethyl acetate. The filtrate was concentrated under reduced pres-
sure, and the resulting residue was purified using neutral silica gel
column
chromatography
(chloroform → chloroform:methanol
2H) 7.40 (s, 1H); MS ESI/APCI Dual m/z 839 [M+H]+
.
ratio = 9:1) to obtain the title compound as a partially purified product
(1.5 g). The title compound (1.5 g) was further purified using neutral
silica gel column chromatography (hexane:ethyl acetate ratio = 7:3 →
2:8) to obtain the title compound as a light-yellow amorphous sub-
stance (854 mg, 60%). 1H NMR (300 MHz, CDCl3) δ ppm 1.08 (d,
J = 6.8 Hz, 3H) 1.12 (d, J = 6.8 Hz, 3H) 1.38 (s, 6H) 1.53 (s, 6H) 1.77
(s, 3H) 2.00 (s, 3H) 2.05 (s, 6H) 3.06 (quin, J = 6.6 Hz, 1H) 3.78–3.83
(m, 1H) 3.84 (s, 3H) 3.97 (s, 2H) 4.07–4.18 (m, 1H) 4.17–4.27 (m, 1H)
4.87 (dd, J = 6.8, 2.9 Hz, 1H) 5.16–5.25 (m, 1H) 5.27–5.40 (m, 2H)
6.18–6.33 (m, 2H) 6.54 (d, J = 16.5 Hz, 1H) 6.77 (s, 1H) 7.03 (d,
J = 8.1 Hz, 2H) 7.10 (s, 1H) 7.29 (d, J = 8.1 Hz, 2H); MS ESI/APCI
5.4.47. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-
oxobut-1-en-1-yl]phenyl}methyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-
glucitol (33e)
Compound 33e (55%) was obtained from 32a and piperazine in a
manner similar to that described for 33d. 1H NMR (300 MHz, CDCl3) δ
ppm 1.06 (d, J = 6.6 Hz, 3H) 1.11 (d, J = 6.6 Hz, 3H) 1.35 (s, 6H) 1.77
(s, 6H) 2.00 (s, 3H) 2.04 (s, 3H) 2.06 (s, 3H) 2.25 (s, 2H) 2.78–2.88 (m,
4H) 2.96–3.12 (m, 1H) 3.55–3.65 (m, 4H) 3.78–3.88 (m, 1H) 3.85 (s,
3H) 3.88–4.04 (m, 2H) 4.09–4.18 (m, 1H) 4.20–4.30 (m, 1H) 4.88 (d,
J = 9.5 Hz, 1H) 5.155.27 (m, 1H) 5.28–5.44 (m, 2H) 6.22–6.33 (m, 1H)
6.41–6.55 (m, 1H) 6.72–6.85 (m, 2H) 6.96–7.06 (m, 2H) 7.14 (s, 1H)
Dual m/z 768 [M+H]+, 790 [M+Na]+
.
5.4.44. 2-{[(3E)-4-(4-{[4-(acetyloxy)-2-(propan-2-yl)-5-
7.23–7.32 (m, 2H); MS ESI/APCI Dual m/z 836 [M+H]+
.
{(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]oxan-2-yl}
phenyl]methyl}phenyl)-2,2-dimethylbut-3-enoyl]amino}-2-
5.4.48. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]
amino}-4-oxobut-1-en-1-yl]phenyl}methyl)-2-methoxy-4-(propan-2-yl)
phenyl]-D-glucitol (33f)
methylpropanoic acid (32b)
Compound 32b (78%) was obtained from 27g and 31 in a manner
similar to that described for 32a. 1H NMR (300 MHz, CDCl3) δ ppm
1.16, 1.18 (each d, J = 6.84 Hz, 3H) 1.40 (s, 6H) 1.54–1.58 (m, 6H)
1.76 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.28 (s, 3H) 2.36 (s,
3H) 2.98–3.10 (m, 1H) 3.71–3.79 (m, 1H) 3.94 (s, 2H) 4.01–4.08 (m,
1H) 4.24 (dd, J = 12.4, 4.5 Hz, 1H) 4.47 (d, J = 9.2 Hz, 1H) 5.07–5.32
(m, 3H) 6.31 (d, J = 16.3 Hz, 1H) 6.35 (s, 1H) 6.55 (d, J = 16.3 Hz, 1H)
6.77 (d, J = 7.6 Hz, 1H) 6.92 (s, 1H) 6.99 (s, 1H) 7.12–7.18 (m, 1H)
Compound 33f (95%) was obtained from 32a and 1methylpiper-
azine in a manner similar to that described for 33d. 1H NMR (300 MHz,
CDCl3) δ ppm 1.05 (d, J = 6.8 Hz, 3H) 1.10 (d, J = 6.8 Hz, 3H) 1.36 (s,
6H) 1.59 (s, 6H) 1.77 (s, 3H) 2.00 (s, 3H) 2.05 (s, 3H) 2.06 (s, 3H) 2.26
(s, 3H) 2.32–2.40 (m, 4H) 2.96–3.12 (m, 1H) 3.59–3.71 (m, 4H)
3.79–3.84 (m, 1H) 3.85 (s, 3H) 3.90–4.05 (m, 2H) 4.10–4.16 (m, 1H)
4.21–4.28 (m, 1H) 4.87 (d, J = 9.6 Hz, 1H) 5.16–5.27 (m, 1H)
5.29–5.44 (m, 2H) 6.28 (d, J = 16.4 Hz, 1H) 6.49 (d, J = 16.4 Hz, 1H)
6.77 (s, 1H) 6.83 (s, 1H) 7.01 (d, J = 8.1 Hz, 2H) 7.13 (s, 1H) 7.25–7.32
7.26 (s, 1H); MS ESI/APCI Dual m/z 810 [M+H]+, 832 [M+Na]+
.
5.4.45. 2-{[(3E)-4-(4-{[4-methoxy-2-(propan-2-yl)-5-
{(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]oxan-2-yl}
phenyl]methyl}-3-methylphenyl)-2,2-dimethylbut-3-enoyl]amino}-2-
methylpropanoic acid (32c)
(m, 2H); MS ESI/APCI Dual m/z 850 [M+H]+
.
5.4.49. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-[(4-{(1E)-3,3-
dimethyl-4-[(2-methyl-1-{[2-(methylamino)ethyl]amino}-1-oxopropan-2-
yl)amino]-4-oxobut-1-en-1-yl}-2-methylphenyl)methyl]-4-(propan-2-yl)
phenyl]-1,5-anhydro-D-glucitol (33g)
Compound 32c (87%) was obtained from 27h and 31 in a manner
similar to that described for 32a. 1H NMR (300 MHz, CDCl3) δ ppm
1.17, 1.14 (each d, J = 7.0 Hz, 3H) 1.38 (s, 6H) 1.55 (s, 6H) 1.76 (s, 3H)
1.98 (s, 3H) 2.04 (s, 6H) 2.30 (s, 3H) 2.94–3.03 (m, 1H) 3.76–3.83 (m,
1H) 3.84–3.95 (m, 4H) 4.06–4.15 (m, 1H) 4.16–4.25 (m, 1H) 4.81 (d,
J = 9.8 Hz, 1H) 5.12–5.20 (m, 1H) 5.23–5.35 (m, 2H) 6.29 (s, 1H) 6.31
(d, J = 16.3 Hz, 1H) 6.52 (d, J = 16.3 Hz, 1H) 6.67 (d, J = 8.1 Hz, 1H)
6.81 (s, 1H) 6.94 (s, 1H) 7.06–7.14 (m, 1H) 7.24 (s, 1H); MS ESI/APCI
Compound 33g (61%) was obtained from 32b and N,N-dimethy-
lethylenediamine in a manner similar to that described for 33d. 1H
NMR (300 MHz, CDCl3) δ ppm 1.13, 1.15 (each d, J = 6.9 Hz, each 3H)
1.38 (s, 6H) 1.53 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s,
3H) 2.23 (s, 6H) 2.31 (s, 3H) 2.37 (s, 3H) 2.41 (t, J = 5.7 Hz, 2H)
2.90–3.03 (m, 1H) 3.25–3.34 (m, 2H) 3.71–3.80 (m, 1H) 3.92 (s, 2H)
4.05 (dd, J = 12.6, 2.2 Hz, 1H) 4.23–4.32 (m, 1H) 4.44–4.52 (m, 1H)
5.11–5.20 (m, 1H) 5.22–5.33 (m, 2H) 6.33 (d, J = 16.6 Hz, 1H) 6.41 (s,
1H) 6.51 (d, J = 16.6 Hz, 1H) 6.68 (d, J = 7.8 Hz, 1H) 6.77 (s, 1H) 7.00
(s, 2H) 7.12 (d, J = 7.8 Hz, 1H) 7.26 (s, 1H); MS ESI/APCI Dual m/z
Dual m/z 782 [M+H]+, 804 [M+Na]+
.
5.4.46. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-
{[2-(dimethylamino)ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-
dimethyl-4-oxobut-1-en-1-yl}phenyl)methyl]-2-methoxy-4-(propan-2-yl)
phenyl}-D-glucitol (33d)
880 [M+H]+, 902 [M+Na]+
.
Water soluble carbodiimide hydrochloride (WSCI·HCl) (37 mg,
0.20 mmol) was added to a chloroform (1.5 mL)/N,N-dimethylforma-
mide (1.5 mL) solution of compound 32a (100 mg, 0.13 mmol), 1-hy-
droxybenzotriazole monohydrate (HOBt·H2O) (30 mg, 0.20 mmol), and
N,N-dimethylethylenediamine (42 µL, 0.39 mmol), and the mixture was
stirred overnight at room temperature. The reaction liquid was poured
5.4.50. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-
oxobut-1-en-1-yl]-2-methylphenyl}methyl)-4-(propan-2-yl)phenyl]-1,5-
anhydro-D-glucitol (33h)
Compound 33h (47%) was obtained from 32b and piperazine in a
13

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
manner similar to that described for 33d. 1H NMR (300 MHz, CDCl3) δ
ppm 1.14, 1.16 (each d, J = 7.0 Hz, each 3H) 1.38 (s, 6H) 1.61 (s, 6H)
1.71 (s, 3H) 1.99 (s, 3H) 2.05 (s, 3H) 2.12 (s, 3H) 2.27 (s, 3H) 2.79–2.87
(m, 4H) 2.87–2.99 (m, 1H) 3.56–3.66 (m, 4H) 3.75–3.94 (m, 3H)
4.12–4.20 (m, 1H) 4.25–4.34 (m, 1H) 4.44–4.52 (m, 1H) 5.23–5.32 (m,
3H) 6.30 (d, J = 16.3 Hz, 1H) 6.48 (d, J = 16.3 Hz, 1H) 6.53 (s, 1H)
6.68 (d, J = 7.8 Hz, 1H) 6.88 (s, 1H) 6.97 (s, 1H) 7.05–7.12 (m, 1H)
(m, 1H) 7.22 (s, 1H); MS ESI/APCI Dual m/z 850 [M+H]+, 872 [M
+Na]+
.
5.4.55. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]
amino}-4-oxobut-1-en-1-yl]-2-methylphenyl}methyl)-2-methoxy-4-
(propan-2-yl)phenyl]-D-glucitol (33m)
7.22 (s, 1H); MS ESI/APCI Dual m/z 836 [M+H]+, 858 [M+Na]+
.
Compound 33m was obtained as a crude product from 32c and 1-
methylpiperazine in a manner similar to that described for 33d. 1H
NMR (300 MHz, CDCl3) δ ppm 1.12 (d, J = 8.5 Hz, 3H) 1.15 (d,
J = 8.5 Hz, 3H) 1.36 (s, 6H) 1.56 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.04
(s, 6H) 2.30 (s, 3H) 2.32 (s, 3H) 2.38–2.50 (m, 4H) 2.85–3.02 (m, 1H)
3.61–3.74 (m, 4H) 3.76–3.84 (m, 1H) 3.81–3.96 (m, 1H) 3.86 (s, 3H)
4.07–4.15 (m, 1H) 4.18–4.27 (m, 1H) 4.75–4.88 (m, 1H) 5.11–5.24 (m,
1H) 5.26–5.37 (m, 2H) 6.22–6.38 (m, 1H) 6.43–6.54 (m, 1H) 6.59–6.70
(m, 2H) 6.81 (s, 1H) 6.96–7.02 (m, 1H) 7.04–7.12 (m, 1H) 7.20–7.26
(m, 1H).
5.4.51. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]
amino}-4-oxobut-1-en-1-yl]-2-methylphenyl}methyl)-4-(propan-2-yl)
phenyl]-1,5-anhydro-D-glucitol (33i)
Compound 33i (61%) was obtained from 32b and 1-methylpiper-
azine in a manner similar to that described for 33d. 1H NMR (300 MHz,
CDCl3) δ ppm 1.13, 1.15 (each d, J = 6.8 Hz, each 3H) 1.37 (s, 6H) 1.60
(s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.27 (s, 3H)
2.30 (s, 3H) 2.33–2.41 (m, 7H) 2.88–3.04 (m, 1H) 3.60–3.70 (m, 4H)
3.72–3.80 (m, 1H) 3.92 (s, 2H) 4.05 (dd, J = 12.6, 2.3 Hz, 1H) 4.27
(dd, J = 12.6, 4.5 Hz, 1H) 4.434.54 (m, 1H) 5.10–5.20 (m, 1H)
5.22–5.32 (m, 2H) 6.31 (d, J = 16.5 Hz, 1H) 6.49 (d, J = 16.5 Hz, 1H)
6.68 (d, J = 8.1 Hz, 1H) 6.86 (s, 1H) 7.00 (s, 2H) 7.08–7.14 (m, 1H)
5.4.56. (1S)-2,4,6-tri-O-acetyl-1-[5-({4-[(1E)-4-({1-[(2-amino-2-
methylpropyl)amino]-2-methyl-1-oxopropan-2-yl}amino)-3,3-dimethyl-4-
oxobut-1-en-1-yl]-2-methylphenyl}methyl)-2-methoxy-4-(propan-2-yl)
phenyl]-1,5-anhydro-3-O-formyl-D-glucitol (33n)
7.24 (s, 1H); MS ESI/APCI Dual m/z 892 [M+H]+, 914 [M+Na]+
.
Compound 33n (99%) was obtained from 32c and 1,2-diamino-2-
methylpropane in a manner similar to that described for 33d. 1H NMR
(300 MHz, CDCl3) δ ppm 1.10 (s, 6H) 1.12 (d, J = 6.8 Hz, 3H) 1.14 (d,
J = 6.8 Hz, 3H) 1.36 (s, 6H) 1.56 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.04
(s, 6H) 2.30 (s, 3H) 2.85–3.02 (m, 1H) 3.13 (d, J = 5.91 Hz, 2H)
3.76–3.84 (m, 1H) 3.81–3.96 (m, 1H) 3.86 (s, 3H) 4.07–4.15 (m, 1H)
4.18–4.27 (m, 1H) 4.75–4.88 (m, 1H) 5.11–5.24 (m, 1H) 5.26–5.37 (m,
2H) 6.22–6.38 (m, 1H) 6.43–6.54 (m, 1H) 6.59–6.70 (m, 1H) 6.81 (s,
1H) 6.96–7.02 (m, 2H) 7.04–7.12 (m, 1H) 7.20–7.26 (m, 1H).
5.4.52. (1S)-2,3,4,6-tetra-O-acetyl-1-[2-(acetyloxy)-5-({4-[(1E)-4-({1-
[(2-amino-2-methylpropyl)amino]-2-methyl-1-oxopropan-2-yl}amino)-
3,3-dimethyl-4-oxobut-1-en-1-yl]-2-methylphenyl}methyl)-4-(propan-2-yl)
phenyl]-1,5-anhydro-D-glucitol (33j)
Compound 33j (21%) was obtained from 32b and 1,2-diamino-2-
methylpropane in a manner similar to that described for 33d. 1H NMR
(300 MHz, CDCl3) δ ppm 1.11–1.17 (m, 6H) 1.11 (s, 6H) 1.39 (s, 6H)
1.53 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.31 (s,
3H) 2.37 (s, 3H) 2.89–3.05 (m, 1H) 3.14 (d, J = 5.9 Hz, 2H) 3.76 (ddd,
J = 9.7, 4.5, 2.1 Hz, 1H) 3.93 (s, 2H) 4.05 (dd, J = 12.5, 2.1 Hz, 1H)
4.27 (dd, J = 12.5, 4.5 Hz, 1H) 4.49 (d, J = 7.5 Hz, 1H) 5.11–5.20 (m,
1H) 5.23–5.31 (m, 2H) 6.26 (s, 1H) 6.29–6.38 (m, 1H) 6.48–6.57 (m,
1H) 6.69 (d, J = 7.9 Hz, 1H) 6.97–7.03 (m, 3H) 7.12 (d, J = 7.9 Hz,
5.4.57. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-{[2-(dimethylamino)
ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-
en-1-yl}phenyl)methyl]-2-methoxy-4-(propan-2-yl)phenyl}-D-glucitol
(34d)
A
triethylamine/water/methanol mixture (1/1/5, 2.5 mL) was
1H) 7.25 (s, 1H); MS ESI/APCI Dual m/z 880 [M+H]+
.
added to compound 33d (103 mg, 0.12 mmol). The reaction mixture
was stirred for 17 h at room temperature, and the solvent was distilled
off under reduced pressure. The resulting residue was purified using
neutral silica gel column chromatography (chloroform → chlor-
oform:methanol ratio = 8:2) to obtain the title compound as a colorless
amorphous substance (62.1 mg, 75%). 1H NMR (600 MHz, CD3OD) δ
ppm 1.07 (d, J = 5.0 Hz, 3H) 1.09 (d, J = 5.0 Hz, 3H) 1.36 (s, 6H) 1.44
(s, 6H) 2.23 (s, 6H) 2.41 (t, J = 6.9 Hz, 2H) 3.10 (quin, J = 6.8 Hz, 1H)
3.26–3.30 (m, 2H) 3.38 (d, J = 6.0 Hz, 2H) 3.45–3.52 (m, 1H)
3.54–3.60 (m, 1H) 3.62–3.69 (m, 1H) 3.79–3.89 (m, 4H) 3.99 (s, 2H)
4.65 (d, J = 9.6 Hz, 1H) 6.39 (d, J = 16.5 Hz, 1H) 6.52 (d, J = 16.5 Hz,
1H) 6.88 (s, 1H) 7.07 (d, J = 8.3 Hz, 2H) 7.23 (s, 1H) 7.31 (d,
J = 8.3 Hz, 2H); 13C NMR (126 MHz, CD3OD) δ ppm 24.1, 25.3, 25.7,
30.7, 38.4, 39.3, 45.6, 46.1, 56.5, 58.1, 59.2, 63.4, 72.3, 75.9, 76.9,
80.3, 82.6, 109.8, 126.3, 127.5, 129.9, 130.4, 130.8, 132.1, 134.8,
136.3, 142.8, 149.8, 158.7, 177.2, 178.4; HRMS ESI/APCI Dual m/z
calcd for C37H55N3O8 670.4062 [M+H]+, found 670.4057.
5.4.53. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-
{[2-(dimethylamino)ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-
dimethyl-4-oxobut-1-en-1-yl}-2-methylphenyl)methyl]-2-methoxy-4-
(propan-2-yl)phenyl}-D-glucitol (33k)
Compound 33k (74%) was obtained from 32c and N,N-dimethy-
lethylenediamine in a manner similar to that described for 33d. 1H
NMR (300 MHz, CDCl3) δ ppm 1.12, 1.14 (each d, J = 6.8 Hz, each 3H)
1.37 (s, 6H) 1.51 (s, 6H) 1.76 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 2.04 (s,
3H) 2.23 (s, 6H) 2.32 (s, 3H) 2.41 (t, J = 6.2 Hz, 2H) 2.86–2.99 (m, 1H)
3.25–3.33 (m, 2H) 3.76–3.90 (m, 6H) 4.07–4.15 (m, 1H) 4.18–4.26 (m,
1H) 4.76–4.85 (m, 1H) 5.13–5.22 (m, 1H) 5.26–5.36 (m, 2H) 6.31 (d,
J = 16.5 Hz, 1H) 6.37 (s, 1H) 6.50 (d, J = 16.5 Hz, 1H) 6.61–6.67 (m,
1H) 6.81 (s, 1H) 6.99 (s, 1H) 7.06–7.12 (m, 1H) 7.24 (s, 1H); MS ESI/
APCI Dual m/z 852 [M+H]+
.
5.4.54. (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-({4-[(1E)-3,3-
dimethyl-4-{[2-methyl-1-oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-
oxobut-1-en-1-yl]-2-methylphenyl}methyl)-2-methoxy-4-(propan-2-yl)
phenyl]-D-glucitol (33l)
5.4.58. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-oxobut-1-en-1-yl]phenyl}
methyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-glucitol (34e)
Compound 33l (38%) was obtained from 32c and piperazine in a
manner similar to that described for 33d. 1H NMR (300 MHz, CDCl3) δ
ppm 1.12, 1.14 (each d, J = 7.0 Hz, each 3H) 1.37 (s, 6H) 1.58 (s, 6H)
1.76 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 2.04 (s, 3H) 2.32 (s, 3H) 2.79–2.86
(m, 4H) 2.88–2.99 (m, 1H) 3.57–3.64 (m, 4H) 3.76–3.95 (m, 6H)
4.07–4.14 (m, 1H) 4.18–4.26 (m, 1H) 4.77–4.84 (m, 1H) 5.13–5.22 (m,
1H) 5.26–5.37 (m, 2H) 6.29 (d, J = 16.2 Hz, 1H) 6.49 (d, J = 16.2 Hz,
1H) 6.64 (d, J = 7.9 Hz, 1H) 6.77–6.83 (m, 2H) 6.99 (s, 1H) 7.05–7.11
Sodium methoxide (4.88 M/MeOH, 10 µL) was added to a solution
of compound 33e (90 mg, 0.11 mmol) in methanol (2.0 mL), and the
mixture was stirred at room temperature for 1 h. A small amount of dry
ice was added to neutralize the reaction mixture, and the solvent was
distilled off under reduced pressure. The resulting residue was purified
using NH-type silica gel column chromatography (chloroform:methanol
ratio = 9:1 → 6:4) to obtain the title compound as a colorless amor-
phous substance (52 mg, 70%). 1H NMR (600 MHz, CD3OD) δ ppm 1.06
14

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
(d, J = 6.8 Hz, 3H) 1.07 (d, J = 6.8 Hz, 3H) 1.34 (s, 6H) 1.42 (s, 6H)
2.67 (s, 4H) 3.04–3.12 (m, 1H) 3.27–3.30 (m, 2H) 3.33–3.38 (m, 2H)
3.43–3.49 (m, 1H) 3.50–3.61 (m, 3H) 3.61–3.66 (m, 1H) 3.80 (s, 3H)
3.83 (d, J = 11.9 Hz, 1H) 3.92–4.00 (m, 2H) 4.63 (d, J = 9.6 Hz, 1H)
6.33–6.39 (m, 1H) 6.44–6.49 (m, 1H) 6.86 (s, 1H) 7.06 (d, J = 8.3 Hz,
2H) 7.21 (s, 1H) 7.27 (d, J = 8.3 Hz, 2H); 13C NMR (126 MHz, CD3OD)
δ ppm 24.1, 24.2, 25.7, 26.3, 30.7, 39.2, 45.7, 46.6, 56.5, 58.1, 63.4,
72.3, 75.9, 76.8, 80.3, 82.6, 109.7, 126.3, 127.4, 130.0, 130.2, 130.8,
132.0, 134.7, 136.2, 142.9, 149.7, 158.7, 173.8, 177.8; HRMS ESI/
APCI Dual m/z calcd for C37H53N3O8 668.3905 [M+H]+, found
668.3880.
5.4.62. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]amino}-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-hydroxy-4-(propan-2-yl)phenyl]-D-glucitol (34i)
Compound 34i (79%) was obtained from 33i in a manner similar to
that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.10 (d,
J = 6.9 Hz, 6H) 1.37 (s, 6H) 1.44 (s, 6H) 2.16 (s, 3H) 2.22–2.38 (m, 7H)
2.87–2.96 (m, 1H) 3.35–3.41 (m, 2H) 3.42–3.51 (m, 2H) 3.51–3.56 (m,
1H) 3.56–3.71 (m, 5H) 3.84 (d, J = 12.4 Hz, 1H) 3.88 (s, 2H) 4.47 (d,
J = 9.6 Hz, 1H) 6.38 (d, J = 16.5 Hz, 1H) 6.46 (d, J = 16.5 Hz, 1H)
6.75 (d, J = 8.3 Hz, 1H) 6.80 (s, 1H) 6.97 (s, 1H) 7.09 (d, J = 8.3 Hz,
1H) 7.22 (s, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 24.1, 24.2,
25.7, 26.3, 30.3, 36.3, 45.7, 46.1, 55.9, 58.1, 63.1, 71.9, 75.6, 79.1,
80.2, 82.5, 114.3, 124.1, 125.0, 129.1, 129.2, 130.2, 130.3, 131.8,
134.6, 136.2, 137.6, 140.9, 149.6, 155.7, 173.8, 177.8; HRMS ESI/
APCI Dual m/z calcd for C38H55N3O8 682.4062 [M+H]+, found
682.4065.
5.4.59. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]amino}-4-oxobut-1-en-1-yl]
phenyl}methyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-glucitol (34f)
Compound 34f (84%) was obtained from 33f in a manner similar to
that described for 34d. 1H NMR (600 MHz, CD3OD) δ ppm 1.07 (d,
J = 6.7 Hz, 3H) 1.05 (d, J = 6.7 Hz, 3H) 1.36 (s, 6H) 1.45 (s, 6H) 2.14
(s, 3H) 2.29 (s, 4H) 3.06–3.16 (m, 1H) 3.34–3.42 (m, 2H) 3.46–3.52 (m,
1H) 3.51–3.73 (m, 6H) 3.79–3.91 (m, 4H) 3.98 (s, 2H) 4.65 (d,
J = 9.6 Hz, 1H) 6.38 (d, J = 16.1 Hz, 1H) 6.48 (d, J = 16.1 Hz, 1H)
6.88 (s, 1H) 7.08 (d, J = 8.3 Hz, 2H) 7.23 (s, 1H) 7.29 (d, J = 8.3 Hz,
2H); 13C NMR (126 MHz, CD3OD) δ ppm 24.1, 24.2, 25.7, 26.3, 30.7,
39.2, 45.7, 46.1, 55.9, 56.5, 58.1, 63.4, 72.3, 75.9, 76.8, 80.3, 82.6,
109.8, 126.3, 127.5, 130.0, 130.1, 130.8, 132.0, 134.8, 136.2, 143.0,
149.7, 158.7, 173.8, 177.8; HRMS ESI/APCI Dual m/z calcd for
5.4.63. (1S)-1-[5-({4-[(1E)-4-({1-[(2-amino-2-methylpropyl)amino]-2-
methyl-1-oxopropan-2-yl}amino)-3,3-dimethyl-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-hydroxy-4-(propan-2-yl)phenyl]-1,5-anhydro-D-
glucitol (34j)
Compound 34j (98%) was obtained from 33j in a manner similar to
that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.02 (s, 6H)
1.05–1.10 (m, 6H) 1.35 (s, 6H) 1.44 (s, 6H) 2.29 (s, 3H) 2.85–2.93 (m,
1H) 3.09 (s, 1H) 3.27–3.30 (m, 1H) 3.34–3.39 (m, 2H) 3.42–3.47 (m,
1H) 3.52 (t, J = 9.4 Hz, 1H) 3.55–3.61 (m, 1H) 3.63–3.69 (m, 1H)
3.80–3.85 (m, 1H) 3.86 (s, 2H) 4.46 (d, J = 9.6 Hz, 2H) 6.35–6.41 (m,
1H) 6.44–6.51 (m, 1H) 6.73 (d, J = 7.8 Hz, 1H) 6.78 (s, 1H) 6.96 (s,
1H) 7.06–7.10 (m, 1H) 7.23 (s, 1H); 13C NMR (126 MHz, CD3OD) δ
ppm 20.0, 24.1, 24.2, 25.3, 25.8, 26.5, 30.3, 36.3, 46.0, 50.7, 53.9,
58.2, 63.1, 71.9, 75.6, 79.1, 80.2, 82.4, 114.3, 124.0, 125.1, 129.1,
130.2, 130.6, 131.8, 134.3, 136.2, 137.5, 140.9, 149.6, 155.7, 177.8,
178.9; HRMS ESI/APCI Dual m/z calcd for C37H55N3O8 670.4062 [M
+H]+, found 670.4052.
C
38H55N3O8 682.4062 [M+H]+, found 682.4047.
5.4.60. (1S)-1,5-anhydro-1-{5-[(4-{(1E)4-[(1-{[2-(dimethylamino)
ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-
en-1-yl}-2-methylphenyl)methyl]-2-hydroxy-4-(propan-2-yl)phenyl}-D-
glucitol (34g)
Compound 34g (80%) was obtained from 33g in a manner similar
to that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.10 (d,
J = 6.92 Hz, 6H) 1.36 (s, 6H) 1.45 (s, 6H) 2.23 (s, 6H) 2.31 (s, 3H) 2.40
(t, J = 6.9 Hz, 2H) 2.87–2.96 (m, 1H) 3.28 (t, J = 6.7 Hz, 2H)
3.34–3.41 (m, 2H) 3.43–3.50 (m, 1H) 3.51–3.57 (m, 1H) 3.67 (dd,
J = 12.2, 2.5 Hz, 1H) 3.84 (d, J = 11.5 Hz, 1H) 3.89 (s, 2H) 4.47 (d,
J = 9.6 Hz, 1H) 6.39 (d, J = 16.1 Hz, 1H) 6.50 (d, J = 16.1 Hz, 1H)
6.75 (d, J = 8.3 Hz, 1H) 6.80 (s, 1H) 6.97 (s, 1H) 7.11 (d, J = 7.8 Hz,
1H) 7.25 (s, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 24.1, 24.2,
25.2, 25.7, 30.3, 36.3, 38.2, 45.5, 46.0, 58.1, 59.2, 63.1, 71.9, 75.6,
79.1, 80.2, 82.4, 114.3, 124.0, 125.1, 129.1, 129.2, 130.2, 130.6,
131.8, 134.5, 136.3, 137.6, 149.6, 155.7, 177.4, 178.6; HRMS ESI/
APCI Dual m/z calcd for C37H55N3O8 670.4062 [M+H]+, found
670.4039.
5.4.64. (1S)-1,5-anhydro-1-{5-[(4-{(1E)-4-[(1-{[2-(dimethylamino)
ethyl]amino}-2-methyl-1-oxopropan-2-yl)amino]-3,3-dimethyl-4-oxobut-1-
en-1-yl}-2-methylphenyl)methyl]-2-methoxy-4-(propan-2-yl)phenyl}-D-
glucitol (34k)
Compound 34k (78%) was obtained from 33k in a manner similar
to that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.13, 1.15
(each d, J = 6.8 Hz, each 3H) 1.36 (s, 6H) 1.45 (s, 6H) 2.21 (s, 6H) 2.32
(s, 3H) 2.39 (t, J = 6.9 Hz, 2H) 2.93–3.02 (m, 1H) 3.24–3.39 (m, 4H)
3.42–3.48 (m, 1H) 3.49–3.54 (m, 1H) 3.58–3.65 (m, 1H) 3.80–3.87 (m,
4H) 3.91 (s, 2H) 4.61 (d, J = 9.6 Hz, 1H) 6.39 (d, J = 16.5 Hz, 1H) 6.50
(d, J = 16.1 Hz, 1H) 6.73 (d, J = 7.3 Hz, 1H) 6.92 (s, 1H) 7.08 (s, 1H)
7.10 (d, J = 7.8 Hz, 1H) 7.25 (s, 1H); 13C NMR (126 MHz, CD3OD) δ
ppm 20.0, 24.1, 24.2, 25.3, 25.7, 30.7, 36.4, 38.4, 45.6, 46.1, 56.5,
58.1, 59.2, 63.5, 72.3, 75.8, 77.0, 80.3, 82.5, 109.7, 125.1, 126.3,
129.2, 130.1, 130.2, 130.6, 131.8, 134.6, 136.4, 137.6, 140.6, 149.8,
158.6, 177.3, 178.4; HRMS ESI/APCI Dual m/z calcd for C38H57N3O8
684.4218 [M+H]+, found 684.4213.
5.4.61. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-hydroxy-4-(propan-2-yl)phenyl]-D-glucitol (34h)
Compound 34h (47%) was obtained from 33h in a manner similar
to that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.10 (d,
J = 6.4 Hz, 6H) 1.36 (s, 6H) 1.44 (s, 6H) 2.31 (s, 3H) 2.70 (s, 4H)
2.90–2.95 (m, 1H) 3.36–3.39 (m, 2H) 3.43–3.61 (m, 7H) 3.65–3.69 (m,
1H) 3.84 (d, J = 11.9 Hz, 1H) 3.88 (s, 2H) 4.46 (d, J = 9.6 Hz, 1H) 6.38
(d, J = 16.1 Hz, 1H) 6.47 (d, J = 16.1 Hz, 1H) 6.76 (d, J = 7.8 Hz, 1H)
6.80 (s, 1H) 6.95 (s, 1H) 7.10 (d, J = 7.3 Hz, 1H) 7.22 (s, 1H); 13C NMR
(126 MHz, CD3OD) δ ppm 20.0, 24.1, 24.2, 25.8, 26.3, 30.3, 36.3, 45.7,
46.6, 58.1, 63.1, 71.9, 75.6, 79.1, 80.2, 82.5, 114.3, 124.0, 124.9,
129.1, 129.2, 130.3, 130.3, 131.7, 134.5, 136.3, 137.6, 140.9, 149.6,
155.7, 173.9, 177.8; HRMS ESI/APCI Dual m/z calcd for C37H53N3O8
668.3905 [M+H]+, found 668.3900.
5.4.65. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
oxo-1-(piperazin-1-yl)propan-2-yl]amino}-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-glucitol (34l)
Compound 34l (94%) was obtained from 33l in a manner similar to
that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.14, 1.16
(each d, J = 6.4 Hz, each 3H) 1.36 (s, 6H) 1.44 (s, 6H) 2.32 (s, 3H) 2.69
(s, 4H) 2.95–3.03 (m, 1H) 3.28–3.38 (m, 2H) 3.42–3.52 (m, 2H)
3.53–3.65 (m, 5H) 3.80–3.84 (m, 1H) 3.84 (s, 3H) 3.92 (s, 2H) 4.61 (d,
J = 9.2 Hz, 1H) 6.39 (d, J = 16.1 Hz, 1H) 6.47 (d, J = 16.1 Hz, 1H)
6.74 (d, J = 7.8 Hz, 1H) 6.92 (s, 1H) 7.06 (s, 1H) 7.10 (d, J = 7.8 Hz,
1H) 7.22 (s, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 24.1, 24.2,
25.7, 25.8, 26.3, 30.7, 36.3, 45.7, 46.6, 56.5, 58.1, 63.4, 72.3, 75.8,
76.9, 80.3, 82.5, 109.7, 124.9, 126.3, 129.2, 130.2, 130.3, 130.3,
15

S. Kuroda et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
131.7, 134.5, 136.3, 137.7, 140.7, 149.7, 158.6, 173.9, 177.8; HRMS
ESI/APCI Dual m/z calcd for C38H55N3O8 682.4062 [M+H]+, found
682.4041.
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5.4.66. (1S)-1,5-anhydro-1-[5-({4-[(1E)-3,3-dimethyl-4-{[2-methyl-1-
(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]amino}-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-methoxy-4-(propan-2-yl)phenyl]-D-glucitol (34m)
Compound 34m (9% in 2 steps) was obtained from 33m in a
manner similar to that described for 34e. 1H NMR (600 MHz, CD3OD) δ
ppm 1.09–1.16 (m, 6H) 1.35 (s, 6H) 1.42 (s, 6H) 2.12–2.16 (m, 3H)
2.23–2.33 (s, 4H) 2.30 (s, 3H) 2.92–3.01 (m, 1H) 3.28 (s, 2H) 3.30–3.38
(m, 1H) 3.41–3.51 (m, 2H) 3.55–3.66 (m, 5H) 3.78–3.86 (m, 4H) 3.90
(s, 2H) 4.59 (d, J = 9.2 Hz, 1H) 6.33–6.39 (m, 1H) 6.42–6.47 (m, 1H)
6.72 (d, J = 7.8 Hz, 1H) 6.90 (s, 1H) 7.04–7.11 (m, 2H) 7.19–7.24 (m,
1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 24.1, 24.2, 25.7, 26.3,
30.7, 36.3, 45.7, 46.1, 55.9, 56.5, 58.1, 63.4, 72.3, 75.8, 76.9, 80.3,
82.5, 109.7, 125.0, 126.3, 129.1, 130.2, 130.2, 130.3, 131.7, 134.6,
136.3, 137.6, 140.7, 149.7, 158.6, 173.8, 177.8; HRMS ESI/APCI Dual
m/z calcd for C39H57N3O8 696.4218 [M+H]+, found 696.4203.
8. Imamura M, Nakanishi K, Suzuki T, et al. Discovery of ipragliflozin (ASP1941): A
novel C-glucoside with benzothiophene structure as a potent and selective sodium
glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes
mellitus. Bioorg Med Chem. 2012;20:3263–3279.
9. Kakinuma H, Oi T, Hashimoto-Tsuchiya Y, et al. (1S)-1,5-Anhydro-1-[5-(4-ethox-
ybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (TS-071) is a potent, selective
sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes
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2012;55:7828–7840.
5.4.67. (1S)-1-[5-({4-[(1E)-4-({1-[(2-amino-2-methylpropyl)amino]-2-
methyl-1-oxopropan-2-yl}amino)-3,3-dimethyl-4-oxobut-1-en-1-yl]-2-
methylphenyl}methyl)-2-methoxy-4-(propan-2-yl)phenyl]-1,5-anhydro-D-
glucitol (34n)
11. Panai S, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a
therapeutic target in diabetes mellitus. Expert Opin Ther Targets. 2016;20:1109–1125.
12. Fushimi N, Fujikura H, Shiohara H, et al. Structure–activity relationship studies of 4-
benzyl-1H-pyrazol-3-yl b-D-glucopyranoside derivatives as potent and selective so-
dium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on post-
prandial hyperglycemia. Bioorg Med Chem. 2012;20:6598–6612.
Compound 34n (65%) was obtained from 33n in a manner similar
to that described for 34e. 1H NMR (600 MHz, CD3OD) δ ppm 1.01 (s,
6H) 1.09–1.15 (m, 6H) 1.35 (s, 6H) 1.43 (s, 6H) 2.31 (s, 3H) 2.91–3.00
(m, 1H) 3.08 (s, 2H) 3.27–3.36 (m, 5H) 3.41–3.46 (m, 1H) 3.47–3.52
(m, 1H) 3.60 (dd, J = 11.9, 6.0 Hz, 1H) 3.80–3.84 (m, 4H) 3.90 (s, 2H)
4.59 (d, J = 9.6 Hz, 1H) 6.36–6.41 (m, 1H) 6.45–6.50 (m, 1H) 6.71 (d,
J = 7.8 Hz, 1H) 6.90 (s, 1H) 7.06 (s, 1H) 7.07–7.10 (m, 1H) 7.20–7.25
(m, 1H); 13C NMR (126 MHz, CD3OD) δ ppm 20.0, 24.0, 24.2, 25.3,
25.8, 27.3, 30.7, 36.4, 46.0, 51.7, 52.5, 56.5, 58.2, 63.4, 72.3, 75.8,
77.0, 80.3, 82.5, 109.7, 125.1, 126.3, 129.2, 130.1, 130.2, 130.6,
131.8, 134.5, 136.3, 137.5, 140.6, 149.8, 158.6, 177.7, 178.6; HRMS
ESI/APCI Dual m/z calcd for C38H57N3O8 684.4218 [M+H]+, found
684.4198.
13. Fushimi N, Teranishi H, Shimizu K, et al. Design, synthesis, and structure–activity
relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl b-D-glycopyrano-
sides substituted with novel hydrophilic groups as highly potent inhibitors of sodium
glucose co-transporter 1 (SGLT1). Bioorg Med Chem. 2013:21748–21765.
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pendent glucose cotransporter 1 (SGLT1) inhibitor TP0438836 for type 2 diabetes
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Acknowledgements
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The authors thank Yoshiki Fukasawa for helpful suggestions and the
collection of the ADME data.
References
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16