Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl glucoside SGLT2 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2011.03.052

In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted. During a series of lead optimization efforts, orth

Full text of DOI:10.1016/j.ejmech.2011.03.052

European Journal of Medicinal Chemistry 46 (2011) 2662e2675
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl
glucoside SGLT2 inhibitors
,
,
*
Suk Ho Lee a b, Min Ju Kim a, Sung-Han Lee a, Jeongmin Kim a, Hyun-Ju Park b, Jinhwa Lee a
a Green Cross Corporation Research Center, 303 Bojeong-Dong, Giheung-Gu, Yongin, Gyeonggi-Do 446-770, Republic of Korea
b College of Pharmacy, Sungkyunkwan University, Cheoncheon-Dong, Jangan-Gu, Suwon, Gyeonggi-Do 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to investigate SAR regarding proximal phenyl ring in novel C-aryl glucoside SGLT2 inhibitors
containing a thiazole motif, a series of chemical modifications on proximal phenyl ring was conducted.
During a series of lead optimization efforts, ortho-allyloxyphenyl 10p or ortho-hydroxyphenyl 11a
showed subnanomolar inhibitory activity against hSGLT2.
Received 1 November 2010
Received in revised form
21 March 2011
Accepted 24 March 2011
Available online 2 April 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
SGLT
Dapagliflozin
Thiazole
Glucoside
Diabetes
1. Introduction
glucose reabsorption based on human mutation studies [8], SGLT2
has become a target of therapeutic interest.
Diabetes has become an increasing concern to the world’s
population. In 2010, approximately 285 million people around the
world will have diabetes, corresponding to 6.4% of the world’s adult
population, with a prediction that the number of people with dia-
betes will have grown to 438 million by 2030 [1]. Type 2 diabetes is
the most common disorder of glucose homeostasis, accounting for
approximately 90e95% of all cases of diabetes [2].
Sodium-dependent glucose cotransporters (SGLTs) couple the
transport of glucose against a concentration gradient with the
simultaneous transport of Naþ down a concentration gradient [3].
Two essential SGLT isoforms have been cloned and identified as
SGLT1 and SGLT2 [4]. SGLT1 is located in the gut, kidney, and heart
where its expression regulates cardiac glucose transport [5]. SGLT1
is a high-affinity, low-capacity transporter and therefore accounts
for a merely small fraction of renal glucose reabsorption [6]. In
contrast, SGLT2 is a low affinity, high-capacity transporter located
exclusively at the apical domain of the epithelial cells in the early
proximal convoluted tubule. It is estimated that 90% of renal
glucose reabsorption is facilitated by SGLT2, while the remaining
10% is mediated by SGLT1 in the late proximal straight tubule [7].
Since SGLT2 appears to be responsible for the majority of renal
Bristol-Myers Squibb has identified dapagliflozin (1), a potent,
selective SGLT2 inhibitor for the treatment of type 2 diabetes [9e11].
At present, 1 is the most advanced SGLT2 inhibitor in clinical trials
[12]. On the other hand, 2, 3, 4 from Johnson & Johnson, Lexicon, and
Pfizer are being tested in various phase of clinical trials (Fig. 1) [13].
In the previous study, C-glucosides bearing a heterocyclic ring
were exploited in order to develop novel SGLT2 targeting antidia-
betic agents, since we envisioned that replacement of the distal or
proximal phenyl ring of 1 with a heterocyclic ring might improve
the overall physicochemical properties of SGLT2 inhibitors [14].
Based on the structure of dapagliflozin, the distal phenyl ring was
surrogated by the corresponding thiazole ring. A series of lead
optimization efforts led to the discovery of thiazole 5 bearing
a furanyl moiety as shown in Fig. 2 [15]. In the present study,
diverse modifications on the C-2 position of the proximal phenyl
ring (as shown in 6) were conducted to establish SAR on the phenyl
ring, while keeping the structure of potent thiazole 5 [16]. Along
this line, we report the synthesis and biological evaluation of
thiazolylmethyl ortho-substituted phenyl glucoside analogs as
novel C-aryl glucoside SGLT2 inhibitors.
2. Chemistry
Preparation of the requisite bromides 15a,15b,15c,17a and 17b is
described in Scheme 1. Thus, commercially available 2-chloro-4-
* Corresponding author. Tel.: þ82 31 260 9892; fax: þ82 31 260 9020.
E-mail address: jinhwalee@greencross.com (J. Lee).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.03.052

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2663
Me
Cl
OEt
O
F
O
S
HO
HO
HO
HO
OH
OH
2
OH
OH
1
Cl
OEt
Cl
OEt
O
MeO
HO
O
O
HO
HO
OH
OH
4
OH
OH
3
Fig. 1. Structures of C-aryl glucoside SGLT2 inhibitors.
hydroxybenzonitrile (7) was converted to the corresponding
bromo-acids 14ae14c bywayof triflic acid-mediated bromination at
C-5 [17], alkylation on C-1 hydroxyl, and subsequent hydrolysis of
cyanides. The reduction of acids 14ae14c with a boraneedimethyl
sulfide complex, and subsequent silylation of the corresponding
alcohol with triisopropylsilyl chloride (TIPSCl) in the presence of
imidazole and 4-(dimethylamino)pyridine (DMAP) generated
bromides 15ae15c in reasonable yields. Similarly, 4-halogenated
benzyloxytriisopropylsilanes 17a, 17b were prepared as shown in
Scheme 1. Bromination using bromine and sulfur was conducted on
2,4-dichlorobenzoic acid (8) or 2-chloro-4-fluorobenzoic acid (9) in
the presence of chlorosulfonic acid [18]. The resulting bromo-acids
were transformed into the corresponding bromides 17a, 17b
following the same procedure previously described.
EDCI, HOBt, and NMM to provide the corresponding amide 21 in
96% yield. Amide 21 smoothly underwent thionation and subse-
quent cyclization by the action of Lawesson reagent in refluxing
THF to lead to thiazole 22. Finally, total removal of benzyl protec-
tion was affected with TMSI at mild heating overnight to produce
the target compound 10a in 50% yield.
Alternative approach toward derivatization on ortho-position of
proximal phenyl ring is described in Scheme 4. Thus, treatment of
allyl ether 23 with sodium borohydride in the presence of a cata-
lytic amount of Pd(PPh3)4 [20], followed by total deprotection of the
remaining benzyl groups by use of BCl3 [21] smoothly provided the
phenol 11a. This pentaol was used for direct alkylation to provide n-
propyl-ether 11b or two-step conversion to 1,2,4-triazolylethox-
yphenyl 11g.
Preparation of key intermediates 20ae20e is described in
Scheme 2. Thus, lithium-halogen exchange, followed by the addi-
tion of the nascent lithiated aromatic compound to perbenzylated
gluconolactone 10, produced a mixture of the corresponding lac-
tols. The lactols were reduced using triethylsilane and BF3 etherate
[19], desilylated and afforded alcohols 18ae18e, respectively. Then
alcohols 18ae18e were converted to bromides using PBr3 in the
presence of catalytic pyridine. The resulting bromides were treated
with KCN in refluxing aqueous EtOH to generate cyanides.
A mixture of the two isomers in each case was separated through
recrystallization from ethanol to produce the required beta-
isomers 19ae19e. Hydrolysis of cyanides 19ae19e with sodium
hydroxide in aqueous ethanol generated the carboxylic acids
20ae20e in quantitative yields, respectively.
The CeC bond substituents on ortho-position of proximal phenyl
ring were also attempted. Preparation of the requisite key interme-
diate 27 is described in Scheme 5. First, 3-amino-4-methylbenzoic
acid (24) which is commercially available was converted to bromide
25 via three steps (bromination, esterification, and chlorination) in
53% yields overall. Next, methyl 2-bromo-5-chloro-4-methyl-
benzoate (25) was transformed into 4-(hydroxymethyl)benzoic acid
26 by benzylic bromination reaction as illustrated in Scheme 5. The
alcohol functionality of 26 was then introduced by treating the
resulting bromide with sodium acetate, followed by basic hydrolysis
of the corresponding acetate with concomitant conversion from
methyl ester to acid as shown in structure 26. Finally, silyl protection
of alcohol 26 with TIPSCl in the presence of imidazole, and subse-
quent boraneedimethylsulfide-mediated reduction of benzoic acid
to the corresponding benzyl alcohol, followed by alkylated with allyl
bromide in the presence of sodium hydride furnished the requisite
bromide 27 in 53% yields for three steps.
Preparation of the thiazole compound is described in Scheme 3.
Thus, the carboxylic acid 20 prepared previously was coupled with
2-amino-1-(furan-2-yl)ethanone hydrochloride in the presence of
Cl
OEt
Cl
N
O
O
S
HO
HO
HO
HO
O
OH
OH
5
OH
1
OH
4
R
Cl
N
2
O
S
HO
HO
O
6
OH
OH
6
Fig. 2. Explorations of C-2 position of proximal ring in novel C-glucoside bearing thiazole 5.

2664
S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
HO
Cl
3. Results and discussion
RO
Br
Cl
O
(2)
RO
Br
Cl
(1)
OH
OTIPS
CN
The cell-based SGLT2 AMG (Methyl-a-D-glucopyranoside) inhi-
bition assay was performed to evaluate the inhibitory effects of all
prepared compounds on hSGLT2 activities [22,23]. Table 1 shows
the structure-activity relationship upon alteration of the C-2
substituent at the glucose employing only the (beta-anomer. We
focused on 2-furyl, 3-furyl, 2-thiophenyl, 3-thiophenyl, phenyl, or
4-F-phenyl ring connected to the distal thiazole ring, since our
previous findings [15] indicate that these small 5-membered aryl
rings favorably affected the biological activity of the examined
thiazolylmethylphenyl glucosides. Initially, 2-furyl 10a, 2-thio-
phenyl 10c, 3-thiophenyl 10d, or phenyl 10e at the proximal
methoxyphenyl ring demonstrated good inhibitory activity against
hSGLT2 (IC50 ¼ 1.29 nMe2.15 nM). When the proximal methox-
yphenyl ring is replaced with the corresponding ethoxyphenyl ring,
there appears to be a tendency that its inhibitory activity against
hSGLT2 drops in approximately twofold as exemplified by 10g
(IC50 ¼ 3.98 nM) or 10h (IC50 ¼ 4.35 nM). However, the in vitro
activity is recovered or even more improved than before as the
ethoxyphenyl ring as a proximal ring is replaced with the corre-
sponding allyloxyphenyl ring. For example, furyls 10m, 10n or
thiophenyls 10o, 10p connected to the distal thiazole ring showed
very promising activity against hSGLT2 (IC50 ¼ 0.934 nMe1.69 nM,
10me10p). Interestingly, 3-thiophenyl connected to the distal
thiazole ring demonstrates improved in vitro inhibitory activity
against hSGLT2 as the number of carbons increases from methyl
10d or ethyl 10j to allyl 10p on ortho-position ether linkage of the
proximal phenyl ring, albeit to a small amount (10d:IC50 ¼ 1.29 nM;
10d:IC50 ¼ 1.18 nM; 10d:IC50 ¼ 0.934 nM).
7
14a (R=Me)
15a (R=Me)
15b (R=Et)
14b (R=Et)
14c (R=allyl)
15c (R=allyl)
X
Cl
O
X
Cl
X
Cl
(3)
(4)
OH
OH
OTIPS
Br
Br
8 (X=Cl)
16a (X=Cl)
16b (X=F)
17a (X=Cl)
17b (X=F)
9 (X=F)
Scheme 1. Preparation of bromides (15a, 15b, 15c, 17a and 17b). (1) (a) triflic acid, NBS,
CH3CN, 57% (b) LiOH monohydrate, dimethyl sulfate, THF, 65 ꢀC, 80% (R ¼ Me) or alkyl
bromide, Cs2CO3, acetone, 65 ꢀC, 79%e85% (R ¼ Et or allyl) (c) NaOH, EtOH/H2O, 100 ꢀC,
95%e100% (2) (a) boraneedimethylsulfide complex, THF, 65 ꢀC, 95%e97% (b) TIPSCl,
imidazole, cat. DMAP, DMF, rt, 89%e93% (3) (a) Br2, sulfur, chlorosulfonic acid, 70 ꢀC,
89%e95% (b) boraneedimethylsulfide complex, THF, 65 ꢀC, 92%e95% (4) TIPSCl,
imidazole, cat. DMAP, DMF, rt, 91%e95%.
Preparation of the target thiazole compounds is described in
Scheme 6. Thus, the carboxylic acid 28 which was prepared
following the procedure similar to Scheme 2, was coupled with 2-
amino-1-(furan-2-yl)ethanone hydrochloride in the presence of
EDCI, HOBT, and NMM in a suitable solvent such as DMF at rt. The
resulting amide underwent thionation and subsequent cyclization
by Lawesson reagent in refluxing THF to result in thiazole 29 in 72%
yields for the two steps. Attempts to deprotect benzyl groups using
boron trichloride in methylene dichloride provided 12e in 20% yield
along with pentaol 12a in 9% yield.
At this juncture, several representative compounds anchored on
(4-chloro-5-(furan-2-yl)thiazol-2-yl)methylphenyl moiety have
been prepared in order to test the effect of the ortho-O-substituents
R
Cl
O
O
O
OH
BnO
BnO
BnO
BnO
(1)
(2)
OBn
OBn
OBn
OBn
10
18a (R=OMe)
18b (R=OEt)
18c (R=allyloxy)
18d (R=Cl)
18e (R=F)
R
Cl
R
O
Cl
O
CN
CO2H
BnO
BnO
BnO
BnO
(3)
OBn
OBn
OBn
OBn
19a (R=OMe)
19b (R=OEt)
19c (R=allyloxy)
19d (R=Cl)
20a (R=OMe)
20b (R=OEt)
20c (R=allyloxy)
20d (R=Cl)
19e (R=F)
20e (R=F)
Scheme 2. Preparation of key intermediates (20ae20e). (1) (a) bromides (15a, 15b, 15c, 17a and 17b), n-BuLi, THF, ꢁ78 ꢀC (b) Et3SiH, BF3OEt2, CH2Cl2, ꢁ55 ꢀC to ꢁ20 ꢀC (c) TBAF,
THF, 0 ꢀC to rt, 51%e85% (3-steps) (2) (a) PBr3, cat. pyridine, ether, 0 ꢀC to rt (b) KCN, EtOH/H2O, 80 ꢀC (c) selective crystallization, 31%e55% (3-steps) (3) NaOH, EtOH/H2O, 100 ꢀC,
97%e100%.

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2665
MeO
O
Cl
MeO
O
Cl
O
O
(1)
(2)
O
BnO
BnO
N
H
BnO
BnO
OH
O
OBn
OBn
OBn
OBn
20
21
MeO
Cl
N
MeO
Cl
N
O
S
BnO
BnO
O
(3)
O
S
HO
O
OBn
HO
OH
22
10a
OBn
OH
Scheme 3. Representative scheme for preparation of derivatives (10ae10r and 13ae13j). (1) 2-amino-1-(furan-2-yl)ethanone hydrochloride, EDC, HOBT, NMM, DMF, rt, 96% (2)
Lawesson reagent, THF, 75 ꢀC, 88% (3) TMSI, CH3CN, 50 ꢀC, 50%.
on the proximal phenyl ring against in vitro hSGLT2. The results are
shown in Table 2. 2-Hydroxyphenyl 11a shows outstanding in vitro
inhibitory activity against hSGLT2, suggesting that hydrogen donor
might be beneficial at this position. Allyloxy 10m or propargyloxy
11c which has terminal sp2 or sp3 character shows favorable
inhibitory activity against hSGLT2 (IC50 ¼ 1.24 nM for 10m;
IC50 ¼ 2.23 nM for 11c). But this effect disappears as it is homolo-
gated as exemplified in butenyloxy 11d (IC50 ¼ 32.8 nM). Hydrox-
yethoxyphenyl 11e regains in vitro inhibitory activity against
hSGLT2 (IC50 ¼ 1.51 nM), showing that the terminal hydroxyl group
is advantageous like hydroxyl group in hydroxyphenyl 11a. As the
hydroxyl group in 11e (IC50 ¼ 1.51 nM) is replaced with the corre-
sponding methoxy as exemplified in 11f, its inhibitory activity
against hSGLT2 shows fourfold decrease (IC50 ¼ 5.55 nM). Nitrogen-
containing groups such as 1,2,4-triazolylethoxyphenyl 11g or N,N-
dimethylphenoxyethanamine 11h are observed to drop in vitro
inhibitory activity in approximately two-orders of magnitude,
demonstrating that amine or amine-characters is intolerant at this
region.
maintain similar level of inhibitory activity against hSGLT2
(IC50 ¼ 2.23 nM), 3-furyl 12b demonstrated only moderate activity
(IC50 ¼ 20.5 nM). When allyl moiety is introduced on oxygen at this
position, its inhibitory activity is observed to drop in approximately
three to fourfold (IC50 ¼ 10.0 nMe38.7 nM for 12ee12h), compared
with hydroxymethylphenyl counterparts, implying that the extra
carbon linker on the ortho-phenyl makes the molecules a bit too
lengthy and suboptimal.
Finally, we installed ortho-halogen instead of alkoxy or carbon
linker on the proximal phenyl ring to explore the halogen effect for
hSGLT2. The results are shown in Table 4. It is noted that a series of
exercise provides comparable in vitro inhibitory activity against
hSGLT2 as exemplified by 2-fluorophenyl 13d (IC50 ¼ 2.12 nM) and
13g (IC50 ¼ 2.24 nM), but none of them are better than hydrox-
yphenyl 11a (IC50 ¼ 0.797 nM). Also these types of compounds
appear to have relatively poor solubility.
4. Conclusion
Next, in order to test the in vitro inhibitory effect of ortho-C-
substituents against hSGLT2, ortho-alkoxy moiety was replaced
with hydroxymethylphenyl (12ae12d) or allyloxymethylphenyl
(12ee12h). The inhibitory activity data of key compounds for
hSGLT2 are shown in Table 3. Although 3-thiophenyl 12d appears to
In summary,
a diverse series of structural modifications
regarding thiazolylmethyl ortho-substituted phenyl glucoside
library were conducted in the present study to establish SAR based
on structure of potent thiazole 5. Among the compounds tested,
O
Cl
HO
Cl
N
N
O
O
S
(1)
S
BnO
BnO
HO
HO
O
O
OBn
OH
OBn
OH
23
11a
(2)
(3)
N
N
O
Cl
O
Cl
N
N
N
O
O
S
S
HO
HO
HO
O
O
HO
OH
OH
OH
OH
11g
11b
Scheme 4. Representative scheme for preparation of derivatives (11ae11h). (1) (a) NaBH4, cat. Pd(PPh3)4, THF, 0 ꢀC to rt, 83% (b) BCl3, CH2Cl2, 0 ꢀC, 47% (2) n-PrBr, K2CO3, acetone,
50 ꢀC, 43% (3) (a) 1,2-dibromoethane, Cs2CO3, DMF, rt (b) sodium 1,2,4-triazole derivatives, DMF, rt, 33%(2-steps).

2666
S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
Cl
MeO2C
Br
Cl
HO2C
Br
Cl
HO2C
NH2
Me
O
(3)
(1)
(2)
OTIPS
OH
Br
Me
27
25
26
24
Scheme 5. Preparation of bromide 27 for preparation of compounds (12ae12h). (1) (a) NBS, DMF, 0 ꢀC, 89% (b) SOCl2, MeOH, 65 ꢀC, 92% (c) aq. HCl, NaNO2, 1,4-dioxane, 0 ꢀC then
CuCl, c-HCl, 0 ꢀC, 65% (2) (a) (i) NBS, AIBN, CCl4, 90 ꢀC (ii) NaOAc, DMF, rt, 51%(2-steps) (b) LiOH monohydrate, THF/MeOH/H2O, rt, 96% (3) (a) TIPSCl, imidazole, cat. DMAP, DMF, rt,
66% (b) boraneedimethylsulfide complex, THF, 65 ꢀC, 85% (c) allyl bromide, NaH, rt, 95%.
2-hydroxyphenyl 11a appears to be tolerated at this position,
showing the best potency in this series against hSGLT2 up to date.
and p-anisaldehyde solution as visualizing agents or HPLC analysis
on an Agilent 1200 series system.
5. Experimental
5.1. Chemistry
All reactions are conducted under an inert atmosphere at room
temperature, unless otherwise noted. n-Butyllithium (Aldrich) was
titrated with N-benzylbenzamide as indicator. All reagents were
purchased at the highest commercial quality and used without
further purification, unless otherwise indicated. All experiment
involving moisture- and/or air-sensitive compounds were per-
formed in oven- and/or flame-dried glassware with rubber septa
under a positive pressure of nitrogen using standard Schlenk
technique. NMR spectra were obtained on a Varian 400-MR
(400 MHz 1H, 100 MHz 13C) spectrometer. NMR spectra were
5.1.1. Preparation of 5-bromo-2-chloro-4-methoxybenzoic acid
(14a)
To a solution of 2-chloro-4-hydroxybenzonitrile (7) (10.0 g,
65.1 mmol) in CH3CN (200 mL) were added triflic acid (10 mL,
71.6 mmol), NBS (16.2 g, 91.2 mmol) at ꢁ30 ꢀC. The mixture was
warmed up to room temperature and stirred at room temperature
for 15 h. The reaction was quenched by addition of aq. saturated
NaHSO3 solution. The mixture was extracted with EtOAc. The
combined organic extract was dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was purified using silica
column chromatography to provide 5-bromo-2-chloro-4-hydrox-
recorded in ppm (
d
) relative to tetramethylsilane (
d
¼ 0.00) as an
internal standard unless stated otherwise and are reported as
ybenzonitrile (9.8 g, 65%). 1H NMR (400 MHz, CD3OD)
d 7.91 (s, 1H),
follows: chemical shift, multiplicity (s ¼ singlet, d ¼ doublet,
7.03 (s, 1H), 4.85 (s, 1H); MHþ 232.
t
¼
triplet,
q
¼
quartet, quint
¼
quintet, sext
¼
sextet,
To a solution of 5-bromo-2-chloro-4-hydroxybenzonitrile
m ¼ multiplet, and br ¼ broad), coupling constant, and integration.
(35.2 g, 151 mmol) in THF (500 mL) were added lithium hydroxide
monohydrate (9.0 g, 197 mmol) and dimethyl sulfate (20 mL,
197 mmol). The reaction mixture was stirred at 75 ꢀC for 15 h. The
mixture was cooled to room temperature and diluted with EtOAc.
The mixture was washed with aq. 50% NaCl solution and dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was purified using silica column chromatography to provide the
intermediate (30.7 g).
To a solution of intermediate (30.7 g) in EtOH (500 mL)/H2O
(250 mL) was added NaOH (127 g, 3.11 mol). The mixture was stirred
at 100 ꢀC for 9 h. The mixture was cooled to room temperature and
evaporated in vacuo to remove EtOH. The residue was diluted with
H2O, cooled to 0 ꢀC and acidified with aq. 6N HCl solution. The titled
compound 14a was precipitated as a solid, filtered off and washed
13C NMR spectra were referenced to the residual DMSO-d6
(
d
¼ 39.7). Mass spectra were obtained with an Agilent 6110
quadruple LC-MSD (ESIþ). Preparative HPLC purifications were
performed on a Gilson purification system. For preparative HPLC,
ca. 100 mg of a product was injected in 1 mL of methanol onto
a SunFire Prep C18 OBD 5
mm 30 ꢂ 100 mm Column with a 30 min
gradient from 5 to 90% acetonitrile in water and a 45 mL/min flow
rate. Biotage SP1 and Isolera purification systems were used for
normal phase column chromatography with ethyl acetate and
hexane. Flash chromatography was performed using E. Merck
230e400 mesh silica gel according to the procedure of Still et al.
Reactions were monitored by either thin-layer chromatography
(TLC) on 0.25 mm E. Merck silica gel plates (60F-254) using UV light
Cl
Cl
O
O
O
O
O
N
(1)
S
BnO
BnO
OH
BnO
BnO
O
OBn
OBn
OBn
OBn
29
28
(2)
Cl
Cl
O
O
N
HO
O
N
+
S
S
HO
HO
HO
O
O
HO
OH
OH
12a
12e
OH
OH
Scheme 6. Representative scheme for preparation of derivatives (12ae12h). (1) (a) 2-amino-1-(furan-2-yl)ethanone hydrochloride, EDC, HOBT, NMM, DMF, rt (ii) Lawesson reagent,
THF, 75 ꢀC, 72%(2-steps) (2) BCl3, CH2Cl2, 0 ꢀC, 20% (for 12e), and 9% (for 12a).

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2667
Table 1
In vitro screening data of compound 10ae10r for hSGLT2 inhibitory activities.
Ar
Compound
R
hSGLT2 IC50 (nM)a
Compound
10g
R
hSGLT2 IC50 (nM)a
Compound
10m
R
hSGLT2 IC50 (nM)a
1
10a
0.49 ꢃ 0.04b
Me
Me
Me
Me
Me
2.15
Et
Et
Et
Et
Et
3.98
4.35
4.29
1.18
2.87
allyl
allyl
allyl
allyl
allyl
1.24
1.54
1.69
0.934
3.38
10b
10c
10d
10e
7.37
1.59
1.29
2.01
10h
10n
10i
10o
10j
10p
10k
10q
10f
Me
6.08
10l
Et
7.55
10r
allyl
4.22
a
These data were obtained by single determinations.
The IC50 value was obtained by in-house multiple determinations.
b
with H2O. The solid was dried under vacuum at 50 ꢀC for 16 h to
To a solution of alcohol (23.2 g, 87.5 mmol) in DMF (250 mL) were
obtain the product (33.7 g, 76%, 2 steps). MHþ 265.
added TIPSCl (77 mL, 358.5 mmol), imidazole (33 g, 481.3 mmol) and
DMAP (4.1 g, 33.6 mmol). The mixture was stirred at room
temperature for 15 h. After dilution with water, the mixture was
extracted with EtOAc. The organic layer was dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The residue was purified
using silica column chromatography to provide the titled compound
5.1.2. Preparation of (5-bromo-2-chloro-4-methoxybenzyloxy)
triisopropylsilane (15a)
To a solution of acid 14a (2.73 g, 11.0 mmol) in THF (300 mL) was
added boraneedimethylsulfide complex (1 M in THF, 13 mL) at 0 ꢀC.
The mixture was stirred 0 ꢀC for 15 min, at room temperature at
30 min, and at 75 ꢀC for 15 h. The mixture was cooled to 0 ꢀC. MeOH
and H2O were added to the cooled mixture to quench the reaction.
After dilutionwith water, the mixturewas extracted with EtOAc. The
organic layer was dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified using silica column
chromatography to provide alcohol (22.9 g, 85%).1H NMR (400 MHz,
15a (38 g, 66%). 1H NMR (400 MHz, CDCl3)
d 7.77 (s, 1H), 6.85 (s, 1H),
4.78 (s, 2H), 3.88 (s, 3H), 1.23e1.15 (m, 3H), 1.10 (d, J ¼ 6.4 Hz, 18H).
5.1.3. Preparation of (5-bromo-2-chloro-4-ethoxybenzyloxy)
triisopropylsilane (15b)
Yield: 40%(5-steps). 1H NMR (400 MHz, CDCl3)
d 7.76 (s,1H), 6.84
(s, 1H), 4.86 (s, 2H), 4.07 (quartet, J ¼ 6.8 Hz, 2H), 1.47 (t, J ¼ 6.8 Hz,
CDCl3)
d
7.65 (s,1H), 6.90 (s, 1H), 4.70 (d, J ¼ 6.4 Hz, 2H), 3.89 (s, 3H).
3H), 1.25e1.17 (m, 3H), 1.11 (d, J ¼ 6.8 Hz, 18H).
Table 2
In vitro screening data of various ortho-substituted thiazoles for hSGLT2 inhibitory activities.
Compound
11a
R
H
hSGLT2 IC50 (nM)a
Compound
11d
R
hSGLT2 IC50 (nM)a
0.797
2.15
3.98
32.8
1.51
5.55
10a
Me
11e
10g
11f
10m
11b
1.24
11g
11h
131
713
21.6
2.23
11c
a
These data were obtained by single determinations.

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S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
Table 3
In vitro screening data of compound 12ae12h for hSGLT2 inhibitory activities.
Cl
RO
N
Ar
O
S
HO
HO
OH
OH
Compound
R
Ar
hSGLT2 IC50 (nM)a
Compound
R
Ar
hSGLT2 IC50 (nM)a
12a
H
5.81
20.5
5.88
12e
allyl
17.5
12b
12c
H
H
12f
allyl
allyl
38.7
16.2
12g
12d
H
2.23
12h
allyl
10.0
a
These data were obtained by single determinations.
5.1.4. Preparation of (4-(allyloxy)-5-bromo-2-chlorobenzyloxy)
and dried invacuoto obtain 5-bromo-2,4-dichlorobenzoic acid (20 g,
94%). 1H NMR (400 MHz, CDCl3)
triisopropylsilane (15c)
d
8.30 (s,1H), 7.63 (s,1H); MHþ 269
Yield: 61%(5-steps). 1H NMR (400 MHz, CDCl3)
d
7.78 (s,1H), 6.85
The titled compound (23.5 g, 57.1 mmol, 83%(2-steps) from 5-
bromo-2,4-dichlorobenzoic acid) was obtained in the same manner
(s, 1H), 6.11e6.01 (m, 1H), 5.49 (doublet and quartet, J ¼ 17.2 Hz,
1.6 Hz,1H), 5.33 (doublet and doublet, J ¼ 10.8 Hz,1.6 Hz,1H), 4.78 (s,
2H), 4.58 (d, J ¼ 1.6 Hz, 2H),1.27e1.15 (m, 3H),1.12 (d, J ¼ 6.8 Hz,18H)
as the synthesis of 15a. 1H NMR (400 MHz, CDCl3)
d 7.61 (s, 1H), 7.29
(s, 1H), 5.01 (s, 2H), 1.27e1.14 (m, 3H), 1.11 (d, J ¼ 6.8 Hz, 18H).
5.1.5. Preparation of (5-bromo-2,4-dichlorobenzyloxy)
triisopropylsilane (17a)
5.1.6. Preparation of (5-bromo-2-chloro-4-fluorobenzyloxy)
triisopropylsilane (17b)
To a solution of benzoic acid 8 (15.0 g, 78.5 mmol) in chlor-
osulfonic acid (60 mL) was added bromine (2.0 mL, 39.3 mmol) and
sulfur (0.15 g). The reaction mixture was stirred at 70 ꢀC overnight
and then cooled to ambient temperature. The reaction mixture was
poured into iced water. The resulting solid was isolated by filtration
5-Bromo-2-chloro-4-fluorobenzoic acid was prepared in the
same manner as the synthesis of 2,4-dichlorobenzoic acid and the
titled compound (Yield: 86% (3-steps)) from 5-bromo-2-chloro-4-
fluorobenzoic acid was obtained in the same manner as the
synthesis of 17a. 1H NMR (400 MHz, CDCl3)
d
7.81 (d, J ¼ 7.6 Hz, 1H),
Table 4
In vitro screening data of compound 13ae13j for hSGLT2 inhibitory activities.
Compound
13a
X
F
F
F
F
F
Ar
hSGLT2 IC50 (nM)a
Compound
13g
X
Ar
hSGLT2 IC50 (nM)a
3.49
5.35
3.88
2.12
4.57
Cl
Cl
Cl
Cl
2.24
13.3
4.77
2.31
13b
13h
13c
13i
13d
13j
13e
13f
F
27.4
a
These data were obtained by single determinations.

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2669
7.12 (d, J ¼ 8.4 Hz, 1H), 4.78 (s, 2H), 1.25e1.18 (m, 3H), 1.10 (d,
J ¼ 6.8 Hz, 18H).
To a solution of crude bromide in CH3CN (100 mL) were added
potassium cyanide (913 mg, 14 mmol) and 18-crown-6 (3.7 g,
14 mmol) at room temperature. The mixture was stirred at 85 ꢀC for
1 h. The mixture was cooled to room temperature and concentrated
in vacuo. After dilution with water, the mixture was extracted with
EtOAc. The organic layer was dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was purified using normal
phase column chromatography to provide beta and alpha anomeric
5.1.7. Preparation of (2-chloro-4-methoxy-5-((3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)
phenyl)methanol (18a)
To a solution of (5-Bromo-2-chloro-4-methoxybenzyloxy)triiso-
propylsilane (15a, 9.7 g, 25.7 mmol) in tetrahydrofuran (100 mL)
at ꢁ78 ꢀC under an atmosphere of nitrogen was added dropwise
n-butyllithium (2.5 M in hexanes, 10.3 mL, 25.7 mmol), and the
mixturewasstirredfor1.5hatthesametemperature. Thenasolution
mixture (4.59 g, 70%). The preceding Intermediate (mixture of a:b-
anomer in about 1:2 ratio) was slurried in ethanol (100 mL) and
heated to reflux with stirring. The reaction mixture was held at
reflux for 1 h to ensure that all of solution had homogenized; it was
then cooled slowly to ambient temperature and stirred overnight at
this temperature. The resulting solid was isolated by filtration and
dried invacuotoyield the titled compound (3.24 g, 4.6 mmol, 49%) as
of 2,3,4,6-Tetra-O-benzyl- -glucopyranone (10, 10.6 g,19.8 mmol) in
D
tetrahydrofuran (50 mL) was added dropwise, and the mixture was
stirred for 1.5 h at the same temperature. The reaction mixture was
quenched by addition of saturated ammonium chloride solution.
After complete addition, the solution was gradually raised to room
temperature. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and
concentrated in vacuo to yield the title compound as a yellow solid
which was used without further purification.
a white solid. 1H NMR (400 MHz, CDCl3)
b-anomer: d 7.40e7.27 (m,
14H), 7.20e7.13 (m, 5H), 6.88e6.74 (m, 3H), 4.93 (d, J ¼ 4.8 Hz, 2H),
4.86 (d, J ¼ 10.8 Hz, 1H), 4.74 (d, J ¼ 9.6 Hz, 1H), 4.64e4.59 (m, 2H),
4.57e4.52 (m, 2H), 4.06 (d, J ¼ 11.2 Hz,1H), 3.85e3.81 (m,1H), 3.77 (s,
3H), 3.75e3.70 (m, 3H), 3.68 (s, 2H), 3.62e3.58 (m, 2H); MNaþ 726.
To
a
stirred ꢁ50 ꢀC solution of (2-chloro-4-methoxy-5-
5.1.9. Preparation of 2-(2-chloro-4-methoxy-5-((2S,3S,4R,5R,6R)-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-
yl)phenyl)acetic acid (20a)
((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahy-
dro-2H-pyran-2-yl)phenyl)methanol (19.8 mmol) in dichloro-
methane (50 mL) was added triethylsilane (6.3 mL, 39.6 mmol)
followed by boron trifluoride diethyl etherate (5.0 mL, 39.6 mmol)
at a rate such that the reaction temperature was maintained
between ꢁ40 and ꢁ50 ꢀC. The solution was allowed to warm
to ꢁ10 ꢀC over 2 h prior to quenching with saturated potassium
carbonate solution. After removal of organic volatiles under
reduced pressure, the residue was partitioned between ethyl
acetate and water. Following extraction of the aqueous layer with
ethyl acetate, the combined organic layers were washed with water
prior to drying over magnesium sulfate. Filtration and concentra-
tion under reduced pressure yield the titled compound as a yellow
oil which was used without further purification.
To a solution of cyanide 19a (3.24 g, 4.6 mmol) in EtOH/H2O
(60 mL/30 mL) was added NaOH (11.04 g, 276 mmol). The mixture
was stirred at 100 ꢀC for 15 h. The mixture was cooled to room
temperature and evaporated in vacuo to remove EtOH. The residue
was diluted with H2O, cooled to 0 ꢀC and acidified with c-HCl
solution. The titled compound 20a was precipitated as a solid,
dissolved with EtOAc and extracted. The organic layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo to
provide the titled compound 20a (3.22 g, 97%). 1H NMR (400 MHz,
CDCl3)
d
7.38e7.21 (m, 14H), 7.17e7.08 (m, 5H), 6.86 (dd, J ¼ 7.2 Hz,
1.2 Hz, 2H), 6.79 (s, 1H), 4.96e4.81 (m, 3H), 4.75e4.64 (m, 1H),
4.56e4.51 (m, 2H), 4.48e4.39 (m, 2H), 3.97 (d, J ¼ 11.2 Hz, 1H),
3.81e3.58 (m, 10H), 3.55e3.49 (m, 1H); MNaþ 745.
To a solution of (2-chloro-4-methoxy-5-((3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)
benzyloxy)triisopropylsilane (19.8 mmol) in tetrahydrofuran
(50 mL) was added tetrabutylammonium fluoride (1.0 M in tetra-
hydrofuran, 59.4 mL, 59.4 mmol) and the reaction mixture stirred
at ambient temperature for 2 h. After removal of organic volatiles
under reduced pressure, the residue was partitioned between ethyl
acetate and saturated ammonium chloride solution. The organic
layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over magnesium sulfate, filtered and concentrated in vacuo.
The crude residue was purified using silica column chromatog-
raphy to yield the titled compound (13.0 g, 19.5 mmol, 98%) as
a white solid. MNaþ 717.
5.1.10. 2-(2-Chloro-4-ethoxy-5-((2S,3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)
phenyl)acetic acid (20b)
Yield: 47% (7-steps). 1H NMR (400 MHz, CDCl3)
d 7.33e7.18 (m,
14H), 7.16e7.06 (m, 5H), 6.94e6.83 (m, 2H), 6.74 (s, 1H), 4.96e4.74
(m, 4H), 4.57e4.41 (m, 3H), 4.39e4.28 (m, 1H), 3.99 (d, J ¼ 11.2 Hz,
1H), 3.82e3.47 (m, 10H), 1.26 (t, J ¼ 6.8 Hz, 3H); MNaþ 759.
5.1.11. 2-(4-(allyloxy)-2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)
phenyl)acetic acid (20c)
Yield: 35% (7-steps). 1H NMR (400 MHz, CDCl3)
d 7.35e7.24 (m,
14H), 7.21e7.18 (m, 2H), 7.17e7.10 (m, 3H), 6.93e6.87 (m, 2H), 6.82 (s,
1H), 5.98e5.84 (m, 1H), 5.34 (dd, J ¼ 17.6 Hz, 1.6 Hz, 1H), 5.19 (dd,
J ¼ 10.8 Hz, 1.2 Hz, 1H), 4.96e4.83 (m, 3H), 4.77e4.64 (m, 1H),
4.63e4.57 (m, 2H), 4.54e4.45 (m, 2H), 4.40 (d, J ¼ 4.0 Hz, 2H), 4.01 (d,
J ¼ 11.2 Hz, 1H), 3.75e3.64 (m, 7H), 3.60e3.54 (m, 1H); MNaþ 771.
5.1.8. Preparation of 2-(2-chloro-4-methoxy-5-((2S,3S,4R,5R,6R)-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-
yl)phenyl)acetonitrile (19a)
To a solution of (2-chloro-4-methoxy-5-((3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)
phenyl)methanol (18a, 6.5 g, 9.35 mmol) inether (200 mL) at 0 ꢀC was
added pyridine (2 drops) and phosphorus tribromide (0.44 mL,
4.67 mmol). The reaction was allowed to slowly warm to room
temperature over 15 h and refluxed for 1 h. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate and
washed with water then brine. The organic extract was dried over
magnesium sulfate, filtered, and evaporated in vacuo to yield the
bromide compound as a yellow oil, which was used without further
purification. MNaþ 779.
5.1.12. 2-(2,4-Dichloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-
(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)acetic acid
(20d)
1H NMR (400 MHz, CDCl3)
d 7.39 (s,1H), 7.37 (s,1H), 7.33e7.25 (m,
13H), 7.19e7.12 (m, 5H), 6.95e6.93 (m, 2H), 4.94 (d, J ¼ 10.8 Hz, 1H),
4.89 (d, J ¼ 10.8 Hz, 1H), 4.86 (d, J ¼ 10.8 Hz, 1H), 4.74 (d, J ¼ 9.6 Hz,
1H), 4.62 (d, J ¼ 10.8 Hz, 1H), 4.60 (d, J ¼ 12.0 z, 1H), 4.52 (d,
J ¼ 12.0 Hz,1H), 4.45 (d, J ¼ 10.8 Hz,1H), 4.04 (d, J ¼ 10.8 Hz,1H), 3.84
(t, J ¼ 8.8 Hz,1H), 3.78e3.69 (m, 5H), 3.61e3.54 (m, 2H); MNaþ 749.

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S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
5.1.13. 2-(2-Chloro-4-fluoro-5-((2S,3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)
phenyl)acetic acid (20e)
J¼ 9.2 Hz,1H), 4.31 (s, 2H), 4.09 (br s, 4H), 3.76 (s,1H), 3.66 (d, J¼ 10.4 Hz,
1H), 3.36 (dd, J ¼ 12.0, 5.2 Hz, 1H), 3.32e3.07 (m, 4H); MHþ 468.
MNaþ 733.
5.1.18. (2S,3R,4R,5S,6R)-2-(4-Chloro-3-((4-phenylthiazol-2-yl)
methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(10c)
5.1.14. Preparation of 2-(2-chloro-4-methoxy-5-((2S,3S,4R,5R,6R)-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-
yl)phenyl)-N-(2-(furan-2-yl)-2-oxoethyl)acetamide (21)
Yield: 51%. 1H NMR (400 MHz, DMSO-d6)
d 7.84 (s, 1H), 7.52 (dd,
J ¼ 4.8, 1.2 Hz, 1H), 7.44 (m, 1H), 7.26 (dd, J ¼ 3.6, 1.2 Hz, 1H),
7.07e7.04 (m, 2H), 4.88 (t, J ¼ 4.0 Hz, 2H), 4.64 (d, J ¼ 5.2 Hz, 1H),
4.41 (d, J ¼ 9.2 Hz, 1H), 4.37 (t, J ¼ 6.0 Hz, 1H), 4.33 (s, 2H), 3.76 (s,
3H), 3.65 (dd, J ¼ 10.8, 5.6 Hz,1H), 3.40e3.29 (m, 1H), 3.28e3.21 (m,
To a mixture of the carboxylic acid 20 (700 mg, 0.97 mmol), 2-
amino-1-(furan-2-yl)ethanone hydrochloride (203 mg, 1.26 mmol),
EDCI (278 mg, 1.45 mmol), and HOBt (262 mg, 1.94 mmol) in DMF
(5 mL) wasadded NMM(0.33 mL, 2.9 mmol). Theresultingmixturewas
stirred at room temperature for 15 h. The reaction mixture was poured
into aq. HCl solution (1.0 M, 25 mL), and extracted with EtOAc. The
organic phase was dried over anhydrous MgSO4, filtered and evapo-
rated under vacuum. The residue was further purified using normal
phase column chromatography to provide the titled amide compound
2H), 3.18e3.11 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d 168.5,
158.0, 138.5, 133.4, 132.9, 132.2, 131.7, 128.8, 128.5, 127.3, 126.8,
126.3, 112.8, 82.1, 79.0, 74.6, 74.3, 71.0, 61.9, 56.6, 36.70; MHþ 484.
5.1.19. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-methoxy-5-((5-(thiophen-
3-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10d)
(775 mg, 0.93 mmol, 96%). 1H NMR (400 MHz, CDCl3)
d 7.66 (m, 1H),
Yield: 52%. 1H NMR (400 MHz, DMSO-d6)
d 7.93 (s, 1H), 7.67 (dd,
7.32e7.23 (m, 14H), 7.20e7.11 (m, 5H), 6.91e6.89 (m, 3H), 6.53 (dd,
J ¼ 3.6, 1.6 Hz, 2H), 6.34e6.32 (m, 1H), 4.92 (d, J ¼ 12 Hz, 2H), 4.86 (d,
J ¼ 10.8 Hz, 1H), 4.76 (d, J ¼ 9.2 Hz, 1H), 4.64e4.60 (m, 2H), 4.54e4.51
(m, 2H), 4.47 (d, J ¼ 4.4 Hz, 1H), 4.05 (d, J ¼ 10.8 Hz, 1H), 3.84e3.80 (m,
1H), 3.74 (s, 6H), 3.69 (s, 2H), 3.65e3.59 (m, 2H); MHþ 830.
J ¼ 2.8, 1.2 Hz, 1H), 7.60 (dd, J ¼ 4.8, 2.8 Hz, 1H), 7.43 (s, 1H), 7.39 (dd,
J ¼ 5.2,1.2 Hz,1H), 7.07 (s,1H), 4.41 (d, J ¼ 9.6 Hz,1H), 4.32 (s, 2H), 4.05
(br s, 4H), 3.76 (s, 3H), 3.64 (d, J ¼ 10.4 Hz, 1H), 3.39e3.35 (m, 1H),
3.32e3.18 (m, 2H), 3.15e3.09 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d
167.9, 157.9, 138.7, 133.9, 133.4, 132.0, 131.7, 128.5, 128.2, 127.4, 126.6,
5.1.15. Preparation of 2-(2-chloro-4-methoxy-5-((2S,3S,4R,5R,6R)-
3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-
yl)benzyl)-5-(furan-2-yl)thiazole (22)
122.4, 112.8, 82.1, 79.0, 74.6, 74.4, 71.0, 61.9, 56.7, 36.70; MHþ 484.
5.1.20. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-methoxy-5-((5-
phenylthiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (10e)
To a solution of the amide (775 mg, 0.93 mmol) in anhydrous THF
(25 mL) was added Lawesson reagent (755 mg, 1.87 mmol). The
reaction mixture was refluxed overnight. After cooling to room
temperature, the reaction mixture was poured into a saturated
NaHCO3 solution, and extracted with EtOAc. The organic phase was
driedoveranhydrousMgSO4, filtered andevaporated under vacuum.
The residue was further purified using normal phase column chro-
matography to provide the titled compound 22 (678 mg, 88%). 1H
Yield: 41%. 1H NMR (400 MHz, DMSO-d6)
d 8.03 (s, 1H),
7.58e7.52 (m, 2H), 7.44 (s, 1H), 7.39e7.34 (m, 2H), 7.31e7.25 (m,
1H), 7.07 (s, 1H), 4.52 (br s, 4H), 4.43 (d, J ¼ 9.6 Hz, 1H), 4.34 (2H),
3.77 (s, 3H), 3.62 (d, J ¼ 10.4 Hz, 1H), 3.37 (dd, J ¼ 12.0, 5.6 Hz, 1H),
3.32e3.07 (m, 4H); MHþ 478.
NMR (400 MHz, CDCl3) d 7.79 (m, 1H), 7.35e7.23 (m, 14H), 7.20e7.13
5.1.21. (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(4-fluorophenyl)thiazol-
2-yl)methyl)-2-methoxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10f)
(m, 5H), 6.90e6.89 (m, 3H), 6.37 (dd, J ¼ 3.2, 1.6 Hz, 2H), 6.31 (d,
J ¼ 2.8 Hz, 1H), 4.90 (d, J ¼ 9.2 Hz, 2H), 4.86 (d, J ¼ 10.8 Hz, 1H), 4.75
(d, J ¼ 8.4 Hz, 1H), 4.64e4.59 (m, 2H), 4.53e4.48 (m, 2H), 4.36 (d,
J ¼ 5.2 Hz,1H), 4.01 (d, J ¼ 10.8 Hz,1H), 3.84e3.79 (m,1H), 3.77e3.69
(m, 3H), 3.75 (s, 3H), 3.64e3.58 (m, 2H); MHþ 828.
Yield: 43%.1H NMR (400 MHz, DMSO-d6)
d 8.00 (s,1H), 7.65e7.57
(m, 2H), 7.44 (s, 1H), 7.25e7.18 (m, 2H), 7.06 (s, 1H), 4.57 (br s, 4H),
4.42 (d, J ¼ 9.2 Hz, 1H), 4.34 (s, 2H), 3.76 (s, 3H), 3.64 (d, J ¼ 10.4 Hz,
1H), 3.36 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.32e3.08 (m, 4H); MHþ 496.
5.1.16. Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-5-((5-(furan-2-
yl)thiazol-2-yl)methyl)-2-methoxyphenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (10a)
5.1.22. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5-((5-(furan-2-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10g)
2-(2-chloro-4-methoxy-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzy-
loxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)-5-
(furan-2-yl)thiazole (678 mg, 0.82 mmol) in acetonitrile (3 mL)
reacted with TMSI (5 mL) at 0 ꢀC. The reaction mixture was stirred
at 50 ꢀC for 1 day. After quenching the reaction with methanol,
solvent was evaporated under reduced pressure. Purification by RP
preparative provided the titled compound (192 mg, 50%) as a white
Yield: 33%. 1H NMR (400 MHz, CD3OD)
d 7.79 (s, 1H), 7.55e7.46
(m, 2H), 7.03 (s, 3H), 6.60(d, J ¼ 3.2 Hz, 1H), 7.03 (s, 1H), 6.50e6.44
(m, 1H), 4.84 (s, 4H), 4.64 (d, J ¼ 9.2 Hz, 1H), 4.43e4.32 (m, 2H),
4.10e4.01 (m, 2H), 3.82 (dd, J ¼ 12.0, 1.6 Hz, 1H), 3.66 (dd, J ¼ 12.0,
5.6 Hz, 1H), 3.57e3.32 (m, 4H), 1.40 (t, J ¼ 7.2 Hz, 3H); 13C NMR
solid. 1H NMR (400 MHz, DMSO-d6)
d 7.89 (s, 1H), 7.69 (m, 1H), 7.44
(100 MHz, DMSO-d6) d 167.91, 156.88, 145.61, 143.28, 137.45, 132.81,
131.28, 128.16, 127.98, 126.71, 113.33, 112.14, 107.38, 81.64, 78.53,
74.22, 73.79, 70.43, 64.33, 61.33, 36.05, 14.53; MHþ 482.
(s,1H), 7.07 (s,1H), 6.74 (d, J ¼ 3.6 Hz,1H), 6.55e6.54 (m,1H), 4.90 (t,
J ¼ 4.8 Hz, 2H), 4.65 (d, J ¼ 5.6 Hz,1H), 4.43e4.37 (m, 3H), 4.34 (s, 2H),
3.76 (s, 3H), 3.62 (m, 1H), 3.38e3.30 (m, 1H), 3.28e3.22 (m, 1H),
3.15e3.12 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d 168.4, 158.0,
5.1.23. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5-((5-(furan-3-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-
pyran-3,4,5-triol (10h)
146.1, 143.8, 140.0, 138.0, 133.4, 131.7, 128.5, 127.3, 112.8, 112.7, 107.9,
82.1, 79.0, 74.6, 74.4, 71.0, 61.8, 56.6, 36.50; MHþ 468.
Yield: 29%. 1H NMR (400 MHz, DMSO-d6)
d 8.01 (s, 1H), 7.83 (s,
1H), 7.71 (t, J ¼ 1.6 Hz, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 6.84e6.78 (m,
1H), 4.82 (s, 4H), 4.39 (d, J ¼ 9.6 Hz, 1H), 4.31 (s, 2H), 4.00 (q,
J ¼ 1.2 Hz, 1H), 3.63 (d, J ¼ 1.04 Hz, 1H), 3.41e3.29 (m, 2H), 3.23 (t,
J ¼ 8.4 Hz, 1H), 3.18e3.04 (m, 2H), 1.29 (t, J ¼ 7.2 Hz, 3H); 13C NMR
5.1.17. (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(furan-3-yl)thiazol-2-yl)
methyl)-2-methoxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10b)
Yield: 15%. 1H NMR (400 MHz, DMSO-d6)
d
8.00 (s, 1H), 7.83(s, 1H),
(100 MHz, DMSO-d6) d 167.41, 156.87, 144.50, 139.72, 138.49, 132.81,
7.70 (t, J ¼ 1.6 Hz,1H), 7.42 (s,1H), 7.06 (s,1H), 6.88e6.83 (m,1H), 4.42 (d,

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2671
131.29, 128.14, 126.80, 116.77, 113.32, 109.13, 81.64, 78.54, 74.24,
73.76, 70.44, 64.33, 61.34, 36.14, 14.54; MHþ 482.
1H), 6.06e5.95 (m, 1H), 5.40 (quartet and doublet, J ¼ 17.2, 1.6 Hz,
1H), 5.22 (qd, J ¼ 10.4, 1.6 Hz, 1H), 4.90 (dd, J ¼ 18.8, 4.8 Hz, 2H),
4.66 (d, J ¼ 5.2 Hz, 1H), 4.59e4.53 (m, 2H), 4.42 (d, J ¼ 9.6 Hz,
1H), 4.38 (t, J ¼ 5.6 Hz, 1H), 4.31 (s, 2H), 3.64 (dd, J ¼ 12.0, 5.6 Hz,
1H), 3.43e3.31 (m, 2H), 3.27e3.20 (m, 1H), 3.19e3.09 (m, 2H);
5.1.24. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5-((5-(thiophen-2-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10i)
13C NMR (100 MHz, DMSO-d6)
d 167.24, 156.39, 144.52, 139.73,
Yield: 43%. 1H NMR (400 MHz, CD3OD)
d
7.86 (s, 1H), 7.53 (s, 1H),
138.56, 133.40, 132.80, 131.45, 129.06, 128.17, 127.09, 116.83,
116.81, 113.57, 109.15, 81.72, 78.57, 74.48, 73.67, 70.41, 68.85,
61.32, 36.14; MHþ 494.
7.43 (dd, J ¼ 5.6, 0.8 Hz, 1H), 7.25 (dd, J ¼ 5.6, 0.8 Hz, 1H), 7.09e7.04
(m, 2H), 4.84 (s, 4H), 4.64 (d, J ¼ 9.2 Hz, 1H), 4.47e3.76 (m, 2H),
4.11e4.02 (m, 2H), 3.83 (dd, J ¼ 12.0, 1.6 Hz, 1H), 3.65 (dd, J ¼ 12.0,
1.2 Hz, 1H), 3.57e3.33 (m, 4H), 1.40 (t, J ¼ 7.2 Hz, 1H); 13C NMR
5.1.30. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-(thiophen-
2-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10o)
(100 MHz, DMSO-d6) d 167.97, 156.86, 137.98, 132.79, 132.33, 131.64,
131.28, 128.30, 128.12, 126.62, 126.31, 125.76, 113.28, 81.61, 78.50,
74.20, 73.74, 70.40, 64.29, 61.31, 36.13, 14.51; MHþ 498.
Yield: 30%. 1H NMR (400 MHz, DMSO-d6)
d 7.84 (s, 1H), 7.52 (dd,
J ¼ 5.2, 1.2 Hz, 1H), 7.44 (s, 1H), 7.27 (dd, J ¼ 3.6, 1.2 Hz, 1H),
7.08e7.02 (m, 2H), 6.06e5.95 (m, 1H), 5.41 (dd, J ¼ 17.6, 1.6 Hz, 1H),
5.22 (dd, J ¼ 11.2, 1.6 Hz, 1H), 4.90 (dd, J ¼ 18.8, 4.8 Hz, 2H), 4.68 (d,
J ¼ 5.2 Hz, 1H), 4.59e4.53 (m, 2H), 4.42 (d, J ¼ 9.6 Hz, 1H), 4.38 (t,
J ¼ 5.6 Hz, 1H), 4.32 (s, 2H), 3.64 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.42e3.31
(m, 2H), 3.29e3.20 (m, 1H), 3.19e3.09 (m, 2H); 13C NMR (100 MHz,
5.1.25. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5-((5-(thiophen-3-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10j)
Yield: 39%. 1H NMR (400 MHz, DMSO-d6)
d 7.79 (s,1H), 7.55e7.46
(m,1H), 7.03 (s,1H), 6.60(d, J ¼ 3.2 Hz,1H), 7.03 (s,1H), 6.51e6.45 (m,
1H), 4.84 (s, 4H), 4.64 (d, J ¼9.2 Hz,1H), 4.43e4.32(m, 2H), 4.10e4.01
(m, 2H), 3.82 (dd, J ¼ 12.0, 1.6 Hz, 1H), 3.66 (dd, J ¼ 12.0, 5.6 Hz, 1H),
3.57e3.32 (m, 4H),1.40 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-
DMSO-d6)
d 167.91, 156.42, 138.09, 133.40, 132.81, 132.40, 131.69,
131.48, 128.36, 128.19, 126.94, 126.36, 125.81, 116.84, 113.59, 81.72,
78.58, 74.35, 73.69, 70.42, 68.86, 61.33, 36.17; MHþ 510.
d6)
d 167.45, 156.88, 138.16, 133.41, 132.81, 131.53, 131.31, 128.15,
127.71, 126.81, 126.09, 121.86, 113.34, 81.66, 78.57, 74.26, 73.79,
70.46, 64.35, 61.36, 54.91, 36.19, 14.56; MHþ 482.
5.1.31. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-(thiophen-
3-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10p)
5.1.26. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5-((5-
phenylthiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (10k)
Yield: 17%. 1H NMR (400 MHz, DMSO-d6)
d 7.93 (s,1H), 7.71e7.65
(m, 1H), 7.67e7.58 (m, 1H), 7.42 (s, 1H), 7.39 (dd, J ¼ 1.6 Hz, 1H), 7.05
(s, 1H), 6.06e5.95 (m, 1H), 5.41 (dd, J ¼ 17.2, 1.6 Hz, 1H), 5.22 (dd,
J ¼ 11.8, 1.6 Hz, 1H), 4.93 (dd, J ¼ 18.8, 4.4 Hz, 2H), 4.70 (d, J ¼ 5.2 Hz,
1H), 4.60e4.53 (m, 2H), 4.48e4.39 (m, 2H), 4.32 (s, 2H), 3.59e3.51
Yield: 31%. 1H NMR (400 MHz, CD3OD)
d 7.87 (s, 1H), 7.56e7.51
(m, 3H), 7.39e7.34 (m, 2H), 7.32e7.26 (m, 1H), 7.03 (s, 1H), 4.84 (s,
4H), 4.64 (d, J ¼ 9.2 Hz, 1H), 4.43e4.33 (m, 2H), 4.09e4.01 (m, 2H),
3.82 (dd, J ¼ 12.0, 1.6 Hz, 1H), 3.64 (dd, J ¼ 12.0, 5.6 Hz, 1H),
3.56e3.37 (m, 4H), 1.40 (t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz,
(m, 1H), 3.41e3.05 (m, 5H); 13C NMR (100 MHz, DMSO-d6)
d 167.29,
156.37, 138.24, 133.40, 132.79, 131.55, 131.44, 128.16, 127.69, 127.09,
126.09,121.83,116.82,113.57, 81.71, 78.58, 74.48, 73.68, 70.41, 68.85,
61.33, 38.87; MHþ 510.
DMSO-d6)
d 168.35, 156.86, 138.31, 138.22, 132.81, 131.30, 130.92,
129.18, 128.17, 128.14, 126.84, 126.22, 113.33, 81.66, 78.56, 74.25,
73.81, 70.46, 64.34, 61.36, 36.05, 14.55; MHþ 492.
5.1.32. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-
phenylthiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (10q)
5.1.27. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-ethoxy-5e((5-(4-
fluorophenyl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (10l)
Yield: 31%. 1H NMR (400 MHz, DMSO-d6)
d 8.04 (s, 1H),
7.58e7.53 (m, 2H), 7.45 (s, 1H), 7.40e7.32 (m, 2H), 7.31e7.26 (m,
1H), 7.06 (s, 1H), 6.07e5.95 (m, 1H), 5.42 (dd, J ¼ 17.6, 1.6 Hz, 1H),
5.22 (dd, J ¼ 11.2, 1.6 Hz, 1H), 4.90 (dd, J ¼ 19.2, 4.8 Hz, 2H), 4.68
(d, J ¼ 5.2 Hz, 1H), 4.62e4.51 (m, 2H), 4.40 (d, J ¼ 11.2 Hz, 1H),
4.38 (t, J ¼ 5.6 Hz, 1H), 4.34 (s, 2H), 3.64 (d, J ¼ 10.4 Hz, 1H),
3.41e3.32 (m, 2H), 3.24 (t, J ¼ 8.0 Hz, 1H), 3.28e3.09 (m, 2H); 13C
Yield: 41%. 1H NMR (400 MHz, CD3OD)
d 7.84 (s, 1H), 7.58e7.52
(m, 2H), 7.51 (s, 3H), 7.15e7.08 (m, 2H), 7.03 (s,1H), 4.84 (s, 4H), 4.64
(d, J ¼ 9.2 Hz, 1H), 4.43e4.32 (m, 2H), 4.10e4.02 (m, 2H), 3.83 (dd,
J ¼ 12.0, 1.6 Hz, 1H), 3.65 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.57e3.34 (m,
4H), 1.40 (t, J ¼ 7.2 Hz, 3H); MHþ 510.
NMR (100 MHz, DMSO-d6)
d 168.23, 156.34, 138.31, 138.21,
5.1.28. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-(furan-2-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10m)
133.39, 132.78, 131.43, 130.89, 129.17, 128.16, 128.13, 127.07,
126.20, 116.81, 113.56, 81.69, 78.56, 74.90, 73.68, 70.40, 68.85,
61.31, 36.26; MHþ 504.
Yield: 17%. 1H NMR (400 MHz, DMSO-d6)
d 7.89 (s, 1H), 7.71e7.62 (m,
1H), 7.44 (s, 1H), 7.06 (s, 1H), 6.74 (d, J ¼ 3.6 Hz, 1H), 6.69e6.63 (m, 1H),
6.06e5.93 (m,1H), 5.41 (dd, J ¼ 17.2,1.6 Hz,1H), 5.22 (dd, J ¼ 10.4,1.6 Hz,
1H), 4.91 (dd, J ¼ 18.8, 3.6 Hz, 2H), 4.68 (d, J ¼ 4.8 Hz,1H), 4.59e4.52 (m,
2H), 4.47e4.29 (m, 4H), 3.69e3.59 (m, 1H), 3.41e3.06 (m, 5H); 13C NMR
5.1.33. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-(4-
fluorophenyl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (10r)
Yield: 24%. 1H NMR (400 MHz, DMSO-d6)
d 8.00 (s, 1H),
(100 MHz, DMSO-d6)
132.81,131.46,128.21,128.02,126.99,116.84,113.59,112.18,107.42, 81.73,
78.58, 74.50, 73.72, 70.42, 68.86, 61.33, 36.06; MHþ 494.
d
167.84, 156.42, 145.64, 143.32, 137.48, 133.41,
7.65e7.57 (m, 2H), 7.45 (s, 1H), 7.21 (t, J ¼ 1.2 Hz, 2H), 7.05 (s, 1H),
6.07e5.95 (m, 1H), 5.42 (dd, J ¼ 17.6, 1.6 Hz, 1H), 5.22 (dd, J ¼ 11.2,
1.6 Hz, 1H), 4.90 (dd, J ¼ 19.2, 4.8 Hz, 2H), 4.69 (d, J ¼ 5.2 Hz, 1H),
4.62e4.51 (m, 2H), 4.43 (d, J ¼ 9.6 Hz, 1H), 4.38 (t, J ¼ 5.6 Hz, 1H),
4.33 (s, 2H), 3.64 (dd, J ¼ 11.2, 5.2 Hz, 1H), 3.42e3.31 (m, 2H),
3.29e3.21 (m, 1H), 3.20e3.09 (m, 2H); 13C NMR (100 MHz, DMSO-
5.1.29. (2S,3R,4R,5S,6R)-2-(2-(Allyloxy)-4-chloro-5-((5-(furan-3-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (10n)
d6)
d 168.81, 163.54, 161.10, 156.87, 138.82, 137.72, 133.89, 133.29,
Yield: 23%. 1H NMR (400 MHz, DMSO-d6)
d
8.01 (s, 1H), 7.83 (s,
131.94, 128.88, 128.02, 127.56, 117.32, 116.72, 116.50, 114.06, 82.21,
1H), 7.71 (t, J ¼ 1.6 Hz, 1H), 7.43 (s, 1H), 7.05 (s, 1H), 6.85e6.79 (m,
79.07, 74.20, 70.91, 69.35, 61.83, 36.75; MHþ 522.

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S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
5.1.34. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5-((5-(furan-2-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13a)
7.40 (d, J ¼ 9.6 Hz, 1H), 4.98e4.92 (m, 3H), 4.45e4.41 (m, 1H), 4.41
(s, 2H), 4.28 (d, J ¼ 8.8 Hz, 1H), 3.68e3.66 (m, 1H), 3.42e3.38 (m,
1H), 3.25e3.21 (m, 3H), 3.16e3.14 (m, 1H); MHþ 484.
Yield: 35%. 1H NMR (400 MHz, DMSO-d6)
d 7.90 (s, 1H), 7.70 (m,
1H), 7.61 (d, J ¼ 7.6 Hz, 1H), 7.40 (d, J ¼ 9.6 Hz, 1H), 6.76 (d,
J ¼ 3.2 Hz, 1H), 6.56e6.55 (m, 1H), 4.95 (triplet and doublet,
J ¼ 10.8, 4.0 Hz, 3H), 4.43 (t, J ¼ 6.0 Hz, 1H), 4.41 (s, 2H), 4.28 (d,
J ¼ 9.2 Hz, 1H), 3.67 (dd, J ¼ 10.4, 5.2 Hz, 1H), 3.43e3.37 (m, 1H),
3.27e3.20 (m, 3H), 3.17e3.13 (m, 1H); 13C NMR (100 MHz, DMSO-
5.1.40. (2S,3R,4R,5S,6R)-2-(2,4-Dichloro-5-((5-(furan-2-yl)thiazol-
2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (13g)
Yield: 29%. 1H NMR (400 MHz, DMSO-d6)
d 7.89 (s, 1H), 7.69 (d,
J ¼ 1.2 Hz, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 6.76 (d, J ¼ 3.6 Hz, 1H),
6.59e6.51 (m, 1H), 4.91 (br s, 4H), 4.49e4.39 (m, 3H), 3.66 (d,
J ¼ 10.4 Hz, 1H), 3.37e3.14 (m, 5H); 13C NMR (100 MHz, DMSO-d6)
d6)
d
167.4, 159.9 (d, J ¼ 248.1), 146.0, 143.9, 138.0, 133.5 (d,
J ¼ 10.7), 132.5 (d, J ¼ 5.1), 132.0, 128.6, 127.4 (d, J ¼ 13.9), 117.0
(d, J ¼ 26.3), 112.7, 108.0, 82.1, 78.7, 75.1, 74.6, 70.7, 61.7, 36.50;
MHþ 456.
d
166.94, 146.02, 143.88, 138.01, 137.65, 134.89, 133.95, 133.59,
132.60, 129.70, 128.69, 112.69, 108.05, 82.22, 78.74, 77.39, 74.82,
70.68, 61.68, 37.37; MHþ 472.
5.1.35. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5-((5-(furan-3-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13b)
5.1.41. (2S,3R,4R,5S,6R)-2-(2,4-Dichloro-5-((5-(furan-3-yl)thiazol-
2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (13h)
Yield: 23%. 1H NMR (400 MHz, DMSO-d6)
d 8.03 (s, 1H), 7.84 (m,
1H), 7.72e7.71 (m, 1H), 7.60 (d, J ¼ 7.2 Hz, 1H), 7.40 (d, J ¼ 9.6 Hz,
1H), 6.83 (m,1H), 4.96 (br s, 4H), 4.38 (s, 2H), 4.28 (d, J ¼ 9.2 Hz,1H),
3.66 (d, J ¼ 10.4 Hz,1H), 3.39 (dd, J ¼ 11.6, 5.6 Hz,1H), 3.28e3.21 (m,
3H), 3.16e3.11 (m, 1H); MHþ 456.
Yield: 31%. 1H NMR (400 MHz, DMSO-d6)
d 8.03 (s, 1H), 7.84(s,
1H), 7.71 (t, J ¼ 1.6 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 6.89e6.83 (m,
1H), 5.03 (br s, 4H), 4.43 (d, J ¼ 9.2 Hz, 1H), 4.40 (s, 2H), 3.66 (dd,
J ¼ 12.0, 1.6 Hz, 1H), 3.39 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.35e3.15 (m,
5H); MHþ 472.
5.1.36. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5-((5-(thiophen-2-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13c)
5.1.42. (2S,3R,4R,5S,6R)-2-(2,4-Dichloro-5-((5-(thiophen-2-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13i)
Yield: 29%. 1H NMR (400 MHz, DMSO-d6)
d 7.85 (s, 1H), 7.62 (d,
J ¼ 7.6 Hz, 1H), 7.53 (dd, J ¼ 5.2, 1.2 Hz, 1H), 7.41 (d, J ¼ 9.6 Hz, 1H),
7.28 (dd, J ¼ 3.6, 1.2 Hz, 1H), 7.06 (dd, J ¼ 5.2, 4.0 Hz, 1H), 5.01e4.95
(m, 3H), 4.46e4.44 (m,1H), 4.40 (s, 2H), 4.28 (d, J ¼ 9.2 Hz,1H), 3.66
(dd, J ¼ 11.6, 3.6 Hz, 1H), 3.43e3.38 (m, 1H), 3.25e3.21 (m, 3H),
Yield: 25%. 1H NMR (400 MHz, DMSO-d6)
d 7.86 (s, 1H), 7.67 (s,
1H), 7.61 (s,1H), 7.54 (dd, J ¼ 5.2,1.2 Hz,1H), 7.29 (dd, J ¼ 3.6, 0.8 Hz,
1H), 7.09e7.04 (m, 1H), 4.71e4.49 (m, 5H), 3.67 (d, J ¼ 10.4 Hz, 1H),
3.41 (dd, J ¼ 12.0, 5.4 Hz, 1H), 3.38e3.17 (m, 6H); 13C NMR
3.17e3.13 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
d
167.4, 159.9 (d,
(100 MHz, DMSO-d6) d 167.01, 138.62, 137.65, 134.84, 133.95,133.60,
J ¼ 248 Hz), 138.6, 133.5 (d, J ¼ 10.8), 132.8, 132.6 (d, J ¼ 5.1), 132.3,
131.9 (d, J ¼ 3.5), 128.9, 127.5 (d, J ¼ 13.9), 126.9, 126.4, 116.9 (d,
J ¼ 26.5), 82.1, 78.7, 75.1, 74.6, 70.7, 61.7, 36.6; MHþ 472.
132.74, 132.63, 132.37, 129.71, 128.86, 126.96, 126.45, 82.23, 78.73,
77.39, 74.80, 70.67, 61.68, 36.82; MHþ 488.
5.1.43. (2S,3R,4R,5S,6R)-2-(2,4-Dichloro-5-((5-(thiophen-3-yl)
thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13j)
5.1.37. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5e((5-(thiophen-3-
yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-
pyran-3,4,5-triol (13d)
Yield: 32%. 1H NMR (400 MHz, DMSO-d6)
d 7.94 (s, 1H),
Yield: 25%. 1H NMR (400 MHz, DMSO-d6)
d
7.94 (s, 1H), 7.70 (dd,
7.77e7.68 (m, 1H), 7.66 (s, 1H), 7.64e7.58 (m, 2H), 7.40 (dd, J ¼ 4.8,
1.6 Hz, 1H), 6.76 (d, J ¼ 3.6 Hz, 1H), 6.59e6.51 (m, 1H), 4.49e4.35
(m, 4H), 3.67 (dd, J ¼ 11.6, 1.6 Hz, 1H), 3.40 (dd, J ¼ 12.0, 5.6 Hz,
J ¼ 3.2, 1.2 Hz, 1H), 7.62e7.60 (m, 2H), 7.42e7.39 (m, 2H), 5.01e4.93
(m, 3H), 4.45 (t, J ¼ 5.6 Hz, 1H), 4.39 (s, 2H), 4.28 (d, J ¼ 8.8 Hz, 1H),
3.69e3.65 (m, 1H), 3.43e3.37 (m, 1H), 3.27e3.21 (m, 3H), 3.17e3.13
1H), 3.37e3.11 (m, 7H); 13C NMR (100 MHz, DMSO-d6)
d 166.47,
(m, 1H); 13C NMR (100 MHz, DMSO-d6)
d
166.9, 159.8 (d,
138.79, 137.62, 135.00, 134.08, 133.90, 133.60, 132.61, 131.93,
129.70, 128.23, 126.61, 122.48, 82.23, 78.74, 77.39, 74.79, 70.70,
61.68, 36.85; MHþ 488.
J ¼ 247.7 Hz), 138.8, 134.0, 133.5 (d, J ¼ 10.7 Hz), 132.5 (d, J ¼ 5.1 Hz),
132.0 (d, J ¼ 3.5 Hz), 131.9, 128.2, 127.4 (d, J ¼ 13.9 Hz), 126.6, 122.5,
116.9 (d, J ¼ 26.4 Hz), 82.1, 78.7, 75.1, 74.6, 70.7, 61.7, 36.6; MHþ 472.
5.1.44. Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-5-((5-(furan-2-
yl)thiazol-2-yl)methyl)-2-hydroxyphenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (11a)
5.1.38. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5-((5-phenylthiazol-
2-yl)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-
triol (13e)
5.1.44.1. Step 1: 5-Chloro-4-((5-(furan-2-yl)thiazol-2-yl)methyl)-2-
((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahy-
dro-2H-pyran-2-yl)phenol. To a solution of allyl ether 23 (3.76 g,
4.40 mmol) in THF (50 mL) were added sodium borohydride (1.0 g,
26.4 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.25 g,
0.22 mmol) at 0 ꢀC. The mixture was stirred at 0 ꢀC for 10 min and at
room temperature for 15 h. Saturated NaHCO3 solution was added
slowly to the mixture to quench the reaction. The mixture was
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified using
normal phase column chromatography to provide the titled
Yield: 24%. 1H NMR (400 MHz, DMSO-d6)
d 8.05 (s, 1H), 7.62 (d,
J ¼ 7.2 Hz, 1H), 7.58e7.56 (m, 2H), 7.42e7.36 (m, 3H), 7.32e7.28 (m,
1H), 4.94 (br s, 4H), 4.41 (d, J ¼ 10.0 Hz, 1H), 3.67 (d, J ¼ 10.4 Hz, 1H),
3.40 (dd, J ¼ 12.0, 6.0 Hz, 1H), 3.28e3.21 (m, 3H), 3.16e3.12 (m, 1H);
13C NMR (100 MHz, DMSO-d6)
d
167.8, 159.8 (d, J ¼ 247.9 Hz), 139.0,
138.8, 133.5 (d, J ¼ 10.8 Hz),132.5 (d, J ¼ 5.1 Hz),132.0 (d, J ¼ 3.5 Hz),
131.3, 129.7, 128.7, 127.4 (d, J ¼ 13.9 Hz), 126.8, 116.9 (d, J ¼ 26.5 Hz),
82.1, 78.7, 75.1, 74.6, 70.7, 61.7, 36.7; MHþ 466.
5.1.39. (2S,3R,4R,5S,6R)-2-(4-Chloro-2-fluoro-5-((5-(4-
fluorophenyl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (13f)
compound (3.2 g, 83%). 1H NMR (400 MHz, CDCl3)
d 7.84 (s,1H), 7.75
(s, 1H), 7.43e7.37 (m, 2H), 7.35e7.24 (m, 3H), 7.21e7.13 (m, 11H),
7.15e6.94 (m, 5H), 6.46e6.36 (m, 3H), 4.92e4.82 (m, 6H),
4.59e4.22 (m, 8H), 3.85e3.55 (m, 4H); MHþ 814.
Yield: 49%. 1H NMR (400 MHz, DMSO-d6)
d
8.01 (s, 1H),
7.63e7.60 (m, 3H), 7.40 (d, J ¼ 9.2 Hz, 1H), 7.22 (t, J ¼ 8.4 Hz, 2H),

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2673
5.1.44.2. Step 2: (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(furan-2-yl)
thiazol-2-yl)methyl)-2-hydroxyphenyl)-6-(hydroxymethyl)-tetrahy-
J ¼ 5.2 Hz,1H), 4.51 (d, J ¼ 9.2 Hz,1H), 4.44 (t, J ¼ 5.6 Hz,1H), 4.37 (s,
2H), 4.03 (t, J ¼ 4.8 Hz, 2H), 3.76e3.63 (m, 3H), 3.48e3.39 (m, 1H),
dro-2H-pyran-3,4,5-triol (11a). To
a
solution of perbenzylated
3.31e3.13 (m, 4H); 13C NMR (100 MHz, DMSO-d6)
d 168.42, 157.39,
thiazole which was prepared in step 1 (261 mg, 0.314 mmol) in
CH2Cl2 (15 mL) was added BCl3 (1.0 M in CH2Cl2, 2.5 mL, 2.51 mmol)
at 0 ꢀC. The mixture was stirred at 0 ꢀC for 10 min. MeOH was added
to the mixture to quench the reaction. The mixture was concen-
trated in vacuo. After dilution with water, the residue was extracted
with EtOAc/H2O. The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was purified using RP preparative HPLC to provide the titled
146.12, 143.79, 137.96, 133.23, 131.56, 129.12, 128.50, 127.50, 114.22,
112.66, 107.91, 81.99, 78.99, 74.85, 74.51, 71.42, 70.92, 61.81, 60.05,
39.37; MHþ 498.
5.1.49. (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(furan-2-yl)thiazol-2-
yl)methyl)-2-(2-methoxyethoxy)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (11f)
Yield: 18%. 1H NMR (400 MHz, DMSO-d6)
d 7.95 (s, 1H), 7.73 (d,
compound 11a (68 mg, 46%). 1H NMR (400 MHz, DMSO-d6)
d
7.93 (s,
J ¼ 1.2 Hz, 1H), 7.40 (s, 1H), 6.90 (s, 1H), 6.78 (d, J ¼ 3.2 Hz, 1H),
6.62e6.55 (m, 1H), 4.94 (t, J ¼ 5.2 Hz, 2H), 4.49e4.39 (m, 2H), 4.33
(s, 2H), 3.75e3.66 (m, 1H), 3.47e3.15 (m, 7H); MHþ 512.
1H), 7.73 (d, J ¼ 1.6 Hz, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 6.78 (d,
J ¼ 3.2 Hz,1H), 6.65e6.57 (m, 1H), 5.10e4.92 (m, 2H), 4.55e4.46 (m,
3H), 4.15e4.09 (m, 2H), 3.78e3.60 (m, 2H), 3.51e3.12 (m, 11H); 13C
NMR (100 MHz, DMSO-d6)
132.65, 131.86, 128.45, 126.87, 125.72, 116.37, 112.64, 107.86, 81.95,
79.02, 74.94, 74.62, 70.85, 61.76, 36.56; MHþ 512.
d
168.87, 156.30, 146.16, 143.76, 137.94,
5.1.50. Preparation of (2S,3R,4R,5S,6R)-2-(2-(2-(1H-1,2,4-triazol-1-
yl)ethoxy)-4-chloro-5-((5-(furan-2-yl)thiazol-2-yl)methyl)phenyl)-
6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (11g)
To a solution of phenol 11a (200 mg, 0.441 mmol) and cesium
carbonate (158 mg, 0.485 mmol) in DMF (10 mL) was added 1,2-
5.1.45. Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-5-((5-(furan-2-
yl)thiazol-2-yl)methyl)-2-propoxyphenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (11b)
dibromoethane (96
mL, 1.11 mmol). The resulting mixture was
stirred at room temperature for 60 h. After dilution with water, the
mixture was extracted with EtOAc. The organic layer was dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was carried on to the next step without further purification.
To a solution of the crude bromide in DMF (10 mL) was added
1,2,4-triazole sodium derivative (122 mg, 1.34 mmol). The mixture
was stirred at room temperature for 15 h. After dilution with water,
the mixture was extracted with EtOAc. The organic layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified using RP preparative HPLC to provide the titled
compound 11g (78 mg, 33%, 2 steps). 1H NMR (400 MHz, DMSO-d6)
To a solution of phenol 11a (150 mg, 0.330 mmol) in acetone
(10 mL) were added 1-iodopropane (1.2 mL, 11.6 mmol) and K2CO3
(1.6 g, 11.6 mmol) at r.t. The mixture was stirred at 50 ꢀC for 40 h.
The mixture was cooled to r.t. and filtered off. The filtrate was
concentrated in vacuo. The residue was purified using RP prepara-
tive to provide the titled compound 11b (70 mg, 43%) as a white
solid. 1H NMR (400 MHz, DMSO-d6)
d
7.91 (s, 1H), 7.72 (d, J ¼ 1.6 Hz,
1H), 7.45 (s, 1H), 7.07 (s, 1H), 6.78 (d, J ¼ 3.2 Hz, 1H), 6.58 (q,
J ¼ 1.6 Hz, 1H), 4.52 (br s, 4H), 4.43 (d, J ¼ 9.6 Hz, 1H), 4.36 (s, 1H),
3.95 (triplet and doublet, J ¼ 6.4, 1.6 Hz, 2H), 4.48e4.75 (m, 4H),
3.67 (d, J ¼ 10.8 Hz, 1H), 3.47e3.37 (m, 2H), 3.26 (t, J ¼ 8.0 Hz, 1H),
3.23e3.11 (m, 2H), 1.73 (sext, J ¼ 6.4 Hz, 2H), 0.99 (d, J ¼ 7.2 Hz, 3H);
MHþ 496.
d
8.59 (s,1H), 8.02 (s,1H), 7.95 (s,1H), 7.77e7.71 (m,1H), 7.47 (s,1H),
7.13 (s, 1H), 6.78 (d, J ¼ 3.2 Hz, 1H), 6.62e6.58 (m, 1H), 5.02e4.92
(m, 2H), 4.71e4.35 (m, 8H), 3.71e3.61 (m, 1H), 3.49e3.41 (m, 1H),
3.38e3.15 (m, 5H); MHþ 549.
5.1.46. (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(furan-2-yl)thiazol-2-
yl)methyl)-2-(prop-2-ynyloxy)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (11c)
5.1.51. (2S,3R,4R,5S,6R)-2-(4-chloro-2-(2-(dimethylamino)ethoxy)-
5-((5-(furan-2-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol trifluoroacetic acid salt(11h)
Yield: 33%. 1H NMR (400 MHz, DMSO-d6)
d 7.91 (s, 1H), 7.72 (d,
J ¼ 1.6 Hz, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.79e6.74 (m, 1H), 6.57 (q,
J ¼ 1.6 Hz, 1H), 4.92 (dd, J ¼ 11.2, 4.8 Hz, 2H), 4.85 (d, J ¼ 2.4 Hz, 2H),
4.71 (d, J ¼ 5.2 Hz, 1H), 4.48e4.75 (m, 4H), 3.68 (dd, J ¼ 10.4, 5.2 Hz,
1H), 3.62 (t, J ¼ 2.4 Hz, 1H), 3.45e3.11 (m, 5H); 13C NMR (100 MHz,
Yield: 21%. 1H NMR (400 MHz, DMSO-d6)
d 9.72 (s, 1H), 7.95 (s,
1H), 7.75 (d, J ¼ 1.2 Hz, 1H), 7.56 (s, 1H), 7.25 (s, 1H), 6.84e6.77 (m,
1H), 6.64e6.58 (m, 1H), 4.58e4.53 (m, 1H), 4.48e4.33 (m, 5H), 3.71
(d, J ¼ 10.4 Hz,1H), 3.61e3.52 (m, 3H), 3.48e3.41 (m,1H), 3.35e3.24
(m, 4H), 3.21e3.16 (m, 1H), 2.98e2.86 (m, H); MHþ 525.
DMSO-d6)
d 167.91, 156.42, 138.09, 133.40, 132.81, 132.40, 131.69,
131.48, 128.36, 128.19, 126.94, 126.36, 125.81, 116.84, 113.59, 81.72,
78.58, 74.35, 73.69, 70.42, 68.86, 61.33, 36.17; MHþ 492.
5.1.52. Preparation of 2-bromo-5-chloro-4-(hydroxymethyl)benzoic
acid (26)
5.1.47. (2S,3R,4R,5S,6R)-2-(2-(But-3-enyloxy)-4-chloro-5-((5-
(furan-2-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (11d)
To a solution of acid 24 (81 g, 535.8 mmol) in DMF (500 mL) was
added NBS portionwise at 0 ꢀC. The mixture was stirred at 0 ꢀC for
70 min. The mixture was poured into H2O (1 L) with stirring. The
product was precipitated and filtered. The solid was washed with
H2O and the solid was dried under vacuum at 50 ꢀC for 24 h to
obtain the bromide (109 g, 89%)
To a solution of bromide (109 g, 473.8 mmol) in MeOH (900 mL)
was added thionyl chloride (70 mL, 947.6 mmol) dropwise at 0 ꢀC.
The mixture was warmed up to r.t. and stirred at 65 ꢀC for 18 h. The
mixture was evaporated in vacuo. The residue was diluted with
EtOAc (500 mL) and washed with aq. sat’d NaHCO3 solution (700
mLꢂ3). The organic layer was dried over anhydrous MgSO4, filtered
and concentrated in vacuo to obtain the ester 25 (107 g, 92%).
To a solution of ester 25 (60.4 g, 229 mmol) in CCl4 (900 mL)
were added NBS (49.0 g, 275 mmol) and AIBN (3.80 g, 22.9 mmol).
The mixture was stirred at 85 ꢀC for 15 h. The mixture was cooled to
room temperature and filtered off through celite to remove
Yield: 19%. 1H NMR (400 MHz, DMSO-d6)
d 7.912 (s, 1H), 7.72 (d,
J ¼ 1.2 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.77 (d, J ¼ 3.2 Hz, 1H), 6.58
(q, J ¼ 2.0 Hz, 1H), 5.99e5.87 (m, 1H), 5.18 (dd, J ¼ 17.2, 1.6 Hz, 1H),
5.09 (d, J ¼ 9.2 Hz, 1H), 5.00 (br s, 2H), 4.52 (br s, 2H), 4.42 (d,
J ¼ 9.6 Hz, 2H), 4.36 (s, 2H), 4.04 (td, J ¼ 6.4, 1.2 Hz, 2H), 4.48e4.75
(m, 4H), 3.67 (d, J ¼ 11.2 Hz, 1H), 3.40 (t, J ¼ 8.8 Hz, 2H), 3.28e3.11
(m, 4H); MHþ 508.
5.1.48. (2S,3R,4R,5S,6R)-2-(4-Chloro-5-((5-(furan-2-yl)thiazol-2-
yl)methyl)-2-(2-hydroxyethoxy)phenyl)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3,4,5-triol (11e)
Yield: 29%. 1H NMR (400 MHz, DMSO-d6)
d 7.92 (s,1H), 7.74e7.71
(m, 1H), 7.47 (s, 1H), 7.12 (s, 1H), 6.77 (d, J ¼ 3.2 Hz, 1H), 6.59e6.53
(m, 1H), 4.97e4.91 (m, 2H), 4.81 (t, J ¼ 6.0 Hz, 1H), 4.70 (d,

2674
S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
insoluble solids. The filtrate was evaporated in vacuo to obtain the
crude benzyl bromide.
(400 MHz, CDCl3) d 7.47 (s, 1H), 7.37 (s, 1H), 7.35e7.22 (m, 13H),
7.20e7.08 (m, 5H), 6.85 (dd, J ¼ 8.0 Hz,1.6 Hz,1H), 5.96e5.81 (m,1H),
5.25 (doublet and quartet, J ¼ 17.2 Hz, 1.6 Hz, 1H), 5.15 (doublet and
quartet, J ¼ 10.4 Hz, 1.2 Hz, 1H), 4.95e4.83 (m, 3H), 4.78e4.49 (m,
4H), 4.43e4.37 (m, 3H), 3.95e3.89 (m, 2H), 3.86 (d, J ¼ 10.8 Hz, 1H),
3.81e3.71 (m, 6H), 3.55 (t, J ¼ 9.2 Hz, 2H); MHþ 785.
To a solution of benzyl bromide (93.6 g, 273 mmol) in DMF
(500 mL) was added NaOAc (56 g, 683 mmol). The mixture was
stirred at room temperature for 20 h and diluted with EtOAc. The
organic layer was washed with aq. 50% NaCl solution and dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The residue
was tritulated with MeOH and the titled compound was precipi-
tated as a solid. The solid was filtered off, washed with MeOH, and
dried under vacuum to obtain the product (36 g, 51%, 2 steps). 1H
5.1.55. Preparation of 2-(4-(allyloxymethyl)-2-chloro-5-
((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-2-yl)benzyl)-5-(furan-2-yl)thiazole (29)
The titled compound was prepared in the same manner as the
synthesis of Scheme 3.
NMR (400 MHz, CDCl3)
d 7.84 (s, 1H), 7.71 (s, 2H), 5.19 (s, 2H), 3.94
(s, 3H), 2.19 (s, 3H); MHþ 321.
To a solution of acetate (33.5 g, 104.1 mmol) in THF/MeOH/H2O
(250 mL/250 mL/90 mL) was added lithium hydroxide mono-
hydrate (13.1 g, 312 mmol). The mixture was stirred at room
temperature for 15 h. The mixture was evaporated in vacuo to
remove organic solvents. The residue was diluted with H2O, cooled
to 0 ꢀC and acidified with aq. 1 N HCl solution. The titled compound
26 was precipitated as a solid, filtered off and washed with H2O. The
solid was dried under vacuum at 50 ꢀC for 15 h to obtain the
product (27.2 g, 96%). MHþ 265.
Yield: 72%(2-steps). 1H NMR (400 MHz, CDCl3)
d
1H NMR
7.58e7.44 (m, 2H), 7.38e7.16 (m, 21H),
(400 MHz, CDCl3)
d
6.91e6.82 (m, 2H), 6.43e6.33 (m, 1H), 5.97e5.83 (m, 1H), 5.27
(doublet and quartet, J ¼ 17.2 Hz, 2.0 Hz, 1H), 5.17 (doublet and
quartet, J ¼ 10.8 Hz, 1.6 Hz, 1H), 4.93e4.82 (m, 3H), 4.77e4.56 (m,
3H), 4.54e4.36 (m, 6H), 3.97e3.85 (m, 3H), 3.81e3.68 (m, 4H),
3.62e3.51 (m, 2H); MHþ 868.
5.1.56. Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-5-((5-(furan-2-
yl)thiazol-2-yl)methyl)-2-(hydroxymethyl)phenyl)-6-
(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (12a)
The titled compound was prepared in the same manner as the
synthesis of Scheme 4.
5.1.53. Preparation of (4-(allyloxymethyl)-5-bromo-2-
chlorobenzyloxy)triisopropylsilane (27)
To a solution of alcohol 26 (23.2 g, 87.5 mmol) in DMF (250 mL)
were added TIPSCl (77 mL, 358.5 mmol), imidazole (33 g,
481.3 mmol) and DMAP (4.1 g, 33.6 mmol). The mixture was
stirred at room temperature for 15 h. After dilution with water, the
mixture was extracted with EtOAc. The organic layer was dried
over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified using normal phase chromatography to
Yield: 20%. 1H NMR (400 MHz, DMSO-d6)
d 7.92 (s, 1H), 7.72 (d,
J ¼ 1.2 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 6.77 (d, J ¼ 3.2 Hz, 1H),
6.60e6.54 (m, 1H), 4.95 (br s, 1H), 4.63 (s, 4H), 4.42 (s, 3H), 4.27 (d,
J ¼ 9.2 Hz, 2H), 3.69 (d, J ¼ 10.0 Hz,1H), 3.43 (dd, J ¼ 11.6,1.6 Hz,1H),
3.32e3.14 (m, 4H); MHþ 468.
provide silyl ester (38 g, 66%). 1H NMR (400 MHz, CDCl3)
d
7.79 (s,
5.1.57. (2S,3R,4R,5S,6R)-2-(4-chloro-5-((5-(furan-3-yl)thiazol-2-yl)
methyl)-2-(hydroxymethyl)phenyl)-6-(hydroxymethyl)-tetrahydro-
2H-pyran-3,4,5-triol (12b)
1H), 7.50 (s, 1H), 4.81 (s, 2H), 2.01 (m, 1H), 1.26e1.15 (m, 6H), 1.15
(d, J ¼ 6.8 Hz, 36H).
To a solution of silyl ester (38.0 g, 65.8 mmol) inTHF (300 mL) was
added boraneedimethylsulfide complex (1M in THF, 13 mL) at 0 ꢀC.
The mixture was stirred 0 ꢀC for 15 min, at room temperature at
30 min, and at 75 ꢀC for 15 h. The mixture was cooled to 0 ꢀC. MeOH
and H2O were added to the cooled mixture to quench the reaction.
After dilution with water, the mixture was extracted with EtOAc. The
organic layer was dried over anhydrous MgSO4, filtered and concen-
trated in vacuo. The residue was purified using normal phase column
chromatography to provide the alcohol (22.9 g, 85%). 1H NMR
Yield: 25%. 1H NMR (400 MHz, DMSO-d6)
d 8.04 (s, 1H), 7.86 (s,
1H), 7.74 (t, J ¼ 1.6 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 6.88e6.83 (m,
1H), 5.05 (br s, 1H), 4.63 (s, 4H), 4.42 (s, 3H), 4.27 (d, J ¼ 9.2 Hz, 2H),
3.69 (d, J ¼ 10.0 Hz, 1H), 3.43 (dd, J ¼ 11.6, 1.6 Hz, 1H), 3.31e3.12 (m,
4H); MHþ 468.
5.1.58. (2S,3R,4R,5S,6R)-2-(4-chloro-2-(hydroxymethyl)-5-((5-
(thiophen-2-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (12c)
(400 MHz, CDCl3)
d
7.80 (s, 1H), 7.44 (s, 1H), 4.78 (s, 2H), 4.71 (d,
Yield: 31%. 1H NMR (400 MHz, DMSO-d6)
d 7.87 (s, 1H), 7.56 (s,
J ¼ 5.2 Hz, 2H), 2.01 (m,1H),1.26e1.16 (m, 3H), 1.12 (d, J ¼ 6.8 Hz,18H).
To a solution of alcohol (31 g, 75.5 mmol) in DMF (300 mL) were
added NaH (60% dispersion in mineral oil, 4.0 g, 98.2 mmol) at 0 ꢀC.
The mixture was stirred at 0 ꢀC for 15 min and allyl bromide (23 mL,
264 mmol) was added to the mixture at 0 ꢀC. The mixture was
warmed up to room temperature and stirred at room temperature
for 2 h. After dilution with water, the mixture was extracted with
EtOAc. The organic layer was dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The residue was purified using normal
phase column chromatography to provide the titled compound 27
1H), 7.54 (d, J ¼ 0.8 Hz, 1H), 7.31 (dd, J ¼ 4.0, 0.8 Hz, 1H), 7.11e7.05
(m, 1H), 4.90 (br s, 1H), 4.63 (s, 4H), 4.41 (s, 3H), 4.27 (d, J ¼ 9.2 Hz,
2H), 3.69 (d, J ¼ 10.0 Hz,1H), 3.43 (dd, J ¼ 11.6,1.6 Hz,1H), 3.33e3.13
(m, 4H); MHþ 484.
5.1.59. (2S,3R,4R,5S,6R)-2-(4-chloro-2-(hydroxymethyl)-5-((5-
(thiophen-3-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (12d)
Yield: 26%. 1H NMR (400 MHz, DMSO-d6)
d 7.97 (s,1H), 7.75e7.70
(m, 1H), 7.66e7.61 (m, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.42 (dd, J ¼ 5.2,
1.2 Hz,1H), 4.96 (br s,1H), 4.63 (s, 4H), 4.40 (s, 3H), 4.28 (d, J ¼ 9.2 Hz,
2H), 3.69 (d, J ¼ 10.4 Hz,1H), 3.44 (dd, J ¼ 11.6,1.6 Hz,1H), 3.33e3.13
(32.1 g, 95%). 1H NMR (400 MHz, CDCl3)
d 7.79 (s, 1H), 7.45 (s, 1H),
6.05e5.91 (m, 1H), 5.35 (quartet and doublet, J ¼ 17.2,S 1.6 Hz, 1H),
5.24 (quartet and doublet, J ¼ 10.4, 1.2 Hz, 1H), 4.82 (s, 2H), 4.53 (s,
2H), 4.11 (triplet and doublet, J ¼ 5.6, 1.2 Hz, 2H), 1.25e1.16 (m, 1H),
1.10 (d, J ¼ 7.2 Hz, 18H).
(m, 4H); 13C NMR (100 MHz, DMSO-d6)
d 167.38, 143.07, 138.74,
137.33, 133.96, 133.57, 132.58, 132.02, 130.82, 128.18, 127.61, 126.60,
122.37, 81.80, 78.91, 76.77, 75.14, 70.76, 61.79, 60.02, 37.35; MHþ 484
5.1.54. Preparation of 2-(4-(allyloxymethyl)-2-chloro-5-
((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)
tetrahydro-2H-pyran-2-yl)phenyl)acetic acid (28)
5.1.60. Preparation of (2S,3R,4R,5S,6R)-2-(2-(allyloxymethyl)-4-
chloro-5-((5-(furan-2-yl)thiazol-2-yl)methyl)phenyl)-6-
(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (12e)
The titled compound (Yield: 25% (7-steps) using bromide 27) was
Yield: 9%. 1H NMR (400 MHz, DMSO-d6)
d
7.92 (s, 1H), 7.72 (d,
obtained in the same manner as the synthesis of Scheme 2. 1H NMR
J ¼ 1.6 Hz, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 6.78 (d, J ¼ 3.2 Hz, 1H),

S.H. Lee et al. / European Journal of Medicinal Chemistry 46 (2011) 2662e2675
2675
6.59e6.54 (m, 1H), 6.03e5.91 (m, 1H), 5.31 (quartet and doublet,
J ¼ 17.2, 1.6 Hz, 1H), 5.19 (quartet and doublet, J ¼ 10.4, 2.0 Hz, 1H),
4.70 (d, J ¼ 12.8 Hz, 2H), 4.55 (d, J ¼ 12.8 Hz, 2H), 4.43 (s, 3H), 4.28
(d, J ¼ 8.8 Hz, 2H), 4.05 (triplet and doublet, J ¼ 5.6, 1.6 Hz, 2H), 3.69
(d, J ¼ 10.0 Hz, 1H), 3.45 (dd, J ¼ 11.6, 5.2 Hz, 1H), 3.32e3.16 (m, 4H);
MHþ 508.
containing 14C-labeled (8 uM) and inhibitor or dimethyl sulfoxide
(DMSO) vehicle at 37 ꢀC for 2 h. Cells were washed twice with
washing buffer (pretreatment buffer containing 10 mM AMG at
room temperature) and then the radioactivity was measured using
a liquid scintillation counter. IC50 was determined by nonlinear
regression analysis using GraphPad PRISM [22,23].
5.1.61. (2S,3R,4R,5S,6R)-2-(2-(Allyloxymethyl)-4-chloro-5-((5-
(furan-3-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (12f)
Acknowledgments
Yield: 10%. 1H NMR (400 MHz, DMSO-d6)
d 8.05 (s, 1H), 7.87 (s,
Dr. Kwang-Seop Song is appreciated for his previous contribution
to the thiazole series. We also appreciate Dr. Eun Chul Huh for his
leadership and valuable advice as CTO at Green Cross Corporation.
1H), 7.74 (t, J ¼ 1.6 Hz, 1H), 7.58 (s, 1H), 7.45 (s, 1H), 6.86e6.82 (m,
1H), 6.03e5.91 (m, 1H), 5.32 (quartet and doublet, J ¼ 18.0, 1.6 Hz,
1H), 5.19 (quartet and doublet, J ¼ 10.4, 2.0 Hz, 1H), 4.70 (d,
J ¼ 12.8 Hz, 2H), 4.55 (d, J ¼ 12.8 Hz, 2H), 4.41 (s, 3H), 4.28 (d,
J ¼ 9.2 Hz, 2H), 4.05 (triplet and doublet, J ¼ 5.6, 1.6 Hz, 2H), 3.69 (d,
J ¼ 10.4 Hz, 1H), 3.44 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.31e3.17 (m, 4H);
MHþ 508.
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5.1.62. (2S,3R,4R,5S,6R)-2-(2-(Allyloxymethyl)-4-chloro-5-((5-
(thiophen-2-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (12g)
Yield: 15%. 1H NMR (400 MHz, DMSO-d6)
d 7.88 (s, 1H), 7.59 (s,
1H), 7.56 (dd, J ¼ 5.2, 1.2 Hz, 1H), 7.45 (s, 1H), 7.31 (dd, J ¼ 2.4, 1.2 Hz,
1H), 7.12e7.07 (m, 1H), 6.04e5.91 (m, 1H), 5.30 (quartet and
doublet, J ¼ 17.2, 1.6 Hz, 1H), 5.18 (quartet and doublet, J ¼ 10.4,
2.0 Hz, 1H), 4.70 (d, J ¼ 12.8 Hz, 2H), 4.61 (d, J ¼ 12.8 Hz, 2H), 4.42 (s,
3H), 4.29 (d, J ¼ 9.2 Hz, 2H), 4.04 (triplet and doublet, J ¼ 5.6, 1.6 Hz,
2H), 3.70 (d, J ¼ 10.0 Hz, 1H), 3.45 (dd, J ¼ 12.0, 5.6 Hz, 1H),
3.32e3.15 (m, 4H); MHþ 524.
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5.1.63. (2S,3R,4R,5S,6R)-2-(2-(Allyloxymethyl)-4-chloro-5-((5-
(thiophen-3-yl)thiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-
tetrahydro-2H-pyran-3,4,5-triol (12h)
Yield: 14%. 1H NMR (400 MHz, DMSO-d6)
d 7.97 (s,1H), 7.74e7.70
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add on therapy to insulin demonstrated improved glycemic control in
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(m, 1H), 7.15e7.11 (m, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.43 (dd, J ¼ 5.2,
1.2 Hz, 1H), 6.04e5.91 (m, 1H), 5.32 (qd, J ¼ 18.0, 1.6 Hz, 1H), 5.18
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3.44 (dd, J ¼ 12.0, 5.6 Hz, 1H), 3.31e3.16 (m, 4H); MHþ 524.
5.2. In vitro assay
5.2.1. Cloning and cell line construction for human SGLT2
Human SGLT2 (hSGLT2) gene was amplified by PCR from cDNA-
Human Adult Normal Tissue Kidney (Invitrogen, Carlsbad, CA). The
hSGLT2 sequence was cloned into pcDNA3.1(þ) for mammalian
expression and were stably transfected into Chinese hamster ovary
(CHO) cells. SGLT2-expressing clones were selected based on
resistance to G418 antibiotic (GeneticinÒ, Invitrogen, Carlsbad, CA)
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a-methyl-D
and activity in the 14C- -glucopyranoside (14C-AMG)
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5.2.2. Inhibitory effects on human SGLT2 activities
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140 mM choline chloride, 2 mM KCl, 1 mM CaCl2, and 1 mM
MgCl2, pH 7.4) at 37 ꢀC for 10 min. They were then incubated in
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