Synthesis and biological evaluation of SGLT2 inhibitors: Gem-difluoromethylenated Dapagliflozin analogs

Article abstract of DOI:10.1016/j.tetlet.2012.02.062

Dapagliflozin is currently the most advanced SGLT2 inhibitor, which has been used in Phase III clinical trials for treatment of diabetes. Here we describe the design and synthesis of Dapagliflozin analogs modified with gem-difluoromethylene group. Their b

Full text of DOI:10.1016/j.tetlet.2012.02.062

Tetrahedron Letters 53 (2012) 2171–2176
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Tetrahedron Letters
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Synthesis and biological evaluation of SGLT2 inhibitors:
gem-difluoromethylenated Dapagliflozin analogs
Zeng-Hao Chen a, Ruo-Wen Wang a, Feng-Ling Qing a,b,
⇑
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Dapagliflozin is currently the most advanced SGLT2 inhibitor, which has been used in Phase III clinical
trials for treatment of diabetes. Here we describe the design and synthesis of Dapagliflozin analogs mod-
ified with gem-difluoromethylene group. Their biological evaluation of in vitro inhibitory activity against
human SGLT2 showed that some of the analogs with CF2 at C-4 are better SGLT2 inhibitors compared
with Dapagliflozin.
Received 27 November 2011
Revised 8 February 2012
Accepted 14 February 2012
Available online 28 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dapagliflozin
SGLT2 inhibitor
Difluoromethylene
Diabetes
Type II diabetes is characterized by hyperglycemia due to a rela-
tive deficiency in insulin secretion accompanied by insulin resis-
tance, which has become a major global public health problem as
its prevalence has rapidly increased over the past decades.1 Re-
cently, the inhibition of sodium glucose cotransporter 2 (SGLT2)
has emerged as a very promising approach to the treatment of type
II diabetes, which can lead to the excretion of plasma glucose into
urine and lower the blood glucose levels in type II diabetic patients.2
The first SGLT inhibitor is Phlorizin, which is a natural O-aryl
ylene units or oxygen atoms.6 Furthermore, the introduction of CF2
as a strong electron-withdrawing group induces a minimal steric
change.6 Although many synthetic analogs have been made on
SAR of Dapagliflozin,7 few were devoted to investigate the influ-
ence brought by strong electron-withdrawing groups. Therefore
we initiated an effort on the synthesis of a series of fluorinated
analogs of Dapagliflozins by incorporation of a gem-difluorometh-
ylene group at C4 position.
The design of 4,4-difluorodapagliflozins 1–20 (Fig. 2) was based
on the following two considerations. First, structural modifications
at positions C2 and C3 result in a significant drop in inhibitory
activity, while changes at positions C4 and C5 have less effect on
activity.7 Secondly, the fluorine atom is normally expected to be
able to mimic some properties of an OH,6 and the gem-difluoro-
methylene group is strongly electron-withdrawing. Therefore, the
negative-charge density of vicinal ring oxygen will be decreased
dramatically, which could be critical for binding affinity. Herein
glycoside composed of a D-glucose and an aromatic ketone (chal-
cone).3 However, Phlorizin has not emerged as a drug for the treat-
ment of diabetes due to its metabolic instability. To solve this
problem, a lot of synthetic efforts have been made through struc-
tural modification. One efficient way is to conjugate aryl moiety
with glucose moiety by C–C bond instead of instable C–O–C bond.4
As a result, many C-aryl glycoside analogs have been designed and
synthesized. Among these analogs, Dapagliflozin (Fig. 1) is cur-
rently the most potent SGLT2 inhibitor and thus has been used in
Phase III clinical trials for the treatment of type II diabetes.4a
Encouraged by this discovery, many efforts have been devoted to
the structure–activity relationship (SAR) studies of Dapagliflozin.
Fluorinated functionalities are key structural units found in var-
ious pharmaceuticals and agrochemicals. Approximately 20% of
pharmaceuticals currently on the market are fluorinated com-
pounds.5 Among them, gem-difluoromethylene group has been
widely employed as an isosteric and isopolar substitution of meth-
HO
O
OH
O
OH
Cl
OEt
O
HO
HO
O
HO
HO
OH
OH
OH
OH
Dapagliflozin
Phlorizin
⇑
Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
Figure 1. O-Aryl glycoside Phlorizin and C-aryl glycoside Dapagliflozin.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.062

2172
Z.-H. Chen et al. / Tetrahedron Letters 53 (2012) 2171–2176
Cl OEt
5 O
HO
HO
2
OH
4
3
OH
Dapagliflozin
-CF2-
5 O
Structure Modification
R1
R2
R1
R2
O
5
4
HO
2
F
HO
OH
3
OH
F
2
F
OH
4
3
OH
F
Diastereoisomers 9-20
Target Molecule 1-8
9
R1 = Cl, R2 = OEt 15
R1 = Cl, R2 = Me
R1 = Cl, R2 = OiPr
R1 = Cl, R2 = OnBu
R1 = Cl, R2 = OnPr
R
R
1 = Me, R2 = OEt
1 = Me, R2 = OnPr
10
11
12
13
14
16
17
18
19
20
1
R
1 = Cl, R2 = OEt
1 = Cl, R2 = OiPr
5
6
7
R1 = Cl, R2 = Et
R1 = Me, R2 = OiPr
R1 = Me, R2 = OMe
R1 = Me, R2 = Et
2
3
4
R
1 = Cl, R2 = Me
R
1 = Cl, R2 = OnPr
R1 = Cl, R2 = OMe
R1 = Me, R2 = OEt
R
R
1 = Cl, R2 = OMe
R
1 = Me, R2 = OiPr
8
R1 = Cl, R2 = Et
Figure 2. Design of difluorodapagliflozins 1–20.
R1
R2
∗
O
O
R1
R2
BnO
∗
O
∗
HO
F
+
OBn
Br
F
F
OH
F
OBn
OH
1-20
OH
OH
BnO
OH
BnO
OH
CHO
O
BnO
BnO
or
+
CF2Br
OBn
OBn
O
F
F
F
F
30
29
Scheme 1. Retrosynthetic analysis of target molecules 1–20.
OH
1. BnBr, NaH, TBAI
2. 75 % HOAc
Br
In, DMF
90 %
O
O
O
+
F
O
F
O
F
F
3. TBSCl, 65 %
21
OBn
OBn
F
1. MsCl, CH2Cl2, Et3N
2. TBAF, THF, 87 %
KOAc, Ac2O, 85 %
130 oC, 12 h
TBSO
O
F
F
F
HO
22
23
OBn
OBn
OBn
K2CO3
MeOH
TBSCl, Et3N
CH2Cl2, rt
TBSO
AcO
HO
F
F
86 %
92 %
HO
F
F
F F
HO
25
AcO
26
24
Scheme 2. Synthesis of alcohol 26.

Z.-H. Chen et al. / Tetrahedron Letters 53 (2012) 2171–2176
2173
OBn
F
OBn
BnBr, NaH, TBAI,
TBSO
K2OsO2(OH)4
TBSO
TBSO
THF, 89 %
F
F
NMO, Acetone / H2O
96 %
F
HO
BnO
27
26
OTBS
OBn OH
OTBS
OBn
BnO
OH
BnO
OH
OH
Bu2SnO, BnBr,
+
F
F
BnO
BnO
BnO
TBAI, PhMe, reflux
89 %
OBn
F
F
F
29
F
28
30
Scheme 3. Synthesis lactone precursors 29 and 30.
we describe the synthesis and biological evaluation of the target
molecules 1–8 and their diastereoisomers 9–20.
figuration of the secondary alcohol 22 under Mitsunobu reaction
conditions9 failed, which was probably caused by steric hindrance.
Exposure of the alcohol 22 to MsCl/Et3N in CH2Cl2 at room temper-
ature followed by deprotection of TBS group furnished epoxide 23
with inverted configuration by an intramolecular nucleophilic sub-
stitution. It should be noted that basic conditions are not suitable
for the ring-opening of 23.8c Thus, treatment of 23 with an excess
of KOAc in Ac2O at 120 °C for 12 h gave the desired diacetate 24 in
85% yield. Removal of the acetyl groups of compound 24 with
K2CO3/MeOH proceeded well to afford diol 25 in 86% yield. Regio-
selective protection of 25 by TBS gave alcohol 26 in 92% yield
(Scheme 2).
The retrosynthetic analysis of fluorinated analogs is shown in
Scheme 1. The target molecules can be accomplished by coupling of
aromatic fragment with difluoromethylenated lactones. Fluorinated
lactones could be delivered from compound 29 or 30 via oxidative
cyclization, which can be prepared from (R)-glyceraldehyde acetonide
and fluorinated building block 3-bromo-3,3-difluoropropene.
The coupling of gem-difluoroallylindium in situ generated from
3-bromo-3,3-difluoropropene and indium in DMF with 1-(R)-glyc-
eraldehyde acetonide gave gem-difluorohomoallyl alcohol 21 as a
major product (Scheme 2).8 Benzylation of the gem-difluorohomo-
allyl alcohol 21 with benzyl bromide in the presence of sodium hy-
dride (0.8 equiv) and catalytic TBAI and followed by deprotection
of the acetonide moiety and regioselective protection of the pri-
mary hydroxyl group gave compound 22. The inversion of the con-
Benzylation of the hydroxyl group of alcohol 26 gave compound
27. The Os-catalyzed dihydroxylation of 27 gave diol 28 in 96%
yield as a mixture of diastereoisomers in 1:1 ratio, which could
not be isolated by column chromatography. In order to achieve
OTBS
BnO
OH
O
O
BnO
OH
BnO
TCCA, TEMPO
OH
TBAF
F
CH2Cl2, 0 o
90 %
C
OBn
BnO
BnO
THF, 92 %
F
OBn
OBn
OBn
F
F
F
F
29
31
32
R1
R2
R1
R2
Et3SiH, BF3•Et2O
O
Br
BnO
F
OH
OBn
69-80 % in two steps
nBuLi, -98 o
C
F
OBn
hemiketal
R1
R2
R1
R2
O
O
HO
BnO
F
F
F
OH
OBn
F
83-90 %
OH
OBn
1-8
33-40
1
2
R
1 = Cl, R2 = OEt, 88%
1 = Cl, R2 = OiPr, 90%
33 R1 = Cl, R2 = OEt, 80%
34 R1 = Cl, R2 = OiPr, 69%
35 R1 = Cl, R2 = OnPr, 69%
R
R1 = Cl, R2 = OnPr, 83%
R1 = Cl, R2 = OMe, 86%
3
4
36 R1 = Cl, R2 = OMe, 76%
37 R1 = Cl, R2 = Et, 69%
5
R1 = Cl, R2 = Et, 83%
R1 = Cl, R2 = Me, 83%
R1 = Me, R2 = OEt, 89%
38 R1 = Cl, R2 = Me, 69%
39 R1 = Me, R2 = OEt, 70%
40 R1 = Me, R2 = OiPr, 72%
6
7
R
1 = Me, R2 = OiPr, 89%
8
Scheme 4. Synthesis of target molecules 1–8 from 29.

2174
Z.-H. Chen et al. / Tetrahedron Letters 53 (2012) 2171–2176
R2
R1
OTBS
BnO
OH
O
HO
BnO
F
OBn
OH
F
F
30
F
OH
9-20
9
R1 = Cl, R2 = OEt, 87%
15 R1 = Cl, R2 = Me, 84%
16 R1 = Me, R2 = OEt, 77%
10 R1 = Cl, R2 = OiPr, 70%
11 R1 = Cl, R2 = OnBu, 82% 17 R1 = Me, R2 = OnPr, 82%
12 R1 = Cl, R2 = OnPr, 72%
18 R1 = Me, R2 = OiPr, 83%
13 R1 = Cl, R2 = OMe, 72%
19 R1 = Me, R2 = OMe, 76%
14 R1 = Cl, R2 = Et,
75%
20 R1 = Me, R2 = Et,
77%
Scheme 5. Synthesis of target molecules 9–20 from compound 30.
Me
Me
Cl
Cl
O
O
p-NO2C6H4COCl, DMAP
HO
RO
F
F
F
Pyridine, CH2Cl2, 82%
OH
OR
F
OH
OR
R = p-NO2C6H4CO
15
41
Scheme 6. Synthesis of compound 41.
selective benzylation of the primary hydroxyl group, 28 was con-
verted to a stannylene acetal, followed by direct alkylation with
BnBr–TBAI.10 This led to a regioselective synthesis of the primary
benzyl ethers 29 and 30 in 89% yield, which can be easily isolated
by column chromatography (Scheme 3).
gliflozin with gem-difluoro group at C4 position, and they all
showed good to excellent inhibitory activities against SGLT2, indi-
cating that position C4 of the sugar core could be modified without
losing biological activities. In contrast, configuration reversions at
C1 and C5 (9–20) resulted in the loss of potency.
Deprotection of the silyl group of 29 with TBAF in THF afforded
31 in 92% yield (Scheme 4). The resulting 1,5-diol 31 was subjected
to oxidative lactonization in the presence of TCCA-TEMPO giving
lactone 32 in 90% yield.8b,11 With lactone 32 in hand, a series of
3-benzyl-phenyl bromides were selected as analogs of chalcone
for the conjugation with the lactone 32. Generally, treatment of
aryl bromides with n-BuLi in THF and toluene at À98 °C followed
by the addition of lactone 32 afforded hemiketals, in which the
b-configuration isomers were selectively formed. Reduction of
hemiketals with triethylsilane and BF3ÁOEt2 gave the C-aryl gluco-
sides 33–40.12 Hydrogenation of 33–40 under the catalysis of pal-
ladium in ethyl acetate, methanol, and 1,2-dichlorobenzene13 at
room temperature gave the target compounds 1–8 in 83–90%
yields.
It had been reported that substituent groups on aromatic rings
are also important,4a,c so the SAR of para-substituted derivatives of
both the central benzene moiety and the distal benzene moiety
was studied. Compound 1 has the same aromatic moiety with
Dapagliflozin, but Dapagliflozin is 2.80-fold more potency than 1
(1.98 nm vs 5.54 nm). When an isopropoxy (2), a n-propoxy (3), a
methoxy (4), an ethyl (5), or a methyl (6) group was chosen as
the substitute group at the distal benzene (R2), compounds 2, 3,
Similarly, fluorinated analogs 9–20 were successfully prepared
starting from compound 30, (Scheme 5).
To determine the absolute configuration of the fluorodapaglif-
lozins, compound 41 was prepared from the reaction of triol 15
with 4-nitrobenzoyl chloride (Scheme 6).
The absolute configuration of 41 was determined by the X-ray
crystal structure (Fig. 3),14 which is coincident with what we had
expected. Therefore, the absolute configurations of the other fluo-
rinated analogs can be confirmed according to the structure of 55.
The in vitro inhibitory activities (IC50) of compounds 1–20 were
assessed by monitoring the inhibition of accumulation of [14C]-la-
beled
a-methyl-D-glucopyranoside (AMG) by Chinese hamster
ovary (CHO) cells, which stably express SGLT2 (Table 1). Phlorizin
and Dapagliflozin were used as references in the in vitro activity
evaluation system.
The synthetic fluorodapagliflozin 1–20 could be classified into
two types based on the sugar core structure,
D-glucitols (1–8)
and -altritols (9–20). -glucitols 1–8 had similar scaffold to Dapa-
L
D
Figure 3. The X-ray crystallographic structure of compound 41.

Z.-H. Chen et al. / Tetrahedron Letters 53 (2012) 2171–2176
2175
Table 1
SGLT2 inhibitory activity of difluoromethylated Dapagliflozin 1–20
R2
R1
R2
HO
R1
O
O
HO
F
F
OH
OH
F
F
OH
OH
FuoroDapagliflozin 9-20
FuoroDapagliflozin 1-8
Compound
HO
R1
R2
IC50 (nM,SGLT2 Inhibitory)
OH
OH
O
O
O
46.03
HO
HO
OH
OH
O
Phlorizin
Cl
OEt
HO
HO
1.98a
OH
OH
Dapagliflozin
Cl
OMe
S
HO
HO
1.68b
OH
ThioDapagliflozin
OH
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OEt
OiPr
OnPr
OMe
Et
5.54
0.50
2.40
0.35
0.42
0.55
17.25
24.74
>5000
—
—
>5000
—
>5000
—
>5000
>5000
—
Me
OEt
OiPr
OEt
OiPr
OnBu
OnPr
OMe
Et
9
10
11
12
13
14
15
16
17
18
19
20
Me
Me
Me
Me
Me
Me
OEt
OnPr
OiPr
OMe
Et
>5000
—
a
Inhibitory activity for Dapagliflozin was 1.1 nM from Ref. 4a.
Data were taken from Ref. 15 —, not detectable.
b
4, 5, and 6 all showed enhanced activity toward SGLT2 compared
with compound 1. Compound 2, 4, 5, and 6 strongly inhibited
SGLT2 activity with IC50 values of less than 0.60 nm, which is
3.6- to 5.6-fold potency than Dapagliflozin. When a methyl was se-
lected for R1 instead of Cl at the central benzene (7 and 8), 7 and 8
had decreased SGLT2 inhibition activity compared with 1 and 2
correspondingly.
It was interesting to find that compound 2, 4, 5, and 6 are better
SGLT2 inhibitors than Dapagliflozin. We speculated that the strong
electron-withdrawing CF2 dramatically decreased the negative-
charge density of ring oxygen atom, which might be important
for binding affinity with SGLT2. A practical way to decrease the
negative-charge density is to replace the glucose by a thioglucose
in Dapagliflozin, for the ring sulfur atom has less negative-charge
density than oxygen atom.15 Thiodapagliflozin has similar electron
property to fluoroDapagliflozins and showed excellent inhibitory
activities (IC50: 1.68 nm, assessed by CHO-K1 cells),15 which might
be less potent than fluorodapagliflozin 2. The replacement of oxy-
gen by sulfur induced not only the electron-density, but also the
size of the sugar ring. While the modification with gem-difluoro
group at C4 can reduce the electron property without change in
the size of sugar ring.
In summary, we designed and synthesized a series of fluoroda-
pagliflozins 1–20 by incorporation of gem-difluoro group at C4 po-
sition. The inhibitory activities of these analogs were evaluated and
compounds 1–8 showed good to excellent inhibitory activities.
Acknowledgments
We thank the National Natural Science Foundation of China
(21072028, 20832008) and the National Basic Research Program
of China (2012CB21600) for funding this work.

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Supplementary data associated with this article can be found, in
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