Gem-dimethyl-bearing C-glucosides as sodium-glucose co-transporter 2 (SGLT2) inhibitors

Article abstract of DOI:10.1002/cjoc.201190222

Three novel gem-dimethyl C-glucosides were designed as sodium-glucose co-transporter 2 (SGLT2) inhibitors, and their syntheses started from D-glucose and three 2-substituted-5-bromobenzoic acids were achieved via a facile 8-step protocol, with the key step being anhydrous aluminum chloride-catalyzed Friedel-Crafts alkylation of tertiary alcohols and phenetol. These three SGLT2 inhibitors were evaluated in vivo with a mice oral glucose tolerance test (OGTT), and the anti-hyperglycemic activities of all these three compounds were comparable with that of the positive control Dapagliflozin. Copyright

Full text of DOI:10.1002/cjoc.201190222

FULL PAPER
gem-Dimethyl-bearing C-Glucosides as Sodium-glucose
Co-transporter 2 (SGLT2) Inhibitors
Shi, Yonghenga,b(史永恒)
Zhao, Guilong*,b(赵桂龙)
Lou, Yuanyuanc(楼袁媛)
Wang, Yulib(王玉丽)
Shao, Huab(邵华)
Liu, Weib(刘巍)
Xu, Weirena,b(徐为人)
Tang, Lida*,b(汤立达)
a School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
b Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of
Pharmaceutical Research, Tianjin 300193, China
c College of Chemistry and Molecular Engineering, Qingdao University of Science and
Technology, Qingdao, Shandong 266042, China
Three novel gem-dimethyl C-glucosides were designed as sodium-glucose co-transporter 2 (SGLT2) inhibitors,
and their syntheses started from D-glucose and three 2-substituted-5-bromobenzoic acids were achieved via a facile
8-step protocol, with the key step being anhydrous aluminum chloride-catalyzed Friedel-Crafts alkylation of tertiary
alcohols and phenetol. These three SGLT2 inhibitors were evaluated in vivo with a mice oral glucose tolerance test
(OGTT), and the anti-hyperglycemic activities of all these three compounds were comparable with that of the positive
control Dapagliflozin.
Keywords sodium-glucose co-transporter 2 (SGLT2), gem-dimethyl, synthesis, Friedel-Crafts alkylation, oral
glucose tolerance test (OGTT)
Introduction
versus SGLT1 and metabolically liable to β-glucose-
dase-mediated cleavage in the small intestine.3 Encour-
aged by the observations found in the investigation of
phlorizin described above, several selective SGLT2 in-
hibitors, such as T-1095,4 sergliflozin5 and dagapliflozin,2
have been developed by the drug discovery industry
based on the structure of phlorizin after exploration of the
molecular structure6 and biological screening7-9 of phlor-
izin derivatives (Figure 1), and we also found a number
of S-glycosides10,11 and N-glycosides12 as SGLT2 inhibi-
tors during the discovery of our own SGLT2 inhibitors.
However, all the SGLT2 inhibitors possessing a
non-C-glucoside structure found in the earlier stage of
drug discovery, such as O-glucosides, S-glucosides and
N-glucosides, have proved to be considerably less potent
than the C-glucosides represented by Dapagliflozin in the
latter stage, and therefore all the non-C-glucosides were
discontinued during the clinical trials. The structure of the
SGLT2 inhibitors that are now still in clinical trials are
almost all C-glucosides (Figure 2). The benzylic methyl-
ene group between the two aryl rings was labile to the
degradation in vivo to be hydroxylated, and the degrada-
tion product was not an SGLT2 inhibitor.13 Based on all
these observations discussed above, we designed and
synthesized a series of C-glucosides 11a—11c with a
gem-dimethyl functionality using Dapagliflozin as struc-
ture template (Scheme 1).
Patients with type 2 diabetes suffer from hypergly-
cemia that is a consequence of impaired insulin secre-
tion in pancreatic β-cells combined with insulin resis-
tance in peripheral tissues, which resulted in a variety of
diabetic complications due to the so-called “glucose
toxicity”.1 Therefore, the goal of the therapy for type 2
diabetic patients is the strict control of blood glucose
levels within the normal range.
Over 99% of plasma glucose that is filtered in the
renal glomerulus is reabsorbed in the renal proximal
tubules by a class of transporter known as sodium-
glucose co-transporter (SGLT), and at least two sub-
types of this co-transporter have been identified so far,
SGLT1 and SGLT2. It has been established that SGLT2
is mainly responsible for this reabsorption process,2 and
therefore, inhibition of renal SGLT2 can lead to the ex-
cretion of plasma glucose into urine by decreasing the
reabsorption of glucose into blood, thus lowering the
blood glucose levels in type 2 diabetic patients. In view
of the fact that inhibition of SGLT1 was associated with
gastrointestinal side effect,2 the selective inhibition of
SGLT2 became a promising novel therapy for the
treatment of type 2 diabetes.
The natural product phlorizin has long been a
well-documented glucosuric agent (Figure 1); however,
phlorizin has proved to be nonselective against SGLT2
*
E-mail: zhao_guilong@126.com; Tel.: 0086-022-23003529; Fax: 0086-022-23006862; tangld@163.net; Tel. and Fax: 0086-022-23006950
Received October 11, 2010; revised January 27, 2011; accepted February 16, 2011.
Project supported by Key Projects of Tianjin Science and Technology Support Plan (No. 10ZCKFSH01300) and National Key Projects for the Inno-
vative Drug (No. 2009ZX09301-008-N-11).
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Chin. J. Chem. 2011, 29, 1192— 1198

gem-Dimethyl-bearing C-Glucosides as Sodium-glucose Co-transporter 2 Inhibitors
Figure 1 Molecular structures of some well-established SGLT inhibitors.
Figure 2 Molecular structures of some SGLT2 inhibitors that are now in clinical trials.
Experimental
with 100 mmol of commercially available 2-substi-
tuted-5-bromobenzoic acids 3a—3c, 70 mL of absolute
ethanol and 70 mL of benzene, and the mixture thus
obtained was stirred in an ice-water bath followed by
dropwise addition of 10 mL of concentrated sulfuric
acid. The resulting mixture was stirred at reflux with
azeotropic removal of water until all the staring benzoic
acids 3a—3c were consumed completely as indicated by
TLC analysis.
Melting points were determined with an XT-4 mi-
croscopic melting point apparatus and uncorrected. H
1
NMR spectra were recorded on a Bruker AV400 spec-
trometer at 400 MHz, with DMSO-d6 as solvent and
TMS as internal standard. The HR-MS data were ob-
tained on an Agilent Q-TOF 6510 mass spectrometer
using electrospray ionization (ESI) technique.
The intermediate 2,3,4,6-tetra-O-trimethylsilyl-D-
glucolactone (2) was prepared from commercially
available D-glucolactone according to known proce-
dures.2,14 All the reagents employed were of analytical
grade unless otherwise noted. The dried THF and tolu-
ene were distilled from sodium/benzophenone ketyl and
the dried dichloromethane was distilled from calcium
hydride.
On cooling, the reaction mixture was slowly poured
into 500 mL of cooled water, and the mixture thus ob-
tained was stirred and extracted with three 100 mL por-
tions of dichloromethane. The combined extracts were
washed with 200 mL×2 of saturated brine until aque-
ous pH＝7, dried over sodium sulfate and evaporated on
a rotary evaporator to afford the crude products 4a—4c
as colorless oils, which were purified by column chro-
matography to yield the pure products 4a—4c as color-
less oils.
General procedure for the preparation of ethyl
2-substituted-5-bromobenzoate (4a— 4c)
Ethyl 5-bromo-2-chlorobenzoate (4a) Colorless
A 250 mL round-bottomed flask equipped with a
Dean-Stark trap and a reflux condenser was charged
1
oil, 92%. H NMR (DMSO-d6, 400 MHz) δ: 7.95 (d,
Chin. J. Chem. 2011, 29, 1192— 1198
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Shi et al.
FULL PAPER
J＝2.4 Hz, 1H), 7.77 (dd, J＝2.4, 8.4 Hz, 1H), 7.53 (d,
J＝8.8 Hz, 1H), 4.32 (q, J＝7.1 Hz, 2H), 1.31 (t, J＝7.0
Hz, 3H). HRMS (ESI-Q-TOF) calcd for C9H9BrClO2
([M(79Br)＋H]＋) 262.9474, found 262.9481; for C9H9Br-
ClO2 ([M(81Br)＋H]＋) 264.9454, found 264.9459.
Ethyl 5-bromo-2-fluorobenzoate (4b) Colorless
5.41 (s, 1H), 1.45 (d, J＝0.8 Hz, 6H). HRMS (ESI-Q-
TOF) calcd for C9H11BrFO ([M(79Br)＋H]＋) 232.9977,
found 232.9979; for C9H11BrFO ([M(81Br) ＋ H] ＋
)
234.9957, found 234.9958.
1-(5-Bromo-2-methylphenyl)-1-methylethanol (5c)
1
Colorless crystals, 91%, m.p. 73—74 ℃; H NMR
1
oil, 91%. H NMR (DMSO-d6, 400 MHz) δ: 7.94 (dd,
(DMSO-d6, 400 MHz) δ: 7.60 (d, J＝2.4 Hz, 1H), 7.27
(dd, J＝2.4, 8.0 Hz, 1H), 7.05 (d, J＝8.4 Hz, 1H), 5.05
(s, 1H), 2.44 (s, 3H), 1.47 (s, 6H). H＋RMS (ESI-Q-TOF)
calcd for C10H14BrO ([M(79Br)＋H] ) 229.0228, found
229.0231; for C10H14BrO ([M(81Br)＋H]＋) 231.0208,
found 231.0212.
J＝2.8, 6.4 Hz, 1H), 7.82—7.86 (m, 1H), 7.33 (dd, J＝
8.8, 10.8 Hz, 1H), 4.31 (q, J＝7.2 Hz, 2H), 1.30 (t, J＝
7.0 Hz, 3H). HRMS (ESI-Q-TOF) calcd for C9H9BrFO2
＋
([M(79Br) ＋ H] ) 246.9770, found 246.9774; for
C9H9BrFO2 ([M(81Br)＋H]＋) 248.9749, found 248.9748.
Ethyl 5-bromo-2-methylbenzoate (4c) Colorless
1
General procedure for the preparation of 4-[1-(2-
substituted-5-bromobenzyl)-1-methylethyl]phenetol
(6a— 6c)
oil, 96%. H NMR (DMSO-d6, 400 MHz) δ: 7.89 (d,
J＝2.0 Hz, 1H), 7.65 (dd, J＝2.2, 8.2 Hz, 1H), 7.28 (d,
J＝8.4 Hz, 1H), 4.28 (q, J＝7.2 Hz, 2H), 2.45 (s, 3H),
1.31 (t, J＝7.0 Hz, 3H). HRMS (ESI-Q-TOF) calcd for
C10H12BrO2 ([M(79Br)＋H]＋) 243.0021, found 243.0018;
for C10H12BrO2 ([M(81Br) ＋ H] ＋ ) 245.0000, found
245.0003.
A dried 250 mL round-bottomed flask was charged
with 70 mmol of starting alcohols 5a—5c, 80 mmol (9.77
g) of phenetol and 150 mL of dried dichloromethane,
and the resulting mixture was stirred and cooled with an
ice-water bath. Subsequently, 90 mmol (12.00 g) of an-
hydrous aluminum chloride was added portionwise in
15 min. After addition, the reaction mixture was stirred
at room temperature for another 3 h until all the starting
alcohols 5a—5c were consumed completely as indicated
by TLC analysis.
General procedure for the preparation of 1-methyl-
1-(2-substituted-5-bromophenyl)ethanol (5a— 5c)
A dried 250 mL round-bottomed flask was charged
with 90 mmol of starting esters 4a—4c, a magnetic bar
and 150 mL of dried THF, flushed with nitrogen and
sealed with a rubber septum. The flask was cooled with
an ice-water bath and the stirring was initiated. Into the
stirred mixture was added dropwise 180 mmol of com-
mercially available methyl magnesium chloride (60 mL;
3 mol/L in THF) through syringe, and after addition the
resulting mixture was stirred at this temperature for an-
other 0.5 h.
The reaction mixture was slowly poured into 400 mL
of cooled saturated brine while stirring, and the resulting
mixture was extracted with three 100 mL portions of
dichloromethane. The combined extracts were washed
with 100 mL×2 of saturated brine, dried over sodium
sulfate and evaporated on a rotary evaporator to give the
crude products 6a—6c as colorless oils, which solidified
to white solids on standing at room temperature. The
crude products 6a—6c were triturated overnight with
100 mL of petroleum ether with five drops of ethyl ace-
tate to furnish the pure products 6a—6c as colorless
crystals after drying in vacuo at room temperature.
4-[1-(5-Bromo-2-chlorophenyl)-1-methylethyl]-
phenetol (6a) Colorless crystals, 83%, m.p. 85—86
The reaction mixture was slowly poured into 500 mL
of saturated brine followed by addition of 300 mL of
dichloromethane, and the resulting mixture was stirred,
brought to pH＝4—5 with glacial acetic acid and fil-
tered off through celite. From the filtrate was separated
the organic phase, and the aqueous phase was back-
extracted with 100 mL of dichloromethane. The com-
bined organic phases were washed with saturated brine,
dried over sodium sulfate and evaporated on a rotary
evaporator to afford the crude products 5a—5c as col-
orless oils, which were purified by column chromatog-
raphy to yield the pure products 5a—5c as colorless
crystals after drying in vacuo at room temperature.
1-(5-Bromo-2-chlorophenyl)-1-methylethanol (5a)
1
℃; H NMR (DMSO-d6, 400 MHz) δ: 7.76 (d, J＝2.4
Hz, 1H), 7.47 (dd, J＝2.4, 8.4 Hz, 1H), 7.25 (d, J＝8.4
Hz, 1H), 6.96 (d, J＝8.8 Hz, 2H), 6.78 (d, J＝9.2 Hz, 2H),
3.96 (q, J＝7.1 Hz, 2H), 1.64 (s, 6H), 1.29 (t, J＝7.0 Hz,
3H). HRMS (ESI-Q-TOF) calcd for C17H19BrClO
([M(79Br)＋H]＋) 353.0308, found 353.0311; for C17H19-
BrClO ([M(81Br)＋H]＋) 355.0287, found 355.0288.
4-[1-(5-Bromo-2-fluorophenyl)-1-methylethyl]-
phenetol (6b) Colorless crystals, 80%, m.p. 76—77 ℃;
1H NMR (DMSO-d6, 400 MHz) δ: 7.54—7.57 (m, 1H),
7.44—7.48 (m, 1H), 6.99—7.07 (m, 3H), 6.77—6.81 (m,
2H), 3.96 (q, J＝6.9 Hz, 2H), 1.60 (s, 6H), 1.29 (t, J＝7.0
Hz, 3H). HRMS (ESI-Q-TOF) calcd for C17H19BrFO
([M(79Br)＋H]＋) 337.0603, found 337.0601; for C17H19-
BrFO ([M(81Br)＋H]＋) 339.0583, found 339.0583.
4-[1-(5-Bromo-2-methylphenyl)-1-methylethyl]-
phenetol (6c) Colorless crystals, 83%, m.p. 72—73
1
Colorless crystals, 88%, m.p. 47—48 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 7.95 (d, J＝2.8 Hz, 1H), 7.44
(dd, J＝2.6, 8.6 Hz, 1H), 7.33 (d, J＝8.0 Hz, 1H), 5.46
(s, 1H), 1.56 (s, 6H). HRMS (＋ESI-Q-TOF) calcd for
C9H11BrClO ([M(79Br) ＋ H]
) 248.9682, found
248.9688; for C9H11BrClO ([M(81Br)＋H]＋) 250.9661,
found 250.9669.
1-(5-bromo-2-fluorophenyl)-1-methylethanol (5b)
1
Colorless crystals, 85%, m.p. 63—64 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 7.72 (dd, J＝2.6, 7.4 Hz, 1H),
1
℃; H NMR (DMSO-d6, 400 MHz) δ: 7.61 (d, J＝2.4
7.42—7.46 (m, 1H), 7.10 (dd, J＝8.6, 11.4 Hz, 1H),
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Chin. J. Chem. 2011, 29, 1192— 1198

gem-Dimethyl-bearing C-Glucosides as Sodium-glucose Co-transporter 2 Inhibitors
Hz, 1H), 7.32 (dd, J＝2.2, 8.2 Hz, 1H), 6.96—7.00 (m,
3H), 6.80 (d, J＝8.8 Hz, 2H), 3.96 (q, J＝6.9 Hz, 2H),
1.68 (s, 3H), 1.56 (s, 6H), 1.29 (t, J＝6.8 Hz, 3H).
HRMS (ESI-Q-TOF) calcd for C18H22BrO ([M(79Br)＋
H] ＋ ) 333.0854, found 333.0859; for C17H19BrClO
([M(81Br)＋H]＋) 335.0834, found 335.0837.
back-extracted with 100 mL of dichloromethane. The
combined extracts were washed with 200 mL×2 of
saturated brine until aqueous pH＝7, dried over sodium
sulfate and evaporated on a rotary evaporator to afford
the crude products 8a—8c as brown oils, which were
used in the next step without further purification.
The crude 8a—8c were dissolved in 50 mL of glacial
acetic acid and 100 mL of acetic anhydride and 50
mmol (4.10 g) of anhydrous sodium acetate were added.
The resulting mixture was stirred at reflux for 0.5 h.
On cooling, the reaction mixture was poured into
400 mL of ice-water, and the resulting mixture was
stirred at room temperature for 5 h and extracted with
three 100 mL portions of dichloromethane. The com-
bined extracts were washed successively with 200 mL
of saturated aqueous sodium bicarbonate and 100 mL×
2 of saturated brine, dried over sodium sulfate and
evaporated on a rotary evaporator to afford the crude
products 9a—9c.
General procedure for the preparation of methyl 1-
{4-substituted-3-[1-(4-ethoxyphenyl)-1-methylethyl]-
phenyl}-α/β-D-glucopyranose (7a— 7c)
A dried 250 mL round-bottomed flask was charged
with 50 mmol of dried 6a—6c, 100 mL of dried THF and
a magnetic bar, flushed with nitrogen and sealed with a
rubber septum. The flask was cooled with liquid nitro-
gen-absolute ethanol to －78 ℃ and the stirring wixture
was initiated. To the reaction mixture was added drop-
wise 60 mmol (37.5 mL; 1.6 mol/L in n-hexane) of
n-butyl lithium through syringe, after addition the result-
ing mixture was stirred at this temperature for another 0.5
h. To the reaction mixture was added dropwise 80 mmol
(37.35 g) of 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone
(2) in 20 mL of dried toluene through syringe. After addi-
tion, the reaction mixture was stirred at this temperature
for another 0.5 h. To the reaction mixture was added 100
mmol (9.61 g) of methanesulfonic acid in 30 mL of ab-
solute methanol. The resulting mixture was warmed
slowly to room temperature and stirred at room tempera-
ture overnight.
The reaction mixture was slowly poured into 200 mL
of saturated aqueous sodium bicarbonate, and the result-
ing mixture was stirred at room temperature for another
0.5 h, brought to pH＝4—5 with concentrated hydrochlo-
ric acid and extracted with three 50 mL portions of di-
chloromethane. The combined extracts were washed with
200 mL×2 of saturated brine until aqueous pH＝7, dried
over sodium sulfate and evaporated on a rotary evapora-
tor to afford the crude products 7a—7c as deep yellow
oils after drying in vacuo at room temperature. These
crude products 7a—7c were used directly in the next step
without further purification.
The crude products 9a—9c were purified by column
chromatography to furnish the pure products 10a—10c
as white foams.
2,3,4,6-Tetra-O-acetyl-1-deoxy-1-{4-chloro-3-[1-(4-
ethoxyphenyl)-1-methylethyl]phenyl}-β-D-glucopy-
ranose (10a) White foam, 44% (overall yield from 6a).
1H NMR (DMSO-d6, 400 MHz) δ: 7.58 (s, 1H), 7.27 (s,
2H), 6.90 (d, J＝8.8 Hz, 2H), 6.76 (d, J＝8.8 Hz, 2H),
5.39 (t, J＝9.6 Hz, 1H), 5.13 (t, J＝9.6 Hz, 1H), 5.05 (t,
J＝9.6 Hz, 1H), 4.78 (d, J＝9.6 Hz, 1H), 4.14—4.15 (m,
2H), 4.06—4.11 (m, 1H), 3.95 (q, J＝6.9 Hz, 2H), 2.02 (s,
3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.82 (s, 3H), 1.64 (s, 6H),
1.28 (t, J＝7.0 Hz, 3H). HRMS (ESI-Q-TOF) calcd for
C31H38ClO10 ([M＋H]＋) 605.2154, found 605.2159.
2,3,4,6-Tetra-O-acetyl-1-deoxy-1-{3-[1-(4-ethoxy-
phenyl)-1-methylethyl]-4-fluorophenyl}-β-D-glucopy-
ranose (10b) White foam, 41% (overall yield from 6b).
1H NMR (DMSO-d6, 400 MHz) δ: 7.39—7.42 (m, 1H),
7.26—7.30 (m, 1H), 7.01 (d, J＝8.4 Hz, 1H), 6.99 (d, J＝
8.4 Hz, 2H), 6.77 (d, J＝8.4 Hz, 2H), 5.38 (t, J＝9.4 Hz,
1H), 5.11 (t, J＝9.8 Hz, 1H), 5.05 (t, J＝9.6 Hz, 1H),
4.72 (d, J＝10.0 Hz, 1H), 4.12—4.13 (m, 2H), 4.06—
4.09 (m, 1H), 3.96 (q, J＝6.9 Hz, 2H), 2.02 (s, 3H), 2.01
(s, 3H), 1.94 (s, 3H), 1.78 (s, 3H), 1.60 (s, 6H), 1.26—
1.30 (t, J＝6.8 Hz, 3＋H); HR-MS (ESI-Q-TOF) calcd for
C31H38FO10 ([M＋H] ) 589.2449, found 589.2448.
2,3,4,6-Tetra-O-acetyl-1-deoxy-1-{3-[1-(4-ethoxy-
phenyl)-1-methylethyl]-4-methylphenyl}-β-D-glucopy-
ranose (10c) White foam, 46% (overall yield from 6c).
1H NMR (DMSO-d6, 400 MHz) δ: 7.43 (s, 1H), 7.12—
7.14 (m, 1H), 7.00 (d, J＝8.0 Hz, 1H), 6.93 (d, J＝8.4 Hz,
2H), 6.78 (d, J＝8.8 Hz, 2H), 5.38 (t, J＝9.6 Hz, 1H),
5.02—5.12 (m, 2H), 4.70 (d, J＝9.6 Hz, 1H), 4.13—4.14
(m, 2H), 4.07—4.10 (m, 1H), 3.96 (q, J＝6.9 Hz, 2H),
2.02 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H), 1.79 (s, 3H), 1.71
(s, 3H), 1.57 (s, 6H), 1.29 (t, J＝7.0 Hz, 3H). HRMS
(ESI-Q-TOF) calcd for C32H41O10 ([M＋H]＋) 585.2700,
found 585.2707.
General procedure for the preparation of 2,3,4,6-
tetra-O-acetyl-1-deoxy-1-{4-substituted-3-[1-(4-eth-
oxyphenyl)-1-methylethyl]phenyl}-β-D-glucopyranose
(10a— 10c)
A dried 250 mL round-bottomed flask was charged
with crude 7a—7c prepared in the above step and 150
mL of dried dichloromethane, and the resulting mixture
was stirred on an ice-water bath. Subsequently, 100 mmol
(11.63 g) of triethylsilane was added in one portion, fol-
lowed by dropwise addition of 50 mmol (7.10 g) of boron
trifluoride etherate. After addition, the reaction mixture
was stirred at room temperature overnight.
To the reaction mixture was slowly added 200 mL of
saturated sodium bicarbonate, and the stirring was con-
tinued for another 0.5 h. The mixture was brought to pH
＝4—5 with concentrated hydrochloric acid, and the
organic phase was separated. The aqueous phase was
Chin. J. Chem. 2011, 29, 1192— 1198
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FULL PAPER
General procedure for the preparation of 1-deoxy-1-
{4-substituted-3-[1-(4-ethoxyphenyl)-1-methylethyl]-
phenyl}-β-D-glucopyranose (11a— 11c)
volume of 10 mL/kg. The control mice received water
only. Blood samples were collected from the orbital vein
0.5, 1, 2, 3 and 4 h after the glucose challenge for the de-
termination of blood glucose levels. The blood glucose
levels were determined using commercially available kits
based on a well-established glucose oxidase method.
The blood glucose concentration-time plot for each
compound was thus plotted, and the inhibition rate was
calculated as follows: inhibition rate＝[AUC(vehicle)－
AUC(compounds 11a — 11c)]/[AUC(vehicle) － AUC
(control)]×100%, wherein the AUC represents the area
under curve for the plot of each compound, vehicle or
control.
A dried 250 mL round-bottomed flask was charged
with 5 mmol (0.11 g) of sodium and 100 mL of absolute
methanol, and the mixture was stirred until all the sodium
disappeared to form a clear solution, into which was added
20 mmol of starting 10a—10c. The stirring was continued
at room temperature until both the starting 10a—10c and
the intermediates formed were consumed completely as
indicated by TLC analysis. Dried strongly acidic resin
(5 g) was added, and the resulting mixture was stirred at
room temperature overnight until the pH＝7.
The mixture was filtered off, and the filtrate was
evaporated on a rotary evaporator to afford the products
11a—11c as white foams, which were further dried on
an oil pump at room temperature to furnish the pure
products 11a—11c as white foams.
Results and discussion
The synthetic route to the target molecules 11a—11c
was depicted in Scheme 1. Commercially available
D-glucolactone 1 was treated with trimethylsilyl chloride
(TMSCl) in the presence of N-methylmorpholine (NMM)
to give pertrimethylsilylated D-glucolactose (2) according
to known procedures.2,13 Commercially available
2-substituted-5-bromobenzoic acids 3a—3c were esteri-
fied with ethanol in the presence of concentrated sulfu-
ric acid and benzene at reflux with azeotropic removal
of water to afford the corresponding esters 4a—4c, which
were subsequently treated with 2 equiv. of methyl mag-
nesium chloride to furnish the tertiary alcohols 5a—5c.
Treatment of the mixture of tertiary alcohols 5a—5c and
phenetol with anhydrous aluminum chloride as catalyst of
Friedel-Crafts alkylation in dichloromethane smoothly
produced the desired gem-dimethyl compounds 6a—6c.
Initial attempts to bring about this conversion with other
acidic catalysts (MsOH, TfOH, TFA, BF3•Et2O and
concentrated H2SO4) all failed due to the complete for-
mation of corresponding olefins resulting from the E1
elimination of a water molecule from the starting terti-
ary alcohols mediated by these acids (Scheme 2). Thus,
tertiary alcohol 5a was treated with a variety of acids in
the presence of phenetol in dichloromethane at 0 ℃ to
room temperature; however, only the elimination prod-
uct olefin 5Ea was detected and isolated and no desired
coupling product 6a was observed in all cases. 1H NMR
(DMSO-d6, 400 MHz) for 5Ea is as follows: 7.46—7.50
(m, 1H), 7.45 (d, J＝2.4 Hz, 1H), 7.39 (d, J＝8.4 Hz,
1H), 5.28—5.29 (m, 1H), 4.96—4.97 (m, 1H), 2.02—
2.03 (m, 3H).
1-Deoxy-1-{4-chloro-3-[1-(4-ethoxyphenyl)-1-meth-
ylethyl]phenyl}-β-D-glucopyranose (11a)
White
foam, 100%. 1H NMR (DMSO-d6, 400 MHz) δ: 7.62 (s,
1H), 7.23 (s, 2H), 6.97 (d, J＝8.8 Hz, 2H), 6.76 (d, J＝
8.8 Hz, 2H), 4.93—4.95 (m, 2H), 4.87 (d, J＝5.6 Hz, 1H),
4.46 (t, J＝5.8 Hz, 1H), 4.09 (d, J＝9.6 Hz, 1H), 3.95 (q,
J＝6.9 Hz, 2H), 3.71—3.75 (m, 1H), 3.44—3.50 (m, 1H),
3.24—3.30 (m, 2H), 3.15—3.22 (m, 2H), 1.65 (s, 3H),
1.65 (s, 3H), 1.29 (t, J＝7.0 Hz, 3H)＋. HRMS (ESI-Q-TOF)
calcd for C23H30ClO6 ([M ＋ H] ) 437.1731, found
437.1728.
1-Deoxy-1-{3-[1-(4-ethoxyphenyl)-1-methylethyl]-
4-fluorophenyl}-β-D-glucopyranose (11b)
White
1
foam, 97%. H NMR (DMSO-d6, 400 MHz) δ: 7.43—
7.45 (m, 1H), 7.23—7.27 (m, 1H), 7.04 (d, J＝8.8 Hz,
2H), 6.95 (dd, J＝8.4, 12.0 Hz, 1H), 6.77 (d, J＝8.8 Hz,
2H), 4.93 (d, J＝4.8 Hz, 2H), 4.81 (d, J＝6.0 Hz, 1H),
4.45 (t, J＝5.8 Hz, 1H), 4.06 (d, J＝9.2 Hz, 1H), 3.96 (q,
J＝6.9 Hz, 2H), 3.69—3.74 (m, 1H), 3.43—3.49 (m, 1H),
3.15—3.32 (m, 4H), 1.61 (s, 3H), 1.60 (s, 3H), 1.29 (t,
J ＝ 7.0 Hz, 3H).＋ HRMS (ESI-Q-TOF) calcd for
C23H30FO6 ([M＋H] ) 421.2026, found 421.2027.
1-Deoxy-1-{3-[1-(4-ethoxyphenyl)-1-methylethyl]-
4-methylphenyl}-β-D-glucopyranose (11c)
White
1
foam, 99%. H NMR (DMSO-d6, 400 MHz) δ: 7.47 (s,
1H), 7.09—7.12 (m, 1H), 6.95—7.01 (m, 3H), 6.78 (d,
J＝8.8 Hz, 1H), 4.90—4.91 (m, 2H), 4.73 (d, J＝5.2 Hz,
1H), 4.43 (t, J＝5.8 Hz, 1H), 4.03 (d, J＝9.2 Hz, 1H),
3.96 (q, J＝7.1 Hz, 2H), 3.70—3,74 (m, 1H), 3.42—3.48
(m, 1H), 3.22—3.25 (m, 3H), 3.17—3.20 (m, 1H), 1.71 (s,
3H), 1.58 (s, 6H), 1.29 (t, J＝7.0 Hz, 3H). HRMS
(ESI-Q-TOF) calcd for C24H33O6 ([M＋H]＋) 417.2277,
found 417.2283.
An alternative attempt that included the conversion of
5a to its corresponding tertiary alkyl chloride 5Ca and the
anticipated subsequent Friedel-Crafts alkylation was also
unsuccessful because part of the tertiary alcohol 5a de-
composed to its corresponding olefin 5Ea while others
was converted to desired tertiary alkyl chloride 5Ca
(Scheme 3). Unfortunately, after aqueous work-up no
desired 5Ca was detected and only 5Ea was observed,
indicating that all the desired 5Ca formed during this
conversion decomposed during the aqueous work-up.
Oral glucose tolerance test (OGTT)
Mice (20—22 g, 6/group) were fasted overnight and
the test compounds 11a—11c (1% CMC-Na; 25 mg/kg
and 20 mL/kg) or only vehicle (1% CMC-Na; 20 mL/kg)
was orally administered. After 2 h, the mice were chal-
lenged with glucose at 2 g/kg intraperitoneally and at a
1196
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1192— 1198

gem-Dimethyl-bearing C-Glucosides as Sodium-glucose Co-transporter 2 Inhibitors
Scheme 1 Synthetic route to target molecules 11a— 11c
Reagents and conditions: (i) TMSCl (6.0 equiv.)/NMM (8.0 equiv.)/THF, 0—35 ℃; (ii) CH2SO4/EtOH/PhH, reflux; (iii) 2MeMgCl/THF, 0—5 ℃;
(iv) AlCl3/PhOEt/CH2Cl2, 0 ℃—r.t.; (v) n-BuLi/THF, －78 ℃; then, 2/toluene, －78 ℃; finally, MsOH/MeOH, r.t.; (vi) Et3SiH/BF3•Et2O, CH2Cl2, 0
—5 ℃ and then r.t.; (vii) NaOAc/Ac2O/AcOH, reflux; (viii) column chromatography; (xi) NaOMe/MeOH, r.t.; then, strongly acidic resin (H＋ form).
Scheme 2 Formation of olefin 5Ea resulting from the elimination of 6a— 6c
Acids: (1) MsOH; (2) TfOH; (3) TFA; (4) BF3•Et2O; (5) CH2SO4.
The aryl bromides 6a—6c were treated with n-butyl
Scheme 3 Unsuccessful synthesis of tertiary chloride 5Ca
lithium at －78 ℃ to produce corresponding aryl lith-
iums, which were trapped in situ with pertrimethylsilyl-
glucolactone 2 to afford methyl 1-C-glucosides 7a—7c
after treatment of the adducts of 6a—6c and 2 with
MsOH/MeOH at room temperature. The methyl 1-C-
glucosides 7a—7c were reduced with Et3SiH/BF3•Et2O
to give rise to the 1-deoxylated products 8a—8c, which
individually consisted of two corresponding anomers.
Subsequently, 8a—8c were peracetylated by treatment
of 8a—8c with acetic anhydride at reflux in the presence
of anhydrous sodium acetate as catalyst to furnish the
corresponding 9a—9c, from which the pure β-anomers
Condtions: (1) SOCl2/CH2Cl2, r.t.; (2) PCl3/CH2Cl2, r.t.
10a—10c were separated and purified by column chro-
Chin. J. Chem. 2011, 29, 1192— 1198
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1197

Shi et al.
FULL PAPER
matography. Finally, the desired products 11a—11c
were generated by treatment of 10a—10c with sodium
methoxide in absolute methanol at room temperature
and subsequent neutralization with dried strongly acidic
resin (H＋ form).
P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.; Pullockaran,
A.; Hagan, D. L.; Morgan, N. N.; Taylor, J. R.; Obermeier,
M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.;
Robertson, J. M.; Wang, A.; Han, S.; Wetterau, J. R.; Jano-
vitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. J.
Med. Chem. 2008, 51, 1145.
Table 1 The Inhibition rates of blood glucose levels of com-
pounds 11a— 11c in OGTT
3
4
Link, J. T.; Sorensen, B. K. Tetrahedron Lett. 2000, 41,
9213.
Compound
Dapagliflozin
78
11a
11b
11c
Tsujihara, K.; Hongu, M.; Saito, K.; Inamasu, M.; Arakawa,
K.; Oku, A.; Matsumoto, M. Chem. Pharm. Bull. 1996, 44,
1174.
Inhibition rate/%
80
60
65
5
6
Katsuno, K.; Fujimori, Y.; Takemura, Y.; Hiratochi, M.;
Itoh, F.; Komatsy, Y.; Fujikura, H.; Isaji, M. J. Pharmacol.
Exp. Ther. 2007, 320, 323.
The antihyperglycemic activity of compounds 11a—
11c was evaluated in vivo with a mice oral glucose tol-
erance test (OGTT), and the inhibition rates of blood
glucose levels were summarized in Table 1. The positive
control Dapagliflozin was prepared according to known
procedures.2,14 As shown in Table 1, 11a—11c were all
comparable with the positive control Dapagliflozin in
terms of antihyperglycemic activity, with 11a being
slightly more potent than positive control Dapagliflozin
and 11b—11c were slightly less potent than Dapagli-
flozin. The potent antihyperglycemic activity exhibited
by these three compounds 11a—11c suggested that the
modification of the diphenylmethane functionality by
the gem-dimethyl group was favorable, and all these
three compounds were promising as the anti-diabetic
agent for the treatment of type 2 diabetes.
In summary, the designed gem-dimethyl-bearing
SGLT2 inhibitors based on Dapagliflozin were synthe-
sized by an exquisite synthetic route, and three obtained
compounds were evaluated by in vivo animal model
OGTT to reveal that addition of the gem-dimethyl func-
tionality was tolerated in terms of pharmacodynamics
since almost no hypoglycemic activity was lost on addi-
tion of the gem-dimethyl functionality.
Ellsworth, B. A.; Meng, M.; Patel, M.; Girotra, R. N.; Wu,
G.; Sher, P. M.; Hagan, D. L.; Obermeier, M. T.; Hum-
phreys, W. G.; Robertson, J. M.; Wang, A.; Han, S.; Wal-
dron, T. L.; Morgan, N. N.; Whaley, J. M.; Washburn, W. N.
Bioorg. Med. Chem. Lett. 2008, 18, 4770.
7
8
9
Ueta, K.; Ishihara, T.; Matsumoto, Y.; Oku, A.; Nawano, M.;
Fujita, T.; Saito, A.; Arakawa, K. Life Sci. 2005, 76, 2655.
Ueta, K.; Yoneda, H.; Oku, A.; Nishiyama, S.; Saito, A.;
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Oku, A.; Ueta, K.; Nawano, M.; Arakawa, K.; Kano-
Ishihara, T.; Matsumoto, M.; Saito, A.; Tsujihara, K.; Anai,
M.; Asano, T. Eur. J. Pharmacol. 2000, 391, 183.
10 Gao, Y. L.; Zhao, G. L.; Liu, W.; Wang, Y. L.; Xu, W. R.;
Wang, J. W. Chin. J. Chem. 2010, 28, 605.
11 Wang, Z. F.; Zhao, G. L.; Liu, W.; Wang, Y. L.; Shao, H.;
Xu, W. R.; Tian, L. J. Chin. J. Org. Chem. 2010, 30, 849 (in
Chinese).
12 Gao, Y. L.; Zhao, G. L.; Liu, W.; Shao, H.; Wang, Y. L.; Xu,
W. R.; Tang, L. D.; Wang, J. W. Indian J. Chem. 2010, 49B,
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13 Obermeier, M.; Yao, M.; Khanna, A.; Koplowitz, B.; Zhu,
M.; Li, W.; Komoroski, B.; Kasichayanula, S.; Discenza, L.;
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1198
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1192— 1198