Improved preparation of (1S,3′R,4′S,5′S,6′R)-5- chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro- 6′-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′, 4′,5′-triol

Article abstract of DOI:10.1016/j.cclet.2013.01.013

A convenient approach for the preparation of (1S,3′R,4′S, 5′S,6′R)-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′, 5′,6′-tetrahydro-6′-(hydroxymethyl)-spiro[isobenzofuran-1(3H), 2′-[2H]pyran]-3′,4′,5′-triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation.

Full text of DOI:10.1016/j.cclet.2013.01.013

Chinese Chemical Letters 24 (2013) 131–133
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Improved preparation of (1S,30R,40S,50S,60R)-5-chloro-6-[(4-ethylphenyl)methyl]-
30,40,50,60-tetrahydro-60-(hydroxymethyl)-spiro[isobenzofuran-1(3H),20-
[2H]pyran]-30,40,50-triol
*
Yong-Hai Liu, Ting-Ming Fu, Chun-Yan Ou, Wen-Ling Fan, Guo-Ping Peng
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
A R T I C L E I N F O
A B S T R A C T
A convenient approach for the preparation of (1S,30R,40S,50S,60R)-5-chloro-6-[(4-ethylphenyl)methyl]-
30,40,50,60-tetrahydro-60-(hydroxymethyl)-spiro[isobenzofuran-1(3H), 20-[2H]pyran]-30,40,50-triol is de-
veloped. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and
the isomers of undesired ortho-products were avoided during the preparation.
ß 2013 Guo-Ping Peng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Article history:
Received 9 November 2012
Received in revised form 23 November 2012
Accepted 3 December 2012
Available online 29 January 2013
Keywords:
Type 2 diabetes
Sodium glucose co-transporter 2
Inhibitor
Preparation
1. Introduction
dimethylbenzene with an unsatisfactory overall yield of 6%. The
synthetic sequence needed twelve steps and was not feasible for
Sodium glucose co-transporter 2 (SGLT2) plays a key role in
maintaining glucose equilibrium in the human body [1]. Much
attention has been given to SGLT2 as a molecular target to
directly enhance glucose excretion and to safely normalize plasma
glucose in the treatment of type 2 diabetes [2]. A promising subset of
SGLT2 inhibitors explored was the carbon glycosides in which the
bondbetweentheglucoseandaglyconeisa carbon–carbonbond[3].
It was reported that (1S,30R,40R,50S,60R)-5-chloro-6-[(4-ethylphe-
nyl)methyl]-30,40,50,60-tetrahydro-60-(hydroxymethyl)-spiro [iso-
benzofuran-1(3H),20-[2H]pyran]-30,40,50-triol 1 may be advancing
to clinical development to directly increase glucose excretion and to
safely normalize plasma glucose in the treatment of type 2 diabetes
[4–6]. Two synthetic routes have been used to synthesize 1. One
method is shown in Scheme 1. The key intermediate 16 was
prepared by a Fridel-Crafts reaction, but the selectivity for the para-
position over the ortho-position was low. In addition, compound 19
was synthesized by a coupling reaction between 18 and 20 in an
unsatisfactory yield and the synthetic route required eleven steps,
which was unsuitable for a large scale production [4,5]. The other
reported procedure was described by Sato Tsutomu et al. [6]. The
target compound was synthesized from 1-bromo-4-chloro-2,5-
industrial scale-ups.
2. Experimental
As shown in Scheme 2, a convenient synthetic route was
developed. Compound 3 was readily prepared by reacting N-
chlorosuccinimide (NCS) with the benzoic acid 2 in CCl4. Acid
3 was treated with SOCl2 in MeOH to afford ester 4. The
treatment of 4 with N-bromosuccimide (NBS) in the presence
of azodiisobutyronitrile (AIBN) in CCl4 gave 5. Compound 6
was produced in
coupling reaction between benzylic halide 5 and 4-ethylphe-
nylboronic acid. Ester 6 was treated with NaBH4 in THF to
a satisfactory yield by a Suzuki cross-
afford alcohol 7. The treatment of
chloride in THF gave silyl ether 8, which was transformed to
the -glucopyranoside 9 in an excellent yield. Compound 9
7 with trimethylsilyl
D
was hydrogenated under 0.1 MPa of hydrogen in the presence
of Pd/C at room temperature to produce 1 in about 39%
overall yield.
3. Results and discussion
Tetra-kis(triphenylphosphine)palladium (0) and palladium
acetate (II), as efficient Pd catalyst precursors, have been used in
the Suzuki coupling reactions that allow aryl halides or benzylic
* Corresponding author.
E-mail address: dreamlyh@sohu.com (G.-P. Peng).
1001-8417/$ – see front matter ß 2013 Guo-Ping Peng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.013

132
Y.-H. Liu et al. / Chinese Chemical Letters 24 (2013) 131–133
MeO2C
Br
Cl
MeO2C
Br
Cl
HO2C
Br
NH2
MeO2C
Br
NH2
d
HO2C
NH2
c
b
a
CO2H
3
14
13
12
MeO2C
11
Cl
O
MeO2C
Cl
Cl
MeO2C
Br
Cl
17
g
HO
f
h
e
Br
Br
Br
COCl
7
16
15
Cl
Cl
Cl
MOMO
O
O
MOMO
OH
i
j
O
k
HO
HO
TMSO
TMSO
Br
18
OH
OTMS
1
OH
19
OTMS
Scheme 1. Reagents and conditions: (a) NBS, DMF, 5 8C; (b) SOCl2, MeOH, reflux; (c) NaNO2, HCl, CuCl2, 1,4-dioxane, H2O, 0 8C; (d) KMnO4, t-BuOH, 18-crown-6, H2O, reflux;
(e) (COCl)2, DMF, DCM, r.t.; (f) AlCl3, ethylbenzene, DCM, ꢀ5 8C; (g) Et3SiH, CF3SO3H, TFA, reflux; (h) NaBH4, MeOH, THF, reflux; (i) MOMCl, DIPEA, DCM, r.t.; (j) n-BuLi, THF,
toluene, (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (20), ꢀ78 8C; (k) CH3SO3H, MeOH, r.t.
Br
Br
CO2Me
Br
Br
MeO C
Cl
Br
d
2
b
c
a
e
CO2Me
Cl
Cl
COOH
Cl
COOH
Br
Cl
5
3
6
2
4
Cl
O
O
Cl
Cl
O
O
TMSO
HO
BnO
HO
HO
g, h
f
i
Br
Br
BnO
OBn
OH
8
7
1
9
OBn
OH
Scheme 2. Reagents and conditions: (a) CCl4, NCS, 80 8C, 95%; (b) SOCl2, MeOH, reflux, 96%; (c) CCl4, NBS, AIBN, reflux, 76%; (d) toluene, Pd(OAc)2, PPh3, 4-ethylphenylboronic
acid, 80 8C, 4 h, 82%; (e) NaBH4, MeOH, THF, reflux, 96%; (f) THF, trimethylchlorosilane, r.t., 95%; (g) THF/toluene, (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-
tetrahydropyran-2-one (10), ꢀ78 8C; (h) THF/toluene, MeSO3H, r.t., 79% (two steps); (i) 10% Pd-C, MeOH, H2 (0.1 MPa), 25 8C, 96%.
halides to be effectively coupled with aryl boronic acids [7–9].
Therefore, a set of experiments were performed in order to
optimize the reaction conditions in the synthesis of 6. As shown in
Table 1, although both types of catalyst precursors gave the
expected coupling product, palladium acetate(II) in the presence of
triphenylphosphine using toluene as solvent at 80 8C and K3PO4 as
base was the most the effective system (Table 1, entry 4) [10]. The
reaction can be carried out with a low catalyst loading and under
mild conditions.
In addition, in order to study the solvent effect in the
deprotection reaction of the benzyl groups in 9, a series of
solvents were screened and the results are shown in Table 2. A
mixture of
1 and 1a were found when benzene, toluene,
chlorobenzene and 1,2-dichlorobenzene were used as solvents
in the deprotection reaction. However, when 20 equiv. of 1,2-
dichlorobenzene was added in the reaction mixture, by-product 1a
could not be detected by LC-MS (Table 2, entry 4) [11–13].
Mechanically, it is possible that the chloro-groups in 1,2-
Table 1
Pd-catalyzed Suzuki cross coupling reaction of 5 with phenylboronic acid.
Entry
Pd (mol%)
T (8C)
Time (h)
Yieldc (%)
1a
2a
3a
4a
5b
6b
7b
8b
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
25
10
10
10
4
11
81
82
82
45
72
61
56
80
80
80
50
48
48
48
24
Reflux
Reflux
Reflux
a
Reaction conditions: benzylic halide 5 (1 mmol), Pd(OAc)2 (1 mol% or 5 mol%), arylboronic acid (1.5 mmol), K3PO4 (2 mmol), Pd(OAc)2/PPh3 ratio = 2, toluene (5 cm3).
Reaction conditions: benzylic halide 5 (1 mmol), Pd(PPh3)4 (5 mol% or 10 mol%), arylboronic acid (1.5 mmol), Na2CO3(4 mmol) in dimethoxyethane (12 cm3).
Isolated yields.
b
c

Y.-H. Liu et al. / Chinese Chemical Letters 24 (2013) 131–133
133
Table 2
Synthesis of compound 1.
Cl
Cl
O
O
O
O
O
O
HO
BnO
HO
HO
H2/Pd
EtOAc/MeOH,12 h
+
HO
OH
BnO
OBn
OBn
OH
1a
1
9
OH
OH
Entry
1
Solvent
Equimolar amounts
Compound 1 yield (%)a
By-product 1a yield (%)a
Benzene
10
20
10
20
10
20
10
20
48
47
49
48
71
80
91
99
51
52
50
50
27
19
7
2
3
4
Toluene
Chlorobenzene
1,2-Dichlorobenzene
0
a
Determined by HPLC analysis of crude products before purification.
[10] Typical procedure for the synthesis of 6: To a solution of 4-ethylphenylboronic
acid (0.225 g, 1.5 mmol) in toluene (5 mL) was added Pd(OAc)2 (2.3 mg,
0.01 mmol) under an argon atmosphere, and PPh3 (1.5 mg, 0.005 mmol) and
K3PO4 (0.4 g, 2 mmol) were added sequentially. The mixture was stirred for
10 min at room temperature, and 5 (0.26 g, 1 mmol) was added. The reaction
mixture was stirred for 4 h at 80 8C under an argon atmosphere, cooled to room
temperature, and treated with water. The resultant mixture was extracted with
EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and
concentrated in vacuo to give yellow oil (0.3 g, 82%).
[11] Typical procedure for the synthesis of 9: To a stirred ꢀ78 8C solution of 8 (0.41 g,
1 mmol) in 1:2 anhydrous THF/toluene (10 mL) was slowly added n-BuLi (1 mL,
1.1 mol/L in hexane) to maintain the temperature below ꢀ70 8C. After stirring for
30 min, this solution was added to a stirred solution of (3R,4S,5R,6R)-3,4,5-
dichlorobenzene can be reduced to produce hydrochloride, which
might inhibit the reduction of the chloro-group in 1.
4. Conclusion
In conclusion, a more efficient synthetic route for the synthesis
1 was developed. The overall yield of the sequence was about 39%
and the undesired ortho-products in the coupling reaction between
the two aryl pieces in the previous reports were avoided using the
current method.
tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-pyran-2-one
10
(0.64 g,
1.2 mmol) in toluene (5 mL) to maintain the temperature below ꢀ65 8C, then
the solution was stirred for 5 h at ꢀ78 8C, and the reaction was quenched by a
solution of methanesulfonic acid (214 mg, 2.2 mmol) in THF (5 mL). The mixture
was stirred for 24 h at room temperature and quenched with saturated NaHCO3.
The mixture was extracted with EtOAc, washed with water and brine, dried over
anhydrous sodium sulfate and concentrated in vacuo to give oil, which was
purified by silicon column chromatography to get a colorless oil (0.62 g, 79%).
Rf = 0.35 (petroleum ether/EtOAc, 8:1, v/v).
Acknowledgments
This work was financially supported by the Open Project
Program of National First-Class Key Discipline for Traditional
Chinese Medicine of Nanjing University of Chinese Medicine, a
Project Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions, PAPD (ysxk-2010).
[12] Typical procedure for the synthesis of 1: To a solution of 9 (2.6 g, 3.33 mmol) in
2:3 EtOAc/MeOH (30 mL), 0.25 g palladium on carbon and 1,2-dichlorobenzene
(10 mL) was added sequentially. The air of the reactor was removed by argon,
then the 0.1 MPa H2 was applied for 12 h at 25 8C. The solvent was filtrated, the
filter cake was washed by EtOAc, and the filtrate was concentrated in vacuo to
give oil. The oil was purified by silicon column chromatography to get a glassy off
white solid (1.35 g, 96%). Rf = 0.35 (MeOH/EtOAc, 1:5, v/v).
References
[1] D. Mathis, L. Vence, C. Benoist, beta-Cell death during progression to diabetes,
Nature 414 (2001) 792–798.
[13] Selected data compounds: 6: 1H NMR: (300 MHz, CDCl3): d 7.96 (s, 1H), 7.54 (s,
1H), 7.32 (d, 2H, J = 7.8 Hz), 7.11 (d, 2H, J = 7.8 Hz), 4.11 (s, 2H), 3.82 (s, 3H), 2.74
(q, 2H, J = 7.8 Hz), 1.26 (t, 3H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3): d 168.9,
150.3, 142.4, 138.9, 134.6, 133.6, 132.8, 130.9, 129.5, 128.7, 121.7, 53.5, 36.3, 28.5,
14.7; MS: m/z 366 [M+]; 389 [M++Na+]; Anal. Calcd. for C17H16BrClO2: C 55.53, H
4.39; Found: C 55.49, H 4.41; 9 1H NMR (300 MHz, CDCl3): d 7.52 (d, 1H,
J = 1.5 Hz), 7.38–7.42 (m, 6H), 7.29–7.32 (m, 9H), 7.17–7.21 (m, 4H), 7.11 (d,
4H, J = 1.2 Hz), 7.08 (d, 2H, J = 8.4 Hz), 4.88–4.96 (m, 3H), 4.72 (S, 2H), 4.56–4.67
(m, 3H), 4.46 (d, 1H, J = 10.8 Hz), 4.16–4.22 (m, 2H), 3.88 (d, 1H, J = 8.4 Hz), 3.82 (s,
1H), 3.66–3.77 (m, 4H), 3.36 (d, 1H, J = 9.6 Hz), 2.60 (q, 2H, J = 7.6 Hz), 1.24 (t, 3H,
J = 7.6 Hz); 13C NMR (100 MHz, CH3OD): d 139.8, 138.6, 137.6, 130.5, 129.5, 129.1,
129.0, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.4, 101.2, 85.6,
84.9, 79.8, 78.9, 78.5, 77.5, 76.4, 75.6, 74.9, 73.6, 70.2, 62.7, 39.4, 28.8, 16.0; MS: m/
z 780 [M+]; 803 [M++Na+]; Anal. Calcd. for C50H49ClO6: C 76.86, H 6.32; Found: C
76.47, H 6.43; 1: 1H NMR (300 MHz, CH3OD): d 1.19 (t, 3H, J = 7.5 Hz), 2.57 (q, 2H,
J = 7.5, 7.8 Hz), 3.41–3.47 (1H, m), 3.64 (dd, 1H, J = 6 Hz), 3.73–3.83 (m, 4H), 3.95
(s, 2H), 5.11 (dd, 2H, J = 7.8, 12.3 Hz), 7.06–7.12 (m, 4H), 7.16–7.23 (m, 3H); 13C
NMR (100 MHz, CH3OD): d 143.3, 142.8, 140.8, 139.7, 138.2, 131.6, 130.8, 129.6,
128.8, 127.8, 125.6, 83.6, 77.2, 72.6, 71.4, 66.1, 62.7, 36.8, 28.6, 15.6; MS: m/z 420
[M+]; 443 [M++Na+]; Anal. Calcd. for C22H25ClO6: C 62.78, H 5.99; Found: C 62.71,
H 6.02.
[2] T. Asano, T. Ogihara, H. Katagiri, Glucose transporter and Na+/glucose cotran-
sporter as molecular targets of anti-diabetic drugs, Curr. Med. Chem. 11 (2004)
2717–2724.
[3] J.R.L. Ehrenkranz, N.G. Lewis, C.R. Kahn, J. Roth, Phlorizin: a review, Diabetes
Metab. Res. Rev. 21 (2005) 31–38.
[4] L. Binhua, X. Baihua, Exploration of O-spiroketal C-arylglucosides as novel and
selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors,
Bioorg. Med. Chem. Lett. 19 (2009) 6877–6881.
[5] L. Binhua, X. Baihua, ortho-Substituted C-aryl glucosides as highly potent and
selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors,
Bioorg. Med. Chem. Lett. 18 (2010) 4422–4432.
[6] S. Tsutomu, H. Kiyofumi, et al., EU Patent, EP 2048153A1, 2009.
[7] L. Sandrine, A. Mohamed, Selective double Suzuki cross-coupling reactions.
Synthesis of unsymmetrical diaryl (or heteroaryl) methanes, Tetrahedron Lett.
44 (2003) 9255–9258.
[8] C. Sultan, E.G. Paris, Palladium catalyzed cross-coupling between phenyl or
naphthylboronic acids and benzylic bromides, Tetrahedron Lett. 40 (1999)
7599–7603.
[9] M.N. Sabrina, L.M. Adriano, Synthesis of diarylmethane derivatives from Pd-
catalyzed cross-coupling reactions of benzylic halides with arylboronic acids,
Tetrahedron Lett. 45 (2004) 8225–8228.