Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2010.02.024

Several syntheses of C-5-spirocycle-containing C-glycosides are discussed. A multigram-scale synthesis capitalizing on a one-pot aldol-Cannizzaro sequence is described. Spiro oxetane formation using an unprotected penta-ol C-glycoside as substrate is also exemplified. Functional assessment of these compounds for potency and selectivity was evaluated at human SGLT2 and SGLT1.

Full text of DOI:10.1016/j.tetlet.2010.02.024

Tetrahedron Letters 51 (2010) 1880–1883
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors
*
Vincent Mascitti , Ralph P. Robinson, Cathy Préville, Benjamin A. Thuma, Christopher L. Carr,
Matthew R. Reese, Robert J. Maguire, Michael T. Leininger, André Lowe, Claire M. Steppan
CVMED Medicinal Chemistry, Pfizer Global Research & Development, Groton Laboratories, Eastern Point Rd, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several syntheses of C-5-spirocycle-containing C-glycosides are discussed. A multigram-scale synthesis
capitalizing on a one-pot aldol-Cannizzaro sequence is described. Spiro oxetane formation using an
unprotected penta-ol C-glycoside as substrate is also exemplified. Functional assessment of these com-
pounds for potency and selectivity was evaluated at human SGLT2 and SGLT1.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 7 January 2010
Revised 2 February 2010
Accepted 4 February 2010
Available online 10 February 2010
Sodium glucose transporter of type 2 (SGLT2) is a low affinity
high capacity Na+/glucose cotransporter of glucose which is found
in the S1 domain of the proximal tubules in the kidney and is
responsible for the transport of ꢀ90% of the glucose in the urine
back to the bloodstream.1 SGLT2 inhibitors should theoretically
promote weight loss and control hyperglycemia in a glucose-
dependent yet insulin-independent manner, thereby making such
therapeutic agents very compelling complements to the current
arsenal of anti-diabetic agents.2
in the pharmaceutical industry over the past few years. These ef-
forts produced several clinical candidates from two distinct series:
O-aryl glycosides (e.g., remogliflozin6 2) and C-aryl glycosides (e.g.,
dapagliflozin7 3). SGLT2 inhibitors such as 4, containing a spiro ring
at the C-1 position of the pyranose (carbohydrate nomenclature)
have also been reported.8
a)
HO
X
Ar
Ar
Ar
O
3
O
O
HO
The early discovery that natural product phlorizin3 (1, Fig. 1) in-
duced glucosuria in humans4 combined with the more recent full
characterization5 of SGLT2 triggered numerous research programs
HO
HO
5
1
HO
OH
PGO
OPG
OH
OH
OPG
OH
5
8
6
Y
Z
O
HO
O
OH
O
OH
Ar =
N
N
8
6
5
5a
X
Y
Z
O
O O
HO
HO
HO
HO
O
Me OMe 8a (PG = Bn)
6a
OH
OH
OH
1
OH
5b
8b (PG = Bn)
8b (PG = Bn)
8b (PG = Bn)
O
Me
Et
Et
6b
6b
6b
2
5c SO2 Me
O
5d
5e
5f
NH Me
Et
Cl
Cl
O
OMe
O
O
Cl
Cl
8e (PG = PMB) 6e
8f (PG = PMB)
O
HO
HO
OEt
6f
O
OH
HO
HO
O
OH
b)
O
OH
3
aq. NaOH,
CH2O
OH
OH
O
HO
HO
4
O
Ar
Ar
Ar
O
O
Figure 1. Structures of some SGLT2 inhibitors.
PGO
PGO
PGO
* Corresponding author. Tel.: +1 860 686 3455.
Figure 2. (a) C-5-spirocyclic C-glycosides as SGLT2 inhibitors and (b) aldol-
E-mail address: vincent.mascitti@pfizer.com (V. Mascitti).
Cannizzaro one-pot sequence.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.024

V. Mascitti et al. / Tetrahedron Letters 51 (2010) 1880–1883
1881
O
O
HO
O
O
a, b, c
HO
BnO
HO
f
d, e
6a
OBn
OBn
BnO
OBn
OBn
7
8a
O
O
O
HO
p-TsO
O
g
O
O
O
O
BnO
OBn
OBn
BnO
OBn
HO
OH
OBn
OH
9
10
5a
Scheme 1. Multigram-scale synthesis of spiro oxetane C-glycoside 5a. Reagents and conditions: (a) PhCH(OMe)2 (1.3 equiv), p-TsOH (cat.), DMF, 60 °C; (b) BnBr (3 equiv),
NaH (3 equiv), DMF, 0–23 °C (82%, 2 steps); (c) LiAlH4 (5 equiv), AlCl3 (4 equiv), Et2O/CH2Cl2, reflux (90%); (d) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 to ꢁ20 °C; (e) NaOH
(1.5 equiv), H2CO (xs), H2O/1,4-dioxane, 23 °C (45%, two steps); (f) n-BuLi (1 equiv), then p-TsCl, then n-BuLi (another 1 equiv), THF, 0–65 °C (65%); (g) Pd black (3 equiv),
HCO2H (80 equiv), EtOH/THF, 23 °C (95%).
Cl
O
Cl
O
HO
HO
O
O
O
a, b, c, d, e
f, g
6e
PMBO
OPMB
HO
OH
OPMB
OH
8e
5e
Scheme 2. Synthesis of spiro oxetane C-glycoside 5e. Reagents and conditions: (a) Ph3CCl (2 equiv), pyridine (2.5 equiv), DMF, 0–23 °C (97%); (b) PMBBr (3.2 equiv), NaH
(5 equiv), DMF, 10–50 °C (29%); (c) BF3–OEt2 (0.9 equiv), CH3OH/CH2Cl2, 0 °C (86%); (d) Dess–Martin periodinane (2 equiv), CH2Cl2, 23 °C (89%); (e) NaOH (2 equiv), H2CO
(20 equiv), i-PrOH/1,4-dioxane (2/1 vol.), 23 °C (48%); (f) n-BuLi (1 equiv), then p-TsCl, then n-BuLi (another 1 equiv), THF, 0–65 °C (70%); (g) TFA (30 equiv), anisole (5 equiv),
CH2Cl2, 23 °C (83%).
We sought novel SGLT2 inhibitors of general structure 5 bearing
a, b, c, d
e, f, g
5c
a spirocyclic ring at the C-5 position (carbohydrate nomenclature)
of the pyranose ring (Fig. 2a). To the best of our knowledge this
constitutes the first example of SGLT2 inhibitors possessing such
a structure.9 Logical precursors to these targets were diols of gen-
eral structure 8 which could be accessed via a one-pot aldol-Can-
nizzaro sequence10 to forge the required tetrasubstituted carbon
in C-5 (Fig. 2b).11
HO
HO
O
BnO
OBn
OBn
5d
8b
Scheme 3. Synthesis of spiro dioxathietane 5c and spiro azetidine 5d. Reagents and
conditions: (a) MsCl (2.6 equiv), Et3N (3 equiv), CH2Cl2, ꢁ30 to ꢁ5 °C; (b) Na2S
(1 equiv), DMF/H2O, 200 °C (21%, 2 steps); (c) m-CPBA (40 equiv), CHCl3, 23 °C
(98%); (d) Pd(OH)2 (0.75 equiv), H2 (50 psi), EtOH, 23 °C (74%); (e) Tf2O (5 equiv),
pyridine (30 equiv), CH2Cl2, ꢁ20 °C; (f) i-Pr2NEt (3 equiv), BnNH2 (xs), 80 °C (75%);
(g) Pd black (7 equiv), HCO2H (xs), EtOH/THF (2/1 vol.), 23 °C (63%).
The multigram-scale synthesis of compound 5a that was used
to supply early in vivo toleration studies in rodents is shown in
Scheme 1. Regioselective protection of 6a by benzylidene masking
the C-4 and C-6 hydroxyl groups was carried out under classical
conditions using benzaldehyde dimethylacetal in the presence of
a catalytic amount of para-toluenesulfonic acid. Subsequent pro-
tection of the remaining secondary C-2 and C-3 hydroxyl groups,
followed by regioselective opening of the benzylidene acetal using
the sterically demanding AlCl3/LiAlH4 reagent12 led to intermedi-
ate 7 (74% yield over three steps). So revealed, the C-6 carbinol
was oxidized under Swern conditions13 to the corresponding alde-
hyde. Subsequent aldol-Cannizzaro reaction with formaldehyde
produced advanced intermediate 8a (45% yield over two steps14).
This intermediate was then converted to the mono-tosylate inter-
mediate 9 by treatment of the diol with 1 equiv of n-BuLi in THF
followed by the addition of 1 equiv of para-toluenesulfonyl chlo-
ride; upon treatment with an additional equivalent of base and
warming at 65 °C, oxetane 10 was formed cleanly in 65% yield.15
Hydrogenolysis of the benzyl protective groups proceeded che-
moselectively to produce the desired final product 5a as a solid
in 95% yield.16 By this route, multigram quantities of compound
5a could be produced; only three chromatographic purifications
were required (intermediates 8a, 10, and final product 5a were
purified by flash chromatography over silica gel).
the secondary hydroxyl groups were protected with p-methoxy-
benzyl groups (PMB). PMB deprotection using trifluoroacetic acid
required the addition of anisole as a PMB cation scavenger to
obtain the final products in both high yield and purity.20
Having developed a robust synthesis of advanced intermediates
of general structure 8, we next explored the synthesis of the C-5
spirodioxathietane and azetidine (Scheme 3).21 Treatment of inter-
mediate 8b with methanesulfonyl chloride in the presence of tri-
ethylamine led to the corresponding bis-mesylate. Reacting the
crude bis-mesylate with sodium sulfide under relatively harsh con-
ditions (200 °C, microwave reactor, 30 min) provided the corre-
sponding thietane (21% yield over two steps). m-CPBA oxidation
of the sulfide followed by hydrogenolysis cleanly produced the de-
sired product 5c in 73% yield over two steps.22 Formation of the
corresponding bis-triflate of 8b under standard conditions fol-
lowed by treatment of this intermediate with an excess of benzyl
amine at 80 °C gave the benzyl-protected azetidine (75% yield over
two steps). Hydrogenolysis of the benzyl protective groups gave 5d
(63% yield).23
Compound 5b17 was synthesized following the same synthetic
path whereas compounds such as 5e18 and 5f19, having an aryl
chloride side chain, required a slightly different protective group
strategy to avoid any potential problem of chemoselectivity in
the final hydrogenolysis step (Scheme 2). For these derivatives,
Inspired by the developments in the field of glycosylation
chemistry using unprotected glycosyl donors24 and regioselective
functionalization of monoprotected carbohydrates25, we also ex-
plored the feasibility of synthesizing the oxetane motif found in
5a starting from an unprotected penta alcohol intermediate such

1882
V. Mascitti et al. / Tetrahedron Letters 51 (2010) 1880–1883
HO
p-TsO
Acknowledgments
HO
HO
c
a
b
O
Ar
O
Ar
8a
5a
We thank Dr. D. A. Price, Dr. J. W. Coe, and Dr. B. D. Stevens for
reviewing this manuscript.
HO
OH
HO
OH
OH
12
OH
11
d
e, f
HO
p-TsO
HO
p-TsO
and/or
References and notes
O
Ar
O
O
Ar
OH
1. Kanai, Y.; Lee, W. S.; You, G.; Brown, D.; Hediger, M. A. J. Clin. Invest. 1994, 93,
397. SGLT1 is a high affinity low capacity Na+/glucose cotransporter found
primarily in the gut and to a smaller extent in the liver, the lungs, and in the S3
domain of the kidneys.
O
O
HO
O
O
O
O
O
2. Idris, I.; Donnelly, R. Diabetes Obes. Metab. 2009, 11, 79.
O
3. Phlorizin is a weak and non-specific SGLT inhibitor. For a recent review see:
Ehrenkranz, J. R. L.; Lewis, N. G.; Kahn, C. R.; Roth, J. Diabetes Metab. Res. Rev.
2005, 21, 31.
Ar =
4. Chassis, H.; Joliffe, N.; Smith, H. W. J. Clin. Invest. 1933, 12, 1083.
5. See Ref. 1; for characterization of the high affinity Na+/glucose cotransporter
SGLT1 see also: Lee, W. S.; Kanai, Y.; Wells, R. G.; Hediger, M. A. J. Biol. Chem.
1994, 269, 12032.
6. Fujimori, Y.; Katsuno, K.; Nakashima, I.; Ishikawa-Takemura, Y.; Fujikura, H.;
Isaji, M. J. Pharmacol. Exp. Ther. 2008, 327, 268.
Scheme 4. Synthesis of 5a from an unprotected C-glycoside derivative. Reagents
and conditions: (a) Pd black (3 equiv), HCO2H (30 equiv), EtOH/THF, 23 °C (97%); (b)
p-TsCl (1.1 equiv), pyridine, 0–23 °C (57%, br sm); (c) NaHMDS (3 equiv), THF, 0–
23 °C (15%); (d) 2,3-butadione, MeC(OMe)3, BF3–OEt2, MeOH, 60 °C; (e) NaHMDS
(2 equiv), THF, 0–23 °C; (f) TFA, H2O, 23 °C (15%, three steps).
7. Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.;
Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.;
Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.;
Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.;
Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. J. Med.
Chem. 2008, 51, 1145.
Table 1
Functional IC50s against human SGLT2 and SGLT1
8. (a) Sato, T.; Honda, K.; Kawai, T.; Ahn, K. H., Patent application WO 013280,
2008.; (b) See also Chen, Y.; Feng, Y.; Xu, B.; Lv, B.; Dong, J.; Seed, B.; Hadd, M. J.
US Patent application 0275907, 2007.; (c) Xu, B.; Lv, B.; Feng, Y.; Xu, G.; Du, J.;
Welihinda, A.; Sheng, Z.; Seed, B.; Chen, Y. Bioorg. Med. Chem. Lett. 2009, 19,
5632.
9. Detailed reviews on SGLT2 inhibitors have recently appeared: (a) Washburn,
W. N. J. Med. Chem. 2009, 52, 1785; (b) Washburn, W. N. Expert Opin. Ther.
Patents 2009, 19, 1485.
10. Schaffer, R. J. Am. Chem. Soc. 1959, 81, 5452; See also Amigues, E. J.; Greenberg,
M. L.; Ju, S.; Chen, Y.; Migaud, M. E. Tetrahedron 2007, 63, 10042.
11. Compounds 6a, 6b, 6e, and 6f were prepared as described in the literature
via addition of the appropriately substituted 3-benzylphenyllithium to
Y
Z
X
O
3
5
1
HO
OH
OH
5
5
X
Y
Z
SGLT2 IC50 (nM)
SGLT1 IC50 (nM)
5a
5b
5c
5d
5e
5f
O
O
SO2
NH
O
Me
Me
Me
Me
Cl
OMe
Et
6.6 2.5 (8)
3.4 0.8 (3)
14 (1)
5100 (1)
23 22 (5)
32 79 (5)
1540 180 (7)
1500 (2)
>10,000 (1)
>10,000 (1)
>9600 (5)
Et
Et
2,3,4,6-tetra-O-trimethylsilyl-b-
D-gluconolactone; see for instance Ref. 7.
Interestingly, nucleophilic additions onto an adequately protected form of
gluconolactone using organometallic species derived from 1,3-dithiane-
containing aryl bromides of the kind below led to moderate yields of the
corresponding methyl ketal intermediate:
OMe
OEt
O
Cl
5600 930 (4)
Y
Z
Z
as 11 (obtained in 97% yield by hydrogenolysis of 8a; Scheme 4).
When reacted with 1 equiv of p-TsCl, 11 provided 12 as a 2/1
mixture of primary mono-tosylates (57% yield based on recovered
starting material). Treatment of this mixture of tosylates with
3 equiv of NaHMDS in THF from 0 to 23 °C gave 5a, albeit in a
modest 15% yield, after purification by flash chromatography over
silica gel. Although the other products from this reaction were
not identified, we hypothesize that these were byproducts arising
from the intramolecular attack of the pendent C-3 and/or C-4 sec-
ondary hydroxyl groups on the primary tosylate. Unfortunately,
masking these hydroxyls and locking the pyranose ring in a rigid
trans-decaline-type conformation did not improve the overall
yield of the sequence (15% overall yield, Scheme 4).
Functional assessment of these compounds for potency and
selectivity was evaluated at human SGLT2 and SGLT1 (Table 1).26
Despite the loss of an H-bond-donating group at C-5, compounds
5a, 5b, 5c, 5e, and 5f proved to be potent and very selective SGLT2
inhibitors. On the other hand, azetidine 5d, which is likely proton-
ated at physiological pH, showed a marked decrease in potency
indicating that a positively charged group may not be tolerated
in this region of the molecule.27
Br
Y
S
S
S
S
O
O
O
TMSO
TMSO
HO
O
OH
OTMS
OTMS
HO
OH
.
12. Lipták, A.; Jodál, I.; Nánási, P. Carbohydr. Res. 1975, 44, 1.
13. Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
14. A typical procedure is described below:
To a solution of oxalyl chloride (2 mL, 20 mmol) in dichloromethane (60 mL) at
ꢁ78 °C was added dimethylsulfoxide (3.4 mL, 48 mmol). The resulting solution
was stirred at ꢁ78 °C for 30 min.
A solution of 7 (5.11 g, 7.92 mmol) in
dichloromethane (40 mL) was then added drop-wise. The resulting mixture
was stirred for 30 min allowing the temperature to rise to ꢁ60 °C.
Triethylamine (10 mL, 72 mmol) was added and the mixture was allowed to
warm to ꢁ20 °C over 1 h. The reaction was quenched by the addition of
aqueous saturated ammonium chloride solution. The organic phase was dried
over magnesium sulfate, filtered, and concentrated. The crude aldehyde was
then dissolved in dioxane (80 mL), and 37 wt % aqueous formaldehyde (12 mL)
followed by aqueous 1 M sodium hydroxide (12 mL) was added . The resulting
mixture was stirred at room temperature for 4 days. The mixture was
neutralized by the addition of aqueous 1 M hydrogen chloride solution and
was extracted with ethyl acetate. The organic phase was separated, dried over
magnesium sulfate, filtered, and concentrated. The residue was purified by
flash chromatography over silica gel eluting with a gradient of 20–40% ethyl
acetate/heptane to afford the intermediate 8a (2.41 g, 45%). MS: 675 (M+H+;
positive mode). 1H NMR (400 MHz, chloroform-d) d ppm 1.98 (dd, J = 10.0,
4.1 Hz, 1H), 2.24–2.27 (m, 1H), 2.28 (s, 3H), 3.51–3.59 (m, 1H), 3.70–3.78 (m,
1H), 3.77 (s, 3H), 3.80–4.02 (m, 6H), 4.07 (d, J = 4.3 Hz, 2H), 4.39 (d, J = 10.5 Hz,
1H), 4.53 (d, J = 9.8 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.87 (d, 1H), 4.96 (d,
J = 10.9 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.87–7.05 (m, 4H), 7.17–7.38 (m, 16H).
15. For oxetane synthesis see: Picard, P.; Leclercq, D.; Bats, J.-P.; Moulines, J.
Synthesis 1981, 550.
In conclusion, we have described several routes to access SGLT2
inhibitors bearing various spirocyclic rings at the C-5 position of
the pyranose. Most notably, a multigram-scale synthesis of potent
and selective SGLT2 inhibitor 5a, capitalizing on a one-pot aldol-
Cannizzaro sequence, was developed. We have also demonstrated
spiro oxetane formation using a fully unprotected penta-ol C-gly-
coside intermediate as substrate.

V. Mascitti et al. / Tetrahedron Letters 51 (2010) 1880–1883
1883
16. Compound 5a: MS: 431 (M þ HCOꢁ2 ; negative mode). 1H NMR (400 MHz,
methanol-d4) d ppm 2.19 (s, 3H), 3.25–3.38 (m, 3H), 3.74 (s, 3H), 3.92 (s,
2H), 4.04 (d, J = 8.8 Hz, 1H), 4.49 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.4 Hz, 1H),
4.82 (d, J = 6.6 Hz, 1H), 4.93 (d, J = 6.6 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.03
(d, J = 8.8 Hz, 2H), 7.11–7.19 (m, 3H).
J = 13.6 Hz), 4.46 (d, 1H, J = 14 Hz), 4.20 (dd, 1H, J = 13.6 and 4.8 Hz), 4.15 (d,
1H, J = 9.6 Hz), 4.03 (dd, 1H, J = 14 and 4.8 Hz), 3.96 (s, 2H), 3.53 (d, 1H,
J = 9.6 Hz), 3.41 (t, 1H, J = 9.2 Hz), 3.23 (t, 1H, J = 9.2 Hz), 2.58 (q, 2H, J = 7.6 Hz),
2.19 (s, 3H), 1.17 (t, 3H, J = 7 Hz).
23. Compound 5d: MS: 384.3 (M+H+). 1H NMR (400 MHz, methanol-d4) d ppm 8.43
(s, 1H), 7.19–6.99 (m, 7H), 4.37 (d, 1H, J = 11.0 Hz), 4.28 (d, 1H, J = 11.1 Hz),
4.12–4.06 (m, 2H), 3.99–3.91 (m, 3H), 3.48–3.33 (m, 3H), 2.58 (q, 2H,
J = 7.6 Hz), 2.20 (s, 3H), 1.19 (t, 3H, J = 7.6 Hz).
17. Compound 5b: MS: 429.2 (M+HCO2ꢁ; negative mode). 1H NMR (400 MHz,
methanol-d4) d ppm 7.16–6.96 (m, 7H), 4.89 (d, 1H, J = 6.8 Hz), 4.79 (d, 1H,
J = 6.8 Hz), 4.59 (d, 1H, J = 6.4 Hz), 4.45 (d, 1H, J = 7.2 Hz), 4.00 (d, 1H,
J = 9.6 Hz), 3.92 (s, 2H), 3.36–3.20 (m, 3H), 2.54 (q, 2H, J = 7.6 Hz), 2.16 (s,
24. Hanessian, S. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; pp 389–412. Chapter 17; (b) Hanessian, S.; Lu, P.-P.;
Ishida, H. J. Am. Chem. Soc. 1998, 120, 13296; (c) Hanessian, S.; Lou, B. Chem.
Rev. 2000, 100, 4443; (d) Hanessian, S.; Mascitti, V.; Lu, P.-P.; Ishida, H.
Synthesis 2002, 1959.
3H), 1.15 (t, 3H, J = 7.6 Hz).
18. Compound 5e: MS: 451 (M+HCO2
;
negative mode). 1H NMR (400 MHz,
ꢁ
methanol-d4): d ppm 3.20–3.28 (m, 2H), 3.34–3.38 (m, 1H), 3.75 (s, 3H), 3.99–
4.08 (m, 3H), 4.48 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 4.82 (d, J = 6.8 Hz,
1H), 4.92 (d, J = 6.8 Hz, 1H), 6.79–6.84 (m, 2H), 7.09–7.11 (m, 2H), 7.23–7.29
25. Moitessier, N.; Englebienne, P.; Chapleur, Y. Tetrahedron 2005, 61, 6839. and
references cited therein.
(m, 2H), 7.36 (d, J = 8.1 Hz, 1H).
19. Compound 5f: MS: 465 (M+HCO2
ꢁ
;
negative mode). 1H NMR (400 MHz,
26. IC50 values were obtained by measuring the inhibition of sodium-dependent
methanol-d4) d ppm 1.35 (t, J = 7.0 Hz, 3H), 3.20–3.34 (m, 3H), 3.92–4.09 (m,
5H), 4.48 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.6 Hz, 1H), 4.82 (d, J = 6.6 Hz, 1H), 4.92
(d, J = 6.8 Hz, 1H), 6.76–6.86 (m, 2H), 7.02–7.13 (m, 2H), 7.21–7.30 (m, 2H),
7.36 (d, J = 8.2 Hz, 1H).
methyl-a-D
-[U-14C]glucopyranoside (AMG) uptake in CHO cells stably
expressing human SGLT1 or 2; Han, S.; Hagan, D. L.; Taylor, J. R.; Xin, L.;
Meng, W.; Biller, S. A.; Wetterau, J. R.; Washburn, W. N.; Whaley, J. M. Diabetes
2008, 57, 1723–1729.
20. Anisole avoids the unwanted formation of side products arising from Friedel–
Craft-type reactions between the PMB cation and the electron-rich aryl ring of
the substrate.
27. For a broader discussion of the structure activity relationship around the
carbohydrate motif of SGLT2 inhibitors see: Robinson, R. P.; Mascitti, V.;
Boustany-Kari, C. M.; Carr, C. L.; Foley, P. M.; Kimoto, E.; Leininger, M. T.; Lowe,
A.; Klenotic, M. K.; MacDonald, J. I.; Maguire, R. J.; Masterson, V. M.; Maurer, T.
S.; Miao, Z.; Patel, J. D.; Préville, C.; Reese, M. R.; She, L.; Steppan, C. M.; Thuma,
B. A.; Zhu, T. Bioorg. Med. Chem. Lett. 2010, doi:10.1016/j.bmcl.2010.01.075.
21. For the synthesis of spiro nucleosides see: Roy, A.; Achari, B.; Mandal, S. B.
Tetrahedron Lett. 2006, 47, 3875.
22. Compound 5c: MS: 450 (M+NH4þ; positive mode); 477 (M+HCO2ꢁ; negative
mode). 1H NMR (400 MHz, methanol-d4) d ppm 7.22–6.99 (m, 7H), 4.55 (d, 1H,