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G. Xu et al. / Tetrahedron Letters 57 (2016) 4684–4687
13C6
HO
HO
13C6
TMSO
TMSO
n-butyllithium (n-BuLi) at À78 °C for 30 min, and the resulted mix-
ture was reacted with protected sugar 13a to give crude lactol 15a
which was directly used for the next step without purification.
Finally, the compound 15a was treated with methanol (MeOH) in
the presence of hydrochloric acid (HCl) to generate desilylated
O
O
O
O
b
a
OH
OTMS
OTMS
OH
D-gluconolactone-[13C6]
13b
Cl
O
O
Cl
O
O
Me
O
methyl b-lactol 16a (the ratio of b/
a was from 20/1 to 30/1) in
13C6
HO
HO
13C6
HO
O
80% overall yield.20
c
O
In general, C-aryl SGLT2 inhibitors belong to b-C-glycosides
because of the poor bioactivities of -C-glycosides. Hence, we
HO
OH
OH
a
OH
OH
16b
7b
7b
turned our attention to investigate the construction of the C-aryl
glycoside 7a by the stereoselective reduction. Generally, the
diastereoselectivity of Lewis acid mediated silane reductions of
O-unprotected glycopyranosides to b-C-glycosides varies from
moderate to high.21 A survey of different conditions was examined,
(crude)
(pure)
d
Scheme 2. Reagents and conditions: (a) TMSCl, N-methylmorpholine, À10 °C-room
temperature, 93%; (b) (1) 14, n-BuLi, toluene, THF, À65 °C to À50 °C, (2) H2O–
MeOH–THF, HCl, 20–25 °C, 80% overall yield; (c) Et3SiH/BF3ÁOEt2, MeCN, DCM, À25
i
as summarized in Table 1. When the reaction was treated with -
to À20 °C, 92%; (d) (1)
L-proline, 95% ethanol–heptane, 80–10 °C, 83%; (2)
methanol–water, 65–10 °C, 93%.
Pr3SiH and TMDS (1,1,3,3-Tetramethyldisilazane) in the presence
of TFA, the stereoselectivity of product 7a was low. In order to
obtain the optically pure 7a, several Lewis acids were also
screened, and the results showed that TMSOTf, In(OTf)3, Cu(OTf)2,
and AlCl3 effectively prompted the stereoselectivity of product 7a
(Table 1, entries 1, 4–6) when Et3SiH was used as the hydride
The relative configurations of the product 7a was unambigu-
ously assigned as (2S, 3R, 4R, 5S, 6R)-form by X-ray crystallographic
analysis of compound 7a (Fig. 3).24 Single crystals of bexagliflozin
7a suitable for X-ray analysis were grown from methanol and
water. The structure of bexagliflozin was further confirmed by
spectroscopic data of 1H and 13C NMR.
Although the 7a was easily purified by flash chromatography on
silica gel, the crude 7a was not easy by crystallization. To obtain
the pure compound 7a, the cocrystallization skill was examined.25
After trying several times, we found that compound 7a could easily
donor.22 It is worth mentioning that when TMSOTf, AlCl3,23 and
21a
BF3ÁOEt2
in the absence of TFA was tried, the desired product
7a was obtained with high stereoselectivity (dr up to 99:1) in good
yields (68–88%) (Table 1, entries 7–9). Especially, the reaction with
AlCl3 (entry 8) was much less sensitive to water content, and it
could be run at a bit higher temperature, which allowed for the fur-
ther development of a more robust process.
form the co-crystals with some amino acid such as
and -proline, while it was not easy to form co-crystals with
phenylalanine and Leucine. The results showed that -phenylala-
nine could form 1:1 co-crystal, and -proline could form 2:1 co-
L-phenylalanine
L
D-
L
L
crystal with 7a (Table 2). Several different solvents were examined,
and the result indicated that the mixture of 95% ethanol and n-hep-
tane could produce the pure 7a.
Next, we focused on the preparation of analogues of bexagliflo-
zin. Scheme 2 illustrates the preparation of carbon-13 labeled bex-
agliflozin 7b. Following the synthetic sequence described above,
carbon-13 labeled bexagliflozin 7b {mp 133.0–134.0 °C} was suc-
cessfully prepared in 57% yield in five continuous steps. The struc-
ture was further confirmed by spectroscopic data of 1H and 13C
NMR.
Conclusions
Figure 3. X-ray crystal structure of bexagliflozin 7a.
In summary, we established a convenient method for highly
diastereoselective synthesis of bexagliflozin 7a and its carbon-13
labeled analogue 7b. The carbon-13 labeled bexagliflozin 7b, a
valuable internal standard for the quantitation of bexagliflozin
from tissue and other heterogeneous biological specimens, was
conveniently prepared in five steps and in 57% overall chemical
Table 2
Co-crystal of 7a with amino acida
yield starting from the commercially available
[
D-gluconolactone-
Cl
O
13C6]. In addition, the cocrystallization skill was firstly used for
O
Conditions
O
7a (crude)
the purification of bexagliflozin and its analogue. Further investi-
gation of bexagliflozin and its analogue in the biological study is
now in progress in our laboratory.
HO
HO
Amino Acid
OH
OH
Bexagliflozin 7a
Acknowledgments
Entrya
Amino acid
Solvent
Co-crystal (Y/N)
1
2
3
4
5
6
EtOH/H2O
Yes
No
L
-Phenylalanine
We thank the National Natural Science Foundation of China
(No. 81402787), the Shanghai Municipal Committee of Science
and Technology (No. 14XD1400300 and 13431900101), and the
Specialized Research Fund for the Doctoral Program of Higher Edu-
cation (No. 20130071110070) for financial support. The authors
also thank the analytical group of Egret Pharma (Shanghai) Limited
for analytical service.
EtOH/H2O
D
-Phenylalanine
EtOH/H2O
Yes
Yes
Yes
No
L-Proline
L-Proline
L-Proline
i-PrOH/H2O
95% EtOH/Heptane
95% EtOH/Heptane
Leucine
All products were confirmed by 1H NMR.
a