ARTICLE IN PRESS
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W. Worawalai et al./Carbohydrate Research ■■ (2016) ■■–■■
naturally available (+)-proto-quercitol (1), through reductive
amination of aminoquercitol bisacetonides (5 and 8) and 1,3-
dihydroxyacetone dimer (9) as a key step. The application of 1 as
a glucomimic core structure along with the modification of the amino
group with N-1,3-dihydroxypropyl moiety led to a new pair of potent
α-glucosidase inhibitors. These results contrast with other related
N-1,3-dihydroxypropylaminocyclitols with larger rings (cycloheptane
and cyclooctane), which are inactive against α-glucosidase. There-
fore, the cyclohexane core structure of (+)-proto-quercitol (1) plays
a superior role in exerting inhibition while the propane-1,3-diol
residue reinforces binding with the active site of the enzyme.
In addition, the inhibitions of 10 and 11 were also more highly
potent than those of related N-ethyl aminoquercitols (12a-13c). Sub-
sequent investigation of the mechanism underlying the inhibition
suggested that compound 11 inhibited rat intestinal maltase and
sucrase in a competitive manner. A docking study of 10 and 11
towards maltase presented similar binding profiles with that of the
antidiabetic drug voglibose, in which key hydrogen bonding such
as OH cyclitol- D387, D503, and H660 were clearly observed. To our
knowledge, this is the first report of the docking study of quercitol-
derived compounds towards α-glucosidase. The aforementioned
findings from our study could be important clues in enhancing in-
sights into the inhibition mechanism of small molecules, particularly
six-membered cyclitols, and inspiring future investigation into other
N-1,3-dihydroxypropylaminocyclitols.
added slowly and the mixture was stirred for 3 h at room temper-
ature. The product was extracted with CH2Cl2 (3 × 50 mL), washed
with brine, dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
silica gel chromatography (50% EtOAc-hexane) to give 3 (317 mg,
81%) as an amorphous solid; 1H NMR (CDCl3, 400 MHz) δ 5.03 (dt,
J = 6.0, 5.4 Hz, 1H), 4.34 (br d, J = 6.0 Hz, 2H), 3.69 (dt, J = 10.4, 6.4 Hz,
1H), 3.60 (m, 1H), 3.07 (s, 3H), 2.31 (m, 1H), 2.21 (m, 1H), 1.50 (s,
3H), 1.41 (s, 6H), 1.34 (s, 3H).
1.4. 5S-Azido-5-deoxy-1,2:3,4-di-O-isopropylidene-(+)-proto-
quercitol (4)
A mixture of 3 (230 mg, 0.71 mmol), sodium azide (465 mg,
7.12 mmol), 15-crown-5-ether (1.5 mL, 7.1 mmol), and DMF (7 mL)
was stirred for 24 h at 100 °C. The reaction mixture was extracted
with EtOAc (3 × 100 mL), washed with brine several times, dried over
anhydrous Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was chromatographed on a column of silica gel
(30% EtOAc-hexane) to give the azide 4 (152 mg, 79%) as an amor-
phous solid; 1H NMR (CDCl3, 400 MHz) δ 4.35 (dd, J = 4.8, 4.8 Hz, 1H),
4.14 (dd, J = 8.4, 5.6 Hz, 1H), 3.58–3.68 (m, 2H), 3.30 (dt, J = 10.6,
4.4 Hz, 1H), 2.30 (m, 1H), 1.89 (m, 1H), 1.52 (s, 3H), 1.37 (s, 3H), 1.35
(s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 111.7, 110.6, 81.0,
76.3, 76.2, 73.1, 57.2, 29.1, 27.9, 26.9, 26.8, 25.9.
1. Experimental
1.5. 5S-Amino-5-deoxy-1,2:3,4-di-O-isopropylidene-(+)-proto-
quercitol (5)
1.1. General methods
To a cool solution of the azide 4 (34 mg, 0.12 mmol) in THF
(1.2 mL) at 0 °C was added LiAlH4 (480 μL, 1 M, 0.48 mmol) dropwise.
The mixture was stirred for 3 h, diluted with 1 M NaHCO3, ex-
tracted by EtOAc (3 × 30 mL), washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography using 20% MeOH-EtOAc to yield
an amine 5 (21 mg, 71%) as a pale yellow oil; 1H NMR (CD3OD,
400 MHz) δ 4.23 (dd, J = 4.8, 4.4 Hz, 1H), 4.07 (dd, J = 8.4, 4.8 Hz, 1H),
3.41 (dd, J = 9.0, 9.0 Hz, 1H), 3.30 (dt, J = 10.6, 3.2 Hz, 1H), 3.13 (dt,
J = 11.6, 4.8 Hz, 1H), 2.08 (m, 1H), 1.51 (dt, J = 11.6, 11.6 Hz, 1H), 1.41
(s, 3H), 1.29 (s, 6H), 1.27 (s, 3H); 13C NMR (CD3OD, 100 MHz) δ 110.5,
109.0, 82.5, 77.7, 76.4, 74.1, 48.6, 32.8, 27.5, 25.8, 25.1.
All moisture-sensitive reactions were carried out under a nitro-
gen atmosphere. All solvents used in the reactions were distilled
prior to use. HRESI-MS spectra were obtained from a micrOTOF
1
Bruker mass spectrometer. H and 13C spectra were recorded by a
Varian Mercury+ 400 NMR spectrometer and the chemical shifts (δ,
ppm) were reported by referencing to solvent residues. TLC profile
analysis was performed on Merck silica gel 60 F254 plates (0.25 mm
thick layer) and visualized under UV (254 nm) followed by dipping
in 10% anisaldehyde or KMnO4 reagents. Column chromatography
was conducted using Merck silica gel 60 (70–230 mesh), Sephadex
LH-20 or Dowex 50W-X8 (H+).
1.2. 1,2:3,4-Di-O-isopropylidene-5R-(+)-proto-quercitol (2)
1.6. 1,2:3,4-Di-O-isopropylidene-5-cyclohexanone (6)
To a solution of (+)-proto-quercitol (64 mg, 0.39 mmol) in DMF
(4 mL) were added 2,2-dimethoxypropane (480 μL, 3.90 mmol) and
p-toluenesulfonic acid monohydrate (7.4 mg, 0.039 mmol) and the
mixture was stirred for 1 h at 80 °C and warmed to room temper-
ature for 24 h. After the reaction was completed, the reaction mixture
was diluted with distilled water and extracted with EtOAc
(3 × 50 mL). The combined organic layers were then washed with
brine, dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column
using 50% EtOAc-hexane to yield bis-acetonide 2 (71 mg, 75%) as
a syrup; 1H NMR (CDCl3, 400 MHz) δ 4.26 (dd, J = 8.0, 6.4 Hz, 1H),
4.20 (ddd, J = 8.0, 5.6, 5.2 Hz, 1H), 4.13 (dd, J = 5.6, 5.6 Hz, 1H), 3.70
(ddd, J = 10.4, 10.2, 6.3 Hz, 1H), 3.53 (dd, J = 10, 8.4 Hz, 1H), 1.92–
To a solution of 2 (585 mg, 2.39 mmol) in DMSO (18.0 mL,
266 mmol) was added acetic anhydride (23 mL, 239 mmol) for 5 h
at room temperature. The reaction mixture was extracted with EtOAc
(3 × 200 mL), washed with brine several times, dried over anhy-
drous Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by silica gel column (20% EtOAc-
hexane) to give 6 (317 mg, 54%) as a colourless powder; 1H NMR
(CDCl3, 400 MHz) δ 4.59 (dd, J = 8.4, 8.0 Hz, 1H), 4.43 (d, J = 8.4 Hz,
1H), 4.07 (dt, J = 10.6, 6.8 Hz, 1H), 3.50 (dd, J = 10.4, 7.6 Hz, 1H), 2.93
(dd, J = 18.0, 7.2 Hz, 1H), 2.42 (dd, J = 18.2, 11.0 Hz, 1H), 1.44 (s, 3H),
1.42 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
203.6, 113.6, 112.3, 82.2, 78.7, 75.2, 70.6, 41.1, 27.1, 27.0, 26.7, 24.7.
2.06 (m, 2H), 1.44 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H); 13
C
1.7. 1,2:3,4-Di-O-isopropylidene-5S-(+)-proto-quercitol (7)
NMR (CDCl3, 100 MHz) δ 111.3, 109.8, 81.1, 79.8, 76.1, 72.1, 68.7, 32.3,
27.8, 27.0, 26.9, 25.5.
To a cool solution of 6 (50 mg, 0.12 mmol) in THF (2 mL) at 0 °C
was added LiAlH4 (825 μL, 1 M, 0.82 mmol) dropwise. The mixture
was stirred for 3 h, diluted with 1 M NaHCO3, extracted by EtOAc
(3 × 30 mL), washed with brine, dried over Na2SO4, filtered and con-
centrated under reduced pressure. The residue was purified by flash
chromatography using 50% EtOAc-hexane to yield 7 (47 mg, 93%)
as an amorphous solid; 1H NMR (CDCl3, 400 MHz) δ 4.24–4.32 (m,
1.3. 1,2:3,4-Di-O-isopropylidene-5R-O-mesyl-(+)-proto-quercitol (3)
To a 273 mg (1.12 mmol) portion of 2 in CH2Cl2 (12 mL) was added
DMAP (trace amount) and triethylamine (1.3 mL, 8.9 mmol). The
mixture was cooled to 0 °C. Mesyl chloride (261 μL, 3.35 mmol) was
Please cite this article in press as: Wisuttaya Worawalai, Pornthep Sompornpisut, Sumrit Wacharasindhu, Preecha Phuwapraisirisan, Voglibose-inspired synthesis of new potent α-glucosidase
inhibitors N-1,3-dihydroxypropylaminocyclitols, Carbohydrate Research (2016), doi: 10.1016/j.carres.2016.04.014