Vol. 26, No. 9 (2014)
Synthesis and Crystal Structure of Monofluorinated Iminosugar Derivative 2749
O2N
NO2
O
Cl
F
HO
HO
O2N
O2N
O
OH
O
F
O
O
O
DMAP, Pyridine
CH2Cl2
N
Bn
O
N
Bn
II
( )
I
( )
Scheme-I: Synthesis of the title compound (I)
OH
OH
µ = 0.111 mm-1 and Z = 2. Absorption correction was
performed by the CRYSTALCLEAR program13. The structure
was solved by direct methods using the SHELXS-97 program14
and refined by full-matrix least-squares techniques on F2 data
using SHELXL-9715. The empirical absorption corrections
were applied to all intensity data.All the hydrogen atoms were
located by using the geometric method, with d(C-H) = 0.95-
0.98 Å and Uiso (H) = 1.2 Ueq (C) or 1.5 Ueq (Cmethyl). The
final full-matrix least squares refinement gave R = 0.0824,
wR = 0.2177 (w = 1/[σ2(Fo)2 + (0.1523P)2 + 0.0000P], where
P = (Fo2 + 2Fc2)/3), S = 0.988, (∆/σ)max = 0.027, (∆ρ)max = 0.739
and (∆ρ)min = -0.356 e/Å3.
NH
HO
HO
N
HO
HO
R
OH
OH
1-deoxynojirimycin (DNJ)
Glyset (Miglitol) R = hydroxyethyl
Zavesca R = Bu
Fig. 1. Two approved iminosugar-based drugs
Synthetic procedure: Compound (II) (22 mg, 0.082 mmol)6,
DMAP (3 mg, 0.0246 mmol) was dissolved in dry pyridine
(1 mL). The solution was cooled to 0 °C, then p-NO2C6H4COCl
(200 mg, 1.08 mmol) in CH2Cl2 (0.3 mL) was added dropwise.
The mixture was warm to room temperature and stirred for
12 h, then at 50 °C for another 12 h. The mixture was cooled
to room temperature, then CH2Cl2 (10 mL) was added in. The
organic phase was washed with saturated sodium bicarbonate,
brine, dried over Na2SO4 and the solvent was removed under
reduced pressure. The residue was purified by flash chromato-
graphy (petroleum ether/ethyl acetate, v/v = 4:1) on silica gel
to give compound (I) as a light yellow solid (37 mg, 80 %
RESULTS AND DISCUSSION
The single crystal was obtained by slow evaporation of
the dichloromethane solution of the title compound (I), which
was recrystallized as air-stable light yellow crystals. The MS,
IR and NMR spectra are in good agreement with the formula
proposed by the X-ray crystallography.
Crystallographic and refinement parameters of the title
compound (I) are listed in Table-1. The selected bond lengths
and angles are given in Tables 2 and 3. The structure was solved
by direct methods. Anisotropic displacement parameters were
applied to all nonhydrogen atoms in full-matrix least-square
refinements based on F2. The hydrogen atoms were set in
calculated positions with a common fixed isotropic thermal
parameter.
25
yield). m.p. 225-226 åC; [α]D = 6.6° (c 2.3, CH3OH); IR
(KBr, νmax, cm-1): 3003, 1716, 1530, 1359, 1268, 1223, 1102,
721; 1H NMR (300 MHz, CDCl3, TMS) δ/ppm: 8.32-8.02 (m,
12H), 7.26-7.20 (m, 5H), 5.75 (s, 1H), 5.40 (s, 1H), 4.96-4.86
(m, 2H), 4.70-4.64 (m, 1H), 3.64 (d, J = 13.5 Hz, 1H), 3.50
(d, J = 13.2 Hz, 1H), 2.96-2.56 (m, 5H); 13C NMR (100.7
MHz, CDCl3) δ/ppm: 161.5, 160.9, 148.3, 148.1, 134.7, 132.2,
132.0, 128.3, 128.2, 128.1, 126.1, 125.8, 124.8, 121.1, 120.1,
69.2, 59.5, 47.2, 36.4; 19F NMR (282 MHz, CDCl3)δ/ppm:
-200.0 (m, 1F); MS (ESI) m/z 717 (M + H)+; HRMS Calcd.
for C35H30N4O12F: 717.1844; Found: 717.1839.
The molecular structure of the title compound (I) is shown
in Fig. 2. The crystal packing diagram of the title compound
(I) is shown in Fig. 3.
From the capped sticks view of compound (I) (Fig. 4), it
can be found that the piperidine ring takes the chair form
conformation in which the C(1)-F(1), C(5)-C(6) and N(1)-
C(15) have equatorial locations and C(2)-O(1) has axial orien-
tation. Obviously, the preferred conformation of the piperidinyl
ring is mainly determined by the group on C(5) because the
large group tends to adopt equatorial orientation for avoiding
steric strain. The distortions of several originally plane conju-
gated systems are also observed in this single crystal (Table-4).
For example, the dihedral angles of O(2)-C(8)-C(9)-C(10),
O(4)-N(2)-C(12)-C(13) and O(10)-C(29)-C(30)-C(31) are up
to -169.4(10), 11.3(13) and -157.8(15) deg, respectively. In
Crystal structure determination: Single crystal of the
title compound (I) suitable for X-ray diffraction analysis was
grown by slow evaporation of the CH2Cl2 solution at room
temperature. The crystal of compound (I) with dimensions of
0.285 mm × 0.267 mm × 0.101 mm was mounted on a Rigaku
RAXIS-RAPID diffractometer equipped with a graphite-
monochromated MoKα radiation (λ = 0.71073 Å) by using
an w scan mode at 293(2) K in the range of 1.79º ≤ θ ≤ 25.50º.
The crystal belongs to monoclinic system with space group
P21/n and crystal parameters of a = 7.2630 (14), b = 20.461
(4), c = 11.456 (2) Å, α = 90, β = 96.877 (4), γ = 90°, V =
1690.3 (6) Å3, Dc = 1.408 g/cm3. The absorption coefficient
sp2
sp3
addition, it is interesting to find out that O(6) and O(9)