Novel methyl 4,6-O-benzylidene-3-ketoglucopyranosid-fused γ-lactam: Synthesis and crystal structure

Article abstract of DOI:10.1007/s10870-011-0079-6

The title compound methyl 4,6-O-benzylidene-3-ketoglucopyranosid-fused γ-lactam was synthesized from 2-oxoglucopyranoside in one pot via multi-step reaction sequence under mild conditions. It was characterized by HRMS, ¹H and ¹³C-NMR, IR, elemental analysis and single crystal X-ray diffraction. The crystal belongs to orthorhombic P2(1)2(1)2(1) space group with unit cell parameters a = 6.1840 (12) A, b = 10.372 (2) A, c = 25.702 (5) A, V = 1648.5 (6) A³, Z = 4, D_c = 1.343 Mg/m³, λ = 0.71073 A, μ(Mo Kα) = 0.102 mm^-1, F(000) = 704. X-ray diffraction analysis reveals that the compound adopts chair-chair conformation. The newly formed γ-lactam moiety is fused to glucopyranoside ring by C2 to form spirosugar. The crystal structure is stabilized by N-H...O2 hydrogen bond.

Full text of DOI:10.1007/s10870-011-0079-6

J Chem Crystallogr (2011) 41:1228–1231
DOI 10.1007/s10870-011-0079-6
ORIGINAL PAPER
Novel Methyl 4,6-O-benzylidene-3-ketoglucopyranosid-fused
c-lactam: Synthesis and Crystal Structure
•
Hong Liu Fuyi Zhang Jin-Peng Li
•
•
•
•
Xuebin Yan Hong-Min Liu Yu-Fen Zhao
Received: 24 October 2009 / Accepted: 15 April 2011 / Published online: 23 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The title compound methyl 4,6-O-benzylidene-
3-ketoglucopyranosid-fused c-lactam was synthesized from
2-oxoglucopyranoside in one pot via multi-step reaction
sequence under mild conditions. It was characterized by
HRMS, 1H and 13C-NMR, IR, elemental analysis and
single crystal X-ray diffraction. The crystal belongs to
orthorhombic P2(1)2(1)2(1) space group with unit cell
Introduction
c-butyrolactams are biologically relevant as GABA receptor
ligands [1–4]. They have also been shown to possess anti-
convulsant and antioxidant activity [5–7]. Gabapentinlac-
tam is neuroprotective in retinal ischaemia [8]. Besides, the
c-butyrolactams can be used as the biosynthetic precursors
of GABA analogues and the key intermediates for the
synthesis of pyrrolidines [9]. The pharmacophore engi-
neered into the carbohydrate is an important method for
obtaining biological analogues. Several examples of sugar-
fused GABA analogues on a galactose or glucose scaffold
have been recently proposed [10, 11]. Sugar lactams
including sugar derived c-butyrolactam are important bio-
logical substances and several sugar-biased lactams were
synthesized [12–16]. The sugar-fused lactams are GABA
analogues and the synthesis of fructose-fused c-butyrolac-
tams was achieved [17]. Their biological activities as
GABA receptor ligands were evaluated. The biological data
indicated the carbohydrate moiety can effectively be used to
modulate drug pharmacokinetic properties and lipophilic-
ity. These results have stimulated our attempts to find
new synthetic route to structurally diverse sugar-fused
c-butyrolactams. In this paper, the novel title compound was
synthesized for the first time and its molecular structure was
˚
˚
parameters a = 6.1840 (12) A, b = 10.372 (2) A, c =
3
3
25.702 (5) A, V = 1648.5 (6) A , Z = 4, Dc = 1.343 Mg/m ,
˚
˚
k = 0.71073 A, l(Mo Ka) = 0.102 mm-1, F(000) = 704.
˚
X-ray diffraction analysis reveals that the compound
adopts chair-chair conformation. The newly formed c-lac-
tam moiety is fused to glucopyranoside ring by C2 to form
spirosugar. The crystal structure is stabilized by N–HÁÁÁO2
hydrogen bond.
Keywords 4,6-O-benzylidene-3-ketoglucopyranosid-
fused c-lactam Á Synthesis Á Crystal structure
H. Liu Á F. Zhang (&) Á J.-P. Li Á X. Yan Á Y.-F. Zhao (&)
Chemistry Department, The Key Lab of Chemical Biology and
Organic Chemistry, Phosphorus Chemical Engineering Research
Center of Henan Province, Zhengzhou University,
450052 Zhengzhou, People’s Republic of China
e-mail: zhangfy@zzu.edu.cn
investigated by HRMS, H and 13C-NMR, IR, elemental
1
analysis, and X-ray crystallographic techniques.
Experimental
Y.-F. Zhao
e-mail: zicb@zzu.edu.cn
Instrument
H.-M. Liu
School of Pharmaceutical Sciences, Zhengzhou University,
100 Science Road, 450001 Zhengzhou,
People’s Republic of China
Melting points were determined on a WC-1 melting point
apparatus and are uncorrected. Infrared spectra were
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J Chem Crystallogr (2011) 41:1228–1231
1229
recorded on a Shimadzu IR-435 instrument using KBr
disks in the 400–4000 cm-1 region. NMR spectra were
taken in CDCl3 on a Bruker DPX-400 spectrometer, and
the chemical shifts are given in d values. High resolution
mass spectrometry spectrum were taken with a ZAB-2SE
double-focusing mass spectrometer (VG Analytical, Man-
chester, UK).
Table 1 Crystal data and structure refinement for the title compound
CCDC deposit no.
Empirical formula
Formula weight
Temperature/K
751673
17H19NO6
C
333.33
291(2)
˚
Wavelength/A
0.71073
Crystal system
Space group
Orthorhombic
P212121
Synthesis
˚
a/A
6.1840(12)
˚
b/A
10.372(2)
The starting material 1 (Scheme 1) was prepared by the
condensation of 2-oxoglucopyranoside [18–21] with die-
thyl malonate in the presence of NaOMe as we reported.
The title compound 2 was synthesized from 1 reacting with
nitromethane followed by reduction.
˚
c/A
25.702(5)
3
˚
Volume/A
1648.5(6)
Z
4
Calculated density/Mg m-3
Absorptions coefficient/mm-1
F(000)
1.343
0.102
704
Synthesis of Methyl 4,6-O-benzylidene-3-
ketoglucopyranosid-fused c-lactam, 2
Crystal size/mm
0.24 9 0.20 9 0.20
2052/2052 [R(int) = 0.0000]
93.2%
Reflections collected/unique
Completeness to 2h = 27.51
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
To a solution of compound 1 (0.50 g, 1.38 mmol) in
MeNO2 (5 mL), KF (0.12 g, 2.07 mmol) was added. The
mixture was stirred at rt under oxygen atmosphere for 48 h.
The solvent was evaporated to dryness and the residue was
dissolved in THF (15 mL). Reduced iron powder (0.32 g,
5.79 mmol), NH4Cl (0.24 g, 4.58 mmol) and H2O (10 mL)
was added. The mixture was heated at 60 °C for 6 h and
then filtered. The solid residue was washed with THF and
the combined solution was evaporated to remove solvent.
The residue was dissolved in EtOAc (25 mL), washed with
H2O (2 9 3 mL) and brine (1 9 3 mL), dried over
Na2SO4 and evaporated to dryness to afford crude product,
which was recrystallized from MeOH to give 2 as a crys-
talline solid (0.29 g, 63%). The single crystal was obtained
after 1 week by slow evaporation of the acetone-methanol
solution of 2. m. p. 135–137 °C; IR mmax (KBr)/cm-1: 3302
(NH), 1752 (C=O), 1703 (CON); dH (400 MHz, CDCl3)
7.50–7.49 (m, 2H, Ph), 7.38–7.36 (m, 3H, Ph), 5.60 (s, 1H,
PhCH), 4.85 (brs, 1H, H-1), 4.38 (dd, 1H, J 4.4 and
10.0 Hz, H-6a), 4.16 (dt, 1H, J 4.4 and 10.0 Hz, H-5), 4.11
(d, 1H, J 10.0 Hz, H-4), 3.96 (t, 1H, J 10.0 Hz, H-6b), 3.40
(OMe), 4.18, 3.31 (d, each 1H, J 10.0 Hz, CH2N), 2.8, 2.54
(d, each 1H, J 17.2 Hz, CH2CO); dC (100 MHz, CDCl3)
197.3 (C3), 173.2 (CON), 136.3, 129.4, 128.3, 126.4 (Ph),
0.9798 and 0.9758
2052/0/222
1.045
R1 = 0.0638, wR2 = 0.0732
R1 = 0.1060, wR2 = 0.0837
0.180 and -0.160
-3
˚
Largest diff. peak and hole/e A
˚
Table 2 Selected bond lengths (A) and bond angles (°)
˚
Bond lengths (A)
C(1)–C(2)
1.545(5)
1.529(4)
1.537(4)
1.552(4)
1.501(4)
1.340(5)
1.448(4)
1.204(3)
1.222(4)
1.412(4)
C(2)–C(3)
C(2)–C(17)
C(2)–C(8)
C(8)–C(9)
C(9)–N(1)
C(17)–N(1)
O(3)–C(3)
O(2)–C(9)
O(5)–C(1)
Bond angles (°)
C(17)–C(2)–C(8)
C(9)–C(8)–C(2)
N(1)–C(9)–C(8)
C(9)–N(1)–C(17)
N(1)–C(17)–C(2)
O(2)–C(9)–N(1)
C(3)–C(2)–C(1)
C(4)–C(3)–C(2)
O(5)–C(1)–C(2)
O(3)–C(3)–C(2)
105.3(3)
108.1(3)
114.8(3)
104.1(3)
102.8(2)
127.0(3)
109.3(3)
111.5(3)
112.5(2)
123.9(3)
O
O
COOMe
O
Ph
O
(i) CH3NO2, KF, rt
O
O
Ph
O
NH
O
(ii) Fe, NH4Cl, 65%
OMe
O
O
OMe
1
2
Scheme 1 The synthesis of 4,6-O-benzylidene-3-keto glucopyrano-
sid-fused c-lactam
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J Chem Crystallogr (2011) 41:1228–1231
105.5 (C1), 102.2 (PhCH), 80.5 (C4), 69.3 (C6), 65.7 (C5),
57.4 (OMe), 55.5 (C2), 42.4 (CH2N), 38.8 (CH2CO).
HRMS (FAB) m/z calcd. for C17H20NO6: 334.1291
(M??1); found: 334.1296. Anal. Calcd for C17H19NO6: C,
61.25; H, 5.75; N, 4.20. Found: C, 61.23; H, 5.74; N, 4.21.
data was summarized in detail in Table 1. Selected bond
lengths and bond angles are listed in Table 2.
Results and Discussion
Crystal Structure Determination
The title compound was synthesized in one pot via multi-
step reactions. In the presence of KF, autoxidation and
nucleophilic addition of nitromethyl anion to a, b-unsatu-
rated ester 1 followed by iron reduction of intermediate
afforded 3-ketoglucopyranosid-fused c-lactam 2, which
Crystallographic data for the title compound was collected
˚
at 291(2) K using Mo-Ka radiation (k = 0.71073 A) on a
Rigaku RAXIS-IV image plate area detector. The data was
corrected for Lorentz and polarization factors and for
absorption by using empirical scan data. The structure was
solved with the SHELX program, and refined by full matrix
least-squares methods based on F2, with anisotropic ther-
mal parameters for the non-hydrogen atoms. The hydrogen
atoms were located theoretically and not refined. Crystal
1
was characterized by HRMS, H and 13C NMR, IR, ele-
mental analysis and X-ray crystallographic analysis. The
M??1 peak at 334.1296 in its HRMS spectrum, together
with elemental analysis indicate the molecular formula to
be C17H19NO6. In the 1H NMR spectrum of the title
compound, the proton at d 4.85 as a singlet was assigned to
H-1. The proton at d 4.11 as a doublet with coupling
constant of 10.0 Hz is ascribed to H-4. The two protons at
d 2.80 and 2.54 (d, each 1H, J 17.2 Hz) are assigned to
a-CH2 of c-lactam moiety. Another two protons at d 4.18
and 3.31 (d, each 1H, J 10.0 Hz) are assigned to CH2N.
These assignments are confirmed by DEPT spectrum,
showing two secondary carbons at d 38.8 (C8) and 42.2
(C17) besides d 69.3 (C6). In 13C NMR spectrum, the
quarternary carbon at d 55.5 is ascribed to C2. The signals
at d 197.3 and 173.2 are assigned to C3 and C9, respec-
tively. All the assignments are based on 2D NMR.
The title compound adopts chair-chair conformation as
shown in Fig. 1. The newly formed c-lactam moiety is
Fig. 1 The molecular structure of the title compound
Fig. 2 The intermolecular
hydrogen bonds of the title
compound
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J Chem Crystallogr (2011) 41:1228–1231
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Acknowledgments We are grateful to the National Natural Science
Foundation of China (No. 20972142, 20972130, 20732004), the State
Key Laboratory of Bio-organic and Natural Products Chemistry, CAS
(08417) for financial support.
fused to glucopyranoside ring by C2 to form spirosugar.
˚
Atoms C2 and C5 are displaced by -0.6354 and 0.7153 A,
respectively, from C3–C4–O5–C1 least-squares plane
˚
(r. m. s. deviation 0.0004 A), giving a flattened chair
conformation. Atoms C5 and C10 deviate by 0.6704 and
˚
-0.6827 A from the C4–O4–C6–O6 plane (r. m. s. devia-
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X-ray crystallographic file in cif format for the structure
determination of the title compound has been deposited
with the Cambridge Crystallographic Data Centre, CDCC:
751673. Copies of this data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: ?44 1223 336033.
123