Stereoselective synthesis and crystal structure of 4,6-O-benzylidene-N- octyl-D-allosamine hydrochloride

Article abstract of DOI:10.1016/j.cclet.2010.02.020

The building block of N-alkyl derivative of allosamidin (chitinase inhibitor), 4,6-O-benzylidene-N-octyl-D-allosamine hydrochloride was stereoselectively synthesized in two steps under mild conditions. Nucleophilic addition of octylamine to 2-oxoglucopyra

Full text of DOI:10.1016/j.cclet.2010.02.020

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 798–801
www.elsevier.com/locate/cclet
Stereoselective synthesis and crystal structure of
4,6-O-benzylidene-N-octyl-D-allosamine hydrochloride
b
a
b,
Fu Yi Zhang a, , Chun Li Wu , Cui Zhang , Hong Min Liu
*
*
a Chemistry Department, The Key Lab of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University,
Zhengzhou 450052, China
b School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
Received 9 November 2009
Abstract
The building block of N-alkyl derivative of allosamidin (chitinase inhibitor), 4,6-O-benzylidene-N-octyl-D-allosamine hydro-
chloride was stereoselectively synthesized in two steps under mild conditions. Nucleophilic addition of octylamine to 2-
oxoglucopyranoside gave a ‘carbonyl group transfer’ product in 62% yield. Subsequent stereoselective reduction of newly formed
C O with NaBH4 produced title compound in 75% yield. X-ray diffraction analysis indicates the title compound adopts syn 1, 2, 3
stereochemistry and chair–chair conformation. The crystal structure is stabilized by hydrogen bonds.
# 2010 Fu Yi Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2-Oxoglucopyranoside; 4,6-O-benzylidene-N-octyl-D-allosamine hydrochloride; X-ray structure
2-Amino-2-deoxysugars are key constituents of a variety of naturally occurring polysaccharides, such as
glycoproteins, glycolipids, and bacterial lipoplysaccharides [1–4]. They are also important building block for the
synthesis of biologically important oligosaccharides having 2-amino-2-deoxysugars [5,6]. Glycals were therefore
used as efficient starting materials for the preparation of the corresponding 2-amino-2-deoxysugars [7–13], which
have widespread use in construction of complex amine-containing polysaccharides. Among these 2-amino-2-
deoxysugars, N-acetylallosamine is the repeat unit in the sugar portion of allosamidin (an interesting chitinase
inhibitor) [9,10,14]. In order to synthesize N-alkyl derivatives of allosamidin, we developed a novel method for the
synthesis of their building blocks [15]. However, the reaction is limited to the less bulky alkylamines and no
crystallographic data is available for these important N-alkyl-D-allosamines.
1. Experimental
Melting points were determined on a WC-1 melting point apparatus and are uncorrected. Infrared spectra were
recorded on a Shimadzu IR-435 instrument using KBr disks in the 400–4000 cmÀ1 region. NMR spectra were taken in
* Corresponding authors.
E-mail addresses: zhangfy@zzu.edu.cn (F.Y. Zhang), liuhm@zzu.edu.cn (H.M. Liu).
1001-8417/$ – see front matter # 2010 Fu Yi Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.02.020

F.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 798–801
799
˚
Scheme 1. Condition and regent: (a) CH3(CH2)7NH2, anhydrous CHCl3, 4 A molecular sieves, CuI, NH4Cl, 50 8C, 40 min, 62%; (b) (i) NaBH4,
anhydrous THF, CH3OH, rt, (ii) CH3COOH, pH 6, and (iii) NaCl/H2O, 75%.
CDCl3 on a Bruker DPX-400 spectrometer. HR-MS were taken with Waters Micromass Q-Tof MicroTM. Anhydrous
CHCl3 was prepared by refluxing it with CaH2. The synthesis of compound 3 is given in Scheme 1.
˚
To a mixture of 2-oxoglucopyranoside 1 [16] (0.50 g, 1.78 mmol), anhydrous CHCl3 (15 mL), 4 A molecular sieves
(1.0 g), NH4Cl (4.8 mg, 0.89 mmol) and CuI (17.0 mg, 0.89 mmol), octylamine (0.32 mL, 1.96 mmol) in anhydrous
CHCl3 (5 mL) was added dropwise with stirring for 10 min. The mixture was heated at 50 8C until TLC indicated the
complete conversion of 1. The molecular sievewas then removed. The solution was diluted with CHCl3 (10 mL), washed
with saturated NaCl solution, driedover Na2SO4, andevaporated to dryness. Theresiduewas recrystallized from CH3OH
to give compound 2: white solid (0.43 g, 62%). Mp: 135–137 8C. IR (KBr) (nmax, cmÀ1): 3464, 3037, 2923, 2850, 1737,
1463, 1404, 1113, 1093, 1075, 965, 750, 699. 1H NMR (400 MHz, CDCl3): d 7.52–7.48 (m, 2H, Ph), 7.38–7.37 (m, 3H,
Ph), 5.72 (brs, 1H, H-1), 5.58 (s, 1H, PhCH), 4.45–4.39 (m, 2H, H-4, H-6a), 4.09 (dt, 1H, J5,6a = 4.4 Hz, J5,4 = J5,
6b = 10.0 Hz, H-5), 3.96 (t, 1H, J6b,5 = J6b,6a = 10.0 Hz, H-6b), 3.91 (brs, 1H, H-2), 3.51 (s, 3H, OMe), 2.91 (brs, 2H,
NCH2), 1.72 (brs, 1H, NH), 1.36–1.26 (m, 12H, (CH2)6), 0.88 (3H, J = 7.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): d
199.2 (C O), 136.5, 129.3, 128.3, 126.4 (Ph), 104.1 (C-1), 101.9 (PhCH), 83.0 (C-4), 69.6 (C-6), 67.2 (C-2), 66.2 (C-5),
55.5 (OMe), 48.5 (NCH2), 31.8, 30.2, 29.4, 29.2, 27.1, 22.7, 14.1 ((CH2)6CH3). HR-MS (FAB): m/z 392.2408 (M+H)+.
To a solution of 2 (0.40 g, 1.02 mmol) in anhydrous THF (8 mL) and CH3OH (8 mL), NaBH4 (0.038 g, 1.02 mmol)
was added. The mixture was stirred at rt for 30 min. Acetic acid (50%) was added until pH value of the solution is equal
to 6.0 and then evaporated. The residue was dissolved in water (25 mL), extracted with EtOAc (4Â 5 mL). The mixture
of the combined organic layer and saturated NaCl (10 mL) was stirred for 30 min and then separated. Slow evaporation
of the organic solution for 10 days at 0 8C gave 3: colourless single crystals (0.33 g, 75%). Mp: 98–100 8C. IR (KBr)
(nmax, cmÀ1): 3390, 3264, 2953, 2856, 1565, 1466, 1380, 752, 699. 1H NMR (400 MHz, CDCl3): d 7.50–7.48 (m, 2H,
Ph), 7.39–7.36 (m, 3H, Ph), 5.60 (s, 1H, PhCH), 5.09 (d, 1H, J1,2 = 4.0 Hz, H-1), 4.61 (brs, 1H, H-3), 4.36 (dd, 1H,
J
J
6a,5 = 5.2 Hz, J6a,6b = 10.0 Hz, H-6a), 4.19 (dt, 1H, J5,6a = 5.2 Hz, J5,4 = J5, 6b = 10.0 Hz, H-5), 3.76 (t, 1H,
6b,5 = J6b,6a = 10.0 Hz, H-6b), 3.60 (dd, 1H, J4,3 = 2.4 Hz, J4,5 = 10.0 Hz, H-4), 3.50 (s, 3H, OMe), 3.36 (brs, 1H, H-
2), 3.00–2.88 (m, 2H, NCH2), 1.89–1.75 (m, 2H, NCH2CH2), 1.33–1.26 (m, 10H, NCH2CH2(CH2)5), 0.88 (t, 3H,
J = 7.2 Hz, CH3). 13C NMR (100 MHz, CDCl3): d 136.8, 129.3, 128.3, 126.2 (Ph), 101.8 (PhCH), 96.3 (C-1), 77.3 (C-
4), 68.8 (C-6), 64.0 (C-3), 57.4 (C-5), 56.3 (OMe), 56.1 (C-2), 45.2 (NCH2), 31.7, 29.1, 29.0, 26.7, 22.6, 20.7 ((CH2)6),
14.0 (CH3). HR-MS (FAB): m/z 410.2500 (M+H2O–HCl)+.
˚
Crystallographic data for 3 was collected at 291(2) K using Mo Ka radiation (l = 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 fullmatrix least-squares
methods based on F2, with anisotropic thermal parameters for the non-hydrogen atoms. The hydrogen atoms were
located theoretically and not refined. The crystal belongs to orthorhombic system, space group P2(1)2(1)2(1), with
3
3
˚
˚
˚
a = 5.1863(10), b = 14.554(3), c = 33.212(7) A, V = 2506.9(9) A , Z = 4, Dc = 1.187 Mg/m , l = 0.71073 A, m(Mo
Ka) = 0.187 mmÀ1, F(0 0 0) = 968. R1 = 0.0519, wR2 = 0.1180 [I > 2s(I)].
2. Results and discussion
In continuation of our study on the application of 2-oxoglucopyranoside [15–17], we herein report the synthesis and
crystal structure of novel N-octyl-D-allosamine hydrochloride 3 (Fig. 1). The crystallographic data of 3 is helpful in
studying the recognition of chitinase with allosamidin and N-alkyl derivatives of allosamidin.
2-Oxoglucopyranoside 1 was prepared by regioselective oxidation of methyl 4,6-O-benzylidene-a-D-glucopyrano-
side according to the known procedure [16]. The reaction of 1 with octylamine at 50 8C generated N-octyl-3-keto-
allosamine 2 in 62% yield in the presence of NH4Cl and CuI simultaneously (Scheme 1). Reduction of 2 with NaBH4

800
F.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 798–801
Fig. 1. The molecular structure of compound 3.
was performed at rt followed by neutralization with acetic acid until pH value of the reaction solution is equal to 6.0.
The solution was then treated with NaCl to give N-octyl-D-allosamine hydrochloride 3 in 75% yield, in which case,
protonation of nitrogen and CH3COOÀ exchange with ClÀ are involved. In 2, due to the steric hindrance of bulky octyl
group, exo attack of hydride to C O is much more favourable than endo attack, which leads to syn 1, 2, 3
stereochemistry of the product 3. The compound 2 and 3 were characterized by HR-MS, 1H NMR, 13C NMR, IR and
elemental analysis. HR-MS of 2 displays (M+H)+ signal at m/z 392.2408, together with elemental analysis indicating
its molecular formula to be C22H33NO5. In the 1H NMR spectrum of 2, two protons at d 5.72 and d 3.91 as two brand
singlets are ascribed to H-1 and H-2, indicating the newly formed octylamino group and methoxy group at C-1 are in
the syn position. Its IR spectrum exhibits C O at 1737 cmÀ1. In the 1H NMR spectrum of 3, the proton at d 5.09 (d,
J = 4.0 Hz) is coupled with the proton at d 3.36 (brs). They are assigned to H-1 and H-2. The proton at d 4.61 (brs) is
ascribed to H-3. These coupling patterns indicate its syn 1, 2, 3 stereochemistry.
Fig. 2. Crystal packing of compound 3 with the hydrogen bonds.

F.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 798–801
801
Table 1
˚
Hydrogen bond in crystal packing of compound 3 (A,8).
D–H
d (D–H)
d (HÁ Á ÁA)
d (D–A)
D–HÁ Á ÁA
A
N1–H1F
O2–H2E
O6–H6E
O6–H6F
N1–H1E
0.918
0.932
0.848
1.118
0.909
2.286
2.237
2.354
2.180
2.383
3.199
3.142
3.192
3.289
2.970
172.81
163.85
169.67
170.84
122.29
Cl1 [Àx + 1, y À 1/2, Àz + 1/2]
Cl1
Cl1
Cl1 [x À 1, y, z]
O6 [Àx, y À 1/2, Àz + 1/2]
X-ray crystallographic analysis indicates compound 3 adopts chair–chair conformation as shown in Fig. 1. The
˚
displacements of atoms C5 and C16 are À0.7274 and 0.6461 A, respectively, from the O4–O5–C6–C4 plane (r.m.s.
˚
˚
deviation 0.0112 A). The atoms C1 and C4 deviate À0.6161 and 0.6611 A, respectively, from the C2–C3–C5–O3
˚
plane (r.m.s. deviation 0.0631 A). This chair is more distorted than the former, due to the congestion of large octyl
˚
group in the sugar ring and hydrogen bond interactions. The associated non-bonding distances are 2.867 A for
˚
C1Á Á ÁC4 and 2.784 A for C5Á Á ÁC16. The dihedral angle between the two planes is 4.88, indicating they are
approximately parallel. The crystal structure is stabilized by several hydrogen bonds, as shown in Fig. 2. ClÀ acts as an
important hydrogen bond acceptor to form four hydrogen bonds, which are N–HÁ Á ÁCl, O2–HÁ Á ÁCl, two O6–HÁ Á ÁCl
(Table 1). Another hydrogen bond N–HÁ Á ÁO6 are formed by O6 as the acceptor.
Acknowledgments
The authors are grateful for the financial supports from the National Natural Science Foundation of China (No.
20972142) and the State Key Laboratory of Bio-organic and Natural Products Chemistry, CAS (No. 08417).
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