Regioselective conversion of anhydro sugars into halohydrins and X-ray study

Article abstract of DOI:10.1515/znb-2004-0318

A rapid, easy, regio- and stereoselective synthesis of 3-halo-3-deoxy sugars using titanium tetrahalides is described. To fully confirm the stereochemistry of the synthetic products, the X-ray structure of benzyl 3-chloro-3-deoxy-β-L-xylopyranoside was de

Full text of DOI:10.1515/znb-2004-0318

Regioselective Conversion of Anhydro Sugars into Halohydrins and
X-Ray Study
Syed Tasadaque A. Shaha, Raid J. Abdel-Jalila, Khalid M. Khanb, Angelica M. Heinricha,
Markus Richterc, and Wolfgang Voeltera
a Abteilung fu¨r Physikalische Biochemie des Physiologisch-chemischen Instituts der Universita¨t
Tu¨bingen, Hoppe-Seyler Straße 4, D-72076 Tu¨bingen, Germany
b HEJ Research Institute of Chemistry, International Center for Chemical Sciences, University of
Karachi, Karachi-75270, Pakistan
c Institut fu¨r Anorganische Chemie der Universita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
Reprint requests to Prof. Dr. Dr. h. c. mult. Wolfgang Voelter. Fax: 0049-7071-293348.
E-mail: wolfgang.voelter@uni-tuebingen.de
Z. Naturforsch. 59b, 337 – 340 (2004); received December 2, 2002
A rapid, easy, regio- and stereoselective synthesis of 3-halo-3-deoxy sugars using titanium tetra-
halides is described. To fully confirm the stereochemistry of the synthetic products, the X-ray struc-
ture of benzyl 3-chloro-3-deoxy-β-L-xylopyranoside was determined.
Key words: Anhydro, Bromodeoxy, Chlorodeoxy and Iododeoxy Sugars, Titanium Tetrahalides
Introduction
regioselectivity is the trans-diaxial opening of oxirane
rings of 2,3-anhydro sugars with a titanium(IV) halide.
The complex has recently been used by Shimizu et
al. to achieve epoxide cleavages in a group of halohy-
drins [15]. Chloro- and iododeoxy sugars were already
prepared in high yield in our own laboratory using a
dichlorobis(benzonitrile) palladium (II) [16] and a ti-
tanium isopropoxide reagent in the presence of iodine
and samarium iodide [17].
Thus, in continuation of our efforts to synthesize
halodeoxy sugars in high yields and regioselectively,
we wish to report herewith a rapid, easy and regiose-
lective route for the synthesis of halodeoxy sugars in
high yields using titanium(IV) halides.
The synthesis of halodeoxy sugars has received con-
tinuous interest in recent years because of their key
role in the access to deoxy, aminodeoxy and unsat-
urated sugars [1]. Moreover, anhydro sugars are sta-
ble intermediates with unique properties of the oxi-
rane ring to serve, both, as a protective group and
readily accessible reaction sites which have led to
their extensive exploitation in carbohydrate synthesis.
Besides, they have the advantage of convenient re-
moval of protection after the desired synthetic strat-
egy has been accomplished [2 – 6]. Furthermore, re-
gioselective conversion of epoxides to halohydrins is
a useful tool for stereospecific syntheses of various
synthons, since optically active epoxides are read-
ily available [7]. A variety of reagents are known to
convert epoxides to halohydrins. In particular, metal
Results and Discussions
The anhydro sugars 1 – 3 exist almost entirely
halides such as FeCl3 [8], SnCl2, SnBr2, SnI2 [9] or in the favored half-chair conformations H0 and
CoCl2 in the presence of chlorotrimethylsilane [10] H0 [17– 23]. Trans-diaxial opening by the tita-
5
5
catalyse the cleavage of oxiranes. Several other meth- nium(IV) halide complex leads to benzyl 3-halo-
ods are also known for the formation of halohydrins 3-deoxy-β-L-xylopyranosides 4 – 6, benzyl 3-halo-3-
on carbohydrate templates, including Raney nickel deoxy-α-D-xylopyranosides 7 – 9 and benzyl 3-halo-
[1], sulfuryl chloride [11], dibromomethyl methyl 3-deoxy-α-D-arabinopyranosides 10, 11, respectively.
ether [12], dichloromethylene-(dimethyl)ammonium The nucleophilic halide attack at position 3 is also fa-
chloride, iron(III) chloride tribenzylamine and lithium vored by steric considerations, as position 2 is compar-
bromide [13], and carbon tetrachloride in the presence atively blocked by the bulky substituent at C-1. The an-
of triphenylphosphine [14]. A reaction yielding high hydro sugars benzyl 2,3-anhydro-β-L-ribopyranoside
c
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338
S. T. A. Shah et al. · Regioselective Conversion of Anhydro Sugars into Halohydrins
Table 1. Details of X-ray data collection and refinement for
compound 4.
Moleculas formula
Formula weight
C12H15ClO4
258.69
Temperature
Wavelength
213(2) K
1.54056 A (Cu-Kα )
˚
Crystal system / space group
Unit cell dimensions
orthorhombic/ P2 2121
a = 5.7958(4) A
1
˚
alpha = 90 deg.
˚
b = 9.147(2) A
beta = 90 deg.
c = 22.148(3) A
˚
gamma = 90 deg.
3
˚
Volume
1174.1(3) A
Z
4
Density (calculated)
Absorption coefficient
F(000)
1.463 g/cm3
2.911 mm−1
544
Crystal size / colour
Theta range for data collection 5.23 to 64.94 deg.
0.60×0.20×0.05 mm / colourless
Scheme 1. Syntheses of halodeoxy sugars via 2,3-anhydro-
pyranosides.
Index ranges
−6 ≤ h ≤ 1,
−10 ≤ k ≤ 10,
0 ≤ l ≤ 26
Reflections collected
Independent reflections
Reflections observed
2690
1997 [R(int) = 0.0559]
1964
Criterion for observation
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices (all)
I > 2σ(I)
Psi scans
0.9428 and 0.6766
Full matrix least squares on F2
1997 / 0 / 215
1.115
R1 = 0.0484,
wR2 = 0.1348
R1 = 0.0478,
wR2 = 0.1342
0.01(3)
Final R indices [I > 2σ(I)]
Fig. 1. ORTEP diagram of benzyl 3-chloro-3-deoxy-β-L-
xylopyranoside (4).
Absolute structure parameter
Extinction coefficient
Largest diff. peak and hole
0.027(2)
0.253 and −0.375 e·A
−3
˚
(1), benzyl 2,3-anhydro-α-D-ribopyranoside (2) and
benzyl 2,3-anhydro-α-D-lyxopyranoside(3) were syn-
thesized according to the literature [24– 26]. In the
present work we found that epoxide ring opening
in this group of 2,3-anhydrosugars with titanium(IV)
halide results in the transformation to the correspond-
ing 3-halo-3-deoxy sugars (Scheme 1).
ray collection and refinement, bond distances and an-
gles for compound 4 are collected in Tables 1 and 2.
Experimental Part
General
All chemicals and reagents were obtained from com-
mercial suppliers and used as such without further purifi-
cation. Solvents were dried and distilled according to stan-
dard procedures. The reactions were monitored by thin-layer
chromatography, carried out on 0.25 mm silica gel plates
(60 F-254, Merck, Darmstadt, Germany). Plates were visu-
alized under UV light (where appropriate), sprayed with an
orcinol/H2SO4/FeCl3 solution and heated to develop. Col-
umn chromatography was performed on silica gel 60 (0.063 –
0.200 mm, Merck, Darmstadt, Germany) using the indicated
It may be concluded from these results that epoxide-
opening by titanium(IV) halide competes with other
available methods in terms of yields and short prepa-
ration time of halodeoxy sugars. The reagent, how-
ever, imparts a greater degree of regioselectivity and
effective control on epoxide migration [27]. NMR
spectroscopy established 1C4 conformations for the
4
halodeoxy sugars 4 – 6, 10 and 11 and C1 conforma-
tions for 7 – 9.
Fig. 1 shows the ORTEP diagram of benzyl 3-
chloro-3-deoxy-β-L-xylopyranoside (4). Details of X-
1
solvent system. H and 13C NMR spectra were obtained in
CDCl3 on a Bruker AC 250 (1H NMR: 250 MHz, 13C NMR:
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S. T. A. Shah et al. · Regioselective Conversion of Anhydro Sugars into Halohydrins
339
˚
Table 2. Bond distances [A] and angles [deg] for com-
pound 4.
Benzyl 3-bromo-3-deoxy-β-L-xylopyranoside (5)
◦
Colourless needles; yield 82%. – M.p. 128 – 129 C; –
[α]D = +85.10◦ (c = 0.04, CHCl3). – 1H NMR (250 MHz,
CD3OD): δ = 7.31 – 7.25 (m, 5H, Ar-H), 4.86 (d, J =
11.1 Hz, 1H, OCHHPh), 4.56 (d, J = 11.1 Hz, 1H,
OCHHPh), 4.28 (d, J = 7.0 Hz, 1H, 1-H), 4.01 (dd, J = 4.8,
11.2 Hz, 1H, 5’-H), 3.68 – 3.92 (m, 2H, 3-H, 4-H), 3.57
(dd, J = 9.7, 7.0 Hz, 1H, 2-H), 3.18 (dd, J = 11.3, 9.1 Hz,
1H, 5-H). – 13C NMR (62.9 MHz, CDCl3): δ = 128.1 –
128.6 (Ar-C), 102.5 (C-1), 73.8 (C-2), 71.7 (C-4), 71.2
(OCH2Ph), 66.85 (C-5), 59.69 (C-3). – MS (FD): m/z =
303. – C12H15BrO4 (303.15): calcd. C 47.54 H 4.99; found
C 47.59, H 5.02.
Cl(3)-C(3)
O(1)-C(5)
O(3)-C(1)
O(4)-C(4)
C(2)-C(3)
C(4)-C(5)
C61)-C(66)
C(62)-C(63)
C(64)-C(65)
1.795(3)
1.432(4)
1.409(4)
1.414(4)
1.528(4)
1.514(5)
1.388(5)
1.391(5)
1.379(5)
O(1)-C(1)
O(2)-C(2)
O(3)-C(6)
C(1)-C(2)
1.426(4)
1.428(4)
1.429(4)
1.521(5)
1.516(4)
1.501(5)
1.392(5)
1.384(5)
1.395(5)
C(3)-C(4)
C(6)-C(61)
C(61)-C(62)
C(63)-C(64)
C(65)-C(66)
C(1)-O(1)-C(5)
O(3)-C(1)-O(1)
O(1)-C(1)-C(2)
O(2)-C(2)-C(3)
C(4)-C(3)-C(2)
C(2)-C(3)-Cl(3)
O(4)-C(4)-C(3)
O(1)-C(5)-C(4)
C(66)-C(61)-C(62)
C(62)-C(61)-C(6)
C(64)-C(63)-C(62)
C(64)-C(65)-C(66)
112.4(2)
111.5(3)
111.1(3)
112.9(3)
110.0(3)
109.9(2)
113.7(3)
111.6(3)
119.3(3)
119.0(3)
120.1(3)
120.4(3)
C(1)-O(3)-C(6)
O(3)-C(1)-C(2)
O(2)-C(2)-C(1)
C(1)-C(2)-C(3)
C(4)-C(3)-Cl(3)
O(4)-C(4)-C(5)
C(5)-C(4)-C(3)
O(3)-C(6)-C(61)
C(66)-C(61)-C(6)
C(63)-C(62)-C(61)
C(65)-C(64)-C(63)
C(61)-C(66)-C(65)
113.3(2)
107.2(2)
110.6(3)
110.0(3)
110.6(2)
105.9(3)
107.7(3)
110.0(3)
121.7(3)
120.3(3)
119.8(3)
120.0(3)
Benzyl 3-iodo-3-deoxy-β-L-xylopyranoside (6)
Colourless needles; yield 91%. – M. p. 144 – 145 ◦C (lit.
145 ◦C [16]); – [α]D = +156.45◦ (c = 0.14, CHCl3). – 13
NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.6 (Ar-C), 102.5
(C-1), 74.2 (C-2), 71.89 (C-4), 71.5 (OCH2Ph), 67.4 (C-5),
40.4 (C-3). – MS (FD): m/z = 350. – C12H15IO4 (350.16):
calcd. C 41.16; H 4.32; found C 41.14, H 4.34.
C
63 MHz) or a Bruker WM 400 spectrometer (1H NMR:
400 MHz, 13C NMR: 100 MHz). The chemical shifts are
reported in parts per million (ppm) on a δ scale with TMS
as internal standard. The EI, FAB and FD mass spectra were
recorded on a Finnigan MAT 312 mass spectrometer con-
nected to a PDO 11/34 (DEC) computer system. Optical ro-
tations were obtained with an LEP AZ polarimeter (Zeiss,
Jena) at 546 nm. All melting points are uncorrected.
Benzyl 3-chloro-3-deoxy-α-D-xylopyranoside (7)
Colourl◦ess needles; yield 92%. – M.p. 158 – 160 ◦C (lit.
159 – 160 C [17]); – [α]D = +18.45◦ (c = 0.20, CHCl3).
–
13C NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.6 (Ar-
C), 97.2 (C-1), 72.4 (C-2), 71.5 (C-4), 69.8 (OCH2Ph), 66.4
(C-5), 62.4 (C-3). – MS (FD): m/z = 258. – C12H15ClO4
(258.69): calcd. C 55.71, H 5.84; found C 55.61, H 5.75.
Benzyl 3-bromo-3-deoxy-α-D-xylopyranoside (8)
General procedure for the preparation of halodeoxy sugars
◦
Colourless needles; yield 75%. – M. p. 125 – 126 C; –
[α]D = +139.13◦ (c = 0.42, CHCl3). – 1H NMR (250 MHz,
CD3OD): δ = 7.24 – 7.40 (m, 5H, Ar-H), 4.71 (d, J =
11.91 Hz, 1H, OCHHPh), 4.53 (d, J = 11.90 Hz, 1H,
OCHHPh), 4.65 (d, J = 7.4 Hz, 1H, 1-H), 4.02 (dd, J = 9.8,
10.4 Hz, 1H, 5-H), 3.47 – 3.77 (m, 4H, 2-H, 3-H, 4-H, 5’-
H). – 13C NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.6 (Ar-
C), 99.0 (C-1), 74.0 (C-2), 72.2 (C-4), 72.3 (OCH2Ph), 64.0
(C-5), 60.4 (C-3). – MS (FD): m/z = 303. – C12H15BrO4
(303.15): calcd. C 47.54, H 4.99; found C 47.52, H 5.00.
To a stirred solution of the 2,3-anhydro sugars 1 – 3
(354 mg, 1 mmol) in 20 ml dry THF, 2 equivalents of the cor-
responding titanium(IV) halide was added dropwise to the
◦
stirre◦d mixture at 0 C under argon. Stirring was continued
at 0 C for 5 – 20 min, until TLC showed no starting 2,3-
anhydro sugar. The reaction mixture was then quenched with
ice-cold water and extracted with ethyl acetate (3 × 20 ml).
The organic layer was then collected, washed with water
(30 ml), brine (30 ml), finally with water and the solvent
evaporated in vacuo. The resulting crude solid was then col-
lected and purified on a column of silica gel (20% ethyl ac-
etate/dichloromethane).
Benzyl 3-iodo-3-deoxy-α-D-xylopyranoside (9)
◦
Colourless needles; yield 81%. – M.p. 75 – 76 C (lit.
◦
75 C [16]); – [α]D = +56.55◦ (c = 0.12, CHCl3). – 13C
NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.6 (Ar-C), 96.7
(C-1), 73.8 (C-2), 71.5 (C-4), 69.8 (OCH2Ph), 62.4 (C-5),
42.5 (C-3). – MS (FD): m/z = 350. – C12H15IO4 (350.16):
calcd. C 41.16, H 4.32; found C 41.20, H 4.28.
Benzyl 3-chloro-3-deoxy-β-L-xylopyranoside (4)
Colourless needles; yield 97%. – M.p. 152 ◦C (lit.
◦
152 C [17]); – [α]D = +6.85◦ c = 0.13, CHCl3). – 13C
NMR (62.9 MHz, CDCl3): δ = 128.6 – 128.2 (Ar-C), 97.11
(C-1), 69.7 (C-2), 72.3 (C-4), 70.6 (OCH2Ph), 66.2 (C-5),
62.3 (C-3). – MS (FD): m/z = 258. – C12H15ClO4 (258.69):
calcd. C 55.71, H 5.84; found C 55.73, H 5.76.
Benzyl 3-chloro-3-deoxy-α-D-arabinopyranoside (10)
C◦olourless needles; yield 94%. – M. p. 142 – 143 ◦C (lit.
142 C [17]); – [α]D = +95.12◦ (c = 0.18, CHCl3). – 13C
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S. T. A. Shah et al. · Regioselective Conversion of Anhydro Sugars into Halohydrins
NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.6 (Ar-C), 96.6 1997 independent reflections were measured within the range
(C-1), 73.3 (C-2), 71.5 (C-4), 69.8 (OCH2Ph), 62.4 (C-5), of θ = 5.23 – 64.94◦. The initial positions for all non-
59.4 (C-3). – MS (FD): m/z = 258. – C12H15ClO4 (258.69): hydrogen atoms were obtained by using direct methods of the
calcd. C 55.71, H 5.84; found C 55.62, H 5.90.
SHELXS-97 program [28]. The structure was refined using
of the SHELXL-97 program [29]. Positional and displace-
ment parameters for non-hydrogen atoms were refined using
a full-matrix least-squares refinement procedure. Atomic po-
sitions of hydrogen atoms were determined from a difference
Fourier map and refined isotropically. Crystal data and crys-
tallographic details are presented in Tables 1 and 2. Fig. 1
shows the ORTEP plot of 4. Atomic parameters, isotropic
displacement parameters, additional bond distances and an-
gles and structure factors for compound 4 have been de-
posited at the Cambridge Crystallographic Data Centre and
allocated the deposition number CCDC 209834.
Benzyl 3-iodo-3-deoxy-α-D-arabinopyranoside (11)
Colourless needles; yield 87%. – M.p. 160 ◦C (lit.
◦
160 C [16]); – [α]D = −48.92◦ (c = 12, MeOH). – 13C
NMR (62.9 MHz, CDCl3): δ = 128.1 – 128.5 (Ar-C), 102.5
(C-1), 72.5 (C-2), 70.8 (OCH2Ph), 70.4 (C-4), 67.2 (C-5),
37.8 (C-3). – MS (FD): m/z = 350. – C12H15IO4 (350.16):
calcd. C 41.16; H 4.32; found C 41.10, H 4.37.
Crystal structure determination of benzyl 3-chloro-3-deoxy-
β-L-xylopyranoside (4)
Acknowledgement
The crystal structure of compound 4 was determined
by the single-crystal X-ray diffraction method. Preliminary
We express our gratitude to Deutscher Akademischer
examination and data collection were performed with Cu- Austauschdienst (DAAD, Bonn, Germany) for a sandwich-
˚
Kα radiation (λ = 1.54056 A) on an ENRAF-NONIUS type scholarship, granted to S. T. A. Shah and A. M.
CAD4 diffractometer operating in the omega scan mode. Heinrich.
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