X-ray diffraction and high-resolution NMR spectroscopy of methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enopyranuronate

Article abstract of DOI:10.1016/j.carres.2007.03.004

Single-crystal X-ray diffraction and high-resolution ¹H and ¹³C NMR spectral data for methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enopyranuronate are reported. The ⁵H₄ conformation was found to be the preferred form for this glycal, both in the crystal lattice and in solution. The factors determining the ⁴H₅ ? ⁵H₄ conformational equilibrium for acetylated glycals are discussed.

Full text of DOI:10.1016/j.carres.2007.03.004

Carbohydrate Research 342 (2007) 1280–1284
Note
X-ray diffraction and high-resolution NMR spectroscopy
of methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-D-
arabino-hex-1-enopyranuronate
Beata Liberek,a,* Dorota Tuwalska,a Antoni Konitza,b and Artur Sikorskia
aFaculty of Chemistry, University of Gdan´sk, Sobieskiego 18, PL-80-952 Gdan´sk, Poland
bDepartment of Inorganic Chemistry, Gdan´sk University of Technology, Narutowicza 11/12, PL-80-952 Gdan´sk, Poland
Received 7 November 2006; received in revised form 2 March 2007; accepted 5 March 2007
Available online 12 March 2007
1
Abstract—Single-crystal X-ray diffraction and high-resolution H and 13C NMR spectral data for methyl 3,4-di-O-acetyl-1,5-an-
5
hydro-2-deoxy-D-arabino-hex-1-enopyranuronate are reported. The H4 conformation was found to be the preferred form for this
glycal, both in the crystal lattice and in solution. The factors determining the 4H5 ¢ 5H4 conformational equilibrium for acetylated
glycals are discussed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Methyl 3,4-di-O-acetyl-D-glucuronal; X-ray diffraction; Single crystal; Torsion angle; 5H4 Conformation
1,5-Anhydro-2-deoxy-1-enitols—trivial name glycals—
are monosaccharides with a double bond between car-
bon atoms C-1 and C-2 of the pyranose ring. Since the
double bond in glycals is adjacent to an anomeric car-
bon atom, these sugars are very useful as glycosylating
agents.1–5
Methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-D-ara-
bino-hex-1-enopyranuronate (4)—commercial name
methyl 3,4-di-O-acetyl-D-glucuronal—was synthesized
from D-glucurono-6,3-lactone (1) according to a well-
known procedure (Scheme 1).11 This involves the base-
catalyzed transesterification of 1, followed by acetyl-
ation; then, the reaction of 2 with hydrobromic acid in
acetic acid, followed by the reduction of a-bromide 3
with zinc dust in aq acetic acid.
Conformational studies of the pyranose ring are
important and have been meticulously investigated:
detailed knowledge of the conformations of sugars is
essential for understanding their physical, chemical,
and biological properties.6,7 The conformations of gly-
cals undoubtedly play a significant role in the stereo-
chemistry of the reactions in which they participate.8–10
This paper reports on single-crystal X-ray diffraction
and high-resolution NMR spectral data for methyl 3,
4-di-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-eno-
pyranuronate (4), a versatile intermediate in the synthe-
sis of glucopyranuronates modified at the anomeric
carbon,11–13 and discusses the conformation of the glu-
curonic acid methyl ester glycal 4 in the crystal lattice
and in solution.
5
In the crystal, 4 adopts the H4 half-chair conforma-
tion (Fig. 1) with ring-puckering parameters14,15
˚
Q = 0.447(4) A, H = 127.4(5)ꢁ and U = 90.9(6)ꢁ. The
5H4 form of 4 is illustrated by the torsion angles listed
in Table 3. For example, the O-6–C-1–C-2–C-3 torsion
angle 3.6ꢁ indicates an almost planar orientation of the
respective atoms. Next, the O-11–C-4–C-5–C-15 torsion
angle of 176.1ꢁ is in agreement with an antiperiplanar
orientation of the 4-OAc and 5-COOMe groups, and
the O-7–C-3–C-4–O-11 torsion angle ꢀ162.5ꢁ confirms
the quasi-antiperiplanar orientation of the 3-OAc and
4-OAc groups. The C-1–C-2–C-3–C-4 (10.6ꢁ) and C-2–
C-1–O-6–C-5 (13.6ꢁ) torsion angles show that the deflec-
tions of carbon atoms C-4 and C-5 from the double-
bond plane are similar and rather small.
*
Corresponding author. Tel.: +48 58 5235344; fax: +48 58 5235472;
e-mail: beatal@chem.univ.gda.pl
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.03.004

B. Liberek et al. / Carbohydrate Research 342 (2007) 1280–1284
1281
O
C
COOCH3
COOCH3
COOCH3
O
HO
O
O
O
OH
a
O
c
b
OAc
OAc
OAc
OAc
AcO
AcO
AcO
Br
OAc
OH
OAc
1
2
3
4
Scheme 1. Reagents: (a) (1) NaOH/CH3OH; (2) Ac2O/pyridine; (b) HBr/AcOH; (c) Zn/AcOH.
In solution, glycals exist in equilibrium between the
5
4H5 and H4 half-chair conformations (Fig. 3). The fol-
lowing factors influence the conformational equilibrium
of peracetylated glycals. The first, known as the allylic
effect, favors the quasi-axial orientation of the allylic
acetoxy group at the C-3 carbon atom8 and in this
way stabilizes the 5H4 form of glycals with the D-arabino
(4 and 5) or D-lyxo (6 and 7) structures (Fig. 3). The sec-
ond factor displays no preference for the quasi-axial ori-
entation of the 3-OAc group when the group bound to
the C-5 carbon atom is oriented axially owing to the
unfavorable 1,3-diaxial interactions occurring between
these two groups. In this way the second factor com-
5
petes with the first one and destabilizes the H4 form
of glycals 4–7. In our opinion, there is also a third factor
affecting the conformational equilibrium of peracetyl-
ated glycals. This factor prefers the 4-OAc group to
be oriented axially when the 3-OAc group is oriented
quasi-equatorially. Two equatorially oriented groups
Figure 1. Structure of 4 showing 25% probability displacements for
ellipsoids.
4
H5
5
H4
COOMe
5
4
2
AcO
3
AcO
3
6
O
1
5
1
6
2
AcO
AcO
AcO
AcO
O
COOMe
93 %8
4
4
OAc
CH2OAc
5
4
2
AcO
3
AcO
3
1
5
6
O
1
6
2
O
59 %16
4
CH2OAc
5
OAc
AcO
4
COOMe
5
AcO
3
1
5
6
O
1
6
2
2
4
O
3
82 %8
COOMe
AcO
6
7
AcO
CH2OAc
5
4
AcO
3
1
5
6
O
1
6
2
2
4
O
3
88 %16
CH2OAc
AcO
Figure 2. Molecular packing of 4 (view along c-axis). The hydrogen
atoms not involved in C–Hꢁ ꢁ ꢁO interactions have been omitted.
Figure 3. The 4H5 ¢ 5H4 conformational equilibrium for glycals 4–7
in solution.

1282
B. Liberek et al. / Carbohydrate Research 342 (2007) 1280–1284
(3-OAc and 4-OAc) adjacent to the double bond of gly-
cals should destabilize such an almost coplanar struc-
ture. This factor has to be taken into account because
it is the only one able to explain why tri-O-acetyl-D-
galactal (7) is more stable than tri-O-acetyl-D-glucal
(5) in the 4H5 conformation in solution (molar fractions
group to be oriented axially when the 3-OAc group is
oriented quasi-equatorially, thereby displacing the con-
formational equilibrium state in the direction of the
4H5 form of 6.
4
in the H5 form: 88% and 59%, respectively).16
1. Experimental
High-resolution NMR spectroscopy of 4 (1H, 13C,
COSY, HSQC, HMBC), especially the most diagnostic
J3,4 = 1,95 Hz and J4,5 = 2,44 Hz coupling constants,
call for the equatorial (H-4 and H-5) or quasi-equatorial
(H-3) orientation of the respective protons, which is
1.1. General methods
Melting point was uncorrected. Optical rotation was
determined at room temperature with a Hilger–Watt
polarimeter in 1-dm tube at the D line of sodium for
solution in CHCl3. The IR spectrum was recorded as
Nujol mulls with a Bruker IFS 66 spectrophotometer.
The NMR spectra were recorded at room temperature
5
evident for the H4 conformation of 4 in chloroform
solution, the same as 4 adopts in the crystal lattice.
According to the Karplus curve,17 measured J3,4
=
1,95 Hz and J4,5 = 2,44 Hz coupling constants are in
good agreement with the gleaned from the crystallo-
graphic data H-3A–C-3–C-4–H-4A torsion angle 76.6ꢁ
and H-4A–C-4–C-5–H-5A torsion angle ꢀ61.9ꢁ (Table
1
on a Unity Plus 500 MHz spectrometer. H NMR spec-
tra were measured at 500 MHz and 13C spectra at
125 MHz in CDCl3 or (CD3)2CO solutions, using the
standard pulse sequence and procedures.
5
3). This additionally confirms the H4 conformation of
4 in solution.
Chemical shifts and coupling constants of 4 recorded
in chloroform are almost identical with the chemical
shifts and coupling constants reported by Thiem and
Ossowski, who stated that a 93% molar fraction of 4
1.2. Methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-D-
arabino-hex-1-enopyranuronate (4)
Compound 4 was synthesized according to literature
20
adopts the H4 conformation in acetone.8 In order to
data:11 82%, mp 84–87 ꢁC, lit.11 88–91 ꢁC; ½aꢂD ꢀ67 (c
5
examine the possible 4H5 ¢ 5H4 conformational equilib-
1.0, CHCl3), lit.11 ꢀ61.3 (c 0.87, CHCl3); Rf 0.54 (1:1
n-heptane–AcOEt); IR: m 1754 and 1731 (C@O), 1646
1
rium the additional H NMR spectra of 4 at rt, ꢀ20,
ꢀ50, and ꢀ80 ꢁC in acetone were recorded. These spec-
tra, irrespective of the temperature, are the same as spec-
trum of 4 recorded at rt in acetone by Thiem and
Ossowski. In the light of these results, we state that
(C@C), 1218 (CO–O) cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d 6.70 (d, 1H, J1,2 5.86 Hz, H-1), 5.44 (ddd,
1H, J4,5 2.44 Hz, H-4), 5.04 (td, 1H, J2,3 5.37, J2,4
1.46 Hz, H-2), 5.01 (dt, 1H, J3,4 1.95, J3,5 1.46 Hz, H-
3), 4.85 (dd, 1H, H-5), 3.82 (s, 3H, COOCH3), 2.14,
2.01 (2s, 2 · 3H, 2 · OAc); 1H NMR (500 MHz,
(CD3)2CO): d 6.73 (d, 1H, J1,2 6.35 Hz, H-1), 5.43 (td,
1H, J4,5 2.69 Hz, H-4), 4.99 (ddd, 1H, J2,3 5.13, J2,4
1.59 Hz, H-2), 4.95 (dd, 1H, H-5), 4.92 (dddd, 1H, J3,4
2.56, J3,5 1.46, J3,1 0.61 Hz, H-3), 3.80 (s, 3H,
COOCH3), 2.10, 1.98 (2s, 2 · 3H, 2 · OAc); 13C NMR
(500 MHz, CDCl3): d 169.73, 169.52 (C@OAc), 167.43
(C@Oester), 146.60 (C-1), 97.47 (C-2), 72.55 (C-5),
67.63 (C-4), 62.83 (C-3), 52.57 (C-6), 21.11, 21.05
(CH3Ac); MALDI-TOFMS: m/z 281.2 [M+Na]+, 297.2
[M+K]+; Anal. Calcd for C11H14O7: C, 51.17; H, 5.46.
Found: C, 51.08; H, 5.48.
5
the H4 form of 4 is strongly dominant in chloroform
and acetone solutions.
In contrast to 4, structurally very similar compounds,
such as 3,4,6-tri-O-acetyl-D-glucal (5) in both crystal lat-
tice18 and solution, and methyl 3,4-di-O-acetyl-D-galac-
turonal (6), prefer the 4H5 conformation in solution
(molar fractions in acetone: 59%16 and 82%,8 respec-
tively). A comparison of the conformational preferences
of 4, 5, and 6 allows us to draw a number of inferences.
5
Firstly, since 4 mostly adopts the H4 form whereas 5
4
prefers the H5 form, the unfavorable 1,3-diaxial inter-
actions between the 3-OAc and 5-COOMe groups (4)
must be weaker than the analogous interactions between
3-OAc and 5-CH2OAc groups (5). These unfavorable
5
interactions in the H4 form of 5 force the change of
1.3. X-ray crystallographic data
conformation, despite the unfavorable orientation of
both 3-OAc and 4-OAc groups in the 4H5 form. In other
words, the equatorial orientation of the 5-CH2OAc
group is of greater importance for the stability of glycals
than the equatorial orientation of the 5-COOMe group.
Secondly, even though 4 and 6 differ solely in their C-
4 carbon atom configurations, they adopt different con-
Diffraction data were collected at room temperature
(298 K) on a KUMA KM-4 four circle diffractometer19
with MoKa radiation (k = 0.71073 A) using the 2H/x
˚
scan mode. Phase angles were initially determined with
the SHELXS program.20 All H atoms were placed geomet-
rically and refined using a riding model with C–
4
formations (5H4 and H5, respectively). This is due to
H = 0.93–0.98 A, and Uiso(H) = 1.2Ueq(C) (C–H =
˚
˚
the above-mentioned factor, which prefers the 4-OAc
0.96 A and Uiso(H) = 1.5Ueq(C) for the methyl H

B. Liberek et al. / Carbohydrate Research 342 (2007) 1280–1284
1283
Table 1. Crystal data and structure refinement for 4
Table 2. Atomic coordinates (·104) and equivalent isotropic displace-
ment parameters (A · 10 ) for 4
2
3
˚
Empirical formula
Formula weight
Temperature (K)
Wavelength (A)
Crystal system
Space group
C11H14O7
258.22
295(2)
0.71073
Triclinic
Atom
x
y
z
Ueq
C-1
C-2
C-3
C-4
C-5
O-6
O-7
C-8
10,183(6)
8573(7)
6562(5)
6483(4)
8828(5)
10,317(4)
6655(3)
6160(5)
6314(7)
5661(7)
5702(3)
3517(5)
2998(7)
2208(4)
9902(5)
8581(4)
9444(8)
11,727(4)
11,342
8694
5178
5481
8688
7767
5143
6132
3722
3548
1390
9620
10,885
8400
7300(6)
7693(5)
6059(5)
3919(4)
4040(4)
5467(4)
6292(3)
7778(5)
7815(6)
8888(5)
3255(3)
1893(4)
1245(7)
1337(4)
4587(4)
3255(3)
3685(8)
5983(4)
8386
9041
6074
2908
2649
7931
6545
8993
384
9706(5)
8525(6)
6389(5)
6062(4)
6914(4)
9140(3)
4547(3)
4072(6)
2170(6)
5073(6)
7355(3)
6346(5)
7856(8)
4490(4)
5631(5)
3566(3)
2211(6)
6444(4)
11,062
9041
6320
4522
6781
2412
890
1975
8226
9154
7166
2300
2706
729
68(1)
68(1)
51(1)
44(1)
48(1)
62(1)
55(1)
59(1)
72(1)
97(1)
52(1)
52(1)
82(1)
74(1)
48(1)
58(1)
78(1)
72(1)
82
˚
ꢀ
P1
Unit cell dimensions
˚
a (A)
7.195(1)
˚
b (A)
7.418(1)
˚
c (A)
7.491(1)
a (ꢁ)
b (ꢁ)
c (ꢁ)
106.25(3)
113.73(3)
106.07(3)
315.0(2)
C-9
O-10
O-11
C-12
C-13
O-14
C-15
O-16
C-17
O-18
H-1A
H-2A
H-3A
H-4A
H-5A
H-9A
H-9B
H-9C
H-13A
H-13B
H-13C
H-17A
H-17B
H-17C
3
˚
V (A )
Z
1
Dcalcd (Mg mꢀ3
)
1.361
0.115
136
Absorption coefficient (mmꢀ1
F(000)
)
Crystal size (mm)
H Range for data collection (ꢁ)
Limiting indices
0.4 · 0.3 · 0.2
3.19–25.24
ꢀ8 6 h 6 8, ꢀ8 6
k 6 8, ꢀ8 6 l 6 5
1926/1136
[Rint = 0.0508]
97.5
81
61
52
57
Reflections collected/unique
Completeness 2H = 50.24ꢁ (%)
Refinement method
Full-matrix
least-squares on F2
1111/3/167
1.033
108
108
108
124
124
124
117
117
117
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R1 = 0.0354
wR2 = 0.0876
R1 = 0.0452
wR2 = 0.0936
0(1)
0.18(3)
0.153 and ꢀ0.160
2465
464
5043
3653
R indices (all data)
Absolute structure parameter
Extinction coefficient
Largest difference in peak and hole (e A
2642
ꢀ3
˚
Ueq is defined as one third of the trace of the orthogonalized Uij tensor.
)
Table 3. Selected torsion angles (ꢁ) for 4
atoms). Crystallographic data, data collections, and
structure refinements are summarized in Table 1; coordi-
nates of atoms and isotropic temperature factors in
Table 2; a selection of crystal’s important geometric
parameters in Table 3, and short contacts data in Table
4.
The crystal structure of 4 was refined to R1 = 0.0452
(1926 reflections, all unique) and R1 = 0.0354 (1111
reflections with F0 > 2r(F0)) by the full-matrix least-
squares method using the SHELXL-97 program21 based
on 167 parameters. Figure 1 illustrates the compound’s
structure, showing the conformation and atom number-
ing system.22 Figure 2 shows the molecular packing in
the crystal, prepared by PLUTO-78.23 The computational
material for publication was prepared using the PLATON
program.14
Torsion angles
(ꢁ)
O-6–C-1–C-2–C-3
C-1–C-2–C-3–O-7
C-1–C-2–C-3–C-4
O-7–C-3–C-4–O-11
C-2–C-3–C-4–O-11
O-7–C-3–C-4–C-5
C-2–C-3–C-4–C-5
O-11–C-4–C-5–O-6
C-3–C-4–C-5–O-6
O-11–C-4–C-5–C-15
C-3–C-4–C-5–C–15
C-2–C-1–O-6–C-5
C-4–C-5–O-6–C-1
C-15–C-5–O-6–C-1
H-1A–C-1–C-2–H-2A
H-2A–C-2–C-3–H-3A
H-3A–C-3–C-4–H-4A
H-4A–C-4–C-5–H-5A
3.6(5)
ꢀ104.9(3)
10.6(4)
ꢀ162.5(2)
76.5(3)
82.0(3)
ꢀ39.0(3)
ꢀ59.7(3)
57.5(3)
176.1(2)
ꢀ66.7(3)
13.6(4)
ꢀ43.8(3)
83.0(3)
3.7
48.2
76.6
ꢀ61.9
Supplementary data
626102) with the Cambridge Crystallographic Data
Center. These data may be obtained, on request, from
The Director, CCDC, 12 Union Road, Cambridge,
Full crystallographic details, excluding structures fea-
tures, have been deposited (Deposition No. CCDC

1284
B. Liberek et al. / Carbohydrate Research 342 (2007) 1280–1284
Table
4. Hydrogen
bonds
for
4
with
distances
(d):
6. Appell, M.; Strati, G.; Willett, J. L.; Momany, F. A.
Carbohydr. Res. 2004, 339, 537–551.
7. Nyerges, B.; Kovacs, A. J. Phys. Chem. A 2005, 109, 892–
897.
8. Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287–
313.
9. Ernst, Ch.; Piacenza, M.; Grimme, S.; Klaffke, W.
Carbohydr. Res. 2003, 338, 231–236.
10. Harders, J.; Garming, A.; Jung, A.; Kaiser, V.; Mone-
nschein, H.; Ries, M.; Rose, L.; Scho¨ning, K.-U.; Weber,
T.; Kirschning, A. Liebigs Ann. 1997, 2125–2132.
11. Wyss, P. C.; Kiss, J.; Arnold, W. Helv. Chim. Acta 1975,
58, 1847–1864.
12. Smiatacz, Z.; Chrzczanowicz, I.; Myszka, H.; Dokurno, P.
J. Carbohydr. Chem. 1995, 14, 723–735.
13. Nishimura, S.-I.; Nomura, S.; Yamada, K. Chem. Com-
mun. 1998, 617–618.
˚
˚
d(Dꢁ ꢁ ꢁA) < R(D) + R(A) + 0.50 A; d(Hꢁ ꢁ ꢁA) < R(H) + R(A) ꢀ 0.12 A
and angle (\) \D–Hꢁ ꢁ ꢁA > 100.0ꢁ
D–H
A
d(D–H) d(Hꢁ ꢁ ꢁA) d(Dꢁ ꢁ ꢁA) \D–Hꢁ ꢁ ꢁA
C-1–H-1A O-14i 0.93
C-3–H-3A O-18ii 0.98
C-5–H-5A O-10iii 0.98
2.57
2.50
2.56
2.57
3.363(4)
3.481(5)
3.376(5)
3.343(7)
144
174
141
138
C-9–H-9B O-7i
0.96
Symmetry codes: (i) 1 + x, 1 + y, 1 + z; (ii) ꢀ1 + x, y, z; (iii) x, ꢀ1 +
y, z.
CB2 1EZ, UK (tel.: +44-1223-336408; fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk).
14. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7–13.
15. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97,
1354–1358.
Acknowledgment
16. Rico, M.; Santoro, J. Org. Magn. Reson. 1976, 8, 49–
55.
17. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectro-
metric Identification of Organic Compounds; John Wiley &
Sons: New York, 1991; pp 196–197.
This research was supported by the Polish State Com-
mittee for Scientific Research under grants DS/8361-4-
0134-7 and BW/8000-5-0052-7.
18. Vangehr, K.; Luger, P.; Paulsen, H. Carbohydr. Res. 1979,
70, 1–11.
19. Kuma KM-4 Software User’s Guide. Version 3.1. Kuma
Diffraction, Wrocław, Poland, 1989.
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21. Sheldrick, G. M. SHELXL-97. Program for Crystal Structure
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22. Johnson, C. K. ORTEP II; Report ORNL-5138, Oak
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