Ethyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate

Article abstract of DOI:10.1023/A:1021347732701

The crystal structure, at 120 K, and solution ¹H and ¹³C NMR spectra of ethyl 1,2,3,4-tetra-O-acetyl-β-D- glucopyranuronate, (8) have been determined. Compound 8 crystallizes in the triclinic space group, P1(Z = 1) with a = 6.0209(3) A, b = 8.9698(5) A, c = 9.9818(8) A, α = 104.965(2)°, β= 98.522(3)°, γ = 106.790(5)°. The Cremer and Pople puckering parameters [Q = 0.602(4) A, θ = 7.1(4)°, φ = 325(3)°] for the pyranose ring in the solid state indicate a near ideal ⁴C₁ chair conformation with a slight distortion in the direction towards ⁰H₅. A number of weak, soft intermolecular C-H ... O hydrogen bonds set up a 3D array. NMR spectra and FAB and EIMS data have been obtained. Solution NMR parameters suggest that the solid state conformation is maintained in solution in chloroform.

Full text of DOI:10.1023/A:1021347732701

C
Journal of Chemical Crystallography, Vol. 33, No. 1, January 2003 ( 2003)
Ethyl 1,2,3,4-tetra-O-acetyl- -D-glucopyranuronate
Thomas C. Baddeley,(1) Iain G. Davidson,(2) Janet M.S. Skakle,(1) and James L. Wardell(1)
Received December 12, 2001
The crystal structure, at 120 K, and solution 1H and 13C NMR spectra of ethyl 1,2,3,4-tetra-
O-acetyl- -D-glucopyranuronate, (8) have been determined. Compound 8 crystallizes in the
˚
˚
triclinic space group, P1(Z = 1) with a = 6.0209(3) A, b = 8.9698(5) A, c = 9.9818(8)
˚
A, = 104.965(2) , = 98.522(3) , = 106.790(5) . The Cremer and Pople puckering
˚
parameters [Q = 0.602(4) A, = 7.1(4) , = 325(3) ] for the pyranose ring in the solid
4
state indicate a near ideal C1 chair conformation with a slight distortion in the direction
0
---
towards H5. A number of weak, soft intermolecular C
H
O hydrogen bonds set up a 3D
array. NMR spectra and FAB and EIMS data have been obtained. Solution NMR parameters
suggest that the solid state conformation is maintained in solution in chloroform.
KEY WORDS: Glucopyranuronic derivatives; conformation; NMR; MS.
---
in classic and strong H-bonding, e.g., O H
Introduction
D-Glucopyranuronic acid (1), its mono- and
O
---
and N H
O interactions, which connect the
molecules into supramolecular assemblies in the
polysaccharide derivatives are widely distributed
in plants and animals.1 This and their numerous
medicinal and industrial applications make them
important compounds.
solid state and in solution. In recent times, weak or
---
ingly been recognised as also being of consider-
able importance in the organization of molecular
assemblies in the solid state.12
soft H-bonds, such as C H
O, have increas-
The structures of various monosaccharide
- and -D-glucopyranuronic acid derivatives are
listed in the Cambridge Structural Data Base,2 at
the Chemical Database Service of the EPSRC at
Daresbury.3 These include hydrated metal -D-
glucopyranuronates, e.g., hydrates of 2,4–6 -D-
glucopyranuronamide7 3 and its mono hydrate [3:
H2O]8, and polyesterified glycoside derivatives,
4,9 5,9 6,10 and 7.11 Compounds containing amido
and/or free hydroxyl groups, such as 2–4, take part
As part of our studies on soft H-
bonds,13 we have determined the crystal struc-
ture of the peresterified D-glucopyranuronic
acid derivative, ethyl 1,2,3,4-tetra-O-acetyl- -D-
glucopyranuronate (8). In 8, as all OH groups are
fully derivatised as ester groups, the only H-bonds
---
present would be of the soft C H
O variety.
Relatively few targeted formations of 8 have
been indicated in the literature. Reaction of ethyl
D-glucopyranuronate with AcONa and Ac2O
produced an ethyl 1,2,3,4-tetra-O-acetyl-D-
glucopyranuronate product, mp 143 C, assumed
to be the -anomer, 8, from its [ ]D value.14
A mixture of 8 and its anomer, ethyl 1,2,3,4-
tetra-O-acetyl- -D-glucopyranuronate (9), was
(1) Department of Chemistry, University of Aberdeen, Meston Walk,
Old Aberdeen AB24 3UE, Scotland.
(2) Quadrant Healthcare Ltd., 1 Mere Way, Ruddington, Nottingham
NG11 6JS, England.
To whom correspondence should be addressed. E-mail: j.skakle@
abdn.ac.uk
33
C
1074-1542/03/0100-0033/0 2003 Plenum Publishing Corporation

34
Baddeley, Davidson, Skakle, and Wardell
D-Glucopyranuronic acid was a commercial
sample.
1,2,3,4-Tetra-O-acetyl- -D-glucopyranuronic
acid (10)
D-Glucopyranururonic acid (1) (5.0 g,
26 mmol) was added with stirring to acetic an-
hydride (25 mL), containing concentrated sulfu-
ric acid (3 drops). The temperature was allowed
to rise to 60 C. After complete dissolution, a fur-
ther quantity (5.0 g) of 1 was added. The solu-
tion was cooled to room temperature and water
added (75 mL). The precipitate of 1,2,3,4-tetra-O-
acetyl- -D-glucopyranuronic acid: monohydrate
(10:H2O) was collected, mp 92–93 C, 9.8 g, 50%.
1H NMR (250 MHz, CDCl3): 2.01, 2.03,
2.06, 2.10 (4s, 4 CH3CO), 2.81 (s, H2O +
CO2H), 4.61 (d, 1H, J = 9.2 Hz, H-5), 5.13 (dd,
1H, J = 6.7, 8.2 Hz, H-2), 5.27 (t, 1H, J = ca
9.0 Hz, H-4), 5.44 (br t, 1H, J = ca. 9.0 Hz, H-3),
5.85 (d, 1H, J = 6.7 Hz, H-1).
obtained from the reaction of diazoethane and
a mixture of 1,2,3,4-tetra-O-acetyl- - and -D-
1
glucopyranuronic acid:15 while the H and13C
NMR spectra of the mixture was reported, no data
for separated compounds were provided. The
melting point of our sample, determined both via a
Kofler hotstage and by DSC, was somewhat lower
at 133–134 C. In order to obtain reliable data for
8, a directed synthesis using well characterised
1,2,3,4-tetra-acetyl-O- -D-glucuronic acid (10)
has been employed. The 1H and13C NMR spectra
are reported along with the crystal structure
of 8.
Synthesis of 8
Compound (10:H2O) was dehydrated
azeotropically with toluene. To a solution of 10
(2.0 g, 5.5 mmol), p-(dimethylamino)pyridine
(6 mg) and EtOH (1 mL, 22 mmol) in acetonitrile
(5 mL) was added 1,3-dicyclohexylcarbodiimide
(DCC) (1.3 g, 6.1 mmol) with stirring. The
reaction mixture was stirred for 3 h, filtered and
the filtrate rotary evaporated. The oily residue
was crystallised from ethanol to give 8: yield
1.0 g, 46%; mp 134–135 C (Kofler hotstage),
132–133 C (DSC): lit value11 mp 143 C.
Experimental
Melting points were determined using a
Kofler hotstage. Solution NMR were obtained
on Bruker 250 MHz and Varian 400 MHz
instruments, IR spectra on Philips Analytical PU
9800 FTIR and Nicolet 205 FTIR instruments,
DSC on a Mettler Toledo DSC 821e instrument.
X-ray data were collected by the EPSRC National
Crystallography Service, at the University of
Southampton on an Enraf Nonius Kappa CCD
diffractometer (graphite-monochromatised Mo
1H NMR (400 MHz, CDCl3): 1.25 (t, J =
7.2 Hz, 3H, CH3CH2), 1.98 (s, 3H, CH3CO), 1.99
(s, 6H, 2 CH3CO), 2.07 (s, 3H, CH3CO), 4.12
(d, 1H, J = 9.2 Hz, H-5), 4.14 (dt, 1H, J = 7.2,
12.6 Hz, CH2) 4.18 (dt, 1H, J = 7.2, 12.6 Hz,
CH2), 5.12 (br t, 1H, J = 7.9, 8.8 Hz, H2), 5.21
(t, 1H, J = 9.2 Hz, H-4), 5.26 (t, 1H, J = ca.
9 Hz, H-3), 5.72 (d, J = 7.9 Hz, 1H, H-1).
˚
K radiation, = 0.71073 A), and MS data were
obtained by the EPSRC National Mass Spectrom-
etry Service Centre, at the University of Wales,
Swansea.
13C NMR (100 MHz, CDCl3):
13.9
(CH3CH2), 20.47[CH3CO], 20.49[CH3CO],

Glucuronate
35
Table 2. Atomic Coordinates ( 104) and Equivalent Isotropic
20.52[CH3CO],
20.7[CH3CO],
62.3[C6],
Displacement Parameters (A 103) for 8
˚
68.9[C4], 70.2[C2], 71.9[C5], 73.21[C3],
== ==
91.3[C1], 166.3[C O at C6], 168.8[C O],
a
Atom
x
y
z
Ueq
==
==
==
169.16[C O], 169.22[C O], 169.9[C O].
IR (KBr) : 1761, 1371, 1225, 1215, 1088,
C1
C2
C3
C4
C5
C6
C7
C8
4400(7)
3712(7)
5309(7)
5359(7)
6081(7)
6141(7)
3441(9)
1415(10)
2291(7)
2993(9)
5811(11)
4446(13)
6518(5)
8632(9)
8698(10)
9218(11)
2677(5)
4141(5)
4353(5)
7193(5)
4317(5)
8311(5)
5460(6)
333(5)
1276(5)
922(5)
105(5)
1385(5)
805(5)
2213(5)
2812(5)
3234(7)
2974(5)
4434(7)
169(8)
2072(4)
3385(4)
4002(4)
2861(3)
1612(4)
400(4)
21(1)
23(1)
23(1)
22(1)
22(1)
23(1)
33(1)
44(1)
27(1)
47(1)
55(2)
63(2)
30(1)
40(1)
42(1)
49(1)
26(1)
27(1)
30(1)
26(1)
24(1)
33(1)
48(1)
33(1)
119(3)
55(1)
33(1)
1
1063, 1039 cm .
MS (FAB+): 413.3 (M + Na)+, 331.2 (M
AcO), 169.0.
MS (ES+): 803.2 (2M + Na)+, 413.2 (M +
627(5)
27(6)
Na)+.
MS (ES ): 361.3 (M Et)+.
C9
4655(4)
5971(5)
6421(6)
7492(6)
3547(5)
4027(6)
508(5)
1721(6)
1402(3)
4494(3)
5106(3)
3443(3)
1060(3)
605(3)
C10
C11
C12
C13
C14
C15
C16
O1
O2
O3
O4
O5
O6
O7
O8
O9
O10
O11
Crystal structure determination
288(8)
3448(5)
3896(6)
3570(6)
2954(7)
1795(3)
2431(3)
426(4)
The sample used in the structure deter-
mination was recrystallised from MeOH. The
structure of 8 was solved by direct methods with
SHELXS-9716 and refined by least squares meth-
ods using SHELXL-97.17 Refinement proceeded
1924(3)
210(3)
Table 1. Crystal Data and Structure Refinement for 8
2325(4)
3254(5)
2346(4)
1000(9)
4325(4)
3079(4)
504(4)
CCDC deposit no.
Color
175193
Colorless
C16H22O11
390.34
120(2)
Triclinic
P1
3868(3)
6680(5)
3265(5)
584(3)
7851(9)
4464(6)
4475(5)
Chemical formula
Formula weight
Temperature (K)
Crystal system
Space group
aUeq is defined as one third of the orthogonalized Ui j tensor.
Cell dimensions
˚
a (A)
6.0209(3)
8.8698(5)
9.9818(8)
104.965(2)
98.522(3)
106.790(5)
483.91(5)
1
smoothly to the values given and all H-atoms
were placed geometrically and refined using a rid-
ing model. The absolute configuration was not
determined by anomalous dispersion effects in
the diffraction measurements, and thus the enan-
tiomer was assigned by reference to an unchang-
ing chiral centre in the synthetic procedure.
Crystal data and structure refinement details
are listed in Table 1. The entire process of data col-
lection, cellrefinement, anddatareductionwasac-
complished by means of the programs DENZO18
and COLLECT:19 correction for absorption was
by means of SORTAV.20 Other software packages
used were ORTEP-3 for Windows,21 PLATON, 22
and OSCAIL.23 Final atom coordinates and equiv-
alent isotropic displacement parameters are listed
in Table 2. Atomic coordinates, bond angles and
lengths, torsional angles, and thermal parameters
˚
b (A)
˚
c (A)
( )
( )
( )
3
˚
Volume (A )
Z
Density (calculated density)
(Mg/m3)
Absorption coefficient (mm
Diffractometer/scan
1.339
1
)
0.115
Enraf Nonius Kappa
CCD area detector
3.64–27.48
6289
range for data collection ( )
Reflections measured
Independent/observed reflections 06289 [Rint = 0.0938]/2106
[I > 2 (I)]
2106/3/249
1.033
R1 = 0.0578,
wR2 = 0.1356
R1 = 0.0844,
wR2 = 0.1515
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2 (I)]
R indices (all data)

36
Baddeley, Davidson, Skakle, and Wardell
˚
Table 3. Selected Bond Lengths (A) and Angles ( ) for 8 at
120(2) K
C5 O5
O5 C1
C1 C2
C2 C3
C3 C4
C4 C5
1.422(5)
1.432(4)
1.513(6)
1.518(6)
1.515(6)
1.535(5)
C1 O1
C2 O2
C3 O3
C4 O4
C5 C6
1.406(5)
1.436(5)
1.440(5)
1.445(5)
1.520(6)
C5 O5 C1
C1 C2 C3
C3 C4 C5
O5 C1 O1
C1 C2 O2
C2 C3 O3
C3 C4 O4
C4 C5 C6
110.6(3)
110.1(3)
108.4(3)
106.0(3)
110.2(3)
107.7(3)
108.4(3)
112.1(3)
O5 C1 C2
C2 C3 C4
C4 C5 O5
C2 C1 O1
C3 C2 O2
C4 C3 O3
C5 C4 O4
O5 C5 C6
109.6(3)
110.9(3)
107.7(3)
108.8(3)
105.2(3)
109.4(3)
107.4(3)
107.2(3)
Fig. 1. Atom arrangements and numbering system for 8.
Crystal structure
have been deposited at the Cambridge Crystallo-
graphic Data Centre: deposition no: 175193.
Crystals of 8, suitable for X-ray determi-
nation, were obtained from methanol solution.
The atom numbering system is shown in Fig. 1.
Selected bond angles and lengths are given in
Table 3.
Results and discussion
A standard procedure was used to ob-
tain 8 from a well-characterised sample of
10 and EtOH, using p-(dimethylamino)pyridine
and DCC as promoters. The composition of
the -, -mixture of 1,2,3,4-tetra-O-acetyl-D-
glucopyranuronic acids obtained on reaction of
1 and acetic anhydride depended greatly on the
reaction conditions. The : ratios were readily
determined from the different 1H1 signals [ :
6.29 (d, J = 3.7 Hz) and : 5.85(d, J = 6.7 Hz)]
in the NMR spectra: 1H1 for the -: -forms,
respectively. Using the procedure outlined in the
experimental section, only the -form was iso-
lated; lower reaction temperatures generally led
to a higher proportion of the -form. Full char-
acterisation of 8 was achieved by X-ray crystal-
lography and also by NMR and IR spectroscopy,
and by FAB and ES mass spectrometry. Com-
plete assignment of the 400 MHz 1H NMR spec-
trum was aided by a 1D-TOCSY experiment. The
CH2 protons in the ethyl ester group at C6 are
diastereotopic. The NMR spectra, especially the
J(H,H) values for ring H atoms, indicate a chair
conformation for the pyranose ring.
The pyranose ring in 7 has a near ideal
4C1 conformation. The Cremer and Pople puck-
ering parameters,24 as calculated by the PLATON
˚
program22 are Q = 0.602(4) A, = 7.1(4) ,
=
325(3) , which suggests a slight distortion in
o
the direction towards H5.25 Structures of the
related compounds, 5–7,9–11also have conforma-
4
---
---
tions close to C1. The anomeric C O [C1 O1]
˚
bond length in 8 at 1.405(5) A is significantly
shorter than all the other ring carbon to oxygen
Table 4. Soft H-Bonds in 8
D
(A)
H
H
A
D
A
D
H
( )
A
˚
˚
˚
D
H
A
(A)
(A)
Intermolecular
C3 H3
C5 H5
C8 H8A
C8 H8B
O8i
O8i
O9ii
O11iii
1.00
1.00
0.98
0.98
2.29
2.35
2.46
2.55
3.155(5)
3.231(5)
3.383(7)
3.517(6)
143.8
146.2
156.1
167.4
Intramolecular
C3 H3
C4 H4
O9
O10
1.00
1.00
2.21
2.28
2.665(6)
2.700(5)
105.7
104.0
Note: Symmetry operation: i: x + 1, y, z; ii: x 1, y, z 1; iii: x,
y + 1, z.

Glucuronate
37
ii
¯ ¯
O9 , which provides chains in the [011] direction; (b)
Fig. 2. H-bonding interactions in 8: (a) C8 H8A
C3 H3
O8i and C5 H5
O8i, which provides chains in the [100] direction; and (c) C8 H8B O11iii, which
provides chains in the [010] direction. Symmetry operations: i: x + 1, y, z; ii: x 1, y, z 1; iii: x, y + 1, z.
---
bond lengths, C(n) O(n); n = 2–4, which range
bonds, both having carbonyl ester oxygen accep-
tors (at C2 and C3), which provides a 3D network.
The sole intramolecular H-bond in 6 has the car-
bonyl oxygen at C4 as the acceptor.10 In contrast,
in 7, the single intermolecular H-bonding involves
the ether oxygen at the anomeric position, i.e., at
C1: intramolecular H-bonding, however, utilises
both carbonyl oxygens (at C2, C3, and C4) and
the ring oxygen as the acceptor centres.11
˚
from1.437(5)to1.457(5)A. Thisagreeswithfind-
ings in other similar fully substituted molecules,
including 5–7.9–11
---
There are various soft C H
O hydrogen
bonds in 8, see Table 4. All four intermolecu-
lar H-bonds involve carbonyl oxygens in 8: the
only carbonyl oxygen not involved in intermolec-
ular H-bonding is O7, i.e., that in the ester unit
at the anomeric position. A 3D network is set up
It is very clear that intermolecular interac-
tions, and thus supramolecular arrangements, are
very difficult to predict.
¯ ¯
fromthecombinationsofchainsinthe[011]direc-
---
tion arising from C8 H8A
O9ii interactions,
O8i
---
chains in the [100] direction from C3 H3
---
and C5 H5
O8i interactions, and chains in
Acknowledgments
O11iii, see
---
the [010] direction from C8 H8
Fig. 2.
We acknowledge the uses of the Chemical
Database Service of the EPSRC at Daresbury, UK, the
National Crystallographic Data Collection Service of
the EPSRC, at the University of Southampton, UK,
and the EPSRC National Mass Spectrometry Service
Centre at the University of Wales, Swansea.
Compounds 5–7 are also fully derivatised -
D-glucuronic acid derivatives, only differing with
8 in each having alkoxy groups at the anomeric po-
sition rather than an ester unit.9–11 However, there
are marked differences in the H-bonding interac-
tions in the four molecules 5–8 in terms of the
numbers of H-bonds present, the division between
inter- and intramolecular H-bonds, and the accep-
tor centres used. In 5, intermolecular H-bonding
involves the carbonyl oxygen in the ester group
at C2, while the intramolecular H-bond acceptors
are the carbonyl oxygens in the C2 and C4 ester
groups. The result in 5 is thus to form chains of
molecules.9 In 6, there are two intermolecular H-
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