Synthesis and characterization of the hexenuronic acid model methyl 4-deoxy-β-l-threo-hex-4-enopyranosiduronic acid

Article abstract of DOI:10.1016/j.carres.2006.06.012

A facile synthetic scheme for the preparation of methyl 4-deoxy-β-l-threo-hex-4-enopyranosiduronic acid utilizing the commercially available methyl α-d-galactopyranoside as starting material has been developed. The synthesis sequence comprises six high yielding reaction steps: TEMPO oxidation, acetylation, methanolysis of the lactone, acetylation, β-elimination, and final removal of the protecting groups. Only one column chromatographic purification is needed throughout the whole sequence. The overall yield is 60%. The final product has been characterized by NMR, Raman, UVRR, FTIR, and HRMS.

Full text of DOI:10.1016/j.carres.2006.06.012

Carbohydrate Research 341 (2006) 2439–2443
Note
Synthesis and characterization of the hexenuronic acid model
methyl 4-deoxy-b-L-threo-hex-4-enopyranosiduronic acid
Immanuel Adorjan,* Anna-Stiina Jaaskelainen and Tapani Vuorinen
¨ ¨
¨
Helsinki University of Technology, Department of Forest Products Technology, PO Box 6300, FIN-02015 HUT, Finland
Received 30 March 2006; received in revised form 13 June 2006; accepted 14 June 2006
Available online 28 July 2006
Abstract—A facile synthetic scheme for the preparation of methyl 4-deoxy-b-L-threo-hex-4-enopyranosiduronic acid utilizing the
commercially available methyl a-D-galactopyranoside as starting material has been developed. The synthesis sequence comprises
six high yielding reaction steps: TEMPO oxidation, acetylation, methanolysis of the lactone, acetylation, b-elimination, and final
removal of the protecting groups. Only one column chromatographic purification is needed throughout the whole sequence. The
overall yield is 60%. The final product has been characterized by NMR, Raman, UVRR, FTIR, and HRMS.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: TEMPO oxidation; b-Elimination; Characterization by FTIR, Raman, UVRR, NMR
Hexenuronic acid (HexA) is widely distributed among
natural polysaccharides such as heparin, chondroitin,
and lepidimoide.1–3 In lepidimoide, for example, the
HexA moiety is important for its growth promoting
activity.2,3 During alkaline pulping 4-O-methylglucu-
ronic acid units, attached to xylan, are converted to
HexA by b-elimination.4,5 HexA was suspected, and
has recently been confirmed, to play an important role
in the brightness reversion of pulp6 as well as to increase
the consumption of bleaching chemicals7,8 and contribute
considerably to the kappa number of oxygen-delignified
kraft pulp.9 Despite the importance of HexA, no fast
and easy chemical synthesis using a commercially
available starting material has been published so far.
Many HexA preparations use 4-O-methylglucurono-
xylan as starting material.10,11 Hot alkali treatment
yields hexenuronoxylan, which is subjected to enzymatic
hydrolysis to afford HexA oligosaccharides after tedious
purification procedures. These procedures yield only
small amounts of the final oligomeric product. Thus
the aim of this work was to establish a fast, simple,
and high yield synthetic pathway involving as few labo-
rious purification steps as possible. The HexA model
described here was designed to be utilized to investigate
in detail all reactions in connection with bleaching and
brightness revision of pulp. Further on the model should
be applied as a calibration standard for analytical appli-
cations. An important key feature of the HexA model is
the a-methoxy substituent at C-1. First of all the reducing
end is protected and thus purely the reactions associated
with the double bond in conjugation to the carboxyl
group can be investigated. Second the a-substituent
simulates the a-bonding in xylan, where the HexA is
attached in pulp.
The commercially available methyl a-D-galactopyran-
oside was chosen as starting material for the synthesis
of methyl 4-deoxy-b-L-threo-hex-4-enopyranosiduronic
acid (4). In principle the cheaper methyl a-D-glucopyr-
anoside could have been used as starting material as
well, but the b-elimination step will be more efficient
when the acidic proton and the leaving group are anti-
periplanar (axial–axial), as in the galacto derivative,
than when they are syn-periplanar (axial–equatorial)
as in the gluco derivative. The synthetic scheme (Scheme
1) comprises six high yielding reaction steps: TEMPO
oxidation, acetylation, lactone opening to yield a methyl
ester, second acetylation, b-elimination and finally
removal of all protecting groups. At first a carboxylic
*
Corresponding author. Tel.: +358 9 451 4250; fax: +358 9 451
4259; e-mail: iadorjan@cc.hut.fi
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.06.012

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I. Adorjan et al. / Carbohydrate Research 341 (2006) 2439–2443
Scheme 1. Synthesis of 4. Reagents and conditions: (a) TEMPO, NaBr, NaOCl, 0 ꢁC; (b) Ac2O, NaOAc, reflux; (c) MeOH, DBU; (d) Ac2O, Py,
DBU; (e) CH2Cl2, DBU; (f) LiOH (MeOH–H2O–THF 5:4:1), Dowex 50 (H+).
group was generated at C-6 by TEMPO oxidation. In
this reaction the stable nitroxyl radical TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) is used as catalyst
to selectively oxidize the primary hydroxyl group at C-6
via the aldehyde to the carboxylic group.12–14 A sodium
hypochlorite/sodium bromide mixture is acting as regen-
erating oxidant in aqueous solution. After the complete
conversion of methyl a-D-galactopyranoside to methyl
a-D-galactopyranosiduronic acid and removal of the sol-
vent, no attempt was made to separate the highly hydro-
philic methyl a-D-galactopyranosiduronic acid from the
salts stemming from the TEMPO oxidation as these do
not hinder the following acetylation and are easily
removed after acetylation by extraction. The acetylation
of the crude methyl a-D-galactopyranosiduronic acid
was carried out with acetic anhydride/sodium acetate
under reflux for 10 min15 and afforded methyl 2,4-di-
O-acetyl-a-D-galactopyranosiduronic acid, c-lactone
(1)16 in high yield. The lactone 1 was converted to
methyl-(methyl 2,4-di-O-acetyl-a-D-galactopyranosid)-
uronate by stirring with methanol and catalytic
amount of DBU. Cleavage of acetyl groups and acetyl
group migration occur as side reactions. As these side
products will yield methyl-(methyl 2,3,4-tri-O-acetyl-a-
D-galactopyranosid)uronate (2) as well upon acetyl-
ation, the crude product obtained after removal of the
solvent was used without further purification. For the
second acetylation reaction, crude methyl-(methyl 2,4-
di-O-acetyl-a-D-galactopyranosid)uronate was dissolved
in a mixture of acetic anhydride–pyridine = 1:1 at room
temperature and catalytic amounts of DBU were added
to accelerate the reaction. These smoother reaction con-
ditions were chosen as they afforded 2 in very high yield.
The two last reaction steps are a b-elimination17,18 and
the removal of the protecting groups. Both reactions re-
quire alkaline conditions so in theory they could be com-
bined in one step. In this reaction scheme it was decided
to separate these two reactions in order to have a better
control over the b-elimination, which is in concurrence
to the deacetylation. Additionally the fully protected
b-elimination product methyl-(methyl 2,3-di-O-acetyl-
4-deoxy-b-L-threo-hex-4-enopyranosid)uronate (3) is
much easier to purify than the final product 4. Thus
reaction conditions, which facilitate the b-elimination,
but at the same time do not lead to deacetylation had
to be chosen. Unfortunately the method using pyridine
as solvent and DBU as base15 led to instant deacetyl-
ation upon DBU addition and no b-elimination product
was obtained. Changing the solvent to dry dichloro-
methane19,20 or toluene afforded 3 in high yield. It has
to be noted that reaction control by TLC using anisalde-
hyde–sulfuric acid as dyeing reagent is complicated as
the color intensity of 3 is considerably lower than that
of 2, but 3 exhibits strong UV activity due to the conju-
gated double bond. As there was no difference in yield
between dichloromethane and toluene, dichloromethane
was finally chosen as solvent. The final step in this syn-
thetic scheme is the cleavage of the acetyl protecting
groups and the methyl ester to yield methyl 4-deoxy-b-
L-threo-hex-4-enopyranosiduronic acid 4. This is accom-
plished by dissolving 3 in a 0.3 M lithium hydroxide
solution (5:4:1 MeOH–water–THF) at 0 ꢁC.21 After
complete conversion, Dowex 50 (H+) is added to
remove lithium hydroxide and to convert 4 into the acidic
form. The solvent is removed by lyophilization to afford
the final product 4 in quantitative yield. It has to be
noted that elemental analysis was performed from the
stable lithium salt. The overall yield of this synthetic
scheme is 60%. One target of this synthetic scheme
was to minimize laborious purifications steps. During
scale up it was discovered that all but the column chro-
matographic purification of 3 can be omitted. It is essen-
tial to obtain 3 in high purity as after the deprotection
no facile purification is available. The presented reaction
sequence was successfully scaled up from 1 g to 5 g starting
material without significant loss in overall yield.

I. Adorjan et al. / Carbohydrate Research 341 (2006) 2439–2443
2441
1. Experimental
1.1. General methods
was deactivated by addition of MeOH (10 mL) and the
solvent was removed under diminished pressure. Traces
of water were removed by coevaporation with toluene.
NaOAc (500 mg) and Ac2O (16 mL) were added to crude
methyl a-D-galactopyranosiduronic acid and heated for
10 min under reflux. After cooling to room temperature,
MeOH (20 mL) was added under ice/water cooling to
deactivate excess of Ac2O. The reaction mixture was neu-
tralized by saturated NaHCO3 solution and extracted
with CH2Cl2. The organic phase was dried over Na2SO4,
filtrated, and the solvent was removed under reduced
pressure. The crude product was purified by column
chromatography (2:1 toluene–ethyl acetate) to yield 1
Optical rotations were measured with a Perkin–Elmer
341 polarimeter. NMR spectra were recorded with a
Bruker AvanceTM DPX400 instrument operating at
400.13 MHz for 1H and 100.62 MHz for 13C using
CDCl3 or D2O as the solvents. Tetramethylsilane was
1
used as internal standard for H spectra in CDCl3, 13C
spectra in CDCl3 were calibrated to the solvent peak
(77.00 ppm), 3-(trimethylsilyl)-1-propanesulfonic acid
sodium salt (DSS) was used as internal standard for
1H spectra in D2O, 13C spectra in D2O were externally
calibrated to 1,4-dioxane (67.40 ppm). 1H and 13C
NMR spectra were measured at 298.2 K. Homo- and
heteronuclear 2D NMR spectroscopy was performed
with Bruker standard software. Chemical shifts are
given in ppm, coupling constants in hertz. FTIR spectra
21
(1.14 g, 4.16 mmol, 81%) as a colorless syrup. ½aꢀD +30
20
(c 0.4, CHCl3), lit.:16 ½aꢀD +28 (c 1.2, CHCl3); Rf 0.53
1
(1:1 toluene–ethyl acetate); H NMR (CDCl3): d 5.47
(d, 1H, J4,5 = 1.2 Hz, H-5), 5,42 (dd, 1H, J1,2 = 2.9 Hz,
J2,3 = 4.8 Hz, H-2), 4.88 (dd, 1H, J3,4 = 1.7 Hz, H-3),
4.7 (d, 1H, H-1), 4.30–4.29 (m, 1H, H-4), 3.54 (s, 3H,
1-OMe), 2.19 (s, 3H, –OAc), 2.13 (s, 3H, –OAc). 13C
NMR (CDCl3): d 170.25 (C-6), 169.40 (–OAc), 169.29
(–OAc), 97.43 (C-1), 78.73 (C-3), 71.13, 71.11 (C-4,
C-5), 67.91 (C-2), 58.06 (1-OMe), 20.61 (–OAc), 20.56
(–OAc); ESI-MS Anal. Calcd for C11H15O8 [M+H]+:
275.0767. Found: 275.0780.
were acquired on
a Bio-Rad 6000 spectrometer
equipped with a MTEC 300 photoacoustic detector.
UVRR spectra were collected with a Renishaw 1000
UV Raman spectrometer (Renishaw, Gloucestershire,
UK) equipped with a Leica DMLM microscope (Leica
Microsystems, Wetzlar, Germany). The light source
was a frequency-doubled Ar+ ion laser (Coherent Inc.,
CA, USA) tuned to an excitation wavelength of
244 nm. The laser beam was focused on the sample with
a 15· objective lens. During measurements, the sample
was spun and the measurements were repeated to obtain
average spectra. Raman spectra were recorded with a
dispersive Kaiser Optical Systems HoloLab Raman
spectrometer equipped with a 785 nm GaAlAs diode
laser and an Olympus BX 60 microscope. TLC was per-
formed on Merck precoated plates (5 · 10 cm, layer
thickness 0.25 mm, silica gel 60 F254); detection was
affected by dipping into anisaldehyde–H2SO4 followed
by charring. For column chromatography, silica gel
VWR Si60 (230–400 mesh) was used. Concentration of
solutions was performed at reduced pressure and
40 ꢁC. Elemental analyses were provided by Professor
Ari Koskinen, Laboratory of Organic Chemistry,
Helsinki University of Technology, Espoo. HRMS
measurements were performed with a Waters LCT
Premier by Dr. Jari Koivisto, Laboratory of Organic
Chemistry, Helsinki University of Technology, Espoo.
1.3. Methyl-(methyl 2,3,4-tri-O-acetyl-a-D-galacto-
pyranosid)uronate (2)
1.3.1.
Methyl-(methyl
2,4-di-O-acetyl-a-D-galacto-
pyranosid)uronate. Methyl 2,4-di-O-acetyl-a-D-galac-
topyranosiduronic acid, c-lactone 1 (1.14 g, 4.16 mmol)
was dissolved in MeOH (50 mL), DBU (50 lL) was
added and the reaction mixture was stirred for 17 h at
room temperature. After complete conversion the
solvent was removed under reduced pressure and the
crude product (1.23 g, 4.02 mmol, 97%) was used without
further purification for the next step. Rf 0.14 (1:1 tolu-
1
ene–ethyl acetate); H NMR (CDCl3): d 5.65 (dd, 1H,
J3,4 = 3.6 Hz, J4,5 = 1.5 Hz, H-4), 5.10–5.04 (m, 2H,
H-1, H-2), 4.54 (d, 1H, H-5), 4.27–4.24 (m, 1H, H-3),
3.76 (s, 3H, –COOMe), 3.44 (s, 3H, –OMe), 2.69 (br s,
1H, –OH), 2.15 (s, 3H, –OAc), 2.13 (s, 3H, –OAc).
13C NMR (CDCl3): d 171.04 (–OAc), 170.56 (–OAc),
167.79 (C-6), 97.67 (C-1), 71.46 (C-4), 70.62 (C-2),
68.45 (C-5), 66.42 (C-3), 56.11 (1-OMe), 52.57
(–COOMe), 20.83 (–OAc), 20.58 (–OAc).
1.2. Methyl 2,4-di-O-acetyl-a-D-galactopyranosiduronic
acid, c-lactone (1)
1.3.2. Methyl-(methyl 2,3,4-tri-O-acetyl-a-D-galacto-
pyranosid)uronate (2). Crude methyl-(methyl 2,4-di-O-
acetyl-a-D-galactopyranosid)uronate (1.23 g, 4.02 mmol)
was dissolved in a pyridine/Ac2O mixture (1:1, 10 mL),
DBU (50 lL) was added and the reaction mixture was
stirred for 5 h at room temperature. After complete con-
version, Ac2O was deacticvated by adding ice to the reac-
Methyl a-D-galactopyranoside (1.00 g, 5.15 mmol),
NaBr (265 mg), and TEMPO (8 mg) were dissolved in
distilled water (50 mL) and cooled to 0 ꢁC. NaOCl solu-
tion (30 mL, 2.5%) was added dropwise while keeping
the pH within 10–11 with sodium hydroxide solution
(0.5 M). After complete conversion excess of NaOCl

2442
I. Adorjan et al. / Carbohydrate Research 341 (2006) 2439–2443
21
tion mixture and stirring for 30 min. The reaction mixture
was neutralized with saturated NaHCO3 solution and
extracted with CH2Cl2. The organic phase was dried over
Na2SO4, filtered, and the solvent was removed under
diminished pressure. The crude product was purified by
column chromatography (4:1 toluene–ethyl acetate) to
½aꢀD +218 (c 0.2, H2O); Rf 0.13 (5:10:1 MeOH–CH2Cl2–
water); UV: kmax 234; UVRR: m 1653; IR (KBr): m 1720,
1655; Raman (cmꢁ1): 860, 828; H NMR (D2O): d 6.13
1
(d, 1H, J3,4 = 3.1 Hz, H-4), 5.08 (d, 1H, J1,2 = 2.6 Hz,
H-1), 4.34 (dd, 1H, J2,3 = 7.6 Hz, H-3), 3.85 (dd, 1H,
H-2), 3.55 (s, 3H, 1-OMe); 13C NMR (D2O): d 166.19
(C-6), 141.19 (C-5), 113.35 (C-4), 101.45 (C-1), 70.40
(C-2), 66.42 (C-3), 57.71 (1-OMe); ESI-MS Anal. Calcd
for C7H9O6 [MꢁH]ꢁ: 189.0399. Found: 189.0398. Anal.
Calcd for C7H9LiO6: C, 42.88; H, 4.63. Found: C, 43.21;
H, 4.91.
21
yield 2 (1.29 g, 3.70 mmol, 92%) as colorless foam. ½aꢀD
22
155 (c 1.2, CHCl3), lit.:15 ½aꢀD +160 (CHCl3); Rf 0.36
1
(1:1 toluene–ethyl acetate); H NMR (CDCl3): d 5.77
(dd, 1H, J3,4 = 3.4 Hz, J4,5 = 1.6 Hz, H-4), 5.41 (dd,
1H, J2,3 = 10.9 Hz, H-3), 5.21 (dd, 1H, J1,2 = 3.6 Hz,
H-2), 5.13 (d, 1H, H-1), 4.61 (d, 1H, H-5), 3.76 (s, 3H,
COOMe), 3.45 (s, 3H, 1-OMe), 2.11 (s, 3H, –OAc), 2.09
(s, 3H, –OAc), 2.00 (s, 3H, –OAc); 13C NMR (CDCl3):
d 170.16 (–OAc), 169.81 (–OAc), 169.73 (–OAc), 167.34
(C-6), 97.55 (C-1), 69.13 (C-4), 68.32 (C-5), 67.55 (C-2),
67.04 (C-3), 56.17 (1-OMe), 52.63 (–COOMe), 20.72
(–OAc), 20.57 (–OAc), 20.50 (–OAc); ESI-MS Anal.
Calcd for C14H20O10Na [M+Na]+: 371.0954. Found:
371.0953. Anal. Calcd for C14H20O10: C, 48.28; H, 5.79.
Found: C, 48.62; H, 5.54.
Acknowledgments
The authors want to thank Professor Ari Koskinen for his
generous support by providing access to NMR, HRMS,
polarimeter and elemental analysis as well as providing
laboratory equipment. Dr. Jari Koivisto is gratefully
acknowledged for recording NMR and HRMS spectra.
Rita Hatakka is acknowledged for providing FTIR, Ra-
man, and UVRR spectra. The financial support by Acad-
emy of Finland, TEKES (National Technology Agency,
Finland), Andritz, Jaakko Po¨yry, Kemira Chemicals, Met-
sa¨-Botnia and Stora Enso is gratefully acknowledged.
1.4. Methyl-(methyl 2,3-di-O-acetyl-4-deoxy-b-L-threo-
hex-4-enopyranosid)uronate (3)
Methyl-(methyl 2,3,4-tri-O-acetyl-a-D-galactopyranosid)-
uronate 2 (1.29 g, 3.70 mmol) was dissolved in dry
CH2Cl2 (5 mL), DBU (600 lL) was diluted in dry
CH2Cl2 (5 mL) and added to the reaction mixture at
room temperature. The reaction mixture was stirred for
20 h and subjected directly to column chromatography
(50:1 CH2Cl2–MeOH) to afford 3 (897 mg, 3.11 mmol,
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.carres.2006.06.012.
21
84%) as colorless syrup. ½aꢀD +255 (c 1, CHCl3), lit.:22
29
½aꢀD +259.9 (c 1.124, MeOH); Rf 0.49 (1:1 toluene–ethyl
References
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H-4), 5.62–5.58 (m, 1H, H-3), 5.31–5.15 (m, 2H, H-1, H-
2), 3.83 (s, 3H, –COOMe), 3.54 (s, 3H, 1-OMe), 2.12 (s,
3H, –OAc), 2.09 (s, 3H, –OAc). 13C NMR (CDCl3): d
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[M+Na]+: 311.0743. Found: 311.0753.
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