Seven-membered ring boronates at trans-diol moieties of carbohydrates

Article abstract of DOI:10.1016/j.tetlet.2008.11.043

MS and ¹H, ¹³C and ¹¹B NMR results are presented revealing the formation of cyclic seven-membered boronate structures at trans-1,2-diol moieties of carbohydrates providing new opportunities for the activation, protection and analysis of glucopyranose-based oligomers and polymers such as cellulose or starch. 'Coordination-induced shifts' in ¹³C NMR spectra were identified for the esterification by boronic acids of carbohydrates, which can be applied for further studies.

Full text of DOI:10.1016/j.tetlet.2008.11.043

Tetrahedron Letters 50 (2009) 469–472
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Seven-membered ring boronates at trans-diol moieties of carbohydrates
*
Marcel Meiland, Thomas Heinze, Wolfgang Guenther, Tim Liebert
Center of Excellence for Polysaccharide Research, Friedrich Schiller University of Jena, Humboldtstrasse 10, 07743 Jena, Germany
a r t i c l e i n f o
a b s t r a c t
MS and 1H, 13C and 11B NMR results are presented revealing the formation of cyclic seven-membered
boronate structures at trans-1,2-diol moieties of carbohydrates providing new opportunities for the
activation, protection and analysis of glucopyranose-based oligomers and polymers such as cellulose
or starch. ‘Coordination-induced shifts’ in 13C NMR spectra were identified for the esterification by
boronic acids of carbohydrates, which can be applied for further studies.
Article history:
Received 17 September 2008
Revised 6 November 2008
Accepted 12 November 2008
Available online 18 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Phenylboronate
13C NMR spectroscopy
11B NMR spectroscopy
trans-1,2-Diol
Methyl-a-D-glucopyranoside
The interaction of widespread glucopyranose-based compounds
with boric acid or its derivatives, for example, salts or boronic
acids, is, in principle, very useful for the analysis, activation, pro-
tection and cross-linking of carbohydrates;1 however, in most
cases the structures formed are poorly understood. In general,
strong bonds with diol moieties of carbohydrates are formed,
resulting in cyclic esters or complexes.1,2 In the most abundant glu-
copyranose-based oligomers and polymers, mainly the trans-1,2-
diol system in positions 2 and 3 is available for a ring formation.
Five- and six-membered rings are not reasonable because of high
ring tension. Nevertheless, beneficial effects of boric acid or its
salts as activating agents in commercial modification procedures
of polyglucans such as cellulose are known but scarcely applied
because of unpredictable reactions.3–7 Controlled processes may
result in new opportunities for the chemical modification and anal-
ysis of glucopyranose-based compounds. In case of oligo- and poly-
glucans, the so-called derivatizing solvents8 could be accessible
where dissolution occurs via intermediate formation of covalent
bonds or complexes leading to soluble, instable derivatives suit-
able for subsequent functionalization under defined homogeneous
conditions.9–11 Therefore, a basic understanding of the borate and
boronate formation of glucopyranose-based compounds is
indispensable.
ety with a model system consisting of methyl-
(Me- -glcp) and phenylboronic acid (PBA) was studied in detail.
Different papers showed that Me- /b-glcp binds the borate
a-D-glucopyranoside
a
-D
a
through their flexible hydroxyls in positions 4 and 6.12,13 Conse-
quently, only the diol structure at positions 2 and 3 of the mono-
saccharide is accessible for further modification, making this
system a reasonable model for the conversion of a oligo- or poly-
glucan. For non-aqueous media, Ferrier first mentioned esterifica-
tion of the secondary hydroxyls of Me-a-D-glcp with PBA after
azeotropic distillation in the presence of benzene, but the products
were only characterized by elemental analysis.14,15 A seven-mem-
bered ring including two boron atoms with the trans-1,2-diol moi-
ety in positions 2 and 3 is suggested. Up to now, NMR spectroscopy
was not able to confirm such a large ring system.16
In a set of experiments, the transformation of Me-a-D-glcp with
PBA was studied by means of mass spectrometry (MS). The phenyl-
boronates (Fig. 1) were prepared by dissolving different ratios of
dry carbohydrates and triphenylboroxole in a mixture of N,N-
dimethylformamide and 2,2-dimethoxypropane, which may result
in different molecular ions and fission products (Fig. 1). A solution
of derivatized methyl-glycopyranoside was evaporated in the MS
probe crucible, and was introduced into the mass spectrometer.
The spectra were measured using electron impact (EI) ionization.17
Although own NMR studies on mixtures of soluble cellodextrins
converted with boric acid in DMSO yielded badly resolved spectra,
the data indicated derivatization of the carbohydrates at the trans-
diol moiety and fast transesterification reactions. In order to limit
the structural diversity, the reaction of the relevant trans-diol moi-
An equimolar conversion of Me-
a-D-glcp with PBA yields a
methyl-4,6-O-phenylboronate- -glucopyranoside (1) that was
a-D
confirmed by a peak for the molecular ion at m/z 280 and one
fragment ion I at m/z 160 for a 1,3,2-dioxaborinane structure. If
an excess of PBA is applied, the methyl-2,3-O-(diphenylpyroboro-
nate)-4,6-O-phenylboronate-a-D-glucopyranoside (2) should be
formed. The MS spectrum of the compound obtained shows signif-
icant fragment ions at m/z 160 (I) and at m/z 250 (II) in addition to
* Corresponding author. Tel.: +49 (0) 3641 948270; fax: +49 (0) 3641 948272.
E-mail address: tim.liebert@uni-jena.de (T. Liebert).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.043

470
M. Meiland et al. / Tetrahedron Letters 50 (2009) 469–472
Figure 1. Boronate structures and expected fission processes.
a peak for the molecular ion at m/z 470, revealing the existence of a
seven- and a six-membered boronate ring. The formation of such a
complex seven-membered ring structure during the reaction of the
carbohydrate with PBA was verified by additional experiments
pletely esterified product 2 should be obtained by a subsequent
transformation of 1 with an excess of triphenylboroxole.
1H NMR spectra of the products obtained by the steps depicted
in Scheme 1 were acquired in DMSO-d6. Spectra of the starting Me-
with methyl-4,6-O-benzylidene-2,3-O-(diphenylpyroboronate)-
a
-
a-D-glcp show relevant signals for the protons of the OH moieties
D
-glucopyranoside (3). Again, a fragment ion at m/z 250 (II) is
and the proton at the anomeric carbon between 4.4 and 4.8 ppm
(Fig. 3a). Separate signals for OH-2 at 4.62 ppm (d), OH-3 at
4.67 ppm (d), OH-4 at 4.79 ppm (d), OH-6 at 4.40 ppm (t) and
H-1 at 4.51 ppm (d) can be determined. This assignment was con-
firmed with NMR correlation methods. After the first step of the
found, and the molecular ion at m/z 472 is detectable. Moreover,
the modification of the carbohydrate with 2,6-dimethylphenylbo-
ronic acid yields a product giving signals of a molecular ion at
m/z 554 and fragment ions at m/z 188 and m/z 306. For a compa-
rable experiment with n-butylboronic acid relevant peaks for frag-
ment ions appeared at m/z 140 and m/z 210. Further evidence is
gained from the comparison of patterns and intensities of mass
peaks with calculated isotope patterns. On the basis of the isotope
distribution of carbon and boron (10B:11B = 1:4.2), the patterns for
the main signals were simulated giving two additional peaks at
lower m/z and two small signals at higher m/z values. A perfect
fit of the predicted pattern with the fragment peaks for ion II of
the 1,3,5,2,4-trioxadiborepane structure, and the signal for the
molecular ion of 2 were found (Fig. 2). These MS studies confirm
the transformation of trans-1,2-diol moiety in positions 2 and 3
with aryl and alkyl boronic acids as first proposed by Robinson
or Ferrier.14,17
In contrast to mass spectrometric analyses of the boronate
structures, which are combined with a separate modification dur-
ing the analytic step (ionization and fission processes), NMR spec-
troscopy may yield direct evidence for the existence of different
cyclic systems at carbohydrates. Nevertheless, NMR studies16 have
not succeeded in directly proving the existence of seven-mem-
bered boronate substituents at trans-1,2-diol groups up to now.
esterification, formation of the Me-4,6(PhB)-
a-D-glcp (1) was con-
cluded from the disappearance of the OH-6 and the OH-4 signal
and the occurrence of two doublets in the 1H NMR spectra
(Fig. 3b). The two downfield-shifted signals could be identified as
protons of OH-2/3 (OH-2 at 4.99 ppm, d, OH-3 at 5.24 ppm, d).
The 1H NMR spectrum of the compound obtained in a second step
shows only one signal in the spectral region discussed (Fig. 3c). The
doublets for the hydroxyl protons are missing. The remaining
signal corresponds to the proton at the anomeric carbon at
4.95 ppm, which is shifted downfield (0.44 ppm) in comparison
to the H-1 of unmodified Me-a-D-glcp. This can be explained with
complete functionalization in position 2. Consequently, these 1H
NMR studies reveal the conversion of all accessible OH functions.
This is the first NMR spectroscopic evidence for the formation of
Me-2,3(PhB)2-4,6(PhB)-
a
-
D
-glcp (2). These findings are supported
by esterification reactions with methyl-4,6-O-benzylidene-
-glucopyranoside (Me-4,6(Bz)-
-glcp). The pyroboronate
Me-4,6(Bz)-2,3(PhB)2-
-glcp (3) was synthesized in a similar
a-D
a-D
a-D
way, and the 1H NMR spectrum shows a comparable shift of the
proton in position 1 and the disappearance of the signals for the
hydroxyl groups in positions 2 and 3. Nevertheless, 1H NMR
spectra did not yield a final proof for the existence of a large cyclic
system, such as a seven-membered ring.
Thus, the stepwise esterification of Me-a-D-glcp with PBA in apro-
tic solvents applying azeotropic removal of water was studied by
NMR spectroscopy. First, the small amount of water produced dur-
ing the esterification was removed with a soxhlet apparatus filled
with molecular sieve. Here, PBA binds to OH-4/6 and forms
Therefore, 11B NMR spectroscopy was applied for the determi-
nation of the boronate ring size. Because of the fact that 11B NMR
spectroscopy is a rather insensitive method, it was necessary to
Me-4,6(PhB)-
a-D-glcp (1) in quantitative yield (Scheme 1). A com-
Figure 2. Comparison of calculated isotope pattern (grey) with fragment peaks for ion II of (a) methyl-2,3-O-(dibutylpyroboronate)-4,6-O-butylboronate-
a-D-
glucopyranoside (2a); (b) Me-2,3(PhB)2-4,6(PhB)- -glcp (2) and molecular ion of (c) Me-2,3(PhB)2-4,6(PhB)-
a-
D
a-D-glcp (2).

M. Meiland et al. / Tetrahedron Letters 50 (2009) 469–472
471
Scheme 1. Synthesis of phenylboronates (1 and 2) of methyl-a-D-glucopyranoside.
Figure 3. 1H NMR spectra (in the region of hydroxyl and anomeric protons) of (a) Me-
d6.
a
-
D
-glcp; (b) Me-4,6(PhB)-
a-
D
-glcp (1); (c) Me-2,3(PhB)2-4,6(PhB)-
a
-D
-glcp (2) in DMSO-
Figure 4. 11B NMR spectra of (a) model compounds 4 (pink), 5 (red) and 6 (blue);
(b) phenylboronate 3 (blue) in comparison with PBA (green) in DMSO-d6.
Figure 5. (a) 2D [1H, 1H] NOESY NMR spectrum of 3 in DMSO-d6; (b) ball-and-stick
model20 of Me-4,6(Bz)-2,3(PhB)2-
-glcp (3).
a-D
prepare model compounds of diol molecules with five-, six- and se-
ven-membered boronate structures for ‘comparison’. In Figure 4a,
spectra of phenylboronate esters of 1,2-ethanediol 4, 1,3-propane-
diol 5 and trans-cyclohexane-1,2-diol 6 are displayed.18 The con-
version of PBA to a five-membered ring boronate (4) leads to a
downfield-shift of the 11B NMR signal in comparison to the PBA.
In contrast, the resonance signal of 2-phenyl-1,3,2-dioxaborinane
(5) is shifted upfield but less than the signal of 6, the seven-mem-
bered ring boronate, in relation to PBA (Fig. 4a). These data were
used to evaluate the boronic acid transformation experiments
An additional indication for the formation of such a complex
moiety was two dimensional NMR spectroscopy of Me-4,6(Bz)-2,3
(PhB)2- -glcp (3). The nuclear Overhauser effect NMR spectro-
-
a
-D
scopy19 (Fig. 5a) shows several cross-peaks for non-covalent cou-
pling of protons, which can only be explained with diboronate
structures in positions 2 and 3 of the carbohydrate. In particular,
the proton in ortho-position of the phenylboronate moiety
(d(o-H) = 7.8 ppm) couples with protons of the carbohydrate back-
bone (arrows in Fig. 5b). On the one hand, there are cross-peaks
indicating a coupling to H-1/2 and on the other hand, coupling to
the methyl protons of anomeric methoxyl group is observed.
Based on this information concerning the formation of a seven-
membered boronate ring at carbohydrates, the trend of signal
movement in 13C NMR spectra as a result of esterification with
PBA was investigated.21 Comparison of the signal distribution of
(Scheme 1). The spectrum of Me-4,6(PhB)-
a-D-glcp (1) shows only
a signal at 28 ppm consistent with the six-membered boronate
model compound 5. The second step usually yields a broad signal
corresponding to a mixture PBA, six- and seven-membered ring
system, but in case of the modification of Me-4,6(Bz)-
a-D-glcp with
PBA a well-defined shoulder at the signal for PBA (blue) is observed
in the 11B NMR spectrum (Fig. 4b). This is a further evidence for a
seven-membered diphenylpyroboronate ring at the trans-1,2-diol
moiety at C-2/3 of the carbohydrate.
Me-a-D-glcp with phenylboronates 1–3 shows (Fig. 6) that bind-
ing-site carbons (e.g., C-2/3 in compound 3) are shifted downfield
in the range of 2–5 ppm, whereas for carbon atoms between or in
neighbourhood (e.g., C-5 or C-3 in compound 1) to functionalized

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M. Meiland et al. / Tetrahedron Letters 50 (2009) 469–472
Figure 6. 13C NMR spectra with depicted ‘coordination-induced shifts’ (arrows) of Me-4,6(PhB)- -glcp (1) and Me-2,3(PhB)2-4,6(PhB)-
a-D a-D-glcp (2) in DMSO-d6 (grey: Me-a-D-
glcp, black: phenylboronate).
carbons an upfield-shift of 1–9 ppm is observed. Due to these iden-
tified ‘coordination-induced shifts’, a transformation of all hydro-
xyl groups of phenylboronate 2 is certified. All carbon peaks
are shifted downfield except the signals for C-5 and C-1. On the
basis of these results, standard 13C NMR spectroscopy can be estab-
lished as a fast and sensitive tool for the investigation of the inter-
action of cellooligomers and finally cellulose with boric acid
derivatives.
References and notes
1. Lehmann, J.; Redlich, H. G. Kohlenhydrate: Chemie und Biologie, 2nd ed.;
Thieme: Stuttgart and New York, 1996; p 102.
2. Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769–774.
3. Engelskirchen, K.; Galinke, J. DE Patent 24,15,154, 1975; Chem. Abstr. 1976, 84,
19478.
4. Tsas, H. E. DE Patent 25,35,311, 1976; Chem. Abstr. 1976, 84, 152509.
5. Majewicz, T. G. U.S. Patent 4,306,061, 1981; Chem. Abstr. 1982, 96, 54146.
6. Majewicz, T. G.; Ropp, W. S. EP Patent 0,041,364, 1981; Chem. Abstr. 1982, 96,
37158.
7. Huybrechts, S.; Detemmerman, A.; De Pooter, J.; Blyweertt, R. E. WO Patent 88
07059, 1988; Chem. Abstr. 1989, 110, 2927.
In summary, detailed NMR studies on the transformation of the
trans-1,2-diol system in Me-a-D-glcp with PBA support the struc-
tures suggested on the basis of MS analyses. NMR analyses con-
firmed the existence of a seven-membered diboronate ring at
trans-1,2-diol moieties of C-2/3 in glucopyranose-based carbohy-
drates for the first time. Analyses of ‘coordination-induced shifts’
in 13C NMR spectra can be applied for further studies on the trans-
formation of glucans with boric acid derivatives. The information
can be used to investigate the structures formed at cellooligomers
towards a basic understanding of the interaction boric acid deriv-
ative with polyglucan.
8. Heinze, T.; Liebert, T.; Koschella, A. Esterification of Polysaccharides, 1st ed.,
Berlin and Heidelberg, 2006; p 53.
9. Klemm, D.; Philipp, B.; Heinze, T.; Heinze, U.; Wagenknecht, W.
Functionalization of Cellulose. In Comprehensive Cellulose Chemistry; Wiley-
VCH: Weinheim, 2001; Vol. 2; p 147.
10. Liebert, T.; Heinze, T.; Klemm, D. J. Macromol. Sci., Pure Appl. Chem. 1996, 33,
613–626.
11. Liebert, T.; Schnabelrauch, M.; Klemm, D.; Erler, U. Cellulose 1994, 1, 249–258.
12. Benner, K.; Kluefers, P.; Labisch, O. Carbohydr. Res. 2007, 342, 2801–2806.
13. Miyazaki, Y.; Yoshimura, K.; Miura, Y.; Sakashita, H.; Ishimaru, K. Polyhedron
2003, 22, 909–916.
14. Ferrier, R. J. J. Chem. Soc. 1961, 2325–2330.
15. Ferrier, R. J. Adv. Carbohydr. Chem. Biochem. 1978, 35, 31–80.
16. Smoum, R.; Rubinstein, A.; Srebnik, M. Magn. Reson. Chem. 2003, 41, 1015–
1020.
Acknowledgements
17. Robinson, D. S.; Eagles, J.; Self, R. Carbohydr. Res. 1973, 26, 204–207.
18. For syntheses of 2-phenyl-1,3,2-dioxaborolane (4), 2-phenyl-1,3,2-
dioxaborinane (5), 1,3,5,2,4-trioxadiborepane model compound (6), see: (a)
Bowie, R. A.; Musgrave, O. C. J. Chem. Soc. 1963, 3945–3949; (b) Sugihara, J. M.;
Bowman, C. M. J. Am. Chem. Soc. 1958, 80, 2443–2446.
This work was financially supported by ‘Fachagentur Nachw-
achsende Rohstoffe e.V.’ (Project 22021905). We would like to
thank Dr. Wolfgang Poppitz (Institute of Inorganic and Analytical
Chemistry, Friedrich Schiller University of Jena) for MS
measurements.
19. 2D [1H, 1H] NOESY NMR spectrum of 3 was measured using a mixing time of
0.4 s. Due to the fact that the rotating correlation time sc for this molecule is
short (molar mass below 500 and NMR sample solution with low viscosity), we
observe NOESY correlation signals with inverse phase to the diagonal signals.
20. Ball-and-stick model was converted by means of ACD/3D-Viewer version 4.5
for Microsoft Windows without consideration of NOESY correlation signals.
21. All 13C NMR spectra are fully assigned by means of 2D NMR techniques. See
Supplementary data.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data for all compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.11.043.