Combined 1H, 13C and 11B NMR and mass spectral assignments of boronate complexes of D-(+)-glucose, D-(+)-mannose, methyl-α-D-glucopyranoside, methyl-β-D-galactopyranoside and methyl-α-D-mannopyranoside

Article abstract of DOI:10.1002/mrc.1301

Complex formation between N-butylboronic acid and D-(+)-glucose, D-(+)-mannose, methyl-α-D-glucopyranoside, methyl-β-D- galactopyranoside and methyl α-D-mannopyranoside under neutral conditions was investigated by ¹H, ¹³C and ¹¹

Full text of DOI:10.1002/mrc.1301

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2003; 41: 1015–1020
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1301
Note
Combined 1H, 13C and 11B NMR and mass spectral
assignments of boronate complexes of D-(+)-glucose,
D-(+)-mannose, methyl-a-D-glucopyranoside,
methyl-b-D-galactopyranoside and
methyl-a-D-mannopyranoside
Reem Smoum,1 Abraham Rubinstein2 and Morris Srebnik1∗
1
Department of Medicinal Chemistry and Natural Products, Faculty of Medicine, The Hebrew University in Jerusalem, POB 12065, Jerusalem
91120, Israel
2
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University in Jerusalem, POB 12065, Jerusalem 91120, Israel
Received 18 June 2003; Revised 15 August 2003; Accepted 25 August 2003
Complex formation between N-butylboronic acid and D-(+)-glucose, D-(+)-mannose, methyl-a-D-
glucopyranoside, methyl-b-D-galactopyranoside and methyl a-D-mannopyranoside under neutral condi-
tions was investigated by 1H, 13C and 11B NMR spectroscopy and gas chromatography–mass spectrometry
(GC–MS) D-(+)-Glucose and D-(+)-mannose formed complexes where the boronates are attached to the
1,2 : 4,6- and 2,3 : 5,6-positions of the furanose forms, respectively. On the other hand, the boronic acid binds
to the 4,6-positions of the two methyl derivatives of glucose and galactose. Methyl a-D-mannopyranoside
binds two boronates at the 2,3 : 4,6-positions. 11B NMR was used to show the ring size of the complexed
sugars and the boronate. GC–MS confirmed the assignments. Copyright  2003 John Wiley & Sons, Ltd.
KEYWORDS: boronate–saccharide complexes; NMR; 1H NMR; 13C NMR; 11B NMR; COSY; HSQC; mass spectra; ring size
means of mass spectrometry.9 In addition, the interaction
of benzeneboronic acid, 4-methoxybenzeneboronic acid and
3-nitrobenzeneboronic acid with D-glucose, D-mannose and
D-fructose at various pH values has been investigated by
means of optical rotation methods.10 The interaction of the
different boronates with the saccharides is specific depend-
ing on the kind of boronic acid and the structure of the
saccharide. For example, monosaccharides bearing five OH
groups tend to form 1 : 2 monosaccharide–phenylboronic
acid complexes.11–15 The phenylboronic acid forms a five-
membered ring with a cis-1,2-diol group, and it can form
a six-membered ring with a trans-CH(OH)CH(CH2OH)-
diol group although the stability is inferior to that of the
five-membered ring. However, the stability order of these
complexes is always the same, depending on the struc-
ture of the monosaccharide.3,16,17 As part of our program to
develop drug carrier platforms based on saccharide–boron
complexes, we are interested in determining the struc-
ture and stability of simple derivatives at first (for some
recent NMR studies of boron complexes, see Ref. 18). In
this work, the synthesis and the structure of the butyl-
boronic acid complexes with D-ꢀCꢁ-glucose, D-ꢀCꢁ-mannose,
methyl-˛-D-glucopyranoside, methyl-ˇ-D-galactopyranoside
and methyl ˛-D-mannopyranoside under neutral conditions
INTRODUCTION
Boronic acids have been shown to form reversibly strong
covalent bonds with the diol functionalities of carbo-
hydrates in form of cyclic esters1–3 with association
constants that range from 10 to 104 ꢀ1, thus, mak-
M
ing them more lipophilic and increasing their transport
through bulk, liquid organic membranes.4 Most monosac-
charides form 1 : 2 saccharide–boronic acid complexes.5,6
Although these sp2-hybridized species are neutral and
favourable to solvent extraction, they are relatively unsta-
ble and easily hydrolyzed in H2O.5 Several boronic acid
derivatives which can selectively bind saccharides have
been prepared. The PMR and mass spectral data of the
benzene- and butaneboronates of arabinose, xylose, L-
fucose, D-glucose, D-fructose and DL-glyceraldehyde have
been reported.7,8 In addition, the benzeneboronates of
methyl-ˇ-D-galactopyranoside, methyl-˛-D-glucopyranoside
and methyl-˛-D-mannopyranoside have been studied by
ŁCorrespondence to: Morris Srebnik, Department of Medicinal
Chemistry and Natural Products, Faculty of Medicine, The Hebrew
University in Jerusalem, POB 12065, Jerusalem 91120, Israel.
E-mail: msrebni@md.huji.ac.il
Contract/grant sponsor: Israel Science Foundation; Contract/grant
number: 663/99-2.
Copyright  2003 John Wiley & Sons, Ltd.

1016
R. Smoum, A. Rubinstein and M. Srebnik
was investigated by 1H, 13C and 11B NMR spectroscopy and
gas chromatography–mass spectrometry (GC–MS).
Preparation of 3
Prepared as described above using methyl-ˇ-galactopyranoside. 1H
NMR (DMSO-d6), υH 0.8320 (CH3), 0.5682 (CH2B), 1.2508 (CH2 near
CH3), 1.2963 (CH2 near CH2B). 13C NMR (DMSO-d6), υC 14.58 (CH3),
15.00 (CH2B), 25.59 (CH2 near CH3), 26.87 (CH2 near CH2B).
EXPERIMENTAL
Representative general synthetic procedure
For the preparation of the 1 : 1 butaneboronate, a solution (2%) of
the sugar (1 mol) in dry pyridine was treated with butaneboronic
acid (1.25 mol). The solution was refluxed for 1–4 h and cooled to
room temperature and the pyridine was evaporated. A solution
(2%) of the crude, liquid product in chloroform was extracted three
times with 10% aqueous copper sulfate to remove both the residual
pyridine and the excess boronic acid. Then the chloroform layer
was extracted three times with distilled water, dried over Na2SO4
and concentrated. Vacuum distillation yielded mobile liquids of
acceptable purity. For the preparation of the 1 : 2 product, a solution
of the glucose (1 mol) in dry pyridine was treated with butaneboronic
acid (3 mol).7
Preparation of 4
Prepared as described above using D-mannose. 1H NMR (DMSO-d6),
υH 0.8406 (CH3), 0.7303 (CH2B), 1.2716 (CH2 near CH3), 1.3110 (CH2
near CH2B). 13C NMR (DMSO-d6), υC 14.50 (CH3), 15.80 (CH2B),
25.46 (CH2 near CH3), 26.54 (CH2 near CH2B).
Preparation of 5
Prepared as described above using methyl-˛-D-mannopyranoside.
1H NMR (DMSO-d6), υH 0.8375 (CH3), 0.5730 (CH2Bꢁ, 1.2416 (CH2
near CH3), 1.304 (CH2 near CH2B). 13C NMR (DMSO-d6), υC 13.81
(CH3), 14.98 (CH2B), 24.83 (CH2 near CH3), 26.19 (CH2 near CH2B).
For the preparation of the butaneboronates of the methylated
sugars, the same procedure was used and the extraction step
was omitted.
Butylboronic acid
For comparison, the NMR data for butylboronic acid are as follows.
1H NMR (DMSO-d6), υH 0.8010 (CH3), 0.5320 (CH2B), 1.1860 (CH2
near CH3), 1.2587 (CH2 near CH2B). 13C NMR (DMSO-d6), υC 14.48
(CH3), 15.79 (CH2B), 25.73 (CH2 near CH3), 27.11 (CH2 near CH2B).
Acetylation of the products for GC–MS analysis was carried out
°
by adding acetic anhydride in pyridine, stirring for 24 h at 20 C. The
solution was evaporated and vacuum dried. An oily product was
obtained.17
The compounds shown in Scheme 1 were thus prepared.
Spectra
1H and 2D NMR spectra were recorded on either a Varian
300 MHz or a Bruker 400 MHz instrument. 13C NMR spectra
were recorded on a Varian 300 MHz spectrometer at a
frequency of 75.9 (13C). 11B NMR spectra were recorded on
both a Varian 300 MHz and a Bruker 400 MHz instrument at
frequencies of 96.29 and a 128.38 MHz, respectively. All
chemical shifts were reported with respect to ꢀCD3ꢁ2SO
(υH 2.5, υC 39.5 ppm). All coupling constants are given
as numerical values. The temperature for all the NMR
Preparation of 1
Prepared as described for the general procedure using D-glucose. 1H
NMR (DMSO-d6), υH 0.7921 (CH3), 0.5663 (CH2B). 1.2126 (CH2 near
CH3), 1.2864 (CH2 near CH2B).
Preparation of 2
Prepared as described for the general procedure using methyl-˛-
D-glucopyranoside. 1H NMR (DMSO-d6), υH 0.8141 (CH3), 0.6017
(CH2B), 1.2228 (CH2 near CH3), 1.2834 (CH2 near CH2B). 13C NMR
(DMSO-d6), υC 14.54 (CH3), 15.00 (CH2B), 25.66 (CH2 near CH3),
26.94 (CH2 near CH2B).
°
experiments was held between 24 and 30 C.
Scheme 1
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 1015–1020

Boronate complexes of saccharides
1017
1H NMR spectra were obtained with a spectral width
the results of Shinkai and co-workers11,12,19,20 and agrees
well with the findings of Norrild and Eggert.14 Also, the
J values are similar to those reported by Coxon21 for the
1,2 : 3,5-di-O-benzylidine-˛-D-glucofuranose ring [J(1,2) 3.6,
Jꢀ2, 3ꢁ < 0.4 and J(3,4) 2.3 Hz]. The only exception in 1 is
the slightly larger value for J(1,2) (4.1 Hz), which indicates
a slightly greater flattening of the furanose ring by the
boronate, and this may be due to the trigonal planar nature
of the boron that might cause a flatter ring.22 Furthermore, the
1J(C1,H1) coupling constant is unexpectedly high (186 Hz,
Table 4). Normally, 1J(C1,H1) is in a range 160–175 Hz.23
This high 1J(C1,H1) gives further evidence of an ˛-furanose
ring complexed in the 1,2-position for glucose as shown
also for the 1,2-O-isopropylidine derivatives of ˛-furanoses
that give an extremely high 1J(C1,H1) value of 186 Hz.14
Therefore, the similarities in the coupling constants suggest
an identical conformation for 1 and that it is an envelope
3E.24 In addition, the acetylated product 6 was investigated
by NMR and GC–MS methods. The NMR spectrum showed
that the OH group on the boronated sugar disappeared,
indicating that an acetyl group replaced the free OH group
at C-6. This implies that the binding sites in 1 are the 1,2-
and 3,5-positions on the glucose and the structure of 1 is ˛-
D-glucofuranose cyclic 1,2 : 3,5-bis(butylboronate) as shown
in Scheme 1. This is in agreement with the findings of Wood
and Siddiqui8 and Norrild and Eggert14 and disagrees with
those of Shinkai et al.19
°
of 8250.8 Hz, a 90 flip angle (5.59 µs) and 8 s relaxation
delay in 32 scans. 13C NMR spectra were obtained with a
spectral width of 22 727.27 Hz with 1 s between transients
°
and the 90 pulse was 7.19 µs. A 5 mm multinuclear probe
was used for the standard 1D ꢀ1H,13 Cꢁ and 2D (COSY,
HSQC) experiments. The two-dimensional homonuclear
H,H-correlation experiments were acquired using phase-
sensitive double quantum filtered COSY. The data were
processed by sinusoidal multiplication in each dimension.
Other parameters were as follows: number of increments
in t1, 1024; number of scans, 1; and relaxation delay,
2 s. The HSQC spectra were recorded using standard
Bruker software (hsqcsi). These spectra were collected with
512 ð 512 data points, a data acquisition of two scans ð F2
and 512 increments in t1. Data were processed using sine
functions for weighting in both dimensions. The spectral
width of 2D spectra were optimized from 1D spectra.
GC–MS experiments
The acetylated derivatives of the boronated sugars were ana-
lyzed on a Hewlett-Packard (HP) G1800B GCD instrument
having a 28 ð 0.25 mm i.d. cross-linked 5% HP ME siloxane
column with a 0.25 µm film thickness, programmed from 70
to 280 C at 25 C minꢀ1, interfaced with an HP Model 5971
mass-selective electron ionization detector.
°
°
For the boronic acid complex of the methyl-˛-D-
glucopyranoside 2, the NMR data show that only one boronic
acid is bound to the sugar. It is bound in the 4,6-position,
RESULTS AND DISCUSSION
For all the monosaccharides, the two products, i.e. the 1 : 1
and the 1 : 2 sugar–butylboronic acid complexes, have almost
identical NMR parameters. The data will be presented for
the 1 : 2 products only (Tables 1–4).
Table 2. 11B chemical shifts (ppm) for the boronic complexes
and butylboronic acid in ꢀCD3ꢁ2CO
The 1H NMR spectrum for 1 shows that there is a triplet
OH signal at 5.04 ppm coupled to H-6a and H-6b (Table 1).
Therefore, 1 possesses a free hydroxymethylene group. 11B
NMR spectrum of 1 (Table 2) shows two peaks at 30.0 and
36.0 ppm, indicating the formation of six and five membered
rings, respectively. The data shown in Table 3 for the J(H,H)
coupling constants indicate that 1 is in the ˛-furanose and not
in the ˛-pyranose form. The small size of J(2,3) and J(3,4) in
the complex excludes the vicinal diaxial arrangements of the
H-2, H-3 and the H-3, H-4 hydrogen atoms, as should be the
case for the pyranose form of glucose. This disagrees with
Butylboronic Six-membered Five-membered
Compound
acid
ring
ring
Butylboronic
acid
33.34
1
2
3
4
5
30.00
29.86
31.30
36.00
35.12
35.63
31.43
Table 1. H chemical shifts (ppm) for the sugar part of the boronic complexes in DMSO-d6
Compound
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
OH-1
OH-2
OH-3
OH-4
OH-6
˛-D-Glucopyranose
1
Methyl-˛-D-Glucopyranoside
2
Methyl-ˇ-D-Galactopyranoside
3
D-Mannose
4
4.88
5.97
4.50
4.63
3.95
4.12
4.88
5.18
4.46
4.57
3.09
4.61
3.18
3.34
3.23
3.22
3.47
4.94
3.56
3.67
3.37
4.31
3.34
3.48
3.59
3.39
3.35
4.61
3.44
3.41
3.01
4.12
3.01
3.41
3.23
4.07
3.39
4.20
3.37
3.43
3.52
4.05
3.27
3.59
3.29
3.85
3.73
4.65
3.22
3.50
3.58
3.49
3.41
3.69
3.49
4.01
3.66
4.12
3.41
3.93
3.43
3.49
5.85
3.93
3.49
3.81
3.45
3.93
3.65
3.73
4.33
5.04
4.46
4.68
5.02
3.66
5.05
4.47
4.74
5.20
4.32
4.89
4.42
4.84
4.87
4.42
4.53
4.56
4.23
4.45
6.06
˛-Methylmannoside
5
4.69
4.68
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 1015–1020

1018
R. Smoum, A. Rubinstein and M. Srebnik
Table 3. J(H,H) coupling constants (Hz) for the sugar part of the boronic complexes
Compound
J(1,2)
J(2,3)
J(3,4)
J(4,5)
J(5,6a)
J(5,6b)
J(6a, 6b)
1a
4.3
3.6
3.66
4.0
7.74
8.0
4.01
1.8
1.6
0.0
9.5
8.15
10
8.27
10
6.22
3.8
2.6
9.5
9.15
10
3.24
3.8
4.21
10
0.0
9.5
9.8
10
315
0.8
4.41
9.8
9.9
2.14
2.8
4.99
2.8
1.96
7.6
4.43
2.8
2.14
5.7
4.99
5.8
1.96
4.4
4.43
6.8
Mc
12.8
9.57
12.8
11.46
11.2
8.67
12.2
9.8
˛-D-glucopyranoseb
2a
Methyl-˛-D-glucopyranosideb
3a
Methyl-ˇ-D-galactopyranosideb
4a
D-Mannoseb
5a
3.2
3.5
9.3
10
3.7
1.9
5.2
5.8
˛-Methylmannosideb
1.6
10
12.0
a In DMSO-d6.
b In D2O (K. Bock, unpublished results).
c Multiplet.
Table 4. 13C chemical shifts (ppm) and 1J(C,H) coupling constants (Hz) for the sugar part of the boronic complexes in DMSO-d6
Compound
C-1 C-2 C-3 C-4 C-5 C-6 J(C1,H1) J(C2,H2) J(C3,H3) J(C4,H4) J(C5,H5) J(C6,H6)
˛-D-Glucopyranose
1
Methyl-˛-D-Glucopyranoside
2
Methyl-ˇ-D-Galactopyranoside 105.1 71.1 68.8 74.0 75.8 61.1
3
D-Mannose
4
92.6 72.8 73.5 71.0 72.4 61.6
103.0 85.1 73.0 74.3 72.4 61.6
99.7 72.0 73.4 70.3 72.6 61.0
101.2 72.8 72.1 75.6 65.0 64.3
164
186
167
172
155
158
166
174
168
170
140
168
142
142
141
144
143
164
145
143
161
146
148
139
142
142
155
142
139
149
143
148
139
106
147
158
145
138
149
139
148
139
66
136
153
144
140
141
145
130
140
86
140
152
135
104.7 70.2 72.8 71.0 68.3 64.5
94.6 72.0 68.0 71.2 73.7 62.1
101.5 80.5 86.0 80.9 74.5 66.7
101.6 70.8 71.6 67.6 74.4 61.8
101.7 70.5 66.9 68.0 65.4 63.5
˛-Methylmannoside
5
results of Ferrier et al.25,26 for the phenyl boronates of methyl-
˛-D-glucopyranoside and methyl-ˇ-D-galactopyranoside.
For the D-(C)-mannose complex (4), 11B NMR gave a
single peak at 35.12 ppm, indicating the formation of a five-
membered ring only, and the 1H NMR spectrum of 4 in
DMSO-d6 shows a hydroxyl peak that connects to proton
1 in the COSY spectra. The data indicate the formation of
a 2,3 : 5,6-ring system with two five-membered rings. The
product shows small J(H,H) values for J(2,3) and J(4,5)
(4.2–4.4 ppm) (Table 3), thus eliminating the possibility of
the diaxial arrangement for these protons that should appear
in the pyranose ring. Therefore, the product is in the furanose
form and it is given the structure of D-mannofuranose cyclic
2,3 : 5,6-bis(butylboronate) (4) (Scheme 1). This agrees well
with the data given for the O-ethyl boron derivatives and the
isopropylidine derivatives of mannose.27
For the methylmannose 5, the data show that it reacts
readily to form the 2,3;4,6-diester. This is evidenced by the
11B NMR spectrum, which shows two peaks at 31.43 and
35.63 ppm indicating the formation of a five- and a six-
membered ring, respectively. This assignment is correlated
by the connectivities in the COSY and the HSQC assignments.
The spectra of the complex solution showed J(H,H) coupling
constants almost unchanged to those of the free sugar and this
shows that the protons remain in the diaxial arrangements
and that the ring remains in the pyranose form. Therefore,
forming a six-membered ring product with the methyl-˛-D-
glucopyranoside remaining in the ˛-pyranose form. This is
indicated by the appearance of two peaks in the H NMR
1
data for the free hydroxyl groups at positions 2 and 3 in
the sugar (Table 1). Also, the 11B NMR data show only one
peak at 30.36 ppm, which is consistent with a six-membered
ring (Table 2). Examination of J(H,H) for the product shows
that there are no significant changes in the vicinal coupling
constants, indicating no change in the conformation of the
pyranose ring upon complexation with the boronic acid.
The methyl-ˇ-galactopyranoside complex 3 is formed
where one butylboronic acid is attached to the sugar
at positions 4 and 6 as indicated by the 1H, 13C and
11B NMR data. The presence of free hydroxyl groups
in the 1H NMR spectra gives correlations in the COSY
to the protons at positions 2 and 3 in the sugar, and
the peak at 31.30 ppm in 11B NMR spectrum is indica-
tive of the formation of a six-membered ring product
at positions 4 and 6. Also, there are no changes in
the J(H,H), coupling constants indicating no change in
the pyranose ring upon complexation with the boronic
acid. Therefore, the monodentate complexes, 2 and 3,
are assigned the structures methyl-˛-D-glucopyranoside
4,6-butylboronate and methyl-ˇ-D-galactopyranoside 4,6-
butylboronate respectively (Scheme 1). This agrees with the
Copyright  2003 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2003; 41: 1015–1020

Boronate complexes of saccharides
1019
Table 5. GC–MS data
Compound
Major fragment ions: m/z (relative abundance, %)
1
2
3
4
5
43(100), 83(10), 127(10), 139(29), 168(29), 210(15), 237(3), 296, 296(8), 297(21)
43(100), 83(18), 115(27), 145(18), 157(23), 200(12), 243(6)
43(100), 74(10), 102(29), 144(15), 183(44), 227(7), 242(3), 270(3)
140(100), 18(6), 43(12), 61(25), 70(20), 111(12), 126(49), 169(3), 186(4), 210(3)
140(100), 18(6), 43(13), 61(25), 70(20), 111(12), 126(49), 169(2), 186(4), 210(2)
the structure of 5 is methyl-˛-D-mannopyranoside 2,3 : 4,6-
bis(butylboronate) (Scheme 1). The results agrees well with
those of Ferrier.25 Whereas 1, 4 and 5 are the only products
obtained with 1 equiv. of butylboronic acid (excess sugar is
observed in the NMR spectra), 2 and 3 are the only products
formed with 2 equiv. of butylboronic acid. This must be due
to the locked-in trans relationship of the two free hydroxyl
groups in 2 and 3, preventing the formation of an additional
ring. On the other hand, all the hydroxyl groups in 1, 4
and 5 are cis, allowing facile formation of an additional
five-membered ring.
The major mass spectral peaks are shown in Table 5. The
data are consistent with the structures indicated by NMR
(Scheme 1).
The prominent base peak at m/z 43 probably arises from
the ion [C2H3O]Cž for the acetylated derivatives of D-(C)-
glucose (6), methyl-˛-D-glucopyranoside (7) and methyl-ˇ-
D-galactopyranoside (8).
The acetylated product of the glucose complex 6 gives
a low-intensity (20%) peak at m/z 297 ꢀM ꢀ 57ꢁ, which is
indicative of the loss of a butyl (CH3CH2CH2CH2) group. For
the acetylated product of the methyl-˛-D-glucopyranoside
complex (7), a prominent peak at m/z 243 ꢀM ꢀ 101ꢁ was
observed that indicates a loss of two CH3CO—and one
CH3 group.
For the acetylated product of the methyl-ˇ-D-galactopy-
ranoside complex (8), GC–MS indicates the presence of a
mixture of two compounds, one completely acetylated and
the other partially acetylated due to boronate coupling. The
first compound either is due to the presence of free sugar or
indicates the removal of the boronates by the acetate groups.
The second product gives a peak with very low intensity
(2.5%) at m/z 270 ꢀM ꢀ 74ꢁ, which is indicative of a loss of
one methoxy ꢀOCH3ꢁ group and a propyl ꢀCH3CH2CH2ꢁ
group or a CH3CO group.
Similarly, the spectra of the acetylated mannose complex
9 gives a peak with a very low intensity (2.5%) at m/z 210
ꢀM ꢀ 144ꢁ and this indicates the loss of an acetate group
and two propyl groups. The ion at m/z 126 represents
the radical ion [C6O2BH11]Cž, which is consistent with the
2,3-butaneboronate substituent (a five-membered boronate
ring). Also, the ion peak at m/z 140 corresponds to
[C7O2BH13]Cž radical ion, which is consistent with the 5,6-
five-membered ring system in the furanose ring.
Also, there are peaks at m/z 126 and 140 indicating the
presence of five- and six-membered rings, respectively.
Additional observable peaks for excess non-reacted
sugars were observed only in the 1H and 13C NMR spectra of
mannose and its methyl derivative. In addition, although the
NMR parameters are identical for the 1 : 1 and 1 : 2 products
with the methyl-ˇ-galactopyranoside 3, the reaction does
not go to completion with a 1 : 1 ratio, i.e. only 50% of
the sugar reacts. This is in accordance with the results
of James et al.5 indicating that the association constants of
boronic acids to monosaccharides decrease in the order D-
glucose × D-galactose > D-mannose.
The methyl derivatives of the sugars were unstable
under aqueous conditions, and this was markedly seen for
the ˛-methylglucopyranoside product 2. The non-bonded
interactions between the axial methoxyl group and H-3 and
H-5 are held to be responsible for destabilizing27 the ˛-
complex and also occur in the methyl-˛-D-glucopyranoside
4,6-butylboronate 2, and so it was expected that this ester
would show greater susceptibility to hydrolysis than the
methyl-ˇ-D-galactopyranoside complex 3 and the methyl-˛-
D-mannopyranoside complex 5.
It is well known that trans-six-membered rings are less
stable than five-membered rings but the equilibrium is
largely determined by the geometric arrangement of the
diols.28,29 With methyl-ˇ-D-galactopyranose 3, the 4,6-six-
membered ring is a cis rather than a trans arrangement, and
it is known from decalin that the cis-fused six-membered
ring system is conformationally flexible whereas the trans
system is fixed. In addition, the presence of a methyl group
at the anomeric positions and the hydroxyls at positions 2
and 3 being trans leaves the 4,6-positions for the attachment
with boronic acid. Also, with methyl-˛-D-mannopyranose 5,
a trans-six-membered ring is formed because of the presence
of a methyl group at the anomeric position that causes the
first butaneboronate to attach itself to the cis-2,3 position and
the second to form the trans-4,6-six-membered ring.
Acknowledgements
The authors thank the Israel Science Foundation, grant 663/99-2, for
support of this work and a fellowship for R.S.
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