Lanthanum-catalyzed aqueous acylation of monosaccharides by benzoyl methyl phosphate

Article abstract of DOI:10.1139/V06-047

It was previously reported that diols dissolved in water (pH 8, EPPS buffer) react with benzoyl methyl phosphate (BMP) in the presence of lanthanide ions to form monobenzoyl esters. We have investigated the possibility of extending this process to include

Full text of DOI:10.1139/V06-047

6
20
Lanthanum-catalyzed aqueous acylation of
monosaccharides by benzoyl methyl phosphate
1
Ian James Gray, Rui Ren, Bernhard Westermann, and Ronald Kluger
Abstract: It was previously reported that diols dissolved in water (pH 8, EPPS buffer) react with benzoyl methyl phos-
phate (BMP) in the presence of lanthanide ions to form monobenzoyl esters. We have investigated the possibility of
extending this process to include formation of esters of monosaccharides in water from lanthanide-catalyzed reactions
with BMP. The combination of methyl-α-D-glucopyranoside and BMP in the presence of lanthanum trichloride gave
selective monoacylation of the 2- and 6-hydroxyl groups in a ratio of 2:1. The likely mechanism involves preferential
bisbidentate coordination of BMP and the diol to lanthanide ion (which explains how an ester forms when water is in
enormous excess) followed by base-catalyzed intramolecular acyl transfer. The method should be generally applicable
where a selective acylation reaction in water as solvent is desirable.
Key words: benzoyl methyl phosphate, lanthanide, catalysis, water, monoacylation, selective.
Résumé : Il a été rapporté antérieurement que les diols dissous dans l’eau (pH de 8 et tampon « EPPS ») réagissent
avec le phosphate de benzoyle et de méthyle (PBM), en présence d’ions de lanthanide, pour conduire à la formation
d’esters monobenzoylés. On a examiné la possibilité d’étendre cette méthode de façon à inclure la formation d’esters
de monosaccharides, par des réactions en milieu aqueux avec du PBM et catalysées par des lanthanides. La combinai-
son de l’α-D-glucopyranoside de méthyle et du PBM, en présence de trichlorure de lanthane, conduit à la monoacétyla-
tion sélective des groupes hydroxyles en positions 2 et 6, dans un rapport de 2 : 1. Le mécanisme probable implique la
coordination bisbidentate préférentielle du PBM et du diol à l’ion lanthanide (qui explique comme un ester peut se for-
mer en présence d’un énorme excès d’eau), qui est suivie d’un transfert de groupe acyle intramoléculaire catalysé par
la base. La méthode devrait être applicable d’une façon générale quand il est désirable d’effectuer une réaction
d’acétylation sélective en utilisant l’eau comme solvant.
Mots clés : phosphate de benzoyle et de méthyle, lanthanide, catalyse, eau, monoacétylation, sélective.
[
Traduit par la Rédaction] Gray et al. 624
Introduction
hydroxyls and the catalysis of group migration add to the
complexity of possible outcomes (4).
We are reporting our work in conjunction with the pro-
duction of an issue of the Canadian Journal of Chemistry
honoring Walter Szarek, whose work in the field of biologi-
cal carbohydrate chemistry exemplifies his insight, perspec-
tive, and creativity. In addition, Walter’s outstanding personal
qualities match his science.
Reactions that accomplish selective monoacylation of car-
bohydrates take advantage of differences in the inherent re-
activity of individual hydroxyl groups (1, 2). For example,
monobenzoates result from reactions of N-benzoyl imidazole
and benzoyl cyanide with protected monosaccharides, pro-
vided that the combination of regioselection and product sta-
bility is sufficient (3). Subtle differences in the reactivity of
Benzoyl methyl phosphate (BMP) is an acyl phosphate
monoester, a class of materials that resists hydrolysis and is
inherently unreactive toward alcohols (5). Yet, acyl phos-
phates are anhydrides that have a high chemical potential for
acyl transfer and are utilized in diverse biochemical
acylation, including the formation of aminoacyl tRNAs. It
was recently reported that BMP can form monobenozyl es-
ters from diols in water in the presence of lanthanide ions
(
6). It is likely that bidentate coordination is the key to the
selective acylation reaction since under similar conditions
there is only a modest acceleration of base-catalyzed hydro-
lysis and formation of methyl esters (in methanol–water
mixtures) (7). The likely mechanism is consistent with
Clarke et al.’s (8) observations of lanthanide-promoted
monoacetylation of diols in nonhydroxylic solvents. They
reported NMR data that characterized an intermediate
bisbidentate-coordinated complex of the lanthanide with a
diol and an anhydride. Ionization of a coordinated hydroxyl
in such an intermediate leads to Lewis acid promoted intra-
molecular attack on the adjacent carbonyl of the coordinated
anhydride to form the ester (7).
Received 8 September 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 10 May 2006.
2
I.J. Gray, R. Ren, and R. Kluger. Davenport Chemistry
Laboratory, Department of Chemistry, University of Toronto,
Toronto, ON M5S 3H6, Canada.
B. Westermann. Department of Bioorganic Chemistry,
Leibniz Institute for Plant Biochemistry, Halle, Germany.
1This article is part of a Special Issue dedicated to Professor
Walter A. Szarek.
Corresponding author (e-mail: rkluger@chem.utoronto.ca).
Based on this background, we have been interested in ex-
tending the utility of BMP as a water-stable benzoylating
agent whose inherent specificity would be associated with
2
Can. J. Chem. 84: 620–624 (2006)
doi:10.1139/V06-047
© 2006 NRC Canada

Gray et al.
621
Fig. 1. HPLC output for lanthanum-promoted reaction of BMP
the formation of lanthanide chelates from adjacent hydroxyls
of the reactant, a description that could find useful applica-
tions in the carbohydrate field. Applications of lanthanide
catalysis of reactions by acyl phosphate monoesters would
be expected to provide for selection among hydroxyl groups
based on the properties of their lanthanide chelates, rather
than on the inherent differences of reactivity among the
hydroxyl groups of the substrate. We have now investigated
the reactions of typical monosaccharides with BMP and
lanthanide ions and find that this combination can introduce
chelation-based selectivity in monobenzoylation reactions
conducted in water.
and 1.
Experimental
Results and discussion
Reagent grade chemicals were used as received. High-
resolution mass spectrometry was performed at the QStar
Chemistry Mass Spectral Facility, University of Toronto.
HPLC analysis and preparation were performed with C18
Our initial studies focused on the monobenzoylation of
methyl-α-D-glucopyranoside (1) with the intention of estab-
lishing a general procedure that extends to the monobenz-
oylation of other monosaccharides.
TM
reversed-phase analytical columns (Waters µBondapak
C18 3.9 mm × 300 mm) and preparative columns (Waters
TM
µBondapak C18 7.8 mm × 300 mm). Samples were eluted
OH
H
with purified water and HPLC grade acetonitrile. Benzoyl
methyl phosphate (BMP) was prepared by the previously re-
ported procedure (6, 9). Acylation of the carbohydrates was
followed by HPLC, detected at 230 nm on a C18 reverse-
phase analytical column, and eluted with 75:25 (v/v) water–
acetonitrile containing 0.1% trifluoroacetic acid (TFA). The
flow rate was 1.5 mL/min. Solvents were filtered and de-
gassed before use. The ratio of acylation and hydrolysis
from BMP was determined from the relative molar amounts
of reactants (carbohydrate:water) to their corresponding
products (ester:acid), according to eq. [1]. The ratio of prod-
ucts was obtained from the areas of the HPLC peaks for the
resulting esters and benzoic acid.
H
O
HO
HO
H
H
OH
H
1
OCH3
As expected, combining 1 with BMP in 100 mmol/L of
EPPS (pH 8) without added lanthanum ion produces no re-
action. Under the same conditions with added lanthanum,
three new HPLC peaks are observed within 1 min (Fig. 1).
We optimized reaction conditions by varying the concentra-
tion and found that 2 equiv. of lanthanum trichloride and
1 equiv. each of BMP and carbohydrate in 100 mmol/L of
EPPS buffer at pH 8, produced a 33% conversion to the
product esters within 2 h, while the remaining substrate
could be recovered and BMP was hydrolyzed.
Each product was separated by preparative HPLC. ESI-
MS analysis revealed two of the peaks to be monobenzoyl
esters of 1, while the third was that of benzoic acid from the
hydrolysis of BMP.
The stability of the esters in the reaction solution was ob-
served over several days in the reaction solution. Product ra-
tios were invariant, indicating that the hydrolysis of the
benzoate esters is not promoted by the metal ions in the so-
lution under these conditions. We have noted that lanthanum
ions promote formation of monoesters from cis-diols by
BMP in water (6). In 1, the geometry of adjacent diols is
constrained by the ring and this will affect coordination as
well as the reactions of the coordinated species. The primary
hydroxyl (6-position) and equatorial hydroxyl groups at po-
sitions 2, 3, and 4 are all potential candidates for benzoyla-
tion. Each of the products peaks was isolated to determine
the pattern of the reaction.
[
1]
krel = (Areaester/Areaacid) × ([H O]/[carbohydrate])
2
Separation of the ester products by was performed by
HPLC. The effluent was continuously monitored at UV
30 nm on a C18 reverse-phase preparative column. The
material in each product peak was freeze-dried and stored at
20 °C. The general structure was ascertained from the mass
2
–
spectrum and refined by NMR analysis.
Methyl 4,6-O-benzylidene-α-D-glucopyranoside was ob-
tained commercially. Methyl 4,6-O-benzylidene-α-D-manno-
pyranoside was prepared by the published method (10, 11).
Benzoylation of methyl-␣-D-glucopyranoside (1) using
BMP
One equivalent of 1 and 2 equiv. of lanthanum trichloride
were dissolved in 100 mmol/Lof EPPS buffer at pH 8.
Freshly prepared BMP (1 equiv.) was added to this solution
and stirred at room temperature. The reaction was monitored
by HPLC (quenched with buffer (pH 8) containing EDTA at
time points) and was complete within about 2 h. The disap-
pearance of the BMP peak signified its conversion into ben-
zoic acid and benzoyl ester products. Relative yields were
calculated using internal standards.
©
2006 NRC Canada

6
22
Can. J. Chem. Vol. 84, 2006
Table 1. 13C NMR chemical shifts for the monobenzoyl esters of 1 in DMSO.
Carbohydrate
C-1
C-2
C-3
C-4
C-5
C-6
1
99.23
96.81
99.59
71.21
74.68
71.62
73.08
71.01
73.18
69.55
70.63
70.15
71.56
73.18
69.59
60.56
61.05
64.33
Ester A
Ester B
OH
OBz
H
H
H
H
O
O
HO
HO
HO
H
HO
H
H
H
OBz
OH
H
OCH3
H
OCH3
Ester A
Ester B
Table 2. Relative rates of acylation and hydrolysis in EPPS buffer (pH 8) with 50 mmol/L of lantha-
num trichloride, 25 mmol/L of BMP, and 25 mmol/L of carbohydrate.
Carbohydrate
Time (min)
krel (25 °C)
krel (0 °C)
Methyl-α-D-mannopyranoside
Methyl-α-D-glucopyranoside
Methyl-β-D-galactopyranoside
D-Ribose
60
60
60
60
50
370
800
100
730
1 310
11 330
8800
Analysis of the 13C NMR spectra of the products (Table 1)
indicate that reaction occurs at 2-OH and 6-OH preferen-
tially.
We have also done a preliminary survey of the reaction
patterns of BMP and lanthanum trichloride with other
monosaccharides (Table 3). From these results we see that
the monobenzoylation process is applicable to a variety of
species with varying efficacy: D-ribose > methyl-β-D-
galactopyranoside > methyl-α-D-glucopyranoside > methyl-
α-D-mannopyranoside.
For the reactants in Table 3, D-ribose gives the highest
overall yield of ester products. However, we have not yet
identified the individual monobenzoylated materials (there
are three in all). The reaction of 2-deoxyribose leads to only
two products, suggesting that one of the chelates involves
the 2-OH. Two monobenzoylated esters were produced from
uridine. There was no reaction with 2-deoxyuridine, as
would be expected if 2,3-chelation is the major mode of re-
action. The other aldohexose methyl pyranosides reacted
similarly to the glucoside, giving two monobenzoylated
products.
Due to competition with water, used as a solvent for the
reaction, it is inevitable that BMP hydrolysis accompanies
the monoacylation reaction. We found that hydrolysis was
significantly less competitive at low temperatures (Table 2).
The same carbohydrate reaction preferences hold at the
lower temperatures, with ester formation being the major
process.
In order for the reaction with BMP with the mono-
saccharide to compete with hydrolysis, the possibility of
bidentate coordination must overwhelm the effect of over-
whelmingly large excess of reaction sites in the water that
serves as the solvent. To test this further, we proposed that
no reaction would occur if the 6-hydroxyl is blocked, which
would prevent the possibility of bidentate coordination. We
used methyl-4,6-O-benzylidene-α-D-glucopyranoside and
methyl-4,6-O-benzylidene-α-D-mannopyranoside. No ester
formation occurs after 5 days with BMP and lanthanum
trichloride under conditions where 1 reacts rapidly. This re-
sult supports the NMR-based analysis for reaction of 1.
More detailed product studies are in progress.
A probable mechanism, illustrated with methyl-α-D-
glucopyranoside, is shown in Scheme 1. This involves inter-
nal addition from the conjugate base of the bisbidentate che-
late of the lanthanide and the two reactants (7, 8), as has
been shown in reactions of diol substrates.
Ph
Ph
O
O
H
OH
O
O
O
O
HO
H
HO
H
H
H
OH
H
H
OCH3
H
OCH
3
Methyl-4,6-O-benzylidene-α-
D
-glucopyranoside
Methyl-4,6-O-benzylidene-α-D-mannopyranoside
©
2006 NRC Canada

Gray et al.
623
Table 3. Products of lanthanum-catalyzed monoacylation.
Carbohydrate
No. of ester productsa
Ester ratiosa
Total ester (%)a
Methyl-α-D-glucopyranoside
Methyl-β-D-galactopyranoside
Methyl-α-D-mannopyranoside
D-Ribose
2
2
2
3
2
2
0
2.2:1
1.1:1
2.0:1
5:1:3
1:1.8
1:1.8
0
33.0
41.0
25.0
91.0
20.0
76.0
0
2
′-Deoxy-D-ribose
Uridine
′-Deoxyuridine
2
Note: Reaction conditions: carbohydrate (1 equiv.), BMP (1 equiv.), LaCl (2 equiv.), 100 mmol/L of EEPS buffer
3
(
pH 8) at room temperature.
a
Relative yields were calculated from HPLC analysis.
Scheme 1. Proposed mechanism for the monobenzoylation of 1.
+2
Ln
O
O
O
P
K
1
Ln+3
+
O
O
P
O
Ph
O
O
OCH3
Ph
OCH3
BMP
LnBMP
Ph
O
OH
O
P
Ln
_
O
H CO
3
O
O
Ph
K2
O
O
OH
-
O
P
K [OH ]
H
Ln
LnBMP + 1
O
H
H CO
3
Ph
O
_
O
O
O
Ln
P
O
H
H CO
3
O
O
HO
O
HO
HO
O
OCH3
O C
Ph
HO
k
+
P
O-Ln
H CO
3
O
C
O
Ph
O
O
HO
HO
OH
OCH3
Conclusions
the geometry of the transition state is controlled by the coor-
dination of the reacting complex. We intend to determine in
further detail the scope, selectivity, and optimal conditions
for this interesting new process. This approach should also
be amenable to detection of species in complex mixtures and
differential recognition, as well as for general synthetic ap-
plications.
We have for the first time shown that lanthanide-promoted
monoesterification reactions of monosaccharides in water
can be achieved by the reaction of an acyl phosphate
monoester with lanthanum chloride. Products form from
both hexoses and pentoses. NMR analysis indicated that the
methyl-α-D-glucopyranoside (1) was benzoylated at the 2-
oxygen and 6-oxygen in a ratio of 2:1. Since the 6-position
is primary and the 2-position is secondary, it is clear that
steric effects do not control the site of the reaction and that
Acknowledgements
We thank the Natural Sciences and Engineering Research
©
2006 NRC Canada

6
24
Can. J. Chem. Vol. 84, 2006
Council of Canada (NSERC) for support of this research
through a Discovery Grant.
5. R. Kluger, A.S.Grant, S.L. Bearne, and M.R. Trachsel. J. Org.
Chem. 55, 2864 (1990).
6
7
. R. Kluger and L.L. Cameron. J. Am. Chem. Soc. 124, 3033
2002).
. L.L Cameron, S.C.Wang, and R. Kluger. J. Am. Chem. Soc.
(
References
1
. U.B. Gangadharmath and A.V. Demchenko. Synlett, 12, 2191
2004).
. M. Nahmany and A. Melman. Org. Biomol. Chem. 2, 1563
2004).
. S.A. Abbabs and A.H. Haines. Carbohydr. Res. 39, 358 (1979).
. G. Hu and A. Vasella. Helv. Chim. Acta, 86, 4369 (2003).
126, 10721 (2004).
(
8. P.A. Clarke, P.L. Arnold, M.A. Smith, L.S. Natrajan, C. Wil-
son, and C. Chan. J. Chem. Soc. Chem. Commun. 2588 (2003)
9. L. Zervas and I. Dilaris. J. Am. Chem. Soc. 77, 5354 (1955).
10. J.J. Patroni and R.V. Stick. Aust. J. Chem. 41, 91 (1988).
11. O. Gronwald and K. Sakurai. Carbohydr. Res. 3, 307 (2001).
2
(
3
4
©
2006 NRC Canada