Chelation-controlled regioselectivity in the lanthanum-promoted monobenzoylation of monosaccharides in water

Article abstract of DOI:10.1016/j.carres.2007.05.024

Monosaccharides are selectively converted to monobenzoates in a base-catalyzed reaction with benzoyl methyl phosphate (BzMP) and a lanthanum salt in water. Yields are reported in terms of formation of the ester, which competes with hydrolysis of BzMP, to

Full text of DOI:10.1016/j.carres.2007.05.024

Carbohydrate Research 342 (2007) 1998–2002
Chelation-controlled regioselectivity in the lanthanum-promoted
monobenzoylation of monosaccharides in water
Ian James Gray and Ronald Kluger*
Davenport Chemistry Laboratory, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
Received 28 March 2007; received in revised form 16 May 2007; accepted 19 May 2007
Available online 2 June 2007
Abstract—Monosaccharides are selectively converted to monobenzoates in a base-catalyzed reaction with benzoyl methyl phosphate
(BzMP) and a lanthanum salt in water. Yields are reported in terms of formation of the ester, which competes with hydrolysis of
BzMP, to give an estimate of the efficiency of the conversion of the sugar. Higher conversions can be achieved using excess reagent.
Regioselectivity is influenced by the structure of the glycoside. For example, the reaction leads to different product distributions
from a- and b-anomers of the glycosides. The reaction combination provides a basis for efficient ester formation in specific geometric
situations, providing a means of identification as well as modification.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Benzoyl methyl phosphate; Lanthanide; Catalysis; Water; Regioselective monoacylation; Aqueous reaction and recognition
1. Introduction
monosaccharides in water (with benzoyl methyl phos-
phate, BzMP11). The pattern of the reaction is consistent
with the proposed formation of a bis-bidentate chelate
of lanthanum from two hydroxyls of the carbohydrate
and the anhydride within BzMP. This is also consistent
with observations of lanthanide catalysis of mono-
acylation of diols in organic solvents.12,13
Efforts to extend the selective, metal-directed acyla-
tion reactions to carbohydrate modifications from
organic solvents to water have been hindered by com-
petitive occupation of the metal ion coordination sphere
by water molecules7,14 Furthermore, carbohydrates have
strong hydrogen bonding interactions with water. These
compete with intramolecular hydrogen-bond networks
that effectively control the relative reactivity of hydroxyl
groups in organic solvents15–17 This contrasts with the
specific recognition of glycosides in water18–20 We have
now examined the reaction patterns of a range of related
glycosides in water with lanthanum–BzMP, giving
monobenzoylation. The results present a combination
of sufficient reactivity and selective recognition to make
this method one that should be of interest for specific
applications that require reactions to be conducted in
water.
The formation of esters in water involves an inherent
competition for the acyl donor between the reacting
hydroxyl group and solvent water. We have found that
acyl phosphate monoesters are useful in these reactions
because ester formation occurs by coordination of a lan-
thanide ion to these molecules along with a vicinal diol.
It was proposed that this reaction proceeds as a specific
base-catalyzed process via a bis-bidentate chelated lan-
thanide in which both the acyl phosphate and diol are
ligands. This pattern suggests that the combination of
lanthanum and an acyl phosphate monoester could lead
to selective monoacylation of carbohydrates in water.
The selectivity would be based on the extent of chelate
formation and reactivity within the chelate. Such a pat-
tern has precedent in metal–carbohydrate interactions
that lead to regioselective acylation1–10 That anticipa-
tion was borne out by the demonstration that lantha-
num salts promote the monobenzoylation of several
*
Corresponding author. E-mail: rkluger@chem.utoronto.ca
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.05.024

I. J. Gray, R. Kluger / Carbohydrate Research 342 (2007) 1998–2002
1999
2. Experimental
2.1. General methods
O-benzoate ester (1a) and 6-O-benzoyl ester (1b), as
summarized in Scheme 1. Similarly, the reaction of
methyl b-D-glucopyranoside with BzMP and lanthanum
produces the corresponding 2-O-benzoyl and 6-O-benz-
oyl esters. In reactions of the methyl a-D-glucopyran-
oside, the 2-O-benzoate ester is formed to a larger
extent than the 6-O-benzoate ester (Table 1). The reac-
tion of the b-glycoside gives the 6-O-benzoate ester in
a 2.5:1 ratio over the 2-O-benzoate ester. No products
with more than one ester group were detected. Our
reported yields are based on the amount of the reagent
BzMP we added, which was equimolar with the carbo-
hydrate. Yields are reported to provide a measure of
the observed rate of benzoylation competing with
hydrolysis of the reagent. Because water is the solvent,
it is necessarily present in great excess. For practical
conversions, we note that the remaining glycoside can
be reacted with additional reagent and the unreacted
glycoside can be recovered. Reagents that function in
organic solvents will not be subject to this competition,
so that reported yields should not serve as a basis for
comparison.
Our observation that reaction of 1 equiv of BzMP
with a methyl glycoside produces two monoesters is con-
sistent with formation of a chelated intermediate in
which the subsequently modified hydroxyls are coordi-
nated to lanthanum. For the esters to be produced,
BzMP must also form a second bidentate chelate on lan-
thanum, permitting the reaction to occur in a bis-biden-
tate array with the conjugate base of a hydroxyl group.
As a probe of the origins of the observed regiospecific-
ity, we reacted methyl b-D-xylopyranoside and 1,6-
anhydro-D-glucopyranose with BzMP and lanthanum
chloride. Based on the proposed coordination scheme,
the xylopyranoside should not be esterified as it cannot
form a chelate with its terminal hydroxyl, which is incor-
porated as an ether into the acetal function at C-1 (Ta-
ble 1). While the 1,6-anhydro-b-D-glucopyranose cannot
react at the C-6 hydroxyl, it can nonetheless coordinate
to lanthanum at that position via a non-bonded electron
pair of the oxygen atom, in addition to coordinating and
Reagent grade chemicals were used as received. High-
resolution mass spectrometry was performed at the
QStar Chemistry Mass Spectral Facility, the University
of Toronto. HPLC analysis and preparation were per-
formed with C18 reversed phase analytical columns
(3.9 mm · 300 mm) and preparative columns (7.8 mm ·
300 mm). Samples were eluted with water and aceto-
nitrile. Solvents were filtered and degassed before use.
BzMP was readily prepared by the reported procedure.21
Ester formation was followed by HPLC and detected at
230 nm upon elution from the analytical column. Reac-
tions were usually complete within 20 min. The products
remained stable in the reaction solution so the samples
were usually left for 2 h to assure completion. The sam-
ple was eluted with 80:20 (v/v) water–acetonitrile con-
taining 0.1% trifluoroacetic acid (TFA) with a flow rate
of 1.5 mL/min. The relative yields of products obtained
in the reactions were determined by integration of the
areas of the HPLC peaks for the esters (from glycosides)
and acid (from hydrolysis) formed from BzMP in the
presence of each glycoside. HPLC (preparative column)
was used to separate the esters resulting from the reac-
tion, with the effluent monitored at 230 nm. The col-
lected material was freeze-dried and stored at ꢀ20 ꢁC.
Confirmation of ester formation was established by
high-resolution mass spectral analysis of parent peaks.
2.2. Lanthanum-catalyzed reactions of BzMP and
glycosides
General procedure: 1–2 equiv of the glycoside and
lanthanum trichloride were combined in 100 mM pH 8
N-(2-hyroxyethyl)piperazine-N0-(3-propanesulfonic acid
(EPPS) buffer solution. BzMP (1.0 equiv) was added
and the solution was stirred at room temperature. The
reaction was monitored periodically by HPLC analysis.
Each aliquot was quenched with a solution of pH 8
EDTA. Reactions were complete within 1 h and the
products remained stable once formed.
2.3. Measurement of yields
BzMP reacts with water as well as with the hydroxyl
groups of the glycosides in this study. The yields are
based on the net amount of benzoate ester produced
compared to the reagent added.
3. Results and discussion
The lanthanum-promoted reaction of BzMP with
Scheme 1. Lanthanum-promoted benzoylation of methyl a-D-gluco-
pyranoside by BzMP.
methyl a-D-glucopyranoside (1) yields two products, 2-

2000
I. J. Gray, R. Kluger / Carbohydrate Research 342 (2007) 1998–2002
Table 1. Esters from the reaction of BzMP with monsaccharides and lanthanum
Reactanta
Ester productsb
Molar ratioc
Yieldc (%)
Methyl a-D-glucopyranoside
Methyl b-D-glucopyranoside
Methyl a-D-galactopyranoside
Methyl b-D-galactopyranoside
Methyl a-D-mannopyranoside
1,6-Anhydro-b-D-glucopyranose
D-Ribose
Methyl D-ribopyranoside (anomeric mixture)
Methyl b-D-xylopyranoside
2-Hydroxy-tetrahydropyran
D-Glucal
2-O-Bz, 6-O-Bz
2-O-Bz, 6-O-Bz
2-O-Bz, 3-O-Bz, 6-O-Bz
2-O-Bz, 3-O-Bz, 6-O-Bz
2-O-Bz, 3-O-Bz, 6-O-Bz
2-O-Bz
2-O-Bz, 3-O-Bz, 4-O-Bz
2-O-Bz, 3-O-Bz, 4-O-Bz
2.8:1
33
13
50
41
25
37
91
80
0
0.1:2.5
1:1.5:1.5
0.1:1:1.1
2:1:1
5:1:3
8:1:1
0
0
0
0
0
a Reaction conditions: substrate (1 equiv), BzMP (1 equiv), LaCl3 (2 equiv), pH 8 EPPS 20 ꢁC.
b Determined by C NMR , MS and HPLC after reaction.
13
c HPLC analysis based on the reagent (benzoylation competes with hydrolysis).
reacting with the conjugate base derived from the hydr-
oxyl at C-2. This observation is consistent with our find-
ing that for this example, the 2-O-benzoate ester forms
exclusively (Table 1). A depiction of the proposed mech-
anism is presented in Scheme 2.
The importance of the presence of the anomeric oxy-
gen in the reacting substrate was tested in the reactions
of 2-hydroxy-tetrahydropyran and D-glucal. In both
cases, no ester products were formed (Table 1). The
mechanism in Scheme 2 is consistent with the combined
preceding results.
We also assessed the extent of esterification of galact-
ose derivatives under the conditions we used with glu-
cose derivatives. Methyl a-D-galactopyranoside and
methyl b-D-galactopyranoside react with BzMP and lan-
thanum chloride to form esters at positions 2, 3, and 6
(respective product ratios: 0.1:3:4 and 1:1.5:1.5.). These
results are consistent with chelation leading to ester for-
mation via the 6-hydroxyl group and either the 2 or 3
hydroxyl groups as illustrated in Scheme 2. Molecular
mechanics modeling (using Cambridge Software’s Chem
3D) reveals that both modes are readily accessible.
We examined the reaction of a mixture of the a- and
b-anomers of methyl ribopyranoside with BzMP and
lanthanum chloride. This produced monobenzoate es-
ters, predominantly at the O-2 position along with small
amounts of the esters at O-3 and O-4. D-Ribose reacts to
give a similar pattern of esters (Table 1). If reaction oc-
curs through the pyranose from, the 2 and 3 hydroxyls
most readily form a chelate of lanthanum. An alterna-
tive chelate that could form via the 4 and 3 hydroxyls
can account for the additional ester formed at the 4
position.
We assessed the effectiveness of non-lanthanide metals
in promoting ester formation. As expected from previ-
ous work, none gave a significant amount of an ester
product (2% or less). On the other hand, all lanthanide
metal ions promoted formation of esters with significant
regioselectivity and yield (Table 2).
Our results suggest that the lanthanide ions promote
ester formation through their ability to achieve the nec-
essary highly coordinated state as well as Lewis acidity.
Although lanthanides in general promote the reaction,
each ion differs in its effect on the regioselectivity of
the overall process. There is a relationship between the
radius of the ion and the product ratio (Table 2 and
Fig. 1), with the larger ions favoring formation of the
ester at the 2-position while the smallest ion gives
the opposite preference. In particular, lanthanum gave
the highest ratio of the 2-O-benzoate ester to the 6-O-
benzoate ester while dysprosium gave equal amounts
(Fig. 1) and ytterbium ion yielded more of the 6-O-
benzoate ester than the 2-O-benzoate ester.
The ability of the combination of an acyl phosphate
monoester and lanthanum chloride to differentiate be-
tween glycosides based on their structure and conforma-
tion was assessed as a possible application for aqueous
molecular recognition. The results summarized in Table 3
OH
HO
HO
HO
HO
OH
HO
HO
HO
HO
O
O
O
O
H3C
La+3
O
O
O
O
O
O
P
OH-
O
+
O
O
Ph
La
O
O
La
O
La
O
O
O
O
O
P
O
O
O
P
O
O
O
P
Ph
Ph
CH3
Ph
CH3
CH3
O
O
O
Scheme 2. Bis-bidentate chelation of lanthanum by 1,6-anhydro-b-D-glucopyranose and BzMP leads to regioselective ester formation. Reaction to
form the ester at O-2 is shown.22

I. J. Gray, R. Kluger / Carbohydrate Research 342 (2007) 1998–2002
2001
Table 2. Products from the reaction of BzMP and methyl a-D-
glucopyranoside in the presence of lanthanide ions
and b-glucopyranosides and galactopyranosides (Table
3, entries 6 and 7). The reaction pattern for the respec-
tive a and b-hexopyranosides gives the following recog-
nition sequence: methyl galactopyranoside > methyl
mannopyranoside > methyl glucopyranoside. This im-
plies that the galactopyranoside stereochemistry is more
favorable for reaction under these conditions.
Metal iona
Product ratiob
Yieldc (%)
2-O-Bz 6-O-Bz
La
Ce
Pr
Nd
Eu
Dy
Yb
2.8
2.7
2.4
2.2
1.4
1.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.6
32
14
20
28
34
24
28
When the reaction was applied to the mixture of
methyl a-D-glucopyranoside and D-ribose (Table 3, entry
11) a 1:15 product ratio was observed for the respective
glycosides. This demonstrates the discrimination be-
tween the pentoses and hexoses. The reaction also distin-
guishes between methyl D-ribosides and D-ribose (entry
12). Therefore, the different structural geometries of the
glycosides lead to differences in the stability of the glyco-
side–metal complex. This would suggest that the reaction
recognizes subtle differences in glycoside structure.
In summary, our results show that coordination
geometry is an important feature in controlling reaction
products, consistent with the mechanism of reaction
involving selective chelate formation. The yields of ester
are variable and relate to the structure of the reactant.
Competing hydrolysis of BzMP prevents the reaction
from being highly efficient in terms of the use of the
reagent. In addition the different reactivity patterns
can help in identification of a reacting species.
a Conditions: methyl a-D-glucopyranoside (1 equiv), BzMP (1 equiv),
Ln (1 equiv), pH 8 EPPS 20 ꢁC.
b Determined by NMR, MS and HPLC.
c HPLC. Yield is based on BzMP (ester as a fraction of ester + acid).
0.8
0.75
0.7
0.65
0.6
0.55
0.5
0.45
0.4
0.35
0.3
0.98
1
1.02 1.04 1.06 1.08 1.1
Ionic Radius
1.12 1.14 1.16 1.18
Acknowledgment
Figure 1. Relative amount of O-2 ester (as a fraction of combined O-2
We thank NSERC for support of this research through
a Discovery Grant.
+3
˚
and O-6 esters) in relation to the ionic radii (A) of lanthanide ions.
demonstrate this by showing the partial and distinct
differences in product ratios for a series of hexopyran-
oside mixtures. Entry 4 demonstrates an 11:1 difference
between the product ratios of methyl b-D-galactopyran-
oside and methyl b-D-glucopyranoside, which is in con-
trast to the result from their a analogs (entry 1). In
addition the reaction demonstrates an ability to recog-
nize the anomeric difference between the respective a
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