Magnesium ion enhances lanthanum-promoted monobenzoylation of a monosaccharide in water

Article abstract of DOI:10.1039/b926851k

Magnesium ion combines selectively with the methyl phosphate by-product in the lanthanum-promoted biomimetic reaction of benzoyl methyl phosphate with monosaccharides.

Full text of DOI:10.1039/b926851k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Magnesium ion enhances lanthanum-promoted monobenzoylation of a
monosaccharide in water†
Raj S. Dhiman and Ronald Kluger*
Received 23rd December 2009, Accepted 3rd March 2010
First published as an Advance Article on the web 15th March 2010
DOI: 10.1039/b926851k
Magnesium ion combines selectively with the methyl phos-
phate by-product in the lanthanum-promoted biomimetic
reaction of benzoyl methyl phosphate with monosaccharides.
organic solvents, where there is no reaction with the solvent to
compete with the reactants.10
A critical operational drawback to a biomimetic process based
on the reaction of lanthanum-coordinated acyl phosphate mo-
noesters is that the alkyl phosphate by-product combines with
the lanthanide, resulting in formation of a salt that removes the
lanthanide ion from solution, requiring stoichiometric amounts
of lanthanide for the reaction.11,12 Furthermore, the presence of
the voluminous lanthanide phosphate gel interferes with product
isolation.
We investigated the use of magnesium salts to provide a
sacrificial ion that would combine selectively with the alkyl
phosphate by-product to produce a solid precipitate (Scheme 1).
This would allow lanthanum to be involved in the acylation process
without being removed, allowing for true lanthanide catalysis
while easily separating the by-product.
Introduction
Reagents that acylate alcohols in water must distinguish a hydroxyl
group of the reactant from a functionally similarly solvent. This
distinction is often a challenge in the development of “green
chemistry”.1 A biomimetic approach to the problem utilizes the
reaction of acyl phosphate monoesters with diols in the presence
of lanthanum salts in water, producing esters through chelation-
directed selectivity.2,3 Acyl phosphate monoesters are functional
analogues of biological acylation agents, acyl adenylates.4 The
latter are formed in the enzyme-catalyzed reactions of carboxylic
acids with ATP. Examples include intermediates in aminoacyl-
tRNA synthetases5 as well as reactions involving ubiquitin-
adenylates.6
Acyl phosphate monoesters are inherently unreactive towards
oxygen-centred nucleophiles but are very reactive towards amines
in water, rapidly producing amides.7 In a recent example the
reactionwasusedtocreatepeptidebondsderivedfromphosphory-
lated amino acids in the synthesis of phospho-peptides.8 Another
important application has been in the identification of kinases in
proteomics by reactions with biotin carboxyl derivatives of ATP
and ADP.9
Scheme 1 Synergistic metal ions: Mg2+ scavenges byproduct to establish
La3+ catalysis.
Directingacylphosphate monoesters to reactwith oxygennucle-
ophiles requires a fundamental change in their inherent reactivity
from attack by an amino group to attack by a hydroxyl group. This
has been achieved by coordination of the reactant to lanthanide
ions as a bis-bidentate chelate of the acyl phosphate monoester
and a cis diol. At the same time, lanthanide coordination facilitates
ionization of a coordinated hydroxyl group, selectively targeting
acylation at the other coordinated hydroxyl group of the diol. The
mutual coordination of the reactant and reagent at the lanthanide
also produces a significant entropic advantage for reaction of the
tethered bifunctional reactant compared to the singly-coordinated
water molecules.2,3 The proposed mechanism is consistent with
structures and mechanisms presented by Clarke and co-workers
for lanthanum-promoted acylation of diols by acetic anhydride in
We note that magnesium ions combine readily with alkyl
phosphate dianions but do not coordinate well with either of the
reactants or esters.13 We report here the effects of added magne-
sium salts on the lanthanum requirements of the monoacylation
reactions of carbohydrates with benzoyl methyl phosphate (BMP).
Results and discussion
The acyl phosphate reagent is unique as it can repel oxygen
based nucleophiles due to its anionic character. The addition
of a lanthanide ion activates the reagent towards all oxygen
nucleophiles but is selective for vicinal diols. This provides simul-
taneous activation towards both esterification and hydrolysis. The
reagent is therefore susceptible to decomposition because of the
hydrolysis pathway but this does not interfere with formation of
the desired product as excess reagent is used and is readily available.
Similar approaches with expendable reagents in combination
with valuable substrates is a necessary and common practice
as exemplified in carbohydrate peracetylation/deacetylation,14
peptide synthesis15 and nucleotide coupling.
Davenport Chemical Laboratories, Department of Chemistry, University
of Toronto, Toronto, Ontario M5S 3H6, Canada. E-mail: rkluger@
chem.utoronto.ca
† Electronic supplementary information (ESI) available: Experimental
details, HPLC data for optimized small scale reactions and NMR
data for preparative scale acylation of Me-a-glucopyranose. See DOI:
10.1039/b926851k
We utilized D-ribose as the test substrate for acylation as
previous results demonstrated that monoacylation proceeds with
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Table 1 Observed regioselectivity of acylation by BMP in the presence of
full consumption of the acyl phosphate, with both ribose and
BMP remaining.19 It is likely that the methyl phosphate by-product
becomes bound to lanthanum, preventing both the carbohydrate
from reacting and lanthanum promoted hydrolysis of the reagent.
This result, alongside the observed regioselectivity, supports the
designated role for magnesium in competing effectively for methyl
phosphate.
Finally, in our choices for metal salts, we compared the
effects of triflate and nitrate counterions in addition to chloride.
Triflate enhances the Lewis acidity of lanthanum as evidenced
by the increased rate of reaction. The use of magnesium triflate
promotes complexation of the methyl phosphate by-product. We
hypothesize that lanthanum is the optimal lanthanide for this
reaction. We base this on the effect of the lanthanide contraction,
where ions with an increasing atomic number also possess a
higher charge relative to size.21 One realistic consequence is that
smaller lanthanides (e.g. YbIII, EuIII) will compete effectively with
magnesium for binding to the phosphate by-product. Examining
the effects of different lanthanides has been clearly demonstrated
in our efforts towards acylation of RNA substrates.22 Lanthanides
with smaller ionic radii impart reduced efficiency of acylation as
their charge-to-size ratio increases their selectivity for phosphates
over diols.
lanthanum and magnesium triflates20
Monosaccharide
Esters obtained
Ratio
Me-a-Glucopyranose
Me-b-Glucopyranose
Me-a-Galactopyranose
Me-b-Galactopyranose
Me-a-Mannopyranose
D-Ribose
2-OBz, 6-OBz
2-OBz, 6-OBz
2-OBz, 3-OBz, 6-OBz
2-OBz, 3-OBz, 6-OBz
2-OBz, 3-OBz, 6-OBz
2-OBz, 3-OBz, 4-OBz
3 : 1
1 : 9
1 : 5 : 5
1 : 3 : 1
2 : 1 : 1
6 : 3 : 1
a high level of efficiency. The most stable carbohydrate-metal
complexes form where the carbohydrate has three adjacent
hydroxyl groups that are in an ax-eq-ax conformation through
the pyranose form.16 Solution and solid-state studies on ribose-
lanthanide complexes clearly demonstrate the preponderance of
this mode.17 Coordination of the hydroxyl groups in this manner
will also exclude water from the lanthanide core. The ax-eq-ax
arrangement allows adjacent hydroxyl groups to assume the cis
orientation that is most favourable for monoacylation to occur
through necessary formation of a chelate.
It has been reported that the ionic strength of the reaction
mixture has an impact on the effectiveness of lanthanide catalysis.2
A prerequisite for this reaction is that the reactive components
orient themselves about the lanthanide core prior to acyl transfer.
An increase in ionic strength reduces the effect of lanthanide
catalysis as it provides electrostatic stabilization of the dissociated
components, precluding formation of the bis-bidentate array. This
effect is observed in the acylation reaction; while a magnesium
concentration of 0.1 M is optimal, we observe that the reaction
rate is reduced at higher concentrations of the added salt.
In conclusion, we have observed synergistic metal-ion-promoted
monoacylation of monosaccharides in water. The introduction of
magnesium ions allows for the lanthanide to function as a true
catalyst. This increases efficiency and permits the reaction to be
done according to principles of “green” chemistry.1
Acknowledgements
The extent of migration of the acyl group in the initial ester
product depends on the solvent and acidity/basicity of the
medium.18 Acyl groups tend to migrate under basic conditions.
Our studies were carried out in solutions at pH = 8.0 but the
mildly alkaline conditions do not affect the integrity or location of
the benzoates during the course of product isolation. We observed
the reaction products over 24 h and found that the distribution of
the ester products is not altered, nor is there any hydrolysis of the
resulting esters. In addition, the orientation of hydroxyl groups
within a particular glycosidic geometry can also affect migration.
However, as benzoyl groups have low migratory aptitudes18 we
cannot further generalize these results.
A critical issue in applying the lanthanum-promoted acylation
reaction is the relationship of regioselectivity to the bis-bidentate
array of the ligands. The only factors that should have significant
impact on the regioselectivity would be the carbohydrate’s reactive
conformation in the transition state and its state of cyclization
(e.g. pyranose or furanose, a or b etc.) as well as the energies of
competing transition states from these chelates. Unless magnesium
disrupts the bis-bidentate array on lanthanum, the reduction in the
concentration of lanthanum will not affect regioselectivity. Indeed,
we find that the relative regioselective preference is the same as in
the absence of magnesium (Table 1).11,12 We note that there are
modest increases in the ratios of the esters obtained in some cases
in the presence of both metal ions.
We thank NSERC Canada for support through a Discovery Grant.
Notes and references
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lanthanum in the absence of magnesium in order to evaluate the
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19 HPLC analysis presented in ESI.
20 From analytical scale reactions and HPLC analysis. Experimental
details presented in ESI.
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