Lead-Catalyzed Aqueous Benzoylation of Carbohydrates with an Acyl Phosphate Ester

Article abstract of DOI:10.1021/acs.joc.7b03142

Biochemical systems utilize adenylates of amino acids to aminoacylate the 3′-terminal diols of tRNAs. The reactive acyl group of the biological acylation agent is a subset of the general class of acyl phosphate monoesters. Those compounds are relatively stable in aqueous solutions, and their alkyl esters are conveniently prepared. It has previously been shown that biomimetic reactions of acyl phosphate monoesters with diols and carbohydrates are promoted by lanthanide salts. However, they also promote hydrolysis of acyl phosphate reagents, and the overall yields are modest. An assessment of the catalytic potential of alternative Lewis acids reveals that lead ions may be more effective as catalysts than lanthanides. Treatment of carbohydrates with benzoyl methyl phosphate (BMP) and triethylamine in water with added lead nitrate produces monobenzoyl esters in up to 75% yield. This provides a water-compatible pathway for novel patterns of benzoylation of polyhydroxylic compounds.

Full text of DOI:10.1021/acs.joc.7b03142

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Article
Lead-Catalyzed Aqueous Benzoylation of
Carbohydrates with an Acyl Phosphate Ester
Yuyang Li, and Ronald Kluger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03142 • Publication Date (Web): 25 Jan 2018
Downloaded from http://pubs.acs.org on January 26, 2018
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Lead-Catalyzed Aqueous Benzoylation of Carbohydrates with an
Acyl Phosphate Ester
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Yuyang Li and Ronald Kluger*
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Davenport Chemistry Laboratories, Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6 Canada
*E-mail: r.kluger@utoronto.ca
Abstract
Biochemical systems utilize adenylates of amino acids to aminoacylate the 3’-terminal diols of
tRNAs. The reactive acyl group of the biological acylation agent is a subset of the general class
of acyl phosphate monoesters. Those compounds are relatively stable in aqueous solutions and
their alkyl esters are conveniently prepared. It has previously been shown that biomimetic
reactions of acyl phosphate monoesters with diols and carbohydrates are promoted by lanthanide
salts. However, they also promote hydrolysis of acyl phosphate reagents and the overall yields
are modest. An assessment of the catalytic potential of alternative Lewis acids reveals that lead
ions may be more effective as catalysts than lanthanides. Treatment of carbohydrates with
benzoyl methyl phosphate (BMP) and triethylamine in water with added lead nitrate produces
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monobenzoyl esters in up to 75% yield. This provides a water-compatible pathway for novel
patterns of benzoylation of polyhydroxylic compounds.
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Introduction
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Enzymes utilize adenylates to aminoacylate the 3’-terminal diols of tRNAs. The key functional
group of the biological acylation agent is an acyl phosphate monoester. These compounds are
relatively stable in aqueous solutions and the simple esters are conveniently prepared. We have
been developing the use of anionic acylation agents in catalyzed reactions with hydroxyls that
permit reactions in water with biologically important compounds that contain adjacent hydroxyl
groups.1-3 Well-established methods for catalytic acylation of hydroxyl groups utilize organotin
compounds4,5, organoboron compounds,6,7 and Lewis acids8-10 as catalysts or as co-reactants with
reagents that are not amenable to use in water. Those processes typically utilize uncharged acyl
donors. They are typically subject to rapid hydrolysis, limiting their usage to dry organic solvents,
conditions that may not be compatible with the solubility of biological targets.11
Previous reports from our laboratory described the use of lanthanide salts to promote
monoacylation of diols with biomimetic acyl phosphate monoesters, establishing the potential of
a combination of an anionic acylation agent, metal ion, and aqueous reaction medium.12 The
resulting products are typically monoacylated with regioselectivity directed toward hydroxyls
located adjacent to a second hydroxyl, consistent with reaction occurring during chelation of the
metal ion by the hydroxyls and the reagent. A recent report of a process that utilizes organic
cations as catalysts with neutral acylation agents in water and organic cations provides a
complementary approach.13
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The pattern of monoacylation of diols from the reactions with acyl phosphate monoesters and
lanthanides in water suggests a transition state that results from the metal ion in bis-bidentate
chelation with both the reactant and the reagent. The chelated acyl phosphate esters become
activated toward the hydroxyls only within in the chelated assembly (Scheme 1). Recent reports
of benzoyl methyl phosphate for the synthesis of a larger scope of compounds have further
demonstrated its use as a biomimetic acylating reagent for highly functionalized bioactive
substrates. 14,15 However, a significant limitation has been the competing catalysis by lanthanides
that promotes the hydrolysis of acyl phosphates as an aspect of their general activation of
phosphate esters.
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Scheme 1 Lanthanum-catalyzed acylation through bis-bidentate coordinated
intermediate
Thus, we sought a method that allows acylation with metal ions by acyl phosphate monoesters
that sufficiently exceeds competing hydrolysis using alternative metal ions as catalysts. We now
find that lead salts provide an improved alternative to lanthanides for monobenzoylation of
carbohydrates with benzoyl methyl phosphate (BMP). We have assessed reactions in
combinations with water alone and as a component of mixed solvent systems. We find that the
pattern of results provides a basis for developing potentially useful alternatives to existing
processes.
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Results and Discussion
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Our observations indicate that monoacylation of diols and nucleotides by an acyl phosphate
monoester is promoted by the presence of lead nitrate in buffered aqueous solutions. The
outcomes of reactions of methyl pyranosides with benzoyl methyl phosphate (BMP) are
summarized in Table 1. The conditions give a distribution of monoester products. While the
hydrolytic competition is slower than with lanthanide-catalyzed reactions, hydrolysis of BMP
remains competitive.
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Table 1 Monobenzoylation of carbohydrates in aqueous buffer with benzoyl methyl
phosphate
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Conversion (%)
Pb(NO3)2
Entry
Carbohydrate
Benzoyl ester products
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Equiv.
2
Me-α-D-
Glucopyranoside
Me-β-D-
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2
3
4
4-O-Bz (10.3), 6-O-Bz (1.1)
4-O-Bz (0.2), 6-O-Bz (1.5)
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2
1
1
Glucopyranoside
Me-α-D-
4-O-Bz (7.2), 3-O-Bz (2.7), 6-O-Bz (9.9)
4-O-Bz (0.5), 3-O-Bz (2.0),6-O-Bz (10.3)
Galactopyranoside
Me-β-D-
Galactopyranoside
Me-α-D-
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6
2
2
2-O-Bz (6.5), 3-O-Bz (4.7), 4-O-Bz (2.3)
Mannopyranoside
Myo-Inositol
1-O-Bz (7.5), 2-O-Bz (2.1), 4-O-Bz (2.7), 5-O-Bz (0.5)
Reaction conditions: Carbohydrate (1 equiv.), BMP (1 equiv.), Pb(NO3)2, 0.2 M EPPS pH 8 aqueous buffer, 25 °C,
24 h. Conversion % based on HPLC area%.
We investigated alternative reaction conditions to minimize hydrolysis and assess acylation of
reactants with multiple reaction sites. The outcomes of reactions of methyl-α-D-manno-
pyranoside, in dry THF are summarized in Table 2. The products that result from adding
monosaccharides to solutions of BMP with lead nitrate at room temperature for 24 hours gave no
ester products. Refluxing the same mixture results in formation of monobenzoylated products (2-
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O-Bz, 3-O-Bz and 6-O-Bz) of 25% (entry 3). However, rapid hydrolysis of BMP results from
water in the hygroscopic BMP. As expected, addition of water (50 mM, 1 equiv.) had no further
effect. However, addition of tertiary amines gives monobenzoylated esters of the sugar. Reaction
with 1.0 equiv. of N,N-diisopropylethylamine (DIPEA) gives three monobenzoylated products in
41% yield in dry THF (entry 5) and 46% yield with 0.05 M water (entry 6). Additional
triethylamine leads to nearly 50 % total yield (entries 7 and 8). Using 2,6-lutidine in place of
triethylamine gives lower yields (25% and 17%; entries 9 and 10). This is consistent with the
amine acting as a Brønsted base in an acylation step that involves transfer of a proton. Increasing
the concentration of the effective amine catalysts (2.5 eq triethylamine and 5 eq. di-isopropyl-
ethyl-amine) gives benzoyl esters in 61% yield (entry 11 and 14). Monobenzoylation reactions
did not proceed with added inorganic bases (K2CO3 and KOtBu). These bases cause precipitation
of the lead salts needed for catalysis (entries 15 and 16).
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We evaluated diverse metal ions as potential catalysts beyond those that we have previously
reported. These include Fe2+, Cu2+, Bi2+, Co2+, Sn2+ and Ni2+ under the same reaction conditions as
described for lead ions. They produce an enhanced rate of hydrolysis of BMP and minimal
formation of esters. .The mechanism we propose requires, coordination, chelation and reaction
with internal hydroxides, conditions that clearly do not work for all metal ions.
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Table 2 Effects of organic base
Benzoylated Yield
Entry
Pb(NO3)2 (equiv.)
H2O (equiv.)
Amine (equiv.)
Temp. (°C)
8
9
(%)
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1
2
reflux
25
0
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1
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1
1
1
1
1
0
0
0
1
0
1
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1
0
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1
1
1
1
0
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0
Not detected
0
<1
3
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
0
25
4
0
14
5
DIPEA (1)
DIPEA (1)
TEA (1)
TEA (1)
Lutidine (1)
Lutidine (1)
TEA (2.5)
TEA (5)
DIPEA (2.5)
DIPEA (5)
K2CO3
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46
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46
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47
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25
10
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12
13
14
15
16
17
61
58
55
61
Not detected
Not detected
KOtBu
Abbreviations: TEA-Triethylamine, DIPEA = di-isopropylethylamine
Our results suggest that the hydrolysis of BMP is accelerated only through its activation by
coordinated lead ions without the internal acceleration by bases that we expect to occur with
coordinated diols. The chelation of the metal ion by adjacent hydroxyl groups enhances their
reactivity relative to that of water (Schemes 2a and 2b)16. This results in an improved yield of
monobenzoylated products compared to hydrolysis of BMP.
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Scheme 2 Modes of activation by Pb2+ ions.
We also analyzed the effect of water in the presence of organic bases (Table 3). Increasing the
proportion of water from 5% to 100% has only a slight effect on the yield (entries 1 to 5). The
use of 2.5 equiv. of TEA and 1.0 equiv. of lead nitrate produces a 40% yield (entry 5).
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Table 3. Outcomes for addition of varying amounts of water to benzoylation reaction mixture.
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Pb(NO3)2
Water
(vol %)
5
Triethylamine
Entry
Ester Yield (%)
Temp. (°C)
(equiv.)
(equiv.)
2.5
1
2
3
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5
80
80
80
80
80
1
1
1
1
1
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25
2.5
50
2.5
75
2.5
100
2.5
Higher concentrations of water do not affect the extent of formation of esters. This may result
from activation by increasing the extent of formation of coordinated lead hydroxides (Scheme
2c). These are among the most potent catalysts of phosphate ester exchange.17 Similar activation
by lead hydroxides should apply to the acylation reaction. In the presence of larger proportions
of water, lead hydroxides could function as internal Brønsted bases toward hydroxyl groups of
coordinated hydroxyls of the substrates. The combination of a Lewis acid and a Brønsted base
will promote ester formation.
For further optimization of the overall process, we assessed the reaction of methyl-α-D-
mannopyranoside with varying amounts of BMP (1 – 3 equiv.) while adjusting the quantities of
amine (1.1 to 5.0 equiv.) and lead nitrate (0 – 3 equiv.). We also varied temperature from 4 °C to
room temperature (Table 4). A combined yield of 76% was obtained when the substrate was
treated with 2.5 equiv. of triethylamine, 1.0 equiv. of lead nitrate and 1.0 equiv. of BMP at 4 °C
for 24 hours (entry 6). A large excess of triethylamine (5 eq.) accelerates the hydrolysis of BMP.
This is likely to be due to the increased basicity of the solution (entry 9). In water-ethanol
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mixtures, the lead-catalyzed monobenzoylation reactions produce lower yields (entry 14 to 16).
This is likely to be due to the competition of the added ethanol for binding sites on lead ions.
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Table 4 Varying combinations of each component and temperature.
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Pb(NO3)2
TEA
(equiv.)
2.5
2.5
5
BMP
Entry
Solvent
Ester Yield (%)
Temp. (°C)
equiv.
(equiv.)
1
2
H2O
H2O
4
25
25
4
0
1
1
1
1
1
1
1
1
2
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
3
1
1
1
12
61
6
3
H2O
4
H2O
1.1
2
29
63
76
71
22
10
29
8
5
H2O
4
6
H2O
4
2.5
3
7
H2O
4
8
H2O
4
4
9
H2O
4
5
10
11
12
13
14
15
16
H2O
4
2
H2O
4
3
H2O
4
2.5
2.5
2.5
2.5
2.5
49
21
31
18
15
H2O
4
25% EtOH
50% EtOH
75% EtOH
4
4
4
The higher yields that we obtain at lower temperatures are consistent with hydrolysis of acyl
phosphates being selectively inhibited under those conditions.18 The highest yield is 75%, which
we obtained with 2.5 eq. TEA. This may be due to the low basicity of the reaction mixture.
Around 50% of the lead hydroxides (pKa = 7.2)17 are deprotonated under those reaction
conditions, accounting for the effective Brønsted base catalysis. Increased amounts of added
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amine promote hydrolysis of BMP. Furthermore, compared with the elevated temperatures
required for reactions in dry THF, monoacylation reactions proceed at 4 °C in water, suggesting
that the intramolecular Brønsted base catalysis by lead-coordinated hydroxyl groups is more
efficient than catalysis by bases in dry solvents.
Table 5. Pb2+-catalyzed monobenzoylation
Products (%)
Entry
Carbohydrate
Monobenzoylated Product
Total
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5
Me-α-D-Glucopyranoside
Me-β-D-Glucopyranoside
Me-α-D-Galactopyranoside
Me-β-D-Galactopyranoside
Me-α-D-Mannopyranoside
4-O-Bz (4), 3-O-Bz (2), 6-O-Bz (33)
4-O-Bz (4), 3-O-Bz (3), 6-O-Bz (38)
45
2-O-Bz (7), 3-O-Bz (6), 4-O-Bz (7),6-O-Bz (28)
48
2-O-Bz (3), 3-O-Bz (6), 4-O-Bz (11),6-O-Bz (38)
57
3-O-Bz (10), 2-O-Bz (7), 4-O-Bz (4), 6-O-Bz (55)
76
1-O-Bz (15), 2-O-Bz (14), 4-O-Bz (12), 5-O-Bz
6
Myo-Inositol
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(6)
7
8
Ethylene glycol
1,2-propanediol
/
24
18
3
1-O-Bz (13), 2-O-Bz (5)
9
1,3-propanediol
/
/
10
Cis-1,2-cyclopentanediol
39
Based on these results, we applied the optimized lead ion-catalyzed monobenzoylation reaction
to other diols and carbohydrates (Table 5). All methyl pyranosides with multiple hydroxyl
groups are converted to monoesters (entries 1 to 5) with the primary hydroxyl group the
preferred reaction site. This is likely to be due to that route having the least steric hindrance
while permitting chelation. Unlike the existing method13, secondary hydroxyl groups were also
benzoylated under our reaction conditions, with 1,2-cis-diols being slightly more favorable. This
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is consistent with our chelation models as the shorter distance between hydroxyl groups
facilitates the coordination of lead ions. However, the overall selectivity pattern among
secondary hydroxyl groups is not yet apparent. This may be due to the large number of possible
chelation modes and bis-bidentate intermediates in pyranosides where all the hydroxyl groups
and the methoxy group are capable of metal ion coordination. The reactivity patterns of these
intermediates are further complicated by the relative acidities of the hydroxyl groups19 and the
associated steric effects. As a result, we find no general pattern for the regioselectivity in this
lead-catalyzed reaction with pyranosides. Monobenzoylation of simpler diols gave lower yields
(entry 6-9). This is likely to be due to the free rotation of hydroxyl groups for simple aliphatic,
acyclic diols. This makes the bis-bidentate complexes required for catalysis less stable20. These
selectivity patterns are similar to those in earlier reports with lanthanides.1
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Scheme 3 Proposed mechanism of Pb2+-catalyzed aqueous monobenzoylation
reaction
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Figure 1 Dependence of kobs for Pb2+ -catalyzed monobenzoylation on ethylene
glycol with 50 mM lead nitrate and 125 mM triethylamine in water at 4 °C
A likely route for the reaction of ethylene glycol with BMP to form a monobenzoylated product
is shown in Scheme 3. Coordination between lead ions and acyl phosphates is expected to be
strong, based on the great affinity of lead for phosphate ions (log K= 3.20).21 We determined
rates of monobenzoylation reactions on ethylene glycol. A plot of initial rates and concentration
shows no curvature, even at 0.15 M of ethylene glycol (Figure 1). The lack of saturation prevents
determination of the extent to which a complex is formed between lead and ethylene glycol.22
This also suggests that the bis-bidentate intermediate (EG-Pb-BMP) is higher in energy than the
bidentate complex (Pb-BMP), consistent with the rapid competing hydrolysis of acyl phosphates.
Organic bases (in dry THF) and lead hydroxides (in water) not only facilitate ionization and
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nucleophilicity of the hydroxyl groups of cis-diols, they also stabilize the bis-bidentate
coordinated intermediate. The combination of these effects is likely to be the source of the
efficiency of the lead-catalyzed reactions.
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Other significant catalytic species may be polynuclear lead hydroxide complexes. Dinuclear and
trinuclear transition metal complexes catalyze the hydrolysis of phosphate esters, with the Lewis
acid activating reaction components.23,24 Lead ions readily form lead-hydroxo complexes in
neutral water.25 Although the detailed speciation of lead-hydroxo complexes under our reaction
conditions is not accessible due to the many variable parameters (pH, concentration of Pb2+ and
counter ions) 26,27, the presence of polynuclear lead hydroxide should be taken into
consideration.25 Double Lewis acid activation could provide greater rate acceleration than single
Lewis acid activation for acylation of diols as coordination between the diol moiety and metal is
necessarily stronger in the doubly coordinated system.
Conclusions
We have developed lead-catalyzed monobenzoylation reactions of carbohydrates and polyols
that function under mild, aqueous conditions as well as in organic solvents. Regioselective
monobenzoylation products can be obtained in water in the presence of BMP and lead nitrate.
The efficient catalysis by lead ion, particularly in water, is accomplished through a combination
of Lewis acid and Brønsted base catalysis. The development of this efficient pathway contributes
not only to direct monobenzoylation of carbohydrates and provides a basis for a better
understanding of the activation process of lead ions. Our results suggest that bis-bidentate
coordination can be combined with base catalysis to provide an internal promoter for acylation.
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Experimental Section
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General monobenzoylation procedure of substrates (methyl D-pyranosides and diols) in water.
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Methyl D-pyranosides or diols (0.125 mmol, 1 equiv.), Pb(NO3)2 (0.125 mmol, 1equiv.) and
triethylamine (0.313 mmol, 2.5 equiv.) were added to 2.5 ml of ice cooled deionized water. To
the solution was added benzoyl methyl phosphate (0.125 mmol, 1 equiv.) and the mixture was
allowed to stir at 4 °C for 3 days. Resulting mixture was centrifuged and supernatant was
analyzed by reversed-phased HPLC (Jupiter 4µ Proteo 90Å, 10% acetonitrile/water, 1 mL/min,
230nm). Collected products were lyophilized and analyzed by 1H NMR analysis and MS.
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Methyl 3-O-benzoyl-α-D-glucopyranoside28.
Colorless solid (2%). 1H NMR (500 MHz, Chloroform-d) δ 8.19 – 7.40 (m, 5H), 5.37 – 5.24 (t,
1H), 4.85 (d, 1H), 4.12 (q, 1H), 3.96 – 3.69 (m, 5H), 3.49 (s, 3H). MS (ESI) Calcd m/z (M +
Na+): 321.09. Found: 321.1.
Methyl 4-O-benzoyl-α-D-glucopyranoside29.
Colorless solid (4%). 1H NMR (500 MHz, Chloroform-d) δ 8.12 – 7.41 (m, 6H), 5.10 (dd, J =
10.1, 9.3 Hz, 1H, H-4), 4.89 (d, J = 3.9 Hz, 1H, H-1), 4.19 – 4.04 (m, 2H), 3.87 – 3.63 (m, 5H),
3.49 (s, 4H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
Methyl 6-O-benzoyl-α-D-glucopyranoside30.
Colorless solid (33%). 1H NMR (500 MHz, Chloroform-d) δ 8.14 – 7.40 (m, 5H), 4.81 (td, J =
6.3, 6.2, 4.2 Hz, 2H), 4.48 (dd, J = 12.3, 2.2 Hz, 1H), 3.85 (dddd, J = 9.9, 4.1, 2.2, 0.6 Hz, 1H),
3.77 (t, J = 9.3, 9.3 Hz, 1H), 3.54 (dd, J = 9.5, 3.9 Hz, 1H), 3.46 (s, 4H). MS (ESI) Calcd m/z (M
+ Na+): 321.09. Found: 321.1.
Methyl 3-O-benzoyl-β-D-glucopyranoside.
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Colorless solid (3%). 1H NMR (500 MHz, Chloroform-d) δ 8.13 – 8.06 (m, 2H), 7.64 – 7.56 (m,
1H), 7.53 – 7.43 (m, 2H), 5.16 (t, J = 9.3 Hz, 1H, H-3), 4.39 (d, J = 7.8 Hz, 1H, H-1), 4.02 – 3.81
(m, 3H), 3.70 – 3.62 (m, 1H), 3.61 (s, 3H), 3.54 – 3.49 (m, 1H). MS (ESI) Calcd m/z (M + Na+):
321.09. Found: 321.1.
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Methyl 4-O-benzoyl-β-D-glucopyranoside.
Colorless solid (4%). 1H NMR (500 MHz, Chloroform-d) δ 8.09 – 8.03 (m, 2H), 7.65 – 7.58 (m,
1H), 7.50 – 7.45 (m, 2H), 5.17 – 5.10 (t, J = 9.3 Hz, 1H, H-4), 4.34 (d, J = 7.8 Hz, 1H, H-1), 3.92
(t, J = 9.2 Hz, 1H), 3.82 (dd, J = 12.6, 2.4 Hz, 1H, H-6a), 3.70 (dd, J = 12.6, 4.6 Hz, 1H, H-6b),
3.61 (m, 4H, OMe and H-5), 3.54 (dd, J = 9.3, 7.7 Hz, 1H ,H-2). MS (ESI) Calcd m/z (M + Na+):
321.09. Found: 321.1.
Methyl 6-O-benzoyl-β-D-glucopyranoside30.
Colorless solid (38%). 1H NMR (500 MHz, Chloroform-d) δ 8.13 – 8.01 (m, 2H), 7.63 – 7.55 (m,
1H), 7.53 – 7.41 (m, 2H), 4.80 (dd, J = 12.2, 4.2 Hz, 1H, H-6a), 4.54 (dd, J = 12.3, 2.2 Hz, 1H,
H-6b), 4.25 (d, J = 7.7 Hz, 1H, H-1), 3.66 – 3.52 (m, 5H), 3.49 (dd, J = 9.7, 8.9 Hz, 1H), 3.39
(dd, J = 9.3, 7.7 Hz, 1H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
Methyl 3-O-benzoyl-α-D-galactopyranoside4
Colorless solid (6%). 1H NMR (500 MHz, Chloroform-d) δ 8.16 – 8.07 (m, 2H), 7.63 – 7.53 (m,
1H), 7.50 – 7.42 (m, 2H), 5.31 (dd, J = 10.2, 3.5 Hz, 1H, H-3), 4.93 (d, J = 3.9 Hz, 1H, H-1),
4.59 (d, J = 2.9 Hz, 1H), 4.18 (dd, J = 10.3, 3.9 Hz, 1H, H-2), 4.13 (d, J = 1.8 Hz, 2H), 4.11 –
4.07 (m, 1H), 3.51 (s, 3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
Methyl 4-O-benzoyl-α-D-galactopyranoside
Colorless solid (7%). 1H NMR (500 MHz, Chloroform-d) δ 8.12 – 8.02 (m, 2H), 7.67 – 7.56 (m,
1H), 7.51 – 7.44 (m, 3H), 5.55 (d, J = 3.2 Hz, 1H), 4.92 (d, J = 3.8 Hz, 1H), 4.12 – 3.94 (m, 3H),
3.69 (dd, J = 11.8, 6.6 Hz, 1H), 3.55 (dd, J = 11.8, 7.3 Hz, 1H), 3.48 (s, 3H). MS (ESI) Calcd
m/z (M + Na+): 321.09. Found: 321.1.
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Methyl 2-O-benzoyl-α-D-galactopyranoside31.
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Colorless solid (7%). 1H NMR (500 MHz, Chloroform-d) δ 8.17 – 8.02 (m, 2H), 7.67 – 7.55 (m,
1H), 7.50 – 7.42 (m, 2H), 5.21 (dd, J = 10.2, 3.7 Hz, 1H, H-2), 5.05 (d, J = 3.7 Hz, 1H, H-1),
4.45 (dd, J = 3.5, 1.4 Hz, 1H), 4.24 – 4.15 (m, 3H), 4.08 (t, J = 1.8 Hz, 1H), 3.42 (d, J = 3.8 Hz,
3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
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Methyl 6-O-benzoyl-α-D-galactopyranoside32.
Colorless solid (28%). 1H NMR (400 MHz, Chloroform-d) δ 8.08 – 7.35 (m, 5H), 4.86 (d, J =
3.7 Hz, 1H, H-1), 4.66 (dd, J = 11.5, 6.1 Hz, 1H, H-6a), 4.49 (dd, J = 11.4, 6.8 Hz, 1H, H-6b),
4.13 – 3.97 (m, 2H), 3.83 (qd, J = 9.8, 9.7, 9.7, 3.4 Hz, 2H), 3.44 (s, 3H). MS (ESI) Calcd m/z
(M + Na+): 321.09. Found: 321.1.
Methyl 3-O-benzoyl-β-D-galactopyranoside4.
Colorless solid (6%). 1H NMR (500 MHz, Chloroform-d) δ 8.16 – 8.08 (m, 2H), 7.64 – 7.54 (m,
1H), 7.50 – 7.43 (m, 2H), 5.09 (dd, J = 10.1, 3.1 Hz, 1H, H-3), 4.60 (dd, J = 3.3, 1.2 Hz, 1H),
4.37 (d, J = 7.7 Hz, 1H, H-1), 4.25 – 4.11 (m, 2H), 4.03 (dd, J = 10.1, 7.8 Hz, 1H, H-2), 3.86 (s,
1H), 3.61 (s, 3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
Methyl 4-O-benzoyl- β-D –galactopyranoside.
Colorless solid (11%). 1H NMR (500 MHz, Chloroform-d) δ 8.11 – 8.05 (m, 2H), 7.64 – 7.57 (m,
1H), 7.50 – 7.42 (m, 2H), 5.53 (dd, J = 3.5, 1.0 Hz, 1H, H-4), 4.31 (d, J = 7.6 Hz, 1H, H-1), 3.93
(dd, J = 9.8, 3.5 Hz, 1H, H-3), 3.86 – 3.74 (m, 3H), 3.62 (s, 3H), 3.59 (m, 1H). MS (ESI) Calcd
m/z (M + Na+): 321.09. Found: 321.1.
Methyl 2-O-benzoyl-β-D-galactopyranoside.
Colorless solid (3%). 1H NMR (500 MHz, Chloroform-d) δ 8.10 – 8.04 (m, 2H), 7.60 – 7.55 (m,
1H), 7.47 – 7.41 (m, 2H), 5.24 (dd, J = 9.8, 8.0 Hz, 1H, H-2), 4.53 (d, J = 8.0 Hz, 1H, H-1), 4.38
(dd, J = 3.7, 1.0 Hz, 1H), 4.27 – 4.09 (m, 2H), 3.86 (dd, J = 9.8, 3.4 Hz, 1H), 3.82 (d, J = 1.9 Hz,
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1H), 3.51 (s, 3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
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Methyl 6-O-benzoyl-β-D-galactopyranoside33.
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Colorless solid (38%). 1H NMR (500 MHz, Chloroform-d) δ 8.10 – 8.02 (m, 2H), 7.63 – 7.55 (m,
1H), 7.52 – 7.42 (m, 2H), 4.70 (dd, J = 11.4, 6.8 Hz, 1H, H-6a), 4.53 (dd, J = 11.3, 6.5 Hz, 1H,
H-6b), 4.25 – 4.16 (m, 1H), 3.99 (dd, J = 3.1, 1.2 Hz, 1H), 3.88 – 3.81 (m, 1H), 3.71 – 3.62 (m,
2H), 3.57 (s, 3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
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Methyl 2-O-benzoyl-α-D-mannopyranoside.
Colorless solid (10%). 1H NMR (500 MHz, Chloroform-d) δ 8.07 – 8.01 (m, 2H), 7.64 – 7.56 (m,
1H), 7.51 – 7.43 (m, 2H), 5.48 – 5.30 (m, 1H), 4.85 (t, J = 2.0, 2.0 Hz, 1H), 4.22 – 4.09 (m, 2H),
4.05 – 3.69 (m, 3H), 3.43 (d, J = 6.7 Hz, 3H). MS (ESI) Calcd m/z (M + Na+): 321.09. Found:
321.1.
Methyl 3-O-benzoyl-α-D-mannopyranoside.
Colorless solid (7%). 1H NMR (500 MHz, Chloroform-d) δ 8.13 – 8.03 (m, 2H), 7.65 – 7.56 (m,
1H), 7.53 – 7.43 (m, 2H), 5.45 – 5.29 (m, 1H), 4.80 (t, J = 2.1, 2.1 Hz, 1H), 4.40 – 4.17 (m, 2H),
4.02 – 3.88 (m, 2H), 3.81 – 3.75 (m, 1H), 3.45 (d, J = 4.2 Hz, 3H). MS (ESI) Calcd m/z (M +
Na+): 321.09. Found: 321.1.
Methyl 4-O-benzoyl-α-D-mannopyranoside34.
Colorless solid (4%). 1H NMR (500 MHz, Chloroform-d) δ 8.09 – 8.03 (m, 2H), 7.65 – 7.58 (m,
1H), 7.50 – 7.44 (m, 2H), 5.28 – 5.21 (t, J = 9.6 Hz, 1H, H-4), 4.86 (d, J = 1.7 Hz, 1H, H-1), 4.13
(dd, J = 9.3, 3.5 Hz, 1H, H-3), 4.02 (dd, J = 3.6, 1.7 Hz, 1H, H-2), 3.87 (ddd, J = 10.0, 4.5, 2.4
Hz, 1H, H-5), 3.81 (dd, J = 12.5, 2.4 Hz, 1H, H-6a), 3.72 (dd, J = 12.5, 4.4 Hz, 1H, H-6b), 3.44
(s, 3H, OMe). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
Methyl 6-O-benzoyl-α-D-mannopyranoside.
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Colorless solid (55%). 1H NMR (500 MHz, Chloroform-d) δ 8.12 – 8.05 (m, 2H), 7.63 – 7.55 (m,
1H), 7.50 – 7.42 (m, 2H), 4.86 (dd, J = 12.3, 4.1 Hz, 1H, H-6a), 4.78 (d, J = 1.6 Hz, 1H, H-1),
4.47 (dd, J = 12.3, 2.3 Hz, 1H, H-6b), 3.97 (dd, J = 3.4, 1.6 Hz, 1H, H-2), 3.87 (dd, J = 9.2, 3.5
Hz, 1H, H-3), 3.82 (dddd, J = 9.9, 4.1, 2.3, 0.6 Hz, 1H, H-5), 3.67 (t, J = 9.6, 9.6 Hz, 1H, H-4),
3.41 (s, 3H, OMe). MS (ESI) Calcd m/z (M + Na+): 321.09. Found: 321.1.
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1-O-Benzoyl-myo-Inositol35.
Colorless solid (15%).1H NMR (400 MHz, D2O) δ 8.26 – 8.07 (m, 2H), 7.75 (t, J = 7.4, 7.4 Hz,
1H), 7.60 (t, 2H), 5.05 (dd, J = 10.3, 2.8 Hz, 1H, H-1), 4.32 (t, J = 2.7 Hz, 1H), 4.04 (t, J = 9.9
Hz, 1H), 3.81 – 3.67 (m, 2H), 3.47 (t, J = 8.9 Hz, 1H). MS (ESI) Calcd m/z (M + Na+): 307.08.
Found: 307.1.
2-O-Benzoyl-myo-Inositol36.
Colorless solid (14%).1H NMR (500 MHz, D2O) δ 8.12 – 8.05 (m, 2H), 7.87 – 7.64 (m, 1H),
7.62 – 7.54 (m, 2H), 5.72 (t, J = 2.5, 2.5 Hz, 1H, H-2), 3.88 – 3.78 (m, 4H), 3.43 (m, 1H). MS
(ESI) Calcd m/z (M + Na+): 307.08. Found: 307.1.
4-O-Benzoyl-myo-Inositol35.
Colorless solid (12%).1H NMR (400 MHz, D2O) δ 8.23 – 7.96 (m, 2H), 7.66 (t, 1H), 7.51 (t, 2H),
5.30 (t, J = 9.7 Hz, 1H, H-4), 4.09 (d, 1H), 3.87 (dd, 1H), 3.73 (t, 1H), 3.63 – 3.54 (m, 2H). MS
(ESI) Calcd m/z (M + Na+): 307.08. Found: 307.1.
5-O-Benzoyl-myo-Inositol.
Colorless solid (6%).1H NMR (500 MHz, D2O) δ 8.21 – 7.46 (m, 5H), 5.06 (t, J = 9.6 Hz, 1H,
H-5), 4.15 (t, J = 2.9 Hz, 1H, H-2), 3.98 (t, J = 9.9 Hz, 2H, H-4, H-6), 3.72 (dd, J = 10.1, 2.9 Hz,
2H, H-1, H-3). MS (ESI) Calcd m/z (M + Na+): 307.08. Found: 307.1.
Acknowledgement
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We thank NSERC Canada for support through a Discovery Grant (A9918).
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Ø HPLC chromatograms of products and their 1H NMR spectra.
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