Regioselective Monoesterification Study of the Diol in 1-C-(4,6-O-Benzylidene-β-D-glucopyranosyl) Acetone

Article abstract of DOI:10.1080/00397911.2015.1093143

1-C-(4,6-O-Benzylidene-β-D-glucopyranosyl) acetone has been studied in a catalytic system consisting of triethylamine-p-dimethylaminopyridine (TEA-DMAP) in the presence of a number of esterification reagents in dichloromethane. It was found that all-protected and monoprotected products form simultaneously. However, the regioselectivity tends to favor the 3-substituted derivative. Structural parameters have been determined by ¹H NMR, ¹³C NMR, ¹H-¹H correlation spectroscopy, and elemental analysis. Furthermore, a possible mechanism for the formation of intramolecular hydrogen-bond networks between the carbonyl group and 2-OH was described. The energy changes of the transition state in this reaction, as determined by a molecular modelling study, provided further evidence to assign the relative reactivities of each individual hydroxyl group.

Full text of DOI:10.1080/00397911.2015.1093143

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Regioselective Monoesterification Study of the
Diol in 1-C-(4,6-O-Benzylidene-β-D-glucopyranosyl)
Acetone
Tao Zhang, Tianyi Wang & Zhijie Fang
To cite this article: Tao Zhang, Tianyi Wang & Zhijie Fang (2015) Regioselective
Monoesterification Study of the Diol in 1-C-(4,6-O-Benzylidene-β-D-glucopyranosyl) Acetone,
Synthetic Communications, 45:22, 2567-2575
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Date: 19 November 2015, At: 04:01

1
Synthetic Communications , 45: 2567–2575, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1093143
REGIOSELECTIVE MONOESTERIFICATION STUDY OF
THE DIOL IN 1-C-(4,6-O-BENZYLIDENE-b-D-
GLUCOPYRANOSYL) ACETONE
Tao Zhang, Tianyi Wang, and Zhijie Fang
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, China
GRAPHICAL ABSTRACT
Abstract 1-C-(4,6-O-Benzylidene-b-D-glucopyranosyl) acetone has been studied in a
catalytic system consisting of triethylamine-p-dimethylaminopyridine (TEA-DMAP) in
the presence of a number of esterification reagents in dichloromethane. It was found that
all-protected and monoprotected products form simultaneously. However, the
regioselectivity tends to favor the 3-substituted derivative. Structural parameters have
1
13
1
1
been determined by H NMR, C NMR, H- H correlation spectroscopy, and elemental
analysis. Furthermore, possible mechanism for the formation of intramolecular
a
hydrogen-bond networks between the carbonyl group and 2-OH was described. The
energy changes of the transition state in this reaction, as determined by a molecular
modelling study, provided further evidence to assign the relative reactivities of each
individual hydroxyl group.
Keywords C-Glycosides; NMR; regioselective protection
INTRODUCTION
In recent years, C-glycosides have received considerable attention owing to
their extraordinary biological properties and stability towards acidic media or enzy-
[1]
matic hydrolysis. Furthermore, as central building blocks of a variety of natural
[
2]
[3]
[4]
products, including tunicamycin, sTn, sialic acid, etc., these functional groups
[
5]
provide important features in chemical synthesis. The enzymatic synthesis of
carbohydrate derivatives proves to be more effective than chemical approaches,
[
6]
particularly in terms of achieving a suitable regioselectivity and stereoselectivity.
Unfortunately, practical applications are scarce due to a limited access of suitable
enzymes. In synthetic carbohydrate chemistry also, the protection and deprotection
Received April 2, 2015.
Address correspondence to Zhijie Fang, School of Chemical Engineering, Nanjing University of
Science and Technology, Nanjing 210094, China. E-mail: zjfang@njust.edu.cn
2
567

2568
T. ZHANG, T. WANG, AND Z. FANG
2 3 2
Scheme 1. (a) PhCHO, ZnCl , 63%; (b) acetylacetone, NaHCO , H O, 90°C, 92%.
reaction of hydroxyl groups prove to be rather challenging to carry out. Therefore,
advanced methods for the synthesis of C-glycosides mimics and oligosaccharides are
required to improve synthetic efficacy. Oligosaccharides with 1→2 and=or 1→3 lin-
[
7]
kages exhibit superior bioactivities and can be found in a variety of natural com-
[8]
[9]
y
[10]
pounds, for example, in ginsenoside, MBr1=Globo-H, Lewis -KLH, etc. This
is why the efficient regioselective protection of the two secondary 2,3-dihydroxyl
groups remains a major synthetic goal in carbohydrate chemistry.
The electronegativity of anomeric atoms, such as N, O, and C, leads to changes
in the electron density of the hexagonal sugar ring system, affecting the selectivity of
esterification reactions of each hydroxyl group. A variety of catalysts have been stud-
ied in an effort to improve the selectivity in O- or S-glycosides, including PTC
[
11]
[12]
[13]
[14]
(phase-transfer catalyst),
Al O ,
fresh Ag O, , MoCl5,
etc. However, we
2
3
2
selected triethylamine-p-dimethylaminopyridine (TEA-DMAP) as the catalytic sys-
tem, mostly due to its high accessibility and availability. NMR spectral analysis
and molecular modelling study were conducted to provide a reasonable explanation
for the monoprotection results obtained. In this report, we described an efficient and
convenient strategy featuring a regioselective and regiocontrolled manipulation of
the hydroxyl groups on glycosides without the need for conventional multistep
protection=deprotection reactions (Scheme 1).
RESULTS AND DISCUSSION
Preparation of 1-C-(4,6-O-Benzylidene-b-D-glucopyranosyl) Acetone
A general procedure for compound 3 usually involves the synthesis of methyl-
1
-C-(b-D-glucopyranosyl)-2-one as the first step with the benzyl reaction being the
second step.
However, conducting this synthetic route proves to be challenging due to the
poor solubility of methyl-1-C-(b-D-glucopyranosyl)-2-one in benzaldehyde and some
product loss being observed in the reaction workup. Furthermore, due to the fact
that some benzaldehyde remains upon washing with petroleum ether, the product
species does not commonly precipitate in ice water. Even though dimethoxyphenyl-
[
15]
methane
as a benzylation reagent offers a good yield, its use proves to be less
economical. Therefore, in an effort to improve the yield and simplify the reaction
[
16]
workup, the synthetic route was reversed.
First, 4,6-O-benzal-glucose was pre-
pared, which was then transformed 1-C-(4,6-O-benzylidene-b-D-glucopyranosyl)
[17]
acetone via Knoevenagel condensation.
The total yield of these two combined
steps was found to exceed 55%, considerable more than using the conventional
method described previously. After one-time recrystallization in ethanol, the product
was obtained in ≥95% purity.

PROTECTION OF DIOLS IN C-GLYCOSIDES
2569
Regioselective Esterification of 1-C-(4,6-O-Benzylidene-b-D-
glucopyranosyl) Acetone
Because of varying steric demands and different electronic effects of each
esterification reagent, alkyl chloride and aryl chloride have been selected to be the
reagents for this synthetic step (cf. Table 1). Dimethylaminopyridine (DMAP) and
4
-chlorobenzoyl chloride in the presence of TEA (triethylamine) were added to a
solution of 1-C-(4,6-O-benzylidene-b-D-glucopyranosyl) acetone (3) in dichloro-
methane. The reaction mixture was stirred at room temperature for a total of 6 h,
resulting in the formation of 2- and 3-monosubstituted as well as 2,3-disubstituted
products at a ratio of 1:9.31:7.24. As shown in Table 1, the product yield for the
3
-substituted species increases when the esterification reagents a to e were used. This
latter finding indicates that high steric hindrance is indeed a key factor for the out-
come of this synthetic step. The electronic effect has been evaluated by using reagents
e–i. It was found that upon decreasing the electron density on the benzene ring, the
product yield for the 3-substituted analog increased accordingly. However, upon
using h and i as esterification reagents, the product yields for both the 3- and the
2
,3-substituted derivatives decreased. This latter finding stands in sharp contrast
to the results obtained in the presence of reagents e–g. Otherside, the product yield
for the 3-substituted analog was found to be larger than for the 2,3-substituted
derivative. The results obtained taken in concert indicate that the use of reactants
exhibiting strong electron-withdrawing effects and=or significant steric hindrance
may lead to an increase in regioselectivity for the formation of the 3-substituted ester
as product.
The selection of the right solvent proves to be another crucial parameter in the
success of the reactions described. In general, a suitable solvent provides a reaction
environment in which raw materials disperse adequately. Good solubility will accel-
erate the speed of a reaction; however, this feature may be a disadvantage for the
regioselectivity of a reaction. Three classic solvents have been selected with varying
polarity, namely CH CN, tetrahydrofuran (THF), and CH Cl . Compound 3 proves
3
2
2
to be less soluble in CH Cl compared to CH CN and THF, which ultimately results
2
2
3
in a slow reaction process but high selectivity. Consequently, TEA-DMAP was cho-
sen as the catalyst system of choice in the reactions detailed in this report.
Proton Affinity Calculation, Activation Energy Estimation, and
Spectroscopic Analysis of the OH- Groups in the Hydrogen-Bond
Networks
The regioselectivity effects of the esterification reagents, solvents, temperature,
and catalysts have been described. However, compound 3 itself also affects the
regioselectivity. The mechanism for the formation of compound 3 in the first step
involves the acyl chloride esterification reagent in combination with DMAP, which
results in the formation of a carboxylate as counteranion. The interaction of a
hydroxyl group with a carbonyl group then generates an unstable adduct. The
second step involves the formation of a high-energy intermediate generating the final
product after deprotonation and cleavage of the leaving group. Upon inspection of
the reaction mechanism, one can see that the key parameters leading to the reaction

2570
T. ZHANG, T. WANG, AND Z. FANG
Table 1. Regioselectivity of the esterification of secondary 2,3-dihydroxyl groups
a
b
Entry
1
Acyl
Solvent
Cat.
4 (%)
5 (%)
6 (%)
Ratio 4:5:6
DCM
THF
CH CN
3
DMAP
DMAP
DMAP
32.28
25.68
38.10
67.72
45.29
55.46
—
1.00:2.05:0.00
1.00:1.76:1.13
1.00:1.46:0.17
29.03
6.43
2
3
DCM
DCM
DMAP
32.66
44.99
22.35
1.00:1.38:0.68
DMAP
29.77
61.97
8.27
1.00:2.08:0.28
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DMAP
DMAP
DMAP
DMAP
DMAP
25.35
9.78
71.85
54.55
56.95
53.05
58.33
2.80
35.68
23.75
41.24
24.31
1.00:2.83:0.12
1.00:5.58:3.65
1.00:2.95:1.23
1.00:9.31:7.24
1.00:3.36:1.40
19.31
5.70
17.36
9
DCM
DMAP
13.50
70.30
16.20
1.00:5.21:1.20
a
Based on reacted material, 80–98% conversion, counted by chromatography.
b
Reaction conditions: Compound 3 1.07 mmol (1 eq); esterification reagent: 1.177 mmol (1.1 eq),
DCM 50 mL, TEA 1.77 (1.5 eq), DMAP 6.4‰.

PROTECTION OF DIOLS IN C-GLYCOSIDES
2571
[
18]
results prove to be proton affinity of each OH group and the activation energy of
the two steps.
It has been reported previously that a semiempirical method (PM3) offers a
suitable tool for obtaining experimental proton affinities of primary alcohols. In this
[
19]
study, we have adopted the PM6 method to evaluate the proton affinity of each
OH group in compound 3.
[
20]
Proton affinities have been calculated according to Eq. (1):
À
þÁ
þ
Proton Affinity ðR ꢀ OHÞ ¼ DHf ðH Þ þ DHf ðR ꢀ OHÞ ꢀ DHf R ꢀ OH
ð1Þ
2
In this equation, ΔH represents the calculated heat of formation. The experi-
f
þ
ꢀ1
mental ΔH (H ) is found to be 1536 KJ mol . The calculated results (PA-2-OH
f
¼
1191.95 KJ=mol, PA-3-OH ¼ 1362.58 KJ=mol) show that the 3-OH is more likely
be protonated. Furthermore, the relative contribution of activation energy in the
[21]
two steps needs to be considered as well.
To provide a reasonable representation, we designed a schematic energy dia-
gram for the DMAP-catalyzed esterification step (cf. Fig. 1). The total energy of
the 2-substituted product as well as the 3-substituted product was obtained by a
DFT method with the Gaussian 03 package at B3LYP=6-31g* level. The results
obtained indicate that the 3-substituted product proves to be more stable with its
total energy being lower than the 2-substituted product (i.e., ΔE4g-5g ¼ 9.45 KJ=mol).
Moreover, since the pyridinium ion proves to be an excellent leaving group, very
little difference between the activation energy of the second step of the 2- and 3-sub-
stituted products can be found, i.e., ΔE2 ≈ ΔE3 . Therefore, the rate-determining
2
2
step for the DMAP-catalyzed esterification of carbohydrates is the first step. Accord-
ing to the synthesis results shown in Table 1, the main reaction product found is the
3
-substituted derivative. Therefore, the yield for the 3-substituted intermediate
should be greater than the yield for the 2-substituted intermediate. As a result, the
activation energy of E3 proves to be lower than E2 (i.e., E2 > E3 ).
1
1
1
1
Figure 1. Proposed energy diagram for the DMAP-catalyzed esterification.

2572
T. ZHANG, T. WANG, AND Z. FANG
Figure 2. Schematic representation of a delocalized positive charge in hydrogen-bond networks.
Moreover, the hydrogen-bond networks (cf. Figure 2) exhibit further effects on the
regioselectivity with the positive charge in the transition state being delocalized. The 2-
OH group as a hydrogen donor can interact with the oxygen atom in the 3-OH group as
well as the carbonyl oxygen. The 3-OH group as a hydrogen donor, however, can only
form a hydrogen-bond network with the 2-OH group. The interactions in these hydro-
1
gen-bond networks can be verified by spectroscopic analyses, e.g., via H NMR.
In compound 3 the proton shift of the 2-OH is found to be larger than 3-OH,
with network I being present by comparing the shifts between the 2- and the 3-substi-
tuted product. Affected by these networks, the proton shifts of the corresponding
hydrogens move to a low field. Compound 3 is able to form a network between the
1
2
-OH and the carbonyl oxygen. Hence, the H NMR shift of the proton in 2-OH
can be found at low field. After esterification reaction, the 3-substituted product
can expose 2-OH and form a hydrogen bond with the carbonyl oxygen, whereas the
2
-substituted product can only generate 3-OH, which has little effect on the surround-
ing hydrogens. As shown in Table 2, the proton in free 2-OH features a larger chemical
shift than the proton in free 3-OH. As a result, the first network (I, II) proves to be
more efficient in the delocalization of the hydroxyl group proton than the second (III).
NMR Spectral Analysis of 2- or 3-Substituted Products
Upon comparison of the spectrum of 3 with the spectrum of 6a (cf. Figure 3),
two peaks (i.e., d ¼ 3.40 and d ¼ 3.76) were found to disappear in the spectrum of 3
but appear at d ¼ 4.95 and d ¼ 5.35 in the spectrum of 6a. The chemical shifts of H-2
and H-3 were found to move to a lower field, indicating that the two hydroxyl groups
Table 2. Representative chemical shifts of free hydroxyl groups
Compound
d3-OH
Compound
d2-OH
3
5
5
5
5
5
5
(3-OH)
3.0
2.7
2.7
2.9
3.1
3.0
2.7
3(2-OH)
3.1
3.2
3.1
3.1
3.5
3.4
3.4
a
b
c
e
f
4a
4b
4c
4e
4f
g
4g

PROTECTION OF DIOLS IN C-GLYCOSIDES
2573
1
3
Figure 3. H NMR spectra of 3, 4a, 5a, and 6a in CDCl and a corresponding coupling figure of 5a.
1
were fully protected by acetyl groups. From the H NMR spectra of 4a and 5a (cf.
Figure 3), it was found that the individual signals at d ¼ 4.85 and d ¼ 5.10 give the
same coupling constant, i.e., J ¼ 9.0 Hz and triplets. This indicated 4a or 5a must
be one of the 2- and 3-monosubstituted products. The question of which is which
1
1
can be determined by using a H- H correlation spectroscopy (COSY) spectrum
(
cf. Figure 4). As shown in the two-dimensional (2D) spectrum, using 5a as an
0
0
example, the upfield coupling correlation between H-1 a and H-1 b (d ¼ 2.68 and
1
1
Figure 4. H- H COSY spectra of 5a.

2574
T. ZHANG, T. WANG, AND Z. FANG
0
2
.92) can be determined. Similarly, all the correlation of H-1 a,b (d ¼ 2.68 and 2.92)
and H-1 (d ¼ 4.30), H-1(d ¼ 4.30) and H-2 (d ¼ 3.45), H-2 (d ¼ 3.45) and H-3 (d
¼
5.10), H-3 (d ¼ 5.10) and H-4 (d ¼ 3.59), H-4 (d ¼ 3.59) and H-5 (d ¼ 3.56), and
H-5 (d ¼ 3.56) and H-6a,b (d ¼ 3.65, 4.30) have also been referenced in Fig. 4.
CONCLUSION
To summarize, we systematically demonstrated experiments directed towards
the regioselective protection of the two structurally similar secondary 2,3-dihydroxyl
groups in 1-C-(4,6-O-benzylidene-b-D-glucopyranosyl) acetone. The results obtained
1
from H NMR spectroscopic and molecular computation analysis show that strong
electron-withdrawing effects and the steric demand of the esterification reagents
provide a general regioselective product trend towards the 3-substituted ester. In
addition, the inspection of the activation energy (E3 < E2 ) offers a simple way to
1
1
explain the formation of a 3-substituted intermediate. Using TEA-DMAP as a cata-
lytic system may be considered as an attractive alternative to existing methodologies
for the regioselective protection of C-glycosides, particularly protection reactions of
the 2,3-dihydroxyl groups.
EXPERIMENTAL
All chemicals were analytical pure and used without further purification.
Reactions were monitored by thin-layer chromatography (TLC) using silica-gel-
coated TLC plates. Detection was performed by UV absorption (254 nm) where
applicable by spraying with 50% sulfuric acid in ethanol followed by charring at
1
50 °C. Melting points (mp) were determined on a WRS-1B digital melting-point
1
13
1
1
apparatus (Shanghai Shenguang Instrument Co., Ltd). H, C, and H- H COSY
NMR spectra were recorded on a Bruker-500 (500=125 MHz) spectrometer and
Bruker-300 (300=75 MHz). Electrospray ionization–liquid chromatography–mass
spectrometry (ESI-LCMS) spectra were obtained on a Shimadzu LCMS-2010EV
mass spectrometer.
General Procedure for the DMAP-Catalyzed Esterification
A solution of acid chloride (1.18 mmol) in CH Cl (10 mL) was added dropwise
2
2
to a solution of 1-C-(4,6-O-benzylidene-b-D-glucopyranosyl) acetone 3 (0.33 g,
.07 mmol), DMAP (6.4 mg), and TEA (0.22 mL, 1.605 mmol) in CH Cl (50 mL)
1
2
2
and stirred at room temperature for 6 h. The resulting mixture was washed first with
saturated NaHCO solution, further with saturated sodium chloride solution, and
3
finally dried over MgSO . After filtration, the crude mixture was evaporated to
4
dryness under reduced pressure. The residue was further purified by flash column
chromatography (PE=EA, 2:1) to afford the product.
ACKNOWLEDGMENT
We thank Dr. Wu X. D. for helpful discussions on NMR analysis.

PROTECTION OF DIOLS IN C-GLYCOSIDES
2575
FUNDING
This work was supported by the Prospective Joint Project of Production,
Education, and Research in Jiangsu Province, China (Grant No. BY2013004-02)
and Jiangsu Province Ordinary University Students on Academic Research and
Innovation Program (Grant No. KYLX_0394).
SUPPLEMENTAL MATERIAL
1
13
1
1
H NMR, C NMR, H- H COSY spectra, and molecular computation data
for this article can be accessed on the publisher’s website.
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