Increased glycosidic bond stabilities in 4-C-hydroxymethyl linked disaccharides

Article abstract of DOI:10.1016/j.carres.2011.08.030

Three new hydroxymethyl-linked non-natural disaccharide analogues, containing an additional methylene group in between the glycosidic linkage, were synthesized by utilizing 4-C-hydroxymethyl-α-D-glucopyranoside as the glycosyl donor. A kinetic study was u

Full text of DOI:10.1016/j.carres.2011.08.030

Carbohydrate Research 346 (2011) 2394–2400
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Increased glycosidic bond stabilities in 4-C-hydroxymethyl linked disaccharides
⇑
Gour Chand Daskhan, Narayanaswamy Jayaraman
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2011
Received in revised form 24 August 2011
Accepted 25 August 2011
Available online 2 September 2011
Three new hydroxymethyl-linked non-natural disaccharide analogues, containing an additional methy-
lene group in between the glycosidic linkage, were synthesized by utilizing 4-C-hydroxymethyl-a-D-
glucopyranoside as the glycosyl donor. A kinetic study was undertaken to assess the hydrolytic stabilities
of these new disaccharide analogues toward acid-catalyzed hydrolysis, at 60 °C and 70 °C. The studies
showed that the disaccharide analogues were stable, by an order of magnitude, than naturally-occurring
disaccharides, such as, cellobiose, lactose, and maltose. The first order rate constants were lower than
that of methyl glycosides and the trend of hydrolysis rate constants followed that of naturally-occurring
Keywords:
Acid hydrolysis
Carbohydrates
Disaccharide analogues
Glycosidic bond
Kinetics
disaccharides. a-Anomer showed faster hydrolysis than the b-anomer and the presence of axial hydroxyl
group also led to faster hydrolysis among the disaccharide analogues. Energy minimized structures,
derived through molecular modeling, showed that dihedral angles around the glycosidic bond in disac-
charide analogues were nearly similar to that of naturally-occurring disaccharides.
Ó 2011 Elsevier Ltd. All rights reserved.
Oxocarbenium ion
1. Introduction
determined to be important, prior to heterolysis of C1–O1 bond. Fur-
ther advancements elucidate a stereoelectronic interpretation for
Studies on understanding the hydrolytic stabilities of glycosidic
bonds occupy a significant place in sugar chemistry.1–5 The rele-
vance of glycosidic bonds to glycosidase activities is an example
par excellence to illustrate rich chemistry surrounding glycosidic
bonds in biological recognition processes.6,7 Chemical and enzy-
matic studies to assess the glycosidic bond stabilities are well-
established, allowing early postulations and later refinements to
evolve in order to account for the observed hydrolytic stabilities
of glycosidic bonds more accurately.8–13 Differences in the rates of
hydrolysis of anomeric and epimeric glycosides were the subject
of sustained introspection. Added with the fact that levels of compu-
tational studies were not accessible few decades ago, refinements of
rationale behind differing hydrolytic rates of glycosidic bonds con-
tinue to evolve with advancements in computational studies. More
acid-catalyzed hydrolysis, wherein a-anomeric O5C1–O1R bond in
the antiperiplanar orientation facilitates protonation, governed by
the so-called ‘antiperiplanar lone pair hypothesis’ (ALPH). Whereas,
when the b-anomer undergoes faster hydrolysis, a possible effect
through ‘synperiplanar lone pair hypothesis’ (SLPH) appeared to
operate.11–13,18,19 Both these hypotheses refer to orientation of the
leaving group O1R with respect to lone pair electrons on O5 upon
protonation of O-1 and the attendant bond reorganizations toward
favorable ring conformations before heterolysis. In accounting reac-
tivities of the anomers, it was advocated that the energetically
accessible half-chair conformation of the b-anomer resulting
through a synperiplanar interaction, toward attaining a boat confor-
mation, is equivalent to half-chair conformation of
a-anomer
resulting from an antiperiplanar interaction. Rationale contradict-
ing ALPH were also put forth on the basis of preferred alternate con-
formations of reactive ground-state of the glycosides.20 Whereas
experiments and theories evolved for the rate of hydrolysis of ano-
meric glycosides, such is also the case to account differences ob-
served with epimeric glycosides. Faster hydrolysis of glycosidic
bonds on glycosides with axial hydroxyl groups than in equatorial
hydroxyl groups is an excellent case to illustrate this phenome-
non.21 The early reasoning that axial hydroxyl groups relieve ring
strain during formation of oxocarbenium ion was refined later,
rather conclusively, as arising due to hyperconjugative and field ef-
fects of axial and equatorial hydroxyl group. Recent studies of Bols
and co-workers,22,23 and Withers and co-workers24 establish the
role of hyperconjugative effects and field effects, in order to account
influence of substituents on glycosidic bond stabilities. Bols put
than a century-old observation that methyl b-
undergoes nearly twice faster hydrolysis than the
case in point. Early suggestions regarding this rate difference per-
tained to steric hindrance in protonating glycosidic oxygen of
D
-glucopyranoside14
-anomer is a
a
a-
anomer and lesser free energy of activation to protonate the same
oxygen in the case of the b-anomer.15–17 The first step of proton-
ation and subsequent heterolysis of C1–O1 bond, leading to the for-
mation of positively charged oxocarbenium ion, are major events
preceding a hydrolysis. Protonation of exocyclic O-1 is well resolved
for pyranosides as the first step. The stabilities, bond reorganiza-
tions, and conformational changes of the protonated species were
⇑
Corresponding author. Tel.: +91 80 2293 2578; fax: +91 80 2360 0529.
E-mail address: jayaraman@orgchem.iisc.ernet.in (N. Jayaraman).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.08.030

G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
2395
forward the rationale of charge-dipole interaction being the driving
force for observed differences in the hydrolysis rates of epimeric
hydroxyl-group containing disaccharide analogue 1, in a good yield.
On the other hand, a glycosylation of acetobromo galactose and 10,
in the presence of HgBr2/Hg(CN)2, followed by removal of protecting
groups afforded 2, in a moderate yield. Appearance of an H-10 signal
at ꢀ4.26 ppm, as a doublet with J = 8.0 Hz, confirmed b-anomeric
glycosidic bond of protected derivative 2 (Scheme 1).
methyl glycosides.22 An equatorial hydroxyl group at b- or
c-posi-
tion in methyl glycosides exerts higher electron withdrawing effect
than an axial hydroxyl group, leading to different rates at which
charge development occurs in the transition state of anomeric C–
O bond heterolysis. This explanation provides the first possibility
wherein differing rates of hydrolysis does not necessarily depend
on the conformational change as the driving force.
In the studies so far, acid-catalyzed glycosidic bond hydrolyses
were performed on stereoisomeric glycosides, having sugar, as well
as, non-sugar moieties at the reducing end. The effect of exocyclic
methyl vs sugar substituent is that the b-anomer undergoes faster
In order to synthesize
a-linked disaccharide 3, 2,3,4,6-tetra-O-
benzyl-
a
-D
-glucopyranosyl trichloroacetimidate28 was used as
the glycosyl donor. TMSOTf-mediated glycosylation of trichloro-
acetimidate and 10, followed by O-deacetylation led to the forma-
tion of protected derivative of 3 (Scheme 2). The anomeric
configuration of newly formed glycosidic bond was confirmed by
1H and 13C spectroscopies. Anomeric proton corresponding to
glucopyranoside residue of protected derivative of 3, at
hydrolysis in the former and that of
a-anomer in the latter case.
Propensities to undergo required bond reorganizations upon con-
jugate acid formation and favorable conformations of reactive
intermediates during hydrolysis lead to the observed differences
between methyl glycosides and disaccharides. An objective of the
present work is to assess glycosidic bond stability of 4-C-hydroxy-
methyl-linked disaccharides (Fig. 1), wherein the glycosidic bond is
interrupted with a methylene moiety. Glycosidic bond expanded
disaccharides might be considered analogues to naturally-occur-
ring disaccharides, in which case, it was of interest to identify
whether the glycosidic bond stability would match that of normal
disaccharides. Following synthesis of new disaccharide analogues
1–3, their acid-catalyzed hydrolytic stabilities were studied, details
of which are presented herein.
ꢀ4.92 ppm, as a doublet with J = 3.6 Hz, indicated
a-anomeric con-
figuration of glycosidic bond.
Toward assessing hydrolytic stabilities of disaccharide ana-
logues 1–3, acid-catalyzed hydrolysis was undertaken. The studies
were conducted in comparison to that of naturally-occurring disac-
charides, namely, cellobiose (11), lactose (12), and maltose (13).
Prior to hydrolysis studies, verification of aqueous solubilities of
1–3 showed following solubilization in water: 1: 0.065 g mLꢁ1; 2:
0.12 g mLꢁ1, and 3: 0.24 g mLꢁ1. These aqueous solubilities are
lower than that for disaccharides:29 11: 0.14 g mLꢁ1
; 12:
0.19 g mLꢁ1, and 13: 0.42 g mLꢁ1. In order to evaluate the kinetics
of acid-catalyzed hydrolysis, 1H NMR spectroscopy was used.
Hydrolysis of 1–3 and 11–13 was performed with DCl in D2O
(2 N), at 60 and 70 °C and 1H NMR spectrum was recorded period-
ically. The analysis was facilitated through assigning distinct pro-
tons. Progress of the glycosidic bond cleavage was monitored by
2. Results and discussion
Synthesis of non-natural disaccharides 1–3 was accomplished
through a glycosylation of a glycosyl donor with 4-C-hydroxymethyl
the appearance of new H-4 of 4-C-hydroxymethyl
D-glucopyra-
nose. The hydrolysis data obtained from 1H NMR spectra were
plotted as a function of time and fitted to an exponential decay
curve. The observed first order rate constants are summarized in
Table 1. Representative 1H NMR profiles corresponding to H-4 res-
a
-
D
-glucopyranoside acceptor as shown in Scheme 1. Synthesis was
initiated from benzyl 2,3,6-tri-O-benzyl-
a-D
-glucopyranoside 4,25
which upon oxidation with Dess–Martin periodinane provided car-
bonyl compound 5. Subsequent Wittig methylenation afforded
derivative 6, in 68% yield. Borane addition, followed by an oxidation
afforded 7 with galacto-configuration at the newly generated
hydroxymethyl group. Subsequent oxidation of 7 with Dess–Martin
periodinane led to galacto-configured 4-C-aldehyde 8, which upon
treatment with Et3N led to epimerization26 to gluco-configuration
at C-4 (9), in a moderate yield. The presence of gluco-configuration
in 9 was confirmed through J-coupled correlation (COSY) spectros-
copy, in which the H-4 nucleus resonated at ꢀ3.0 ppm as a doublet
of an apparent triplet with J = 2.6, 10.8 Hz. Aldehyde 9 was reduced
subsequently to alcohol 10 with NaBH4 in MeOH, in a good yield
(Scheme 1).
Synthesis of new disaccharides was accomplished through a gly-
cosylation of glycosyl donor and 10. Glycosylation of acetobromo
glucose27 with acceptor 10, in the presence of Hg(CN)2 and HgBr2,
afforded protected disaccharide 1, in a moderate yield. The appear-
ance of H-1 nucleus corresponding to glucopyranoside residue of
protected derivative 1 at ꢀ4.30 ppm, as a doublet with J = 8.0 Hz,
confirmed the presence of the b-glycosidic bond. The protected
derivative 1 was O-deacetylated under Zemplén condition, followed
by removal of benzyl group, using Pd/C and H2 to afford free
onance of 1 and that of hydrolysis product 4-C-hydroxymethyl D-
glucopyranose and the associated exponential decay curve are
shown in Figure 2. For comparison, hydrolysis data of methyl
glycosides, namely, methyl-b-
D-glucopyranoside (14), methyl-
b- -galactopyranoside (15), and methyl-a-D
D
-glucopyranoside
(16), obtained under identical conditions, are also given.
The kinetic data showed that among three new disaccharide ana-
logues 1–3, the rate of hydrolysis was least for 1 and highest for 2,
thereby following the trend that glycosides with one or more axial
hydroxyl groups tend to undergo faster the hydrolysis than those
with only equatorial hydroxyl groups. On the other hand, hydrolysis
rate of 2 was 5.7 times slower than 12, 1 was 17.5 times slower than
11, and 3 was 33 times slower than 13 at 60 °C. Differences in pair-
wise rates of hydrolysis of 11 and 14, 12, and 15 were not as high as
that seen with 1–3, except 13 and 16 pair. Similar differences among
the glycosides could also be observed at 70 °C. The presence of
hydroxymethyl-linkage in the glycosidic bond of 1–3 reduced the
hydrolysis rate significantly when compared to 11–16 in general.
Faster rates of protonation and stabilities of conjugate acid lead to
faster hydrolyses of disaccharides, when compared to methyl glyco-
sides 14–16. Bond reorganization occurs upon protonation, so as to
HO
HO
OH
OH
O
OH
OH
OH
O
O
O
OH
HO
HO
HO
HO
O
O
O
OH
HO
HO
HO
HO
HO
O
O
HO
HO
OH
HO
3
1
2
HO
OH
Figure 1. Molecular structures of hydroxylmethyl-linked disaccharides.

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G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
OBn
OBn
O
HO
OBn
O
(i) BH3-Me2S, THF, rt, 1.5 h
Dess-Martin periodinane
CH2Cl2, rt, 1.5 h, 90 %
O
X
HO
BnO
BnO
BnO
BnO
BnO
(ii) 30 % H2O2, NaOH (3 N)
0 °C-rt, 2 h, 49 %
BnO
OBn
OBn
OBn
7
4
5 : X = O
Ph3PCH3I, nBuLi,
THF, 0 °C-rt, 2 h,
68 %
Dess-Martin periodinane
CH2Cl2, rt, 1 h, 87 %
6: X = CH2
R1
OH
(i) Donor, HgBr2, Hg(CN)2, 4 Å MS,
CH2Cl2, rt, 12 h
R1
OBn
OBn
O
O
OH
HO
BnO
O
R2
HO
R2
BnO
NaBH4, MeOH
O
O
HO
HO
0 °C-rt, 2 h, 89%
BnO
(ii) NaOMe (cat.), MeOH, 6 h; H2,
Pd/C (10 %), MeOH / EtOAc, 2 d,
61 % (for 1) or 58% (for 2)
BnO
OBn
HO
OBn
OH
10
8 : R1 = CHO, R2 = H
9 : R1 = H, R2 = CHO
1 : R1 = H; R2= OH 2 : R1 = OH; R1= H
Et3N, 38 °C
12 h, 79 %
Donor: acetobromo glucose (for 1) or acetobromo galactose (for 2)
Scheme 1.
OBn
O
OH
O
BnO
BnO
HO
(i) TMSOTf, Et2O, rt, 30 min.
HO
BnO
O
OH
O
10
HO
O
(ii) H2, Pd/C (10 %),
NH
HO
Cl3C
MeOH / EtOAc, 3 d, 62 %
3
OH
OH
Scheme 2.
Table 1
First order rate constant for the acid-catalyzed hydrolysis of glycosidic bond in 1–3 and 11–16
Compound
Temp (°C)
1
2
3
11
4.39
19.20
12
13
14
2.11
12.35
15
16
Rate of hydrolysis (k)a
60
70
0.25
1.08
1.37
4.78
0.49
2.10
7.85
35.80
16.2
61.15
5.60
21.04
0.97
6.45
a
ꢂ105 sꢁ1 molꢁ1
.
Figure 2. (a) Stack plot of few representative temperature dependent 1H NMR spectra of hydrolysis of 1, wherein (i) corresponds to H-4 of 1 and (ii) H-4 of 4-C-
hydroxymethyl
(a).
D-glucopyranose. (b) Kinetic plot of formation of 4-C-hydroxymethyl
D-glucopyranose as a function of time, monitored by the evolution of resonance (ii) in
shift the transition state of C1–O1 heterolysis toward the oxocarbe-
nium ion conformation. Thus, when comparing maltose (13) and
cellobiose (11), maltose hydrolyze faster. An opposite trend of b-
methyl glucopyranoside 14 hydrolyze faster than the a-anomer 16

G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
2397
Figure 3. Structures of 1–3 derived from energy minimization protocol.
was thought to arise through an effect of SLPH (vide supra), wherein
synpreiplanar arrangement of b-anomer is as favorable for bond
under an acid catalyzed condition, showed that the glycosidic bond
was hydrolytically more stable than naturally-occurring disaccha-
rides and methyl glycopyranosides, as judged from hydrolysis rates
assessed at two different temperatures. The rate of hydrolysis
followed a trend observed normally for the naturally-occurring
disaccharides. Energy minimized structures, derived through
molecular modeling, revealed that the disaccharides analogues
possessed dihedral angles around the glycosidic linkage nearly sim-
ilar to that of naturally-occurring disaccharides. The study shows
the possibility to derive hydrolytically more stable disaccharides,
retained with O-glycosidic linkage for the first time.
reorganization as the antiperiplanar arrangement of the
The trend of -anomer 3 undergoing faster hydrolysis than b-ano-
mer 1 is analogous to -anomer 13 undergoing faster hydrolysis
a-anomer.
a
a
than b-anomer 11. An effect resulting from ALPH would thus be
appropriate for the faster hydrolysis of 3 as much as with 13. The ob-
served rate differences between natural disaccharides 11–13 and
non-natural disaccharide analogues 1–3 may arise from altered
rates protonation of glycosidic oxygen, even when the ALPH ac-
counts the trend of hydrolysis rates. Axially oriented hydroxyl group
in 2 contributes to the highest observed rate of hydrolysis, possibly
through the recently established hyperconjugation effect (vide su-
pra).22 Activation energies and entropies30 remain to be assessed
so as to assess how the pre-equilibration step of protonation of ano-
meric oxygen and anomeric C–O bond heterolysis is affected in the
disaccharide analogues 1–3. Further studies are required to verify
these and more issues concerned with the hydrolysis trends in 1–3.
In order to derive low energy structures of 1–3 and to compare
with structures of disaccharides 11–13, molecular modeling of
new disaccharide analogues were performed using Gaussian 09
software at B3LYP/6-31G⁄ level theory. The structures derived from
the modeling are shown in Figure 3, wherein pyranose were seen
to retain 4C1 conformation. The dihedral angles around glycosidic
linkage and the anomeric bond length were, respectively, 1:
ꢁ83.658, 1.3887 Å; 2: ꢁ81.580, 1.3882 Å, and 3: 67.463,
1.4025 Å. The corresponding values for disaccharides were, respec-
tively, 11: ꢁ75.837, 1.3952 Å31; 12: ꢁ93.413, 1.3980 Å32, and 13:
116.099, 1.4151 Å.33 These values indicate that the presence of
additional methylene group in 1–3 did not deviate the interglycos-
idic linkage conformation greatly from that of natural disaccha-
rides 11–13.
4. Experimental
4.1. General methods
Solvents were dried and distilled according to literature proce-
dures.35 All chemicals were purchased from commercial sources
and were used without further purification. Silica gel (100–
200 mesh) was used for column chromatography and TLC analysis
was performed on commercial plates coated with Silica Gel 60
F254. Visualization of the spots on TLC plates was achieved by UV
radiation or spraying 5% sulfuric acid in ethanol. High resolution
mass spectra were obtained from Q-TOF instrument by electrospray
ionization (ESI). 1H and 13C NMR spectral analyses were performed
on a spectrometer operating at 300 MHz, 400 MHz, and 75 MHz,
100 MHz, respectively, in CDCl3, D2O solutions, unless otherwise
stated. Chemical shifts are reported with respect to tetramethylsil-
ane (TMS) for 1H NMR and the central line (77.0 ppm) of CDCl3 for
13C NMR. Coupling constants (J) are reported in Hz. Standard abbre-
viations s, d, t, dd, br s, m refer to singlet, doublet, triplet, doublet of
doublet, broad singlet, multiplet. For disaccharide derivatives 1–3,
H-1 denotes anomeric proton of hydroxymethyl containing sugar
moiety and H-10 denotes anomeric proton of pyranoside moiety.
Studies on carbohydrate mimetics assume importance in order
to understand several biological recognition processes mediated by
carbohydrates. An approach to such mimetics is to replace the gly-
cosidic oxygen with a hetero-atom so as to endow increased
hydrolytic stabilities toward enzymatic degradations. Sulfur, sele-
nium, carbon, and nitrogen links at the anomeric carbon emerged
as viable options toward this objective.34 To the extent that in-
creased hydrolytic stabilities were observed for the disaccharide
analogues presented herein, the analogues open up possibilities
of newer mimetics that are retained with the glycosidic oxygen.
4.2. Synthesis and characterization
4.2.1. Benzyl 2, 3, 6-tri-O-benzyl-a-D-xylo-hexulopyranoside (5)
Dess-Martin periodinane (2.94 g, 6.94 mmol) was added to a
solution of 425 (2.5 g, 4.62 mmol) in CH2Cl2 (25 mL) and stirred at
room temperature for 1.5 h under N2 atmosphere. The reaction mix-
ture was diluted with water (100 mL), extracted with CHCl3
(3x60 mL), washed with aq NaHCO3 (2x50 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The residue was purified (hex-
ane/EtOAc = 9:1) to afford 5 (2.25 g, 90%), as a gummy oil. Rf = 0.33
(hexane/EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz) d 7.43–7.23 (band,
20H, aromatic), 5.01 (d, 1H, J = 4.4 Hz, PhCH2), 4.96 (d, 1H, J = 3.6 Hz,
H-1), 4.81–4.53 (m, 7H, PhCH2), 4.48 (d, 1H, J = 10.8 Hz, H-3), 4.34
(dd, 1H, J = 3.4, 5.8 Hz, H-5), 3.88 (dd, 1H, J = 3.4, 10.8 Hz, H-6a),
3.80 (dd, 1H, J = 3.4, 10.8 Hz, H-6b), 3.67 (dd, 1H, J = 3.6, 10.8 Hz,
H-2); 13C NMR (CDCl3, 100 MHz) d 202.1, 137.7, 137.8, 137.8,
3. Conclusion
A study of glycosidic bond hydrolysis of disaccharide analogues
presenting an additional methylene group in between the glycoside
bond was accomplished. Three new disaccharide analogues having
hydroxymethyl glycosidic linkage were prepared, by utilizing a 4-
C-hydroxymethyl
D-glucopyranoside as the glycosyl acceptor.
Hydrolytic stabilities of these new disaccharide analogues, studied

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G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
136.5, 128.4, 128.3, 128.3, 128, 127.9, 127.8, 127.7, 127.6, 95.7, 82.6,
4.2.5. Benzyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-formyl-a-D-
glucopyranoside (9)
80.2, 74.4, 73.6, 73.6, 73.0, 69.8, 67.5. HRMS m/z: [M+Na]+ calcd for
C
34H34O6Na, 561.2253; found 561.2255.
A solution of 8 (0.69 g, 1.25 mmol) in Et3N (10 mL) was stirred
at 38 °C for 12 h. The reaction mixture was concentrated in vacuo
and crude reaction mixture purified (hexane/EtOAc = 1:8) to afford
9 (0.55 g, 79%), as a gummy oil. Rf = 0.30 (9:1 hexane/EtOAc); 1H
NMR (CDCl3, 400 MHz) d 9.65 (d, 1H, J = 2.6 Hz, CHO), 7.40–7.25
(band, 20H, aromatic), 4.93 (d, 1H, J = 10.8 Hz, PhCH2), 4.87 (d,
1H, J = 3.4 Hz, H-1), 4.73–4.43 (m, 7H, PhCH2), 4.31 (dd, 1H,
J = 9.4, 10.8 Hz, H-3), 4.13–4.06 (m, 1H, H-5), 3.59 (dd, 1H, J = 3.4,
9.4 Hz, H-2), 3.51 (d, 2H, J = 4.2 Hz, H-6a,b), 3.0 (app. dt, 1H,
J = 2.6, 10.8 Hz, H-4); 13C NMR (CDCl3, 100 MHz) d 200.4, 138.2,
137.9, 137.6, 137.1, 128.4, 128.0, 127.8, 127.7, 95.7, 80.6, 75.4,
75.2, 73.5, 72.6, 70.2, 69.2, 67.4, 56.7. HRMS m/z: [M+Na]+ calcd
for: C35H36O6Na, 575.2410; found 575.2422.
4.2.2. Benzyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-methylene-a-D-
hexopyranoside (6)
nBuLi (2.6 mL, 1.6 M, 4.18 mmol) was added dropwise over a
period of 10 min. to a solution of Ph3PMeI (2.5 g, 6.27 mmol) in
THF (25 mL) at 0 °C. After 15 min,
a solution of 5 (2.25 g,
4.18 mmol) in THF (25 mL) was added dropwise and stirring was
continued for 2 h. The reaction mixture was diluted with H2O
(150 mL) and extracted with CHCl3 (3 ꢂ 50 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo, and purified (hexane/
EtOAc = 8:1) to afford 6 (1.54 g, 68%), as a colorless oil. Rf = 0.45
(hexane/EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz) d 7.43–7.26
(band, 20H, aromatic), 5.36 (s, 1H, methylene), 4.99 (s, 1H, methy-
lene), 4.90 (d, 1H, J = 3.6 Hz, H-1), 4.86–4.71 (m, 4H, PhCH2), 4.60–
4.56 (m, 4H, PhCH2), 4.39–4.42 (m, 2H, H-3, H-5), 3.78 (dd, 1H,
J = 4.8, 10.0 Hz, H-6a), 3.66 (dd, 1H, J = 6.0, 10.0 Hz, H-6b), 3.48
(dd, 1H, J = 3.6, 9.6 Hz, H-2); 13C NMR (CDCl3, 100 MHz) d 142.6,
138.5, 138.4, 138.0, 137.3, 128.4, 128.3, 128.2, 127.8, 127.1,
127.6, 127.5, 127.5, 107.7, 95.9, 81.6, 79.2, 73.8, 73.4, 73.2, 69.6,
68.9, 68.1. HRMS m/z: [M+Na]+ calcd for C35H36O5Na, 559.2460;
found 559.2469.
4.2.6. Benzyl 2,3,6-tri-O-benzyl-4-C-hydroxymethyl-a-D-
glucopyranoside (10)
NaBH4 (0.05 g, 1.4 mmol) was added to a solution of 9 (0.55 g,
0.99 mmol) in MeOH (18 mL) at 0 °C and stirred for 2 h. Solvents
were removed in vacuo and the resulting residue dissolved in
EtOAc (3 ꢂ 45 mL), diluted with H2O (100 mL), dried (Na2SO4), fil-
tered, and concentrated in vacuo. The crude product was purified
(hexane/EtOAc = 4:1) to afford 10 (0.49 g, 89%), as a colorless oil.
Rf = 0.39 (4:1 hexane/EtOAc); [
a
]
D
+49.1 (c 1, CHCl3); 1H NMR
4.2.3. Benzyl 2,3,6-tri-O-benzyl-4-C-hydroxymethyl-
galactopyranoside (7)
a
-
D
-
(CDCl3, 400 MHz) d 7.42–7.27 (band, 20H, aromatic), 5.0 (d, 1H,
J = 10.8 Hz, PhCH2), 4.88 (d, 1H, J = 3.6 Hz, H-1), 4.72–4.45 (m, 7H,
PhCH2), 3.97 (dd, 1H, J = 9.6, 10.4 Hz, H-3), 3.91–3.87 (m, 1H, H-
5), 3.70 (dd, 1H, J = 3.6, 11.4 Hz, CH2aOH), 3.61–3.58 (m, 4H, H-2,
CH2bOH, H-6a,b), 1.91–1.85 (m, 1H, H-4); 13C NMR (CDCl3,
100 MHz) d 138.5, 138.1, 137.6, 137.3, 128.5, 128.4, 128.3, 128.2,
127.9, 127.8, 127.7, 127.6, 95.6, 81.4, 75.7, 75.2, 73.5, 72.3, 70.5,
68.8, 68.6, 59.7, 46.2. HRMS m/z: [M+Na]+ calcd for: C35H38O6Na,
577.2566; Found 577.2572.
A solution of BH3–Me2S (2 M) (1.8 mL, 3.6 mmol) was added
dropwise to a solution of 6 (1.54 g, 2.87 mmol) in THF (25 mL) at
room temperature, under N2 atmosphere and stirred for 1.5 h.
The reaction mixture was cooled at 0 °C, aq NaOH (3 N) (1 mL)
and aq. H2O2 (30%) (1 mL) were added dropwise subsequently.
After 2 h, the reaction mixture was diluted with H2O (100 mL)
and extracted with Et2O (3 ꢂ 60 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting residue was purified (hex-
ane/EtOAc = 4:1) to afford
Rf = 0.37 (hexane/EtOAc = 4:1); [
7
(0.79 g, 49%), as
a
gummy oil.
4.2.7. (4-Deoxy-4-methyl-(1,2,3,6-tetra-O-benzyl-a-D-
glucopyranosyl)-(2,3,4,6-tetra-O-acetyl)-b-D-glucopyranoside
a]
+62.7 (c 1, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) d 7.4–7.24 (band, 20H, aromatic), 4.86 (d, 1H,
J = 3.8 Hz, H-1), 4.77–4.67 (m, 4H, PhCH2), 4.60–4.53 (m, 4H,
PhCH2), 4.14–4.10 (m, 2H, H-3, H-5), 3.95 (dd, 1H, J = 5.6, 11.4 Hz,
H-7a), 3.78 (dd, 1H, J = 5.6, 11.4 Hz, H-7b), 3.68 (dd, 1H, J = 3.8,
10.2 Hz, H-2), 3.57–3.50 (m, 2H, H-6a,b), 2.36–2.38 (m, 1H, H-4);
13C NMR (CDCl3, 125 MHz) d 138.3, 137.4, 137.2, 128.4, 128.3,
128.2, 127.7, 127.7, 127.6, 95.9, 78.6, 76.6, 76.5, 73.6, 73, 70.3,
68.9, 68.1, 57.8, 43.5. HRMS m/z: [M+Na]+ calcd for: C35H38O6Na,
577.2566; Found 577.2556.
(protected derivative of 1)
A
mixture of 10 (0.16 g, 0.28 mmol), Hg(CN)2 (0.11 g,
0.43 mmol), HgBr2 (0.10 g, 0.28 mmol), and molecular sieves 4 Å
(1 g) in CH2Cl2 (20 mL) was stirred at room temperature under
N2 atmosphere. After 10 min, acetobromo glucose27 (0.29 g,
0.72 mmol) in CH2Cl2 (15 mL) was added dropwise and stirred
for 12 h at room temperature, under N2 atmosphere. The reaction
mixture was neutralized with Et3N (1 mL), filtered through celite
pad, filtrate washed with H2O (150 mL) and aq. Na2S2O3 (10%).
The organic layer was dried (Na2SO4) concentrated in vacuo and
purified (hexane/EtOAc = 1:4) to afford protected derivative of 1
4.2.4. Benzyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-formyl-a-D-
galactopyranoside (8)
(0.18 g, 68%), as an oil. Rf = 0.23 (hexane/EtOAc = 3:1); [
a] +34.9
D
Dess–Martin periodinane was added to a solution of 7 (0.79 g,
1.42 mmol) in CH2Cl2 (20 mL), stirred at room temperature for
1 h under N2 atmosphere. The reaction mixture was diluted with
H2O (150 mL), extracted with CHCl3 (2 ꢂ 50 mL), washed with aq
NaHCO3 (2x50 mL) dried (Na2SO4), filtered, and concentrated in va-
cuo. The resulting residue was purified (hexane/EtOAc = 8:1) to af-
(c 1, CHCl3); 1H NMR (CDCl3, 400 MHz) d7.43–7.25 (band, 20H, aro-
matic), 5.17–4.93 (band, 6H), 4.89 (d, 1H, J = 3.6 Hz, H -1), 4.71 (q,
a
1H, J = 12.0 Hz), 4.63 (dd, 2H, J = 2.6, 12.0 Hz), 4.53 (q, 1H, J = 6 Hz),
4.48–4.45 (m, 2H), 4.30 (d, 1H, J = 8.0 Hz, Hb-10), 4.21–4.16 (m, 2H),
4.06–4.03 (m, 1H), 3.99 (dd, 1H, J = 2.6, 12.8 Hz), 3.94 (t, 1H,
J = 3.0 Hz), 3.59–3.50 (m, 3H), 3.38 (dd, 1H, J = 2.6, 10.0 Hz), 2.01
(s, 3H), 1.99 (s, 3H), 1.98–1.97 (m, 1H, H-4), 1.95 (s, 3H), 1.89 (s,
3H); 13C NMR (CDCl3, 100 MHz) d 170.6, 170.2, 169.3, 168.7,
138.9, 138.1, 138, 137.2, 128.5, 128.4, 128.3, 127.9, 127.8, 127.6,
100.6, 95.7, 81.3, 75.5, 75.3, 73.4, 72.7, 72.6, 71.7, 71.2, 69.6,
68.8, 68.6, 68.3, 65.4, 61.8, 43.8, 20.7, 20.5, 20.3, 20.2. HRMS m/z:
[M+Na]+ calcd for: C49H56O15Na, 907.3517; found 907.3511.
ford 8 (0.69 g, 87%), as an oil. Rf = 0.25 (hexane/EtOAc = 9:1); [a]
D
+75.5 (c 1, CHCl3); 1H NMR (CDCl3, 400 MHz) d 9.91 (d, 1H,
J = 5.2 Hz, CHO), 7.40–7.25 (band, 20H, aromatic), 5.0 (d, 1H,
J = 3.8 Hz, H-1), 4.79–4.43 (m, 8H, PhCH2), 4.22–4.18 (m, 2H, H-3,
H-5), 3.97 (dd, 1H, J = 3.8, 10.0 Hz, H-2), 3.53 (dd, 1H, J = 4.2,
10.2 Hz, H-6a), 3.46 (dd, 1H, J = 5.2, 10.2 Hz, H-6b), 3.02 (dt, 1H,
J = 2.6, 5.2 Hz, H-4); 13C NMR (CDCl3, 100 MHz) d 201.3, 138.1,
137.5, 136.9, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 96.4, 76.6, 76.5, 73.3, 72.2, 73.2, 70.1, 69.3, 68.0,
54.5. HRMS m/z: [M+Na]+ calcd for: C35H36O6Na, 575.2410; Found
575.2403.
4.2.8. (4-Deoxy-4-methyl glucopyranosyl)-b-D-glucopyranoside
(1)
A solution of protected derivative of 1 (0.18 g, 0.19 mmol) in
MeOH (10 mL) was admixed with NaOMe in MeOH (0.3 mL,

G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
2399
0.5 M), stirred for 6 h, neutralized with amberlite IR-120 resin (H+)
and solvents evaporated in vacuo. The crude residue was dissolved
in MeOH/EtOAc (1:1, 30 mL), added with Pd/C (10%, 0.11 g) and
stirred under a positive pressure of H2 gas for 2 days, filtered
through celite and solvents evaporated in vacuo to afford 1
TMSOTf (6 lL, 0.027 mmol, 0.1 equiv) in Et2O (15 mL) was stirred
for 30 min., at room temperature, the reaction mixture was then
quenched with Et3N (1 mL), solvents removed in vacuo and the res-
idue purified (hexane/EtOAc = 7.5:1) to afford protected compound
of 3 (0.198 g, 68%), as an oil. Rf = 0.4 (hexane/EtOAc = 3:0.5); [a]
D
(0.068 g, 90%,
a
/b = 1:1.5), as a foamy solid; Rf = 0.18 (6:2:1
+34.9 (c 1, CHCl3); 1H NMR (CDCl3, 400 MHz) d 7.31–7.13 (band,
CHCl3/MeOH/H2O); 1H NMR (D2O, 400 MHz)
d
5.19 (d, 1H,
40H, aromatic), 4.92 (d, 1H, J = 3.6 Hz, H -10), 4.9–4.51 (m, 16H,
a
J = 3.6 Hz, H -1), 4.51 (d, 1.5H, J = 7.8 Hz, Hb-1), 4.35 (d, 2.5H,
PhCH2), 4.48–4.29 (m, 6H), 4.22–4.17 (m, 1H), 3.89 (t, 1H,
J = 9 Hz), 3.75–3.67 (m, 2H), 3.61–3.54 (m, 2H), 3.50 (dd, 1H,
J = 3.6, 9.8 Hz), 3.40–3.33 (m, 1H), 2.13–2.04 (m, 1H, H-4); 13C
NMR (CDCl3, 100 MHz): d 138.9, 136.6, 138.3, 138.2, 138.1, 137.9,
137.5, 137.3, 128.2, 127.9, 127.8, 127.6, 127.5, 127.5, 127.4,
127.3, 97.8, 96.1, 83.9, 82.1, 81.3, 79.5, 77.7, 75.5, 75.2, 75.0,
73.5, 73.2, 73.0, 72.5, 70.7, 69.7, 69.3, 69.0, 68.3, 64.6, 43.2. HRMS
m/z: [M+Na]+ calcd for: C69H72O11Na = 1099.4972; found
1099.4978.
a
J = 8.0 Hz, Hb-10), 4.06–4.03 (m, 2.5H) 3.85 (ddd, 5H, J = 2, 4.4.0,
12.0 Hz), 3.80–3.56 (m, 10H), 3.50–3.38 (m, 5H), 3.44–3.38 (m,
2.5H), 3.32 (dt, 2.5H, J = 1.6, 10.4 Hz), 3.21 (dt, 2.5H, J = 1.6,
9.6 Hz), 3.17 (q, 2.5H, J = 7.2 Hz), 1.76–1.71 (m, 2.5H, H-4); 13C
NMR (D2O, 100 MHz) d 102.4, 102.3, 95.7, 75.8, 75.6, 75.5, 74.2,
72.9, 72.6, 72.5, 70.5, 69.6, 69.5, 66.9, 65.8, 65.7, 61.4, 60.6, 46.5,
43.2. HRMS m/z: [M+Na]+ calcd for: C13H24O11Na = 379.1216;
found 379.1226.
4.2.9. (4-Deoxy-4-methyl (1,2,3,6-tetra-O-benzyl-
a-
D
-
4.2.12. (4-Deoxy-4-methyl glucopyranosyl)-
a-D-
glucopyranosyl)-(2,3,4,6-tetra-O-acetyl)-b-D-galactopyranoside
glucopyranoside (3)
(protected derivative of 2)
A solution of protected derivative of 3 (0.19 g, 0.17 mmol) in
MeOH and EtOAc (1:1 v/v, 35 mL) was hydrogenolyzed over Pd/C
(10%, 0.08 g) at room temperature under positive pressure of H2
gas for 3 days, filtered through Celite and evaporated in vacuo, to af-
Glycosylation of 10 (0.19 g, 0.34 mmol) with acetobromo gal-
actose27 (0.35 g, 0.85 mmol) in CH2Cl2 (25 mL) in presence of
Hg(CN)2 (0.13 g, 0.51 mmol), HgBr2 (0.12 g, 0.34 mmol) and molec-
ular sieves 4 Å (1 g) was performed as described above for the syn-
thesis of protected derivative of 1. Purification (hexane/
EtOAc = 3:1) of reaction mixture afforded protected derivative of
ford 3 (0.057 g, 91%,
MeOH/H2O = 6:3:1); 1H NMR (D2O, 400 MHz):
J = 3.6 Hz, H -10), 4.71 (d, 2.8H, J = 3.6 Hz, H -1), 4.43 (d, 1.8H,
a/b = 1:1.8), as a foamy solid. Rf = 0.4 (CHCl3/
d
5.0 (d, 1H,
a
a
2 (0.2 g, 66%), as an oil. Rf = 0.2 (hexane/EtOAc = 4:1); [
a
]
+32.5
J = 8.0 Hz, Hb-1), 3.76–3.51 (m, 18.4H), 3.43–3.37 (m, 8H), 3.34–
3.32 (m, 7.2H), 3.31–3.10 (m, 2.8H), 1.62–1.58 (m, 2.8H, H-4); 13C
NMR (CDCl3, 100 MHz) d 103.1, 98.7, 95.7, 75.9, 75.7, 74.6, 74.1,
72.9, 72.5, 72.2, 71.5, 70.6, 70.4, 69.8, 69.6, 63.7, 61.5, 60.5, 48.8,
43.3. HRMS m/z: [M+Na]+ calcd for: C13H24O11Na = 379.1216; found
379.1218.
D
(c 1, CHCl3); 1H NMR (CDCl3, 400 MHz) d7.43–7.25 (band, 20H, aro-
matic), 5.34 (dd, 1H, J = 1.0, 3.6 Hz), 5.13 (dd, 1H, J = 8.0, 10.4 Hz),
4.99 (d, 1H, J = 10.8 Hz, PhCH2), 4.94 (dd, 1H, J = 3.6, 10.4 Hz,),
4.89 (d, 1H, J = 3.6 Hz, H -1), 4.77–4.44 (band, 7H, PhCH2), 4.26
a
(d, 1H, J = 8.0 Hz, H b-10), 4.20 (dd, 1H, J = 2.8, 9.6 Hz), 4.12–3.96
(m, 4H), 3.77 (dt, 1H, J = 1.0, 7.2 Hz,), 3.59 (dd, 1H, J = 2.4,
10.4 Hz), 3.56 (d, 1H, J = 3.6 Hz) 3.53 (t, 1H, J = 3.4 Hz), 3.40 (dd,
1H, J = 2.4, 9.6 Hz), 2.14 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.95 (s,
3H, CH3), 1.94–1.93 (m, 1H, H-4), 1.89 (s, 3H, CH3); 13C NMR
(CDCl3, 100 MHz) d 170.4, 170.3, 170.1, 168.8, 139.0, 138.2,
138.0, 137.3, 128.5, 128.3, 127.9, 127.8, 127.6, 101.0, 95.4, 81.3,
75.4, 75.2, 72.4, 72.3, 70.8, 70.5, 69.6, 68.8, 68.7, 66.5, 66.9, 65.3,
61.2, 43.7, 20.7, 20.6, 20.5, 20.4. HRMS m/z: [M+Na]+ calcd for:
C49H56O15Na, 907.3517; found 907.3514.
4.3. Kinetic studies of hydrolysis as monitored by 1H NMR
spectroscopy
Kinetic studies of acid-catalyzed hydrolysis of 1–3, 11–16 (5–
6 mg) were performed in DCl/D2O (2 N) (600 lL), in an NMR tube
maintained at 60 1 °C and 70 1 °C, in a thermostated water
bath. 1H NMR spectrum was recorded periodically by monitoring
the peak intensities of either H-4 proton of 4-C-hydroxymethyl
glucopyranose formed from 1 to 3 or anomeric proton (11–16) of
gluco- or galactopyranoside, resulting from hydrolysis. Integration
of chemical shift at 1.45 ppm, corresponding to H-4 nucleus of 4-C-
hydroxymethyl glucopyranose formed upon hydrolysis in 1–3, was
considered for rate constant studies. Average integrations of chem-
ical shifts, corresponding to anomeric H-1 of gluco- or galactopyr-
anose formed upon hydrolysis, were considered for rate constant
4.2.10. (4-Deoxy-4-methyl glucopyranosyl)-b-D-
galactopyranoside (2)
A solution of protected derivative of 2 (0.2 g, 0.22 mmol) in
MeOH (15 mL) was admixed with NaOMe/MeOH (0.4 mL, 0.5 M),
the reaction mixture stirred for 6 h, neutralized with amberlite
IR-120 resin (H+), solvents evaporated in vacuo. The crude residue
was dissolved in MeOH/EtOAc (1:1, 30 mL), added with Pd/C (10%,
0.11 g) and stirred under a positive pressure of H2 gas for 2 days,
filtered through Celite and solvents evaporated in vacuo to afford
analysis: 11, 13, 14, and 16: 4.33 and 3.78 ppm (
a
- and b-glucopyr-
anose); 12 and 15: 4.56 and 3.94 ppm (
a
- and b-galactopyranose).
1H NMR peak intensity profiles as a function of time were secured
till complete hydrolysis, plotted and the plots were fit to a first-
order exponential decay function, from which first-order rate con-
stants (k) were derived. The fitting curves of all hydrolysis rates
showed correlation coefficients (r2) more than 0.999.
2 (0.07 g, 88%,
a/b = 1:2), as a foamy solid. Rf = 0.20 (CHCl3/
MeOH/H2O = 6:2:1); 1H NMR (D2O, 400 MHz) d 5.08 (d, 1H,
J = 3.2 Hz, H -1), 4.41 (d, 2H, J = 8.0 Hz, Hb-1), 4.17 (d, 3H,
a
J = 7.8 Hz, Hb-10), 3.98–3.92 (m, 6H), 3.74–3.72 (m, 9H), 3.65–3.45
(m, 15H), 3.39–3.31 (m, 6H), 3.07–3.03 (t, 3H, J = 8.8 Hz), 1.61–
1.59 (m, 3H, H-4); 13C NMR (CDCl3,100 MHz) d 103.0, 102.9, 95.8,
92.3, 75.5, 75.1, 74.3, 72.6, 72.5, 72.4, 70.6, 70.5, 68.8, 68.6, 67.0,
65.7, 61.5, 61.0, 43.3, 43.2. HRMS m/z: [M+Na]+ calcd for:
C13H24O11Na = 379.1216; found 379.1208.
4.4. Molecular modeling procedure
Molecular modeling studies were performed using MacroModel
8.0 software,36 running on a SGI-Irix machine. The molecules were
built using standard template present in the software, in their
respective geometries before initiating the minimization. The
AMBER⁄ force field was chosen for the minimization, in water
using GB/SA continuum solvent model approach and a dielectric
constant of 80. Optimizations were performed with the Polak–
Ribiere algorithm and the termination condition was RMS gradient
4.2.11. (4-Deoxy-4-methyl-(1,2,3,6-tetra-O-benzyl-a-D-
glucopyranosyl)-(2,3,4,6-tetra-O-benzyl)-a-D-glucopyranoside
(protected derivative of 3)
A mixture of 10 (0.15 g, 0.27 mmol) and 2,3,4,6-tetra-O-benzyl-
a-D
-glucopyranosyl trichloroacetimidate28 (0.25 g, 0.36 mmol) and

2400
G. C. Daskhan, N. Jayaraman / Carbohydrate Research 346 (2011) 2394–2400
of 0.05 kcal molꢁ1 or a maximum of 10,000 iterations. Monte-Carlo
search was conducted for each molecule by varying the dihedral
angle around the glycosidic linkage. All optimized conformers
within 3 kcal molꢁ1 of the global minimum were saved. The lowest
10 conformers from the conformational search were further opti-
mized at B3LYP/6-31G⁄ level theory in gas phase, using G09 soft-
ware.37 The lowest energy conformer from ab initio calculations
was used to find out bond lengths and bond angles.
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Acknowledgments
We thank Department of Biotechnology, New Delhi, for a finan-
cial support. Council of Scientific and Industrial Research, New
Delhi, is acknowledged for a research fellowship to G.C.D.
Supplementary data
Supplementary data (kinetic plots of compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.carres.2011.08.030.
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