Synthesis of novel 2-deoxy-β-benzyl-C-glycosides by highly stereo- and chemoselective hydrogenation of exo-glycals

Article abstract of DOI:10.1016/j.carres.2014.04.009

Novel 2-deoxy-β-benzyl-C-glycosides were prepared in good yields and excellent stereoselectivity by a route involving the Wittig reaction of glycosyl phosphonium salts and reduction of exo-glycals as key steps. Hydrogenation of benzyl protected enol ethers was performed with Pd/C(en) as an effective chemoselective catalyst to afford exclusively β anomers.

Full text of DOI:10.1016/j.carres.2014.04.009

Accepted Manuscript
Note
Synthesis of novel 2-deoxy-β-benzyl-C-glycosides by highly stereo- and che-
moselective hydrogenation of exo-glycals
Gisela Díaz, Agustín Ponzinibbio, Rodolfo Daniel Bravo
PII:
S0008-6215(14)00161-X
http://dx.doi.org/10.1016/j.carres.2014.04.009
CAR 6726
DOI:
Reference:
Carbohydrate Research
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 February 2014
5 April 2014
12 April 2014
Please cite this article as: Díaz, G., Ponzinibbio, A., Bravo, R.D., Synthesis of novel 2-deoxy-β-benzyl-C-glycosides
by highly stereo- and chemoselective hydrogenation of exo-glycals, Carbohydrate Research (2014), doi: http://
dx.doi.org/10.1016/j.carres.2014.04.009
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Synthesis of novel 2-deoxy-β-benzyl-C-glycosides by highly stereo- and chemoselective hydrogenation of exo-
glycals.
Gisela Díaz, Agustín Ponzinibbio,* Rodolfo Daniel Bravo.
Laboratorio de Estudio de Compuestos Orgánicos (LADECOR), Departamento de Química, Facultad de Ciencias
Exactas, Universidad Nacional de La Plata. 47 y 115, (1900) La Plata, Argentina.
*corresponding autor. Tel. +54 221 4243104 Fax. +54 221 4226947. E-mail: ponzinibbio@quimica.unlp.edu.ar
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Abstract: Novel 2-deoxy--benzyl-C-glycosides were prepared in good yields and excellent stereoselectivity by a
route involving the Wittig reaction of glycosyl phosphonium salts and reduction of exo-glycals as key steps.
Hydrogenation of benzyl protected enol ethers was performed with Pd/C(en) as effective chemoselective catalysts to
afford exclusively the anomers.
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Key words: Wittig reaction, exo-glycals, hydrogenation, palladium catalyst, C-glycosides.
C-Glycosides are an important class of bioactive molecules of extensive therapeutic potential.1 Preliminary structure-
activity studies revealed some structural features related with the potency of the cytotoxic activity. In a large series
of C-glycosides screened,  equatorial configuration at anomeric carbon, unsaturated aglycons and O-benzyl
protective groups, led to the highest antiproliferative and apoptotic activity against human cancer cell lines.2 The O-
benzyl group, besides increasing cell permeability, may favor an aromatic interaction with the receptor, resulting in
increased binding affinity.3 Since glycosylarenes exhibit diverse biological activities, including antitumor and antiviral
action 4 and considering the characteristics mentioned above, we decided to carry out an effective synthesis of O-
benzyl protected β-benzyl-C-glycosides.
C-glycosydes are well know carbohydrates and different synthetic pathways for their synthesis have been described
over the years.5 C-Glycosyl compounds having a carbon-carbon double bond at the anomeric center, e.g., 1a,b, are
less familiar compounds. In principle, such olefins could be of interest as precursors of C-glycosides if the double
bond can be transformed with high stereocontrol. For a long time we have been interested in the synthesis and
reactivity of glycosyl phosphonium tetrafluoroborates salts.6 This methodology was a key step in the preparation of
galactopyranosyl alanine,7 C-disaccharides, C,O-trisaccharides,8 2-deoxy ketopyranoses 9 and carbohydrate
derivatives with a spiro-isoxazoline moiety.10
We wish to report a method for the synthesis of exo-glycals and their further transformation to C-glycosides by a
highly stereo- and chemoselective hydrogenation.
The exo-glycals were prepared by the Wittig reaction of the -mixture of the 2-deoxigalactosyl phophonium salt 11
with several aromatic aldehydes to give the olefinated sugars (Scheme 1).
+
-
H
O
PPh3BF4
BnO
BnO
O
i
BnO
BnO
R
O
H
OBn
OBn
R
Scheme 1. Reagents and conditions: (i) BuLi, THF, - 90 °C (1 h), -90 °C to rt (12 h).
After filtration on silica gel the exocyclic enol ethers were obtained spectroscopically pure as a mixture of isomers in
the yields and E/Z ratios shown in Table 1. To the best of our knowledge, compounds 1a,b, 3a,b, 4a,b, 5a,b and 6a,b
were not yet described in literature. The E and Z configurations were assigned on the basis of the chemical shift of
the vinyl protons.12 The mixture of E and Z isomers was not separated and used directly in the next steps.
Starting aldehydes
Benzaldehyde
Product/ Yield Ratio (E/Z)a
1a,b/55
2a,b/53
3a,b/50
4a,b/55
36/64
35/65
37/63
32/68
39/61
4-Chlorobenzaldehyde
2-Chlorobenzaldehyde
4-isopropylbenzaldehyde
4-(dimethylamino)benzaldehyde 5a,b/56

4-Anisaldehyde
6a,b/58
36/64
a. E/Z ratios determined by 1H NMR of the reaction mixture.
Table 1. Wittig reaction of 2-deoxigalactosyl phosphonium salt with several aldehydes.
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2
3
4
5
The simple reduction of the double bond of exo-glycals has been investigated.13 In order to obtain the desired C-
glycosides we studied the exo-cyclic hydrogenation with Pd catalysts using exo-glycals 1a,b and 2a,b as model
compounds (Scheme 2).
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9
H
1
O
O
RO
RO
H
BnO
2
Pd/C 5%
X
BnO
X
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OR
OBn
1a,b X = H
2a,b X = Cl
7 X = H, R = Bn
8 X = Cl, R = Bn
9 X = H, R = H
Scheme 2. Formation of C-glycosides by hydrogenation of exo-glycals 1a,b and 2a,b.
An exo cyclic double bond conjugated to an aromatic moiety requires higher hydrogen pressure conditions to be
reduced than aliphatic chains.14 Unfortunately double bond reduction without removal of benzyl-protecting groups
was not achieved under mild conditions so that an intractable mixture of products was obtained. Longer reaction
times and higher hydrogen pressure promoted debenzylation and catalytic hydrodechlorination (HDC) reactions to
22 afford the unprotected C-glycoside 9 using both 1a,b and 2a,b as substrates.
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The development of modified Pd catalysts for chemoselective hydrogenation has been a long-standing goal in
synthetic chemistry.15 The Pd/C-ethylenediamine complex, a non pyrophoric catalyst compared to commercial Pd/C,
was first prepared by Sajiki et al. 16 Catalytic hydrogenations with Pd/C(en) catalyst displays good selectivity in the
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reduction of reducible functionalities such as olefin, acetylene, nitro and azido in the presence of an O-benzyl
protective group.17 Therefore, we planned to use the Pd/C(en) as a catalyst for the chemoselective hydrogenation of
the enol ether function with retention of benzyl protective groups.
At first we examined the reaction of 1a,b in several solvents and pressure conditions as seen in table 2. The results
show that the hydrogenation of the exo-cyclic double bond proceeded smoothly with excellent yields in EtOH under
2.5 atm hydrogen pressure. The obtained C-glycosylarene was fully characterized by NMR spectroscopy. As
expected, the C-glycosyl chain lies on the  face as shown by the proton coupling constants and the presence of NOE
effect between H-2 and H-6. This high stereoselectivity has been previously described in the hydrogenation of exo-
glycals.13,18
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Pressure (atm)
Solvent
THF
Cat. (wt%)a
Time (h)
Yield (%)
1
10
25
10
10
25
10
12
12
3
0
1
THF
0
2,5
2,5
2,5
2,5
THF
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82
85
95
MeOH
MeOH
EtOH
3
3
3
a. Prepared as previously reported. (19)
Table 2. Exo-glycal (1a,b) hydrogenation using Pd/C(en) catalyst.
Encouraged by the initial results, the reaction was then carried out with a variety of exo-glycals under the
experimental conditions shown below. (table 3)
Entry
Exo-glical
1a,b
2a,b
3a,b
4a,b
Pd Catalyst
Pd/C(en)
Product
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8
10
11
Yield (%)
1
2
3
4
95
97
90
94

5
6
7
5a,b
5a,b
6a,b
5a,b
12
13
--
91
97
Pd/C 5%
Pd/C(en)
Table 3. Stereo- and chemoselective catalytic hydrogenation of exo-glycals.
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As seen in entries 1-4 and 7 the desired products were obtained in excellent yields and no products derived from
debenzylation or hydrodechlorination reactions were detected. As expected the Pd/C(en) catalyst inhibits the
halogen removal from the aromatic moiety typically produced in hydrogenations with Pd/C.19 The hydrogenation
reaction of exo-glycals 5a,b described above failed due to the poisoning effect of reagents over the palladium
catalyst,20 the reaction was successfully accomplished with Pd/C 5% in EtOH at 2.5 atm. Here again, the double bond
reduction proceeded with high stereocontrol, compound 12 has being obtained as a single anomer in excellent
yields.
In conclusion, our methodology allowed us to prepare C-glycosides in very good yields and excellent stereoselectivity
from exo-glycals. We have used an effective and chemoselective hydrogenation method with retention of benzyl
protective groups using Pd/C(en) as a catalyst in EtOH under which enol ethers were easily hydrogenated. Further
applications of the above method for the synthesis of various C-glycosides linked to a heterocyclic moiety will be
presented in due course. Also studies on the antiproliferative activity against human hepatocellular liver carcinoma
(HepG2) and human lung adenocarcinoma (A549) cell lines are currently in progress.21
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1. Experimental
1.1 General
23 Thin layer chromatography (TLC) was performed on Merck 60 F254 plates. Reactions were monitored by TLC on silica
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gel, with detection by UV light (254 nm) or by charring with sulfuric acid. Flash chromatography was performed using
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silica gel (230-400 mesh). H and 13C NMR spectra were recorded on a Varian Mercury Plus 200 (200.055 and
50.309 MHz, respectively) using Me4Si as the internal standard in CDCl3 or DMSO-d6. HSQC and COSY spectra were
used to establish peak assignments in 1H and 13C NMR. High-resolution mass spectra were recorded on a Finnigan
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Model MAT 95 mass spectrometer. Tetrahydrofuran (THF) was refluxed with sodium and benzophenone until a
characterictic blue colour was evident and then fractionally distilled. All reactions sensitive to moisture were carried
out under argon atmosphere using oven-dried glassware. The hydrogenation experiments were performed in a glass
reactor.
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1.2 Wittig reaction
To a suspension of (3,4,6-Tri-O-benzyl-2-deoxy--D-galactopyranosyi)-triphenylphosphonium tetrafluoroborate
(770 mg, 1 mmol) in abs. THF (5 ml) at −90°C, n-BuLi (625 L, 1.6 M in hexane, 1 mmol) was added over a period of 5
min. A solution of benzaldehyde (107 mg, 1 mmol) in abs. THF (2 mL) was added over a period of 10 min and the
reaction was kept for 1 h at −90°C and then allowed to come to room temperature overnight. After evaporation in
vacuo the solution of the residue in ethyl acetate was washed twice with NaHCO3 (5%), twice with water, dried over
MgSO4 and concentrated in vacuo. The oily residue was treated with ethyl acetate/diethyl ether and then filtrated to
separate off the triphenylphosphine oxide. After evaporation of the solvent in vacuo the residue was
chromatographed on silica gel (eluent: hexane/ethyl acetate 8:2, containing 0.1% triethylamine) to afford 1a,b as
spectroscopically pure oil (458 mg, 55%, mixture E/Z=15:85).
1.3 Hydrogenation procedure using Pd/C as catalyst
After three vacuum/H2 cycles to replace air inside the reaction tube with hydrogen, the substrate (0.25 mmol) and
5% Pd/C (10 wt% of the substrate) were mixed in THF, MeOH or EtOH (1.0 ml) and then vigorously stirred at room
temperature under 2 atm of hydrogen for 12h. The reaction mixture was filtered through a pad of celite, and the
filtrate was concentrated in vacuo to afford a white solid.
1.3.1 C-Benzyl 2-deoxy--D-galactopiranoside (9)
White solid. 1H RMN: (200MHz, DMSO-d6) : 1.24-1.60 (m, 2H, 3-H), 2.56 (dd, 1H, J=6.8, J=13.4, 1-Ha), 2.83 (dd, 1H,
J=6.3, J=13.4, 1-Hb), 3.25-3.59 (m, 6H, 5-H, 4-H, 6-H, 7-H), 3.85-4.98 (vbs, 3H, -OH), 7.07-7.33 (m, 20H, Ph). 13C RMN:
(50,3MHz, DMSO-d6) : 34.7 (C-3), 42.4 (C-1), 61.6 (C-7), 67.6 (C-5), 69.6, 76.7, 79.6 (C-2, C-4, C-6), 126.6, 128.8,
129.9, 139.2 (Ph). Anal. Calcd for C13H18O4: C, 65.53; H, 7.61; O, 26.86. Found: C, 65.53; H, 7.61; O, 26.86.
1.4 General procedure for the hydrogenation using Pd/C(en) as catalyst

After three vacuum/H2 cycles to replace air inside the reaction tube with hydrogen, the mixture of substrate (0.25
mmol) and 5% Pd/C(en) (10 wt% of the substrate) in EtOH (1.0 ml) was vigorously stirred at room temperature under
2.5 atm of hydrogen for 3h. The reaction mixture was then filtered through a pad of celite, and the filtrate was
concentrated in vacuo to afford an oil. The crude product was chromatographed on silica gel (eluent: hexane:ethyl
acetate 8:2 containing 0.1% triethylamine) to give the pure product as a colorless syrup.
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1.4.1 C-Benzyl 3, 4, 6-tri-O-benzyl-2-deoxy--D-galactopiranoside (7)
Colorless syrup. 1H RMN: (200MHz, CD3Cl) : 1.63-1.95 (m, 2H, 3-H), 2.63 (dd, 1H, J=7.1, J=13.7, 1-Ha), 2.98 (dd, 1H,
J=6.2, J=13.7, 1-Hb),3.35-3.56 (m,5H, 4-H, 6-H, 7-H), 3.77 (bs, 1H, 5-H), 4.35 (s, 1H, CH2Ph), 4.37 (s, 1H, CH2Ph), 4.45
(s, 2H, CH2Ph), 4.58 (AB, 1H, J=11.8, CH2Ph), 4.85 (AB, 1H, J=11.8, CH2Ph), 7.07-7.33 (m, 20H, Ph). 13C RMN: (50,3MHz,
CD3Cl) : 32.4 (C-3), 42.5 (C-1), 70.1 (C-7), 70.4 (CH2Ph), 72.6 (C-5), 73.7 (CH2Ph), 74.4 (CH2Ph), 77.7, 79.2, 77.9 (C-2,
C-4, C-6), 126.4-129.7 (Ph), 138.4 (C-Ph), 138.6 (C-Ph), 138.7 (C-Ph), 139.2 (C-Ph). Anal. Calcd for C34H36O4: C, 80.28;
H, 7.13; O, 12.58. Found: C, 80.28; H, 7.13; O, 12.58.
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Acknowledgment
Authors wish to thank Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), UNLP and
CONICET for their financial support to the present work.
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S., Ed.; Marcel Dekker, Inc: New York, 1997; pp 527–542.
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Postema, M. H. D. C-Glycoside Synthesis; CRC: USA, 1995; 8476 (c) Beau, J.-M.; Gallagher, T. Top. Curr. Chem.
1997, 187, 1-54; (d) Nicotra, F. Top. Curr. Chem. 1997, 187, 55-83; (e) Sinay, P. Pure Appl. Chem. 1997, 69,
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Pretsch, E.; Buhlmann, P.; Affolter, C. Structure Determination of Organic Compounds; Springer Verlag:
Berlin, 2000; 3rd English ed. Also the assignment was confirmed by comparison with earlier exo-glycals
prepared by us. See: 5 and 8.
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Graphical Abstract
H
-
+
Stereo- and
chemoselective
hydrogenation
O
PPh3BF4
O
O
BnO
BnO
BnO
BnO
BnO
BnO
R
R
Wittig reaction
OBn
OBn
OBn

Highlights
1- Synthesis of exo-glycals by the Wittig reaction of glycosl phophonium salts.
2- Effective and selective hydrogenation using Pd/C(en)catalyst
3- Optimization of experimental conditions.
4- Synthesis of novel 2-deoxy-β-benzyl-C-glycosides