Ultrasound-assisted synthesis of C-glycosides

Article abstract of DOI:10.1016/j.tetlet.2010.10.113

A significant rate enhancement was observed in the preparation of allyl and allenyl-C-glycosides from glycosyl acetate or methyl O-glycoside precursors when ultrasound irradiation was employed as an energy source. The C-glycosides were obtained in 77-96%

Full text of DOI:10.1016/j.tetlet.2010.10.113

Tetrahedron Letters 51 (2010) 6776–6778
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ultrasound-assisted synthesis of C-glycosides
Dilip V. Jarikote a,b, Ciaran O’Reilly a,b, Paul V. Murphy a,b,
⇑
a School of Chemistry, National University of Ireland, Galway, Ireland
b School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A significant rate enhancement was observed in the preparation of allyl and allenyl-C-glycosides from
glycosyl acetate or methyl O-glycoside precursors when ultrasound irradiation was employed as an
energy source. The C-glycosides were obtained in 77–96% yields in <20 min using TMSOTf as promoter.
These results show that sonication provides rapid and efficient access to useful C-glycoside-based build-
ing blocks.
Received 8 September 2010
Revised 9 October 2010
Accepted 22 October 2010
Available online 30 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
C-glycosides
Ultrasound
In recent years C-glycoside formation has been one of the more
studied topics in carbohydrate chemistry.1 This is due to the rela-
tive difficulty encountered in the synthesis of C-glycosides as well
as the potential of such glycomimetics in medicine and biology.
The C-glycoside analogues of O-glycosides can be resistant to gly-
cosylhydrolases, for example.2 It has been established that C-glyco-
side analogues of naturally occurring O-glycosides can often
display interesting differences in their reactivity and biological
activity in a variety of contexts.3
was incomplete after 2 h using conventional heating showing that
ultrasonic radiation significantly enhances the C-glycosidation
reaction. These conditions were then tested for their suitability
to prepare other protected C-glycoside derivatives (Tables 1 and
2). The rate enhancement was also observed for formation of a
variety of 1-allyl- and 1-allenyl-C-glycosides with a-configuration,
which were all easily obtained in <20 min from the corresponding
methyl glycoside or glycosyl acetate precursor (Tables 1 and 2); the
precursors 1–6 were derived from D-glucose, D-mannose and D-gal-
Synthesis of many different C-glycoside derivatives can com-
mence from allyl or allenyl-C-glycoside-based precursors.4 Meth-
ods which lead to an improvement in the yields and/or to the
rates of formation of these C-glycoside building blocks would be
helpful for researchers working in these areas.
actose. Increasing the reaction temperature for the preparation of
such C-glycosides instead of using ultrasonic radiation was not
found to be useful. The reactions of 1–6 were significantly faster
in the presence of ultrasound radiation than similar reactions car-
ried out at room temperature which generally required 24–40 h.10
As an example, the mannoside derivative 4 was completely con-
verted into the C-glycoside 10 (isolated yield of 95%) in just
15 min; in the absence of ultrasonication there was almost no
Recently, ultrasonic energy5 has been employed successfully to
facilitate or improve a number of traditional reactions which in-
clude protecting group manipulations,6 copper catalysed azide–al-
kyne cycloaddition reactions,7 acyl migrations,6 glycosylation
reactions6 and Suzuki/Heck type reactions.8 We thus investigated
the effect of ultrasonic radiation on C-glycoside formation. As part
of an on-going research programme9 we required access to a num-
ber of C-glycosides and were interested to evaluate any potential
advantage of using non-traditional energy sources to carry out C-
glycoside building block synthesis. In the first experiment tried
product observed after 2 h. The
a-configuration assigned to the
mannoside products 10 and 16 was supported by coupling con-
stants (JH1–C1 ꢀ150 Hz), which are larger than those observed for
b-anomers (JH1–C1 ꢀ143 Hz) in related compounds.11
A small
amount of the b-anomer of 9 and 15 was generated from the ally-
lation and allenylation of 3 (ꢀ7%); the b-anomers for all other C-
glycosides were found to be present in yields <2%.
we found that the allylation of methyl 2,3,4,6-tetra-O-benzyl-
a
-
In a typical reaction procedure12 the saccharide precursor
(100 mg) was dissolved in acetonitrile in a Biotage microwave
vial and treated with TMSOTf and the silylated nucleophile. The
tube was sealed and placed in an ultrasonic cleaning bath (fre-
quency 50/60 Hz  230 V) until the reaction was complete by
TLC. The C-glycosidation was complete within 15–20 min and
the products were isolated in good yields after work-up and
D-glucopyranoside (1), in the presence of TMSOTf and allyltrimeth-
ylsilane was complete within 15 min when the reaction was car-
ried out in the presence of ultrasound radiation. This reaction
⇑
Corresponding author. Tel.: +353 91 492465; fax: +353 91 525700.
E-mail address: paul.v.murphy@nuigalway.ie (P.V. Murphy).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.113

D. V. Jarikote et al. / Tetrahedron Letters 51 (2010) 6776–6778
6777
Table 1
Table 2
Synthesis of l-allyl-C-glycosides from 1 to 6
Synthesis of l-allenyl-C-glycosides 1–6
TMS
PO
PO
PO
PO
PO
PO
PO
O
O
O
O
TMS
PO
, TMSOTf, CH3CN
, TMSOTf, CH3CN
OR
OR
•
Entry Reactant
Product
Yield (%) Time (min)
Entry Reactant
Product
Yield
(%)
Time
(min)
OBn
O
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
1
78
80
15
15
BnO
BnO
BnO
7
8
1
OMe
1
77
78
15
15
BnO
BnO
13
14
OMe
1
•
OAc
O
OAc
O
OAc
O
OAc
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
2
BnO
BnO
BnO
2
2
OMe
BnO
BnO
2
OMe
•
OBn
O
OBn
O
OBn
O
OBn
O
O
O
3
BnO
90
20
BnO
O
O
3
83
20
BnO
BnO
BnO
BnO
3
OMe
BnO
BnO
9
15
3
OMe
•
BnO
BnO
AcO
AcO
BnO
BnO
BnO
AcO
AcO
O
O
BnO
O
O
BnO
BnO
BnO
BnO
BnO
BnO
4
5
6
95
89
83
15
20
20
4
96
87
15
20
10
4
16
OAc
4
OAc
•
BnO
BnO
BnO
BnO
BnO
OBn
O
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
5
BnO
BnO
BnO
BnO
17
5
11
OMe
5
OMe
•
BnO
BnO
BnO
OBn
O
OBn
O
BnO
BnO
BnO
OBn
O
OBn
O
BnO
6
87
20
BnO
BnO
BnO
BnO
18
6
BnO
OAc
12
6
•
OAc
Supplementary data
purification (see Tables 1 and 2). The structure of all new prod-
ucts was supported by 1H NMR and 13C NMR spectroscopy as well
as high resolution mass spectrometry.13 All known compounds
had analytical data in agreement with those reported previ-
ously.10,4b–e
In conclusion, ultrasonication has led to an improvement in the
reaction conditions for the preparation of C-glycosides, as has been
shown in the preparation of a series of glucose, mannose and gal-
actose derivatives. The allylation and allenylation were performed
at ambient temperature with excellent enhancements of reaction
rates by use of ultrasonic irradiation in a sealed tube. Under these
conditions the desired stereoselectivity of the products and high
yields were recorded. These building blocks are currently being
used in the synthesis of new carbohydrate derivatives of biological
interest.
Supplementary data (general experimental conditions and
NMR spectra for new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.113.
References and notes
1. (a) Terauchi, M.; Abe, H.; Matsuda, A.; Shuto, S. Org. Lett. 2004, 6, 3751–3754;
(b) Vieira, A. S.; Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.; Ludtke, D. S.;
Stefani, H. L. A. Org. Lett. 2008, 10, 5215–5218; (c) Cox, J. M.; Rainier, J. D. Org.
Lett. 2001, 3, 2919–2922; (d) Fletcher, S.; Jorgensen, M. R.; Miller, A. D. Org. Lett.
2004, 6, 4245–4248.
2. (a) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99–110; (b) Dwek, R. A.
Chem. Rev. 1996, 96, 683–720; (c) Bertozzi, C. R.; Kiessling, L. L. Science 2001,
291, 2357–2364.
3. (a) Kolympadi, M.; Fontanella, M.; Venturi, C.; André, S.; Gabius, H.-J.; Jiménez-
Barbero, J.; Vogel, P. Chem. Eur. J. 2009, 15, 2861–2873; (b) Chen, G.; Chien, M.;
Tsuji, M.; Franck, R. W. ChemBioChem 2006, 7, 1017–1022.
4. (a) Zou, W.; Shao, H.; Wu, S.-H. Carbohydr. Res. 2004, 2475–2485; (b) Xie, J. Eur.
J. Org. Chem. 2002, 2002, 3411–3418; (c) Girard, C.; Miramon, M.-L.; de
Solminihac, T.; Herscovici, J. Carbohydr. Res. 2002, 337, 1769–1774; (d) Kobertz,
W. R.; Bertozzi, C. R.; Bednarski, M. D. Tetrahedron Lett. 1992, 33, 737–740; (e)
Brenna, E.; Fuganti, C.; Grasselli, P.; Serra, S.; Zambotti, S. Chem. Eur. J. 2002, 8,
1872–1878.
Acknowledgements
The authors are grateful to the Science Foundation Ireland (RFP/
06/CHO32) and European Commission (Marie Curie EIF Grant no.
220948) for their generous funding.

6778
D. V. Jarikote et al. / Tetrahedron Letters 51 (2010) 6776–6778
5. (a) Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68, 8261–8263; (b) Jarikote, D. V.;
Deshmukh, R. R.; Rajagopal, R.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Ultrason.
Sonochem. 2003, 10, 45–48; (c) Chen, M.-Y.; Lu, K.-C.; Lee, A. S.-Y.; Lin, C.-C.
Tetrahedron Lett. 2002, 43, 2777–2780; (d) Adewuyi, Y. G. Ind. Eng. Chem. Res.
2001, 40, 4681–4715; (e) Kardos, N.; Luche, J. L. Carbohydr. Res. 2001, 332, 115–
131; (f) Gholap, A. R.; Venkatesan, K.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Green Chem. 2003, 5, 693–696.
6. Deng, S.; Gangadharmath, U.; Chang, C.-W. T. J. Org. Chem. 2006, 71, 5179–
5185.
7. Zhang, J.; Chen, H.-N.; Chiang, F.-I.; Takemoto, J. Y.; Bensaci, M.; Chang, C.-W. T.
J. Comb. Chem. 2007, 9, 17–19.
1H; OCH2Ph), 4.39 (dd, J = 15.1 Hz and 2.4 Hz, 1H; OCH2C„), 4.21 (dd,
J = 15.1 Hz and 2.4 Hz, 1H; OCH2C„), 4.11 (ddd, J = 10 Hz, 5 Hz and 5 Hz, 1H;
H-1), 3.78–3.74 (m, 1H; H-3) overlapping with 3.72–3.69 (m, 3H; H-2 and H-6),
3.60 (dt, J = 5.7 Hz and 5 Hz, 1H; H-5), 3.47 (dd, J = 10.4 Hz and 8.5 Hz, 1H; H-
4), 2.50–2.46 (m, 2H; CH2CH@), 2.40 (t, J = 2.4 Hz, 1H; C„CH). 13C NMR (CDCl3,
125 MHz): d = 138.5, 138.2, 138.1 (each s, aromatic C), 134.63 (s, CH alkene),
128.4, 128.38, 128.27, 128.0, 127.78, 127.71, 127.64, 127.51 (each s, aromatic
CH), 116.89 (s, CH2 alkene), 82.3, 79.99, 79.92 (3s, CH), 77.80 (s, C„CH), 75.4,
74.2 (2s, OCH2Ph), 73.6 (s, CH), 73.4 (s, OCH2Ph), 73.05 (s, CH2–C„CH), 70.86
(s, CH), 69.14 (s, C-6), 59.89 (s, C„CH), 29.78 (s, CH2CH@). HRMS (ESI): found
535.2460 [M+Na]+, C33H36O5Na requires 535.2460.
8. (a) Rajagopal, R.; Jarikote, D. V.; Srinivasan, K. V. Chem. Commun. 2002, 616–
617; (b) Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V. Chem. Commun. 2001,
1544–1545.
Compound 13: 1H NMR (CDCl3, 500 MHz): d = 7.31–7.24 (m, 18H; aromatic H),
7.14–7.12 (m, 2H; aromatic H), 5.44 (q, J = 5.8 Hz, 1H; allenyl CH), 4.94 (d,
J = 10.9 Hz, 1H; OCH2Ph), 4.85–4.83 (m, 2H; allenyl CH2), 4.82–4.81 (m, 1H,
OCH2Ph), 4.8 (d, J = 11.3 Hz, 2H; OCH2Ph), 4.66 (d, J = 3.7 Hz, 2H; OCH2Ph), 4.61
(dd, J = 10.9 Hz and 6.4 Hz, 1H; H-1), 4.48 (dd, J = 3.2 Hz and 1.0 Hz, 2H;
OCH2Ph), 3.83–3.75 (m, overlapping signals 3H, H-3, H-2, overlapping signals
1H; H-5), overlapping signals 3.72–3.68 (m, 1H; H-4) overlapping signals 3.63
(dd, J = 8.5 Hz and 7.5 Hz, 2H; H-6). 13C NMR (CDCl3, 125 MHz): d = 209.4
(allenyl @C@), 138.8, 138.2, 138.19, 138.15 (s, aromatic C), 128.4, 128.37,
128.37, 128.35, 128.33, 127.98, 127.93, 127.78, 127.75, 127.70, 127.6, 127.56
(s, aromatic CH), 85.6 (allenyl CH), 82.6, 79.9 (2s, CH), 78.1 (CH2 allenyl), 75.5,
75.1 (2s, OCH2Ph), 73.5 (s, CH), 72.8, 72.36 (2s, OCH2Ph), 72.0 (s, CH), 68.9 (s, C-
6). HRMS (ESI): found 585.2617 [M+Na]+, C37H38O5Na requires 585.2617.
Compound 15: 1H NMR (CDCl3, 500 MHz): d = 7.36–7.31 (m, 15H; aromatic H),
5.7 (q, J = 5.7 Hz, 1H; allenyl CH), 4.90 (d, J = 10.8 Hz, 1H; OCH2Ph), 4.86–4.83
(m, 2H; allenyl CH2), 4.80 (d, J = 10.7 Hz, 1H; OCH2Ph), 4.72–4.70 (m, 1H;
OCH2Ph), 4.65 (d, J = 4.6 Hz, 2H; OCH2Ph), 4.61 (dd, J = 7.4 Hz and 3.1 Hz, 1H;
H-1), 4.54 (d, J = 8.7 Hz, 1H; OCH2Ph), 4.39 (dd, J = 15.1 Hz and 2.4 Hz, 1H;
OCH2C„), 4.21 (dd, J = 15.1 Hz and 2.3 Hz, 1H; OCH2C„), 3.80–3.70 (m, 5H;
overlapping signals of H-3, H-2, H-5 and H-6), 3.51 (dd, J = 11.6 Hz and
J = 9.7 Hz, 1H; H-4), 2.40 (t, J = 2.3 Hz, 1H; C„CH). 13C NMR (CDCl3, 125 MHz):
d = 209.4 (allenyl @C@), 138.5, 138.1, 137.5 (each s, aromatic C), 128.46,
128.40, 128.38, 128.33, 128.31, 127.29, 128.09, 127.96, 127.94, 127.9, 127.8,
127.76, 127.70, 127.66, 127.56 (each s, aromatic CH), 85.5 (CH), 82.3 (CH2C„),
79.8 (s, CH2), 77.80 ((OCH2C„), 75.5, 74.26, 73.5 (3s, OCH2Ph), 72.8, 72.02, 71.9
(3s, CH), 70.86 (s, CH), 69.08 (s, C-6), 60.00 (s, C„CH), 29.70 (s, CH2CH@). HRMS
(ESI): found 533.2305 [M+Na]+, C33H34O5Na requires 533.2304.
9. (a) Jarikote, D. V.; Murphy, P. V. Eur. J. Org. Chem. (Microreview) 2010, 26, 4959–
4970; (b) Andre, S.; Velasco-Torrijos, T.; Leyden, R.; Gouin, S.; Tosin, M.;
Murphy, P. V.; Gabius, H.-J. Org. Biomol. Chem. 2009, 7, 4715–4725; (c) Leyden,
R.; Velasco-Torrijos, T.; Andre, S.; Gouin, S.; Gabius, H.-J.; Murphy, P. V. J. Org.
Chem. 2009, 74, 9010–9026; (d) Pilgrim, W.; Murphy, P. V. Org. Lett. 2009, 11,
939–942; (e) Murphy, P. V. Eur. J. Org. Chem. 2007, 4177–4187; (f) O’Brien, C.;
Polakova, M.; Pitt, N.; Tosin, M.; Murphy, P. V. Chem. Eur. J. 2007, 13, 902–909.
10. Hung, S.-C.; Lin, C.-C.; Wong, C.-H. Tetrahedron Lett. 1997, 38, 5419–5422.
11. Panek, J. S.; Sparks, M. A. J. Org. Chem. 1989, 54, 2034–2038.
12. To
methyl
2,3,4,6-tetra-O-benzyl-
a-
D
-glucopyranoside
(1)
(100 mg,
0.18 mmol) in dry MeCN (2.0 mL) under N2 at room temperature, allyl
trimethylsilane or propargyltrimethylsilane (0.36 mmol) was added, followed
by dropwise addition of trimethylsilyl triflate (20 mg, 0.09 mmol) before
closing the vessel. The reaction mixture was then sonicated for 15 min, after
which it was quenched with saturated aqueous NaHCO3 (2.0 mL), diluted with
EtOAc (5.0 mL) and washed with brine (3.0 mL). The separated organic extracts
were combined, dried (MgSO4), filtered and the solvent was removed under
reduced pressure to give an oil. Chromatography of the oil (cyclohexane–
EtOAc, 8:1) gave 7 or 13.
13. Analytical data for selected compounds:
Compound 9: 1H NMR (CDCl3, 500 MHz): d = 7.36–7.26 (m, 15H; aromatic H),
5.86–5.77 (m, 1H; alkene CH), 5.13–5.06 (m, 2H; alkene CH2), 4.91 (d,
J = 10.8 Hz, 1H; OCH2Ph), 4.80 (d, J = 10.8 Hz, 1H; OCH2Ph), 4.68 (d, J = 11.6 Hz,
1H; OCH2Ph), 4.70 (dd, J = 11.6 Hz and 2.6 Hz, 2H; OCH2Ph), 4.52 (d, J = 11.9 Hz,