A convenient synthesis of pseudoglycosides via a Ferrier-type rearrangement using metal-free H3PO4 catalyst

Article abstract of DOI:10.1016/j.tetlet.2008.11.103

A mild and efficient synthesis of pseudoglycals has been developed using a metal-free catalytic system. Phosphoric acid proved to be an excellent catalyst for conversion of 2,4,6-tri-O-acetyl-d-glycal to 2,3-unsaturated O-glycosides. A wide range of alcoh

Full text of DOI:10.1016/j.tetlet.2008.11.103

Tetrahedron Letters 50 (2009) 676–679
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A convenient synthesis of pseudoglycosides via a Ferrier-type
rearrangement using metal-free H3PO4 catalyst
*
Bala Kishan Gorityala, Shuting Cai, Rujee Lorpitthaya, Jimei Ma, Kalyan Kumar Pasunooti, Xue-Wei Liu
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient synthesis of pseudoglycals has been developed using a metal-free catalytic system.
Phosphoric acid proved to be an excellent catalyst for conversion of 2,4,6-tri-O-acetyl- -glycal to 2,3-
unsaturated O-glycosides. A wide range of alcohols including naturally bioactive compounds could be
Received 17 October 2008
Revised 20 November 2008
Accepted 25 November 2008
Available online 30 November 2008
D
coupled with the glycal to give the desired products in good to excellent yields and with high levels of
a
-selectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
2,3-Unsaturated O-glycosides have been recognized as impor-
tant building blocks in many bioactive molecules1 and play a sub-
stantial role in the synthesis of compounds such as
oligosaccharides,2 uronic acids,3 biologically active natural prod-
ucts,4 and antibiotics.5 Since the Ferrier rearrangement was discov-
ered in 1964,6 there have been many reports on the development
of this direct method to 2,3-unsaturated glycosides. The Ferrier
reaction typically involves the allylic rearrangement of glycals with
nucleophilic substitution under acidic conditions.7 This rearrange-
ment is believed to proceed through a cyclic allylic oxocarbonium
intermediate that is formed via displacement of the C-3 substitu-
ent in a glycal, followed by preferential attack of a nucleophile
via the quasi-equatorial orientation.8
Regarding atom economy, it is crucial to use a low amount of
the catalyst. We found that H3PO4 could be loaded as low as
0.2 equiv with respect to the starting material. There was no dra-
matic increase in yield and selectivity, when the amount of
H3PO4 was increased. Typically, H3PO4 was added to the mixture
of glycal and alcohol (1 equiv) in dichloromethane at room temper-
ature. When the reaction was complete, the solvent was evapo-
rated, and subsequent purification of the crude product by short-
column chromatography gave the desired pseudoglycosides. The
structure and stereochemistry of the glycosylated products were
elucidated from 1H, 13C, and 2D NMR spectroscopic data. The re-
sults reported in Table 1 show that a variety of alcohols could be
utilized and gave the desired 2,3-unsaturated glycosides (2a–p)
in excellent yields (82–97%). Moreover, the reaction conditions
are very mild and rapid, and no side products were formed.
Based on the anomeric ratios obtained from 1H NMR spectra, it
is evident that the catalytic reactions using allyl alcohol, pentan-3-
A pioneering study with BF3ꢀEt2O9 led to a number of other Le-
wis acids being used in these reactions. The use of Lewis acids, such
12
as SnCl4,10 InCl3,11 Yb(OTf)3, FeCl3,13 LiBF4,14 BiCl3,15 ZnCl2,16
Dy(OTf)3,17 Sc(OTf)3,18 and ZrCl4,19 has contributed to the advance-
ment of the acid-catalyzed allylic rearrangement of glycal deriva-
tives. However, each catalyst suffers from drawbacks such as low
yields, formation of side products, and cost and amount of catalyst.
With the objective of developing a viable procedure for the synthe-
sis of 2,3-unsaturated glycosides, we focused on finding a cheap
and efficient catalyst that would give high anomeric selectivity
and yields. To our best knowledge, phosphoric acid (H3PO4) has
not been used as a catalyst in this area. H3PO4 is used as a catalyst
in many reactions, for example, Diels–Alder20 and oligomeriza-
ol, and 2-naphthol as nucleophiles produced a-anomers as the sole
products (Table 1, entries 6, 7, and 14). The bulky and long carbon
chain nucleophiles were able to give good selectivities (up to 20:1
a/b ratio). Apart from these, anomeric mixtures were formed with
the -anomer being formed predominantly (at least 5:1).
a
Encouraged by these results, we next explored the scope of this
route for the synthesis of pseudoglycals connected to various bio-
logically important natural products (Table 1, entries 15 and 16).
tion,21 and also as
a benchmark for other phosphoric acid
catalysts.22 The widespread use of H3PO4 as a catalyst can be
attributed to the fact that it is cheap and easily available. In the
present study, we describe the successful implementation of phos-
phoric acid (H3PO4) as a catalyst in the Ferrier rearrangement for
the synthesis of 2,3-unsaturated O-glycosides (Scheme 1).
OAc
OAc
O
H3PO4
O
OR
+
ROH
CH2Cl2, rt
10-15 min
AcO
AcO
OAc
1
2
* Corresponding author. Tel.: +65 6316 8901; fax: +65 6791 1961.
E-mail address: xuewei@ntu.edu.sg (X.-W. Liu).
Scheme 1. A synthetic model for the ferrier rearrangement.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.103

B. K. Gorityala et al. / Tetrahedron Letters 50 (2009) 676–679
677
Table 1
Ferrier reaction of 2,3-tri-O-acetyl-D-glycal with alcohols in the presence of the H3PO4
Entry
Product
Time (min)
Yield (%)
93
a
/ba
OAc
O
AcO
1
10
8:126
O
2a
OAc
O
AcO
AcO
2
3
10
15
15
10
10
15
15
10
10
10
15
88
89
85
86
92
84
97
85
87
93
92
10:1
O
3
2b
OAc
O
8:127
5:128
10:129
a26
Br
O
2c
OAc
O
AcO
AcO
4
O
O
2d
OAc
O
5
O
2e
OAc
O
AcO
AcO
6
O
2f
OAc
O
7
a31
O
2g
OAc
O
AcO
AcO
8
20:132
20:126
20:133
5:1
O
2h
OAc
O
9
O
2i
OAc
O
AcO
AcO
10
11
12
O
2j
OAc
O
O
2k
OAc
O
AcO
8:130
O
2l
(continued on next page)

678
B. K. Gorityala et al. / Tetrahedron Letters 50 (2009) 676–679
Table 1 (continued)
Entry
Product
Time (min)
Yield (%)
89
a
/ba
OAc
O
AcO
13
14
15
10
20
15
20
10:134
O
2m
OAc
O
AcO
AcO
AcO
82
87
91
a35
O
2n
OAc
O
11:136
O
2o
OAc
O
16
6:137
O
2p
a
The a
/b ratio was determined from the anomeric proton ratio in the 1H NMR spectra.
For example, borneol23 and citronellol24 glycosides are challenging
targets to study and transform because of their diverse biological
activities and their structural complexity. They are generally syn-
thesized by enzymatic25 as well as Koenigs–Knorr–Zemplen23
methods, which are expensive, lengthy, and tedious procedures.
Under our catalytic conditions, borneol and citronellol pseudogly-
cosides were obtained in 87% and 91% yields and in anomeric ratios
of 11:1 and 6:1, respectively.
In summary, we have demonstrated a practical synthesis of 2,3-
unsaturated O-glycosides via the Ferrier rearrangement. H3PO4 is
an effective and viable catalyst in the reaction with various alco-
hols to furnish many complex pseudoglycals. The simple work-
up, rapid reactions, low cost, and the commercial availability of
the catalyst are significant advantages of this method.
9. (a) Descotes, G.; Martin, J. C. Carbohydr. Res. 1977, 56, 168; (b) Klaffke, W.;
Pudlo, P.; Springer, D.; Thiem, J. L. Ann. Chem. 1991, 6, 509.
10. Bhate, P.; Harton, D.; Priebe, W. Carbohydr. Res. 1985, 144, 331.
11. (a) Babu, B. S.; Balsubramanian, K. K. Tetrahedron Lett. 2000, 41, 1271; (b) Das,
S. K.; Reddy, K. A.; Roy, J. Synlett 2003, 1607.
12. Takhi, M.; Rahman, A.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 4053.
13. Masson, C.; Soto, J.; Besodes, M. Synlett 2000, 1281.
14. Yadav, J. S.; Reddy, B. V. S.; Chandraiah, L.; Reddy, K. S. Carbohydr. Res. 2001,
332, 221.
15. Swamy, N. R.; Venkateswarlu, A. Synthesis 2002, 598.
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17. Yadav, J. S.; Reddy, B. V.; Reddy, J. S. J. Chem. Soc., Perkin Trans. 1 2002, 2390.
18. Yadav, J. S.; Reddy, B. V.; Murthy, C. V.; Kumar, G. M. Synlett 2000, 1450.
19. Smitha, G.; Reddy, S. C. Synthesis 2004, 834.
20. Takagi, R.; Kondo, A.; Ohkata, K. J. Mol. Catal. A: Chem. 2007, 1, 120.
21. Klerk, A. D.; Leckel, D. O.; Prinsloo, N. M. Ind. Eng. Chem. Res. 2006, 45, 6127.
22. Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909.
23. Mastalic, J.; Jerkovic, I.; Vinkovic, M.; Dzolic, Z.; Vikic-Topic, D. Croat. Chem.
Acta 2004, 77, 491.
24. Oka, N.; Ikegami, A.; Ohki, M.; Sakata, K.; Yagi, A.; Watanabe, N. Phytochemistry
1998, 47, 1527.
Acknowledgments
25. Yamauchi, T.; Hara, M.; Mihashi, K. Phytochemistry 1972, 1, 3345.
26. Zhang, G.; Liu, Q.; Shi, L.; Wang, J. Tetrahedron 2008, 64, 339.
27. Ferrier, R. J.; Petersen, P. M. Tetrahedron 1990, 46, 1.
28. Surya Kiran, N.; Malla Reddy, S.; Srinivasulu, M.; Venkateswarlu, Y. Synth.
Commun. 2008, 38, 170.
We gratefully thank Nanyang Technological University and the
Ministry of Education, Singapore for the financial support.
29. Yadav, J. S.; Subba Reddy, B. V.; Sunder Reddy, J. S. J. Chem. Soc., Perkin Trans. 1
2002, 2390.
30. Das, S. K.; Reddy, K. A.; Roy, J. Synlett 2003, 1607.
References and notes
31. Typical experimental procedure: To
a mixture of 2,4,6-tri-O-acetyl-D-glycal
1. (a) Fraser-Reid, B. Acc. Chem. Res. 1985, 18, 347; (b) Ferrier, R. J. Adv. Carbohydr.
Chem. Biochem. 1969, 24, 199; (c) Toshima, K.; Tatsuda, K. Chem. Rev. 1993, 93,
1503; (d) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576; (e)
Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43, 218; (f) Dorgan, B. J.;
Jackson, R. F. W. Synlett 1996, 859; (g) Schmidt, R. R.; Angerbauer, R. Carbohydr.
Res. 1981, 89, 159; (h) Schmidt, R. R.; Angerbauer, R. Carbohydr. Res. 1981, 89,
193; (i) Schmidt, R. R.; Angerbauer, R. Carbohydr. Res. 1979, 72, 272; (j)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996, 35, 1380; (k) Liu,
Z. J. Tetrahedron: Asymmetry 1999, 10, 2119.
2. Bussolo, V. D.; Kim, Y. J.; Gin, D. Y. J. Am. Chem. Soc. 1998, 120, 13515.
3. (a) Schmidt, R. R.; Angerbauer, R. Carbohydr. Res. 1981, 89, 159; (b) Angerbauer,
R.; Schmidt, R. R. Carbohydr. Res. 1981, 89, 193.
4. Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. Rev. 1993, 62, 579.
5. Williams, N. R.; Wander, J. D. In The Carbohydrates in Chemistry and
Biochemistry; Academic Press: New York, 1980.
(100 mg, 0.37 mmol) and pentan-3-ol (1 equiv) in dichloromethane (1 ml)
was added 0.2 equiv of phosphoric acid at room temperature. The mixture was
stirred for the appropriate amount of time (Table 1, entry 7), and the extent of
reaction was monitored by TLC analysis. The reaction mixture was then filtered
and rinsed with dichloromethane. Evaporation of the solvent under reduced
pressure, followed by purification of the residue by silica gel column
chromatography, gave the desired 2,3-unsaturated glycoside (2g): ½ ꢁ
a 2D4
+313.9 (c 0.2 CHCl3); 1H NMR (300 MHz, CDCl3) d 5.84 (d, J = 10.5 Hz, 1H),
5.80 (d, J = 10.5 Hz, 1H), 5.25 (dt, J = 9.3, 1.4 Hz, 1H), 5.09 (s, 1H), 4.20 (dd,
J = 12.1, 5.7 Hz, 1H), 4.16–4.11 (m, 2H), 3.55 (pent, J = 5.9 Hz, 1H), 2.06 (s, 3H),
2.05 (s, 3H), 1.57–1.48 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 170.8, 170.3, 128.7, 128.2, 93.4, 81.2, 66.9, 65.3, 63.1,
27.1, 26.1, 20.9, 20.7, 10.0, 9.3; IR (NaCl neat)
m ;
1743, 1369, 1230, 1033 cmꢂ1
HRMS (ESI) m/z [M+Na]+ Calcd for C15H24O6Na 323.1471, found 323.1462.
32. Cyclohex-2-enyl
4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
6. Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 570.
7. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455.
(2h): obtained as a mixture of two diastereomers; ½a D24
ꢁ
+38.7 (c 0.5 CHCl3);
1H NMR (500 MHz, CDCl3) d 5.87–5.81 (m, 3H), 5.76 (m, 1H), 5.29 (d, J = 8.8 Hz,
1H), 5.19 (d, J = 17.4 Hz, 1H), 4.25–4.16 (m, 4H), 2.09 (s, 3H), 2.08 (s, 3H), 2.03
(m, 1H), 1.97–1.92 (m, 2H), 1.83–1.72 (m, 2H), 1.58 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 170.8, 170.3, 131.5, 128.9, 128.7, 128.4, 128.3, 94.0, 72.7,
8. (a) Ferrier, R. J.; Sankey, G. H. J. Chem. Soc. C 1966, 2345; (b) Wieczorek, B.;
Thiem, J. J. Carbohydr. Chem. 1998, 17, 785; (c) Levy, D. E.; Tang, C. In The
Chemistry of C-Glycosides; Pergamon Press: Tarrytown, NY, 1995; (d) Postema,
M. H. D. In C-Glycosides Synthesis; CRC Press: Boca Raton, FL, 1995; (e) Csuk, R.;
Shaade, M.; Krieger, C. Tetrahedron 1996, 52, 6397.
66.8, 65.4, 63.1, 30.1, 25.0, 20.9, 19.2; IR (NaCl neat)
m 1743, 1371, 1230,

B. K. Gorityala et al. / Tetrahedron Letters 50 (2009) 676–679
679
1033 cmꢂ1; HRMS (ESI) m/z [M+Na]+ Calcd for C16H22O6Na 323.1314, found
323.1310.
129.10, 128.9, 127.0, 126.9, 124.6, 123.1, 120.8, 119.9, 112.8, 75.2, 64.2, 62.4,
21.0, 20.8; IR (NaCl neat)
1747, 1226, 1039 cmꢂ1; HRMS (ESI) m/z [M+Na]+
calcd for C20H20O6Na 379.1158, found 379.1147.
36. (+)-Borneol 4,6-di-O-acetyl-2,3-dideoxy- -erythro-hex-2-enopyranoside (2o):
+72.6 (c 0.8 CHCl3); 1H NMR (500 MHz, CDCl3) d 5.84–5.79 (m, 2H), 5.27
m
33. Cyclooctanyl 4,6-di-O-acetyl-2,3-dideoxy-
a-D-erythro-hex-2-enopyranoside (2j):
½
a 2D4
ꢁ
+156.7 (c 1.0 CHCl3); 1H NMR (500 MHz, CDCl3) d 5.84 (d, J = 10.2 Hz, 1H),
a-D
5.78 (dt, J = 10.2, 2.3 Hz, 1H), 5.26 (dd, J = 9.6, 1.4 Hz, 1H), 5.11 (s, 1H), 4.21 (d,
J = 12.1 Hz, 1H), 4.12 (m, 2H), 3.83 (hept, J = 4.2 Hz, 1H), 2.08 (s, 3H), 2.06 (s, 3H),
1.76 (m, 1H), 1.71–1.69 (m, 4H), 1.59–1.40 (m, 9H); 13C NMR (125 MHz, CDCl3) d
170.8, 170.3, 128.65, 128.63, 92.8, 78.6, 66.8, 65.5, 63.2, 53.4, 33.0, 31.3, 27.3,
½ ꢁ
a 2D4
(d, J = 9.8 Hz, 1H), 4.99 (s, 1H), 4.21 (dd, J = 12.2, 5.6 Hz, 1H), 4.12 (dd, J = 12.2,
2.2 Hz, 1H), 4.10–4.09 (m, 1H), 3.82 (dt, J = 6.6, 2.1 Hz, 1H), 2.24–2.22 (m, 1H),
2.07 (s, 3H), 2.06 (s, 3H), 1.96–1.90 (m, 1H), 1.70–1.64 (m, 2H), 1.59 (t,
J = 4.5 Hz, 1H), 1.23–1.17 (m, 2H), 0.94–0.82 (s, 3H), 0.81(s, 3H), 0.80 (s, 3H);
13C NMR (125 MHz, CDCl3) d 170.7, 170.2, 128.4, 128.2, 96.1, 85.8, 66.8, 66.7,
64.1, 48.8, 47.7, 46.6, 38.9, 28.2, 28.2, 26.6, 20.9, 20.7, 19.7, 13.6; IR (NaCl neat)
27.2, 25.2, 22.9, 20.9, 20.7; IR (NaCl neat)
m
1743, 1373, 1234, 1036 cmꢂ1; HRMS
(ESI) m/z [M+Na]+ calcd for C18H28O6Na 363.1784, found 363.1771.
34. 3-Phenylprop-2-ynyl 4,6-di-O-acetyl-2,3-dideoxy-
a
-
D
-erythro-hex-2-enopyranoside
(2m): ½a 2D4
ꢁ
+196.0 (c 0.5 CHCl3); 1H NMR (500 MHz, CDCl3) d 7.46–7.42 (m, 2H),
m
1747, 1369, 1230, 1041 cmꢂ1; HRMS (ESI) m/z [M+Na]+ calcd for C20H30O6Na
7.32–7.28 (m, 3H), 5.93 (d, J = 17.5 Hz, 1H), 5.87 (d, J = 17.5 Hz, 1H), 5.33 (s,
2H), 4.53 (s, 2H), 4.26 (dd, J = 12.1, 5.1 Hz, 1H), 4.18 (dd, J = 12.1, 2.4 Hz, 1H),
4.14 (m, 1H), 2.09 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz, CDCl3) d 170.7,
170.2, 131.8, 129.6, 128.6, 128.3, 127.4, 122.3, 92.7, 86.5, 84.3, 67.2, 65.2, 62.8,
389.1940, found 389.1938.
37. (S)-(ꢂ)-b-Citronellol 4,6-di-O-acetyl-2,3-dideoxy-
a-D-erythro-hex-2-enopyranoside
(2p): ½a 2D4
ꢁ
+41.5 (c 0.5 CHCl3); 1H NMR (500 MHz, CDCl3) d 5.86 (d, J = 10.4 Hz,
1H), 5.87 (d, J = 10.4 Hz, 1H), 5.29 (dd, J = 9.6, 1.1 Hz, 1H), 5.08 (t, J = 7.0 Hz,
1H), 5.01 (s, 1H), 4.23 (dd, J = 12.1, 5.4 Hz, 1H), 4.16 (dd, J = 12.1, 2.2 Hz, 1H),
4.10–4.07 (m, 1H), 3.82 (dd, J = 7.4, 2.2 Hz, 1H), 3.55–3.50 (m, 1H), 2.08 (s, 3H),
2.07 (s, 3H), 1.99–1.93 (m, 2H), 1.67–1.65 (m, 4H), 1.59–1.55 (m, 4H), 1.41–
1.30 (m, 2H), 1.17–1.12 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 170.8, 170.3, 131.2, 128.9, 127.9, 124.7, 94.3, 67.0, 66.9, 65.3, 63.1,
55.8, 51.4, 20.9, 20.7; IR (NaCl neat)
(ESI) m/z [M+H]+ calcd for C19H21O6 345.1338, found 345.1339.
35. 2-Naphthyl 4,6-di-O-acetyl-2,3-dideoxy- -erythro-hex-2-enopyranoside (2n):
+151.5 (c 1.0 CHCl3); 1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 7.77 (m,
m
1743, 1371, 1234, 1037 cmꢂ1; HRMS
a-D
½ ꢁ
a 2D4
1H), 7.76–7.66 (m, 2H), 7.48 (m, 1H), 7.46 (m, 1H), 7.10 (t, J = 8.9 Hz, 1H), 6.30
(m, 1H), 5.98 (dt, J = 10.2, 1.6 Hz, 1H), 5.96 (dt, J = 10.2, 1.6 Hz, 1H), 5.66 (ddd,
J = 6.47, 2.83, 1.88 Hz, 1H), 4.36–4.34 (m, 2H), 4.08 (dt, J = 9.2, 3.0 Hz, 1H), 2.14
(s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, CDCl3) d 170.8, 170.1, 154.0, 129.13,
37.2, 36.5, 29.4, 25.7, 25.4, 20.9, 20.8, 19.3, 17.6; IR (NaCl neat)
m 1743, 1371,
1232, 1035 cmꢂ1; HRMS (ESI) m/z [M+Na]+ calcd for C20H32O6Na 391.2097,
found 391.2089.