Hg(OTf)2-catalyzed glycosylation using alkynoate as the leaving group

Article abstract of DOI:10.1016/j.tetlet.2006.04.114

A novel Hg(OTf)₂-catalyzed glycosylation procedure has developed using alkynoic acid residues as the leaving group under mild reaction conditions and efficient catalytic turnover. The process is particularly useful for the glycosylation of hind

Full text of DOI:10.1016/j.tetlet.2006.04.114

Tetrahedron Letters 47 (2006) 4729–4731
Hg(OTf)2-catalyzed glycosylation using alkynoate
as the leaving group
Hiroshi Imagawa,* Atsushi Kinoshita, Takashi Fukuyama, Hirofumi Yamamoto
and Mugio Nishizawa*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashirocho, Tokushima 770-8514, Japan
Received 4 March 2006; revised 21 April 2006; accepted 25 April 2006
Available online 22 May 2006
Abstract—A novel Hg(OTf)2-catalyzed glycosylation procedure has developed using alkynoic acid residues as the leaving group
under mild reaction conditions and efficient catalytic turnover. The process is particularly useful for the glycosylation of hindered
alcohols.
Ó 2006 Elsevier Ltd. All rights reserved.
X-
Much attention has been focused on development of
+
BnO
BnO
BnO
efficient glycosylation methodologies due to the biologi-
cal significance of a lot of complex oligosaccharides and
glycoconjugates.1 After introduction of the Koenigs–
Knorr method, the classic glycosylation using stoichio-
metric amounts of mercuric salt,2 many modern glyco-
sylation reactions have been developed.3 Lewis acids
have been employed to activate leaving groups such as
glycosyl trichloroacetimidate,4 thioglycoside,5 n-penten-
yl glycoside,6 glycosyl fluoride,7 and glycosyl phos-
phate.8 Recently, Ferrier type catalytic glycosylation
reaction has been developed using glycal as the glycosyl-
ation donor and a variety of metal-salts as catalysts.9
Mukaiyama also developed unique catalytic glycosyl-
ation procedures.10 Most of these glycosylation reactions
involve oxonium cation 2 as the common intermediate,
and generation the of 2 under a milder condition is crit-
ical to achieving efficient glycosylation. Herein, we
describe a novel mercuric triflate [Hg(OTf)2]-catalyzed
glycosylation using alkynoate as the leaving group, a
reaction that is particularly useful for the glycosylation
of hindered alcohols. This procedure is the first example
of a mercuric salt-catalyzed glycosylation reactions at
least to our knowledge, and corresponds to the catalytic
version of pentenyl ether and ester glycosylations
reported by Frase-Reid and Kunz, respectively,6
Scheme 1.
O
BnO
BnO
BnO
BnO
BnO
BnO
O
O
X
OR
BnO
BnO
BnO
HOR
1
2
3
Scheme 1.
Recently, we found that mercury(II) trifluoromethane-
sulfonate (mercuric triflate),11,12 and its tetramethylurea
(hereafter TMU) complex showed highly efficient cata-
lytic activity for hydration of terminal alkynes leading
to methyl ketones,13 hydroxylative 1,6-enyne cyclization
to give exo-methylene five-membered ring products,14
arylalkyne cyclization leading to dihydronaphthalenes,15
cyclization of 1-alkyn-5-one leading to 2-methylfur-
anes,16 and aryl-ene-yne cyclization affording poly-
carbocycles.17 We also disclosed
x-alkynoic acids 4 with catalytic amount of Hg(OTf)2Æ
3TMU to afford d-methylene-d-lactones 5 in quantita-
tive yield18 (Scheme 2).
a
reaction of
Hg(OTf)2•3TMU
(1 mol%)
HO
O
O
O
CH3CN, rt
99%
4
5
BnO
BnO
BnO
O
O
O
BnO
6
*
Corresponding authors. Tel.: +81 8862 29611; fax: +81 8865
53051; e-mail: mugi@ph.bunri-u.ac.jp
Scheme 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.114

4730
H. Imagawa et al. / Tetrahedron Letters 47 (2006) 4729–4731
Table 1. Hg(OTf)2 catalyzed glycosylation
HOTf
BnO
BnO
BnO
O
O
O
Entry ROH Additive Time Glycoside Yielda (a/b)b
O
O
Hg(OTf)2
HgOTf
(min)
BnO
7
9
1
2
3
4
5
6
11
12
13
11
12
13
None
None
None
TMUc
TMUc
TMUc
30
30
30
240
240
240
14
15
16
14
15
16
70
85
91
94
90
89
(24:76)
(25:75)
(31:69)
(25:75)
(26:74)
(31:69)
OTf-
H
+
+
O
BnO
BnO
BnO
O
O
HgOTf
OTf-
+ Hg(OTf)2
5
BnO
10
8
HOR
a Isolated yield.
b Determined by HPLC.
c TMU (15 mol %) was employed.
3
Scheme 3.
ated during the reaction of 6 and 11, resulted from the
acid-catalyzed condensation of lactone 5 and alcohol
11. Thus, the yield of 14 was reduced to 70%. Hindered
sec-and tert-alcohols did not induce the side reaction.
When Hg(OTf)2Æ3TMU was employed as the catalyst,
the yield of the reaction from 11 to give 14 was dramat-
ically improved to 94%, though longer reaction period
was required. Alcohols 12 and 13 were also converted
to 15 and 16 by the reaction with Hg(OTf)2Æ3TMU,
respectively, in reasonable yields (entries 4–6).
The result led us to generate oxonium cation 2 in a cat-
alytic manner, and we designed novel glycosyl donor
molecule 6 that has an alkynoate as the leaving group.
The proposed reaction mechanism is shown in Scheme
3. A p complexation of Hg(OTf)2 with alkyne as shown
in 7 should generate oxonium cation 8 as well as vinyl-
mercuric lactone 9. Cation 8 will be attacked by
ROH leading to glycoside 3 and TfOH, and the latter
protonates 9 generating alternative oxonium cation 10.
Subsequent demercuration provides lactone 5 and
meanwhile regenerates the catalyst Hg(OTf)2.
Next, we examined glycosylations of donors 4-pentyno-
ate 18 and 2,2-dimethyl-4-pentynoate 19 with 11 using
5 mol % of Hg(OTf)2Æ3TMU in CH3CN at room tem-
perature for 4 h. Since an insignificant difference was ob-
served between these esters 94% yield (a/b 24:76) from
18 and 99% yield (a/b 24:76) from 19, we decided to
use commercially available 5-hexynoic acid residue as
the leaving group for further reactions. The solvent
and temperature effects were investigated for the reac-
tion of 6 with tert-butyl alcohol 13 (Table 2). As seen
in entry 3 of Table 1, the reaction in CH3CN afforded
glycoside 16 in 91% yield in a/b 31:69.19 The reaction
in CH3NO2 and CH2Cl2 afforded 16 in almost 1:1 mix-
ture of stereoisomers in lower yields (Table 2, entries 1
and 2), but the reaction in diethyl ether and toluene
afforded the a-isomer predominantly (entries 3 and 4).
A reaction at lower temperature (0 °C) in CH3CN re-
sulted increased b-stereoselectivity a/b 22:78 (entry 5)
in 90% yield after 4 h.
Therefore, we examined the reaction of glycosylation
donor 6 with alcohols 11, 12 and 13 by using 5 mol %
of Hg(OTf)2 in CH3CN at room temperature (Scheme
4). The glycosylation of primary alcohol 11 resulted in
the lowest yield affording 14 in 70% yield, while the gly-
cosylation of sec-alcohol 12 and tert-alcohol 13 pro-
duced 15 and 16 in 85% and 91% yields, respectively,
as seen in Table 1 (entries 1–3). By-product 17, gener-
ROH
BnO
O
BnO
BnO
Hg(OTf)2
(5 mol%)
O
O
BnO
14-16
CH3CN, rt
6
(1.2 eq) (α/β 43:57)
HO
HO
O
We then investigated further glycosylation of a variety
of hindered alcohols with 6 (Scheme 5). The reaction
of less reactive sec-alcohols such as menthol, (À)-bor-
neol and methyl 2,3,6-O-benzyl-a-D-galactopyranoside
at 0 °C for 4 h in CH3CN afforded the corresponding
glycosides 20, 21, and 22, respectively, in good yield.
HO
11
12
13
BnO
BnO
BnO
BnO
O
BnO
O
BnO
O
BnO
BnO
14
15
BnO
O
O
O
BnO
Table 2. Hg(OTf)2-catalyzed glycosylation of 13 with 6 leading 16
O
BnO
O
BnO
Entry Temperature Solvent
Time Yielda (a/b)b
(min)
16
17
1
2
3
4
5
rt
rt
rt
rt
CH3NO2
CH3Cl2
Diethylether
Toluene
30
15
30
30
240
74
81
68
52
90
(49:51)
(60:40)
(74:26)
(70:30)
(22:78)
BnO
BnO
BnO
BnO
O
O
BnO
O
O
O
O
BnO
BnO
BnO
18
19
0 °C
CH3CN
(α/β 24:76)
(α/β 24:76)
a Isolated yield.
b Determined by HPLC.
Scheme 4.

H. Imagawa et al. / Tetrahedron Letters 47 (2006) 4729–4731
4731
825; (b) Kunz, H.; Werning, P.; Schultz, M. Synlett 1990,
631–632.
7. (a) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett.
1981, 431–432; (b) Nicolaou, K. C.; Dolle, R. E.;
Papahatjis, D. P.; Randall, J. L. J. Am. Chem. Soc.
1984, 106, 4189–4192; (c) Hashimoto, S.; Hayashi, M.;
Noyori, R. Tetrahedron Lett. 1984, 25, 1379–1382; (d)
Suzuki, K.; Maeta, H.; Matsumoto, T.; Tsuchihashi, G.
Tetrahedron Lett. 1988, 29, 3571–3574.
BnO
BnO
BnO
O
O
BnO
O
BnO
O
BnO
BnO
BnO
20
21
87% (α/β 18:82)
72% (α/β 23:77)
BnO
8. Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc.
Chem. Commun. 1989, 685–687.
O
O
BnO
OBn
O
BnO
BnO
BnO
9. (a) Babu, B. S.; Balasubramanian, K. K. Tetrahedron Lett.
2000, 41, 1271–1274; (b) Rafiee, E.; Tangestaninejad, S.;
Habibi, M. H.; Mirkhani, V. Bioorg. Med. Chem. Lett.
2004, 14, 3611–3614; (c) Babu, R. S.; Zhou, M.; O’Doh-
erty, G. A. J. Am. Chem. Soc. 2004, 126, 3428–3429; (d)
Kim, H.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126,
1336–1337; (e) Hotha, S.; Tripathi, A. Tetrahedron Lett.
2005, 46, 4555–4558; (f) Lin, H. C.; Du, W. P.; Chang, C.
C.; Lin, C. H. Tetrahedron Lett. 2005, 46, 5071–5076.
10. (a) Takeuchi, K.; Higuchi, S.; Mukaiyama, T. Chem. Lett.
1997, 969–970; (b) Mukaiyama, T.; Wakiyama, Y.;
Miyazaki, K.; Takeuchi, K. Chem. Lett. 1999, 933–934;
(c) Takeuchi, K.; Tamura, T.; Mukaiyama, T. Chem. Lett.
2000, 29, 122–123; (d) Takeuchi, K.; Tamura, T.; Mukai-
yama, T. Chem. Lett. 2000, 29, 124–125; (e) Jona, H.;
Takeuchi, K.; Mukaiyama, T. Chem. Lett. 2000, 29, 1278–
1279; (f) Jona, H.; Maeshima, H.; Mukaiyama, T. Chem.
Lett. 2001, 30, 726–727; (g) Mukaiyama, T.; Chiba, H.;
Funasaka, S. Chem. Lett. 2002, 32, 392–393; (h) Hashi-
hayata, T.; Mandai, H.; Mukaiyama, T. Bull, Chem. Soc.
Jpn. 2004, 77, 169–178; (i) Pongdee, R.; Wu, B.; Sulikow-
ski, G. A. Org. Lett. 2001, 3, 3523–3525; (j) McDonald, F.
E.; Wu, M. Org. Lett. 2002, 4, 3979–3981; (k) Colinas, P.
A.; Lieberknecht, A.; Bravo, R. D. Tetrahedron Lett. 2002,
43, 9065–9068; (l) Suzuki, T.; Watanabe, S.; Yamada, T.;
Hiroi, K. Tetrahedron Lett. 2003, 44, 2561–2563.
11. Nishizawa, M.; Morikuni, E.; Asoh, K.; Kan, Y.; Ueno-
yama, K.; Imagawa, H. Synlett 1995, 169–170.
BnO
O
O
O
BnO
BnO
BnO
BnO
22
23
OMe
80% (α/β 24:76)
88% (α/β 40:60)
BnO
BnO
O
O
BnO
BnO
24
90% (α/β 18:82)
Scheme 5.
Reaction of even more sterically hindered tert-alcohols
such as (1s,2s,5s)-(À)-2-hydroxy-3-pinanone and 1-ada-
mantanol at 0 °C for 4 h provided 23 and 24, respec-
tively, in excellent yields.19
Acknowledgement
This study was financially supported by a Grant-in-
Aid from the Ministry of Education, Culture, Sports,
Science and Technology of the Japanese Government.
Supplementary data
12. Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y.
Tetrahedron Lett. 1983, 24, 2581–2584.
13. Nishizawa, M.; Skwarczynski, M.; Imagawa, H.; Sugi-
hara, T. Chem. Lett. 2002, 12–13.
14. Nishizawa, M.; Yadav, V. K.; Skwarczynski, M.; Takao,
H.; Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609–
1611.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.04.114.
References and notes
15. Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett.
2004, 6, 3679–3681.
16. Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.;
Sugihara, T. Org. Lett. 2003, 5, 4563–4565.
17. (a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett 2005,
703–705; (b) Imagawa, H.; Iyenaga, T.; Nishizawa, M.
Org. Lett. 2005, 7, 451–452.
18. Imagawa, H.; Fujikawa, Y.; Tsuchihiro, A.; Kinoshita, A.;
Yoshinaga, T.; Takao, H.; Nishizawa, M. Synlett 2006,
639–640.
1. (a) Esko, J.; Freeze, H.; Hart, G.; Marth, J. Essentials of
Glycobiology; Cold Spring Harbor: New York, 1999; (b)
Dwek, R. A.; Butters, T. A. Chem. Rev. 2002, 102, 283–
284.
2. Koening, W.; Knorr, E. Ber. 1901, 34, 957.
3. (a) Demchenko, A. V. Synlett 2003, 1225–1240; (b)
Pellissier, H. Tetrahedron 2005, 61, 2947–2993; (c) Nico-
laou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001,
40, 1576–1624; (d) Davis, B. G. J. Chem. Soc., Perkin
Trans. 1 2000, 2137–2160; (e) Preperative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997; Reviews for recent glycosylation see: (f) Boons, G. J.
Tetrahedron 1996, 52, 1095–1121; (g) Toshima, K.; Tats-
uta, K. Chem. Rev. 1993, 93, 1503–1531.
4. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25,
212–235.
5. Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am.
Chem. Soc. 1983, 105, 2430–2434.
6. (a) Fraser-Reid, B.; Konradsson, P.; Mootoo, D.;
Udodong, U. J. Chem. Soc. Chem. Commun. 1988, 823–
19. Typical experimental procedure is as follows: a solution of
1-adamantanol (22.3 mg, 0.146 mmol) and glycoside 6
(110 mg, 0.173 mmol) in CH3CN (2.9 mL) was azeotropi-
˚
cally dried through molecular sieves 4 A using a dropping
funnel. To this was added 0.1 M CH3CN solution of
Hg(OTf)2 (72 lL, 0.0072 mmol) at 0 °C. After stirring for
4 h at the same temperature, Et3N (1 mL), and then
aqueous NaHCO3 solution were added, and the mixture
was extracted with ether. The dried and concentrated
organic material was subjected to column chromatogra-
phy on ODS (CH3CN/H2O 10:1/100:1) to give 24 (a/b
18:82, 88.9 mg, 90% yield).