Selenoethers are essentially chemically inert toward a
broad range of reagents, such as hard Lewis acids, alkylating
agents, strong bases, nucleophiles, and reductive conditions,
but they react readily with soft Lewis acids, radicals and
peroxides.3 Thus, the selenoether linkage is compatible with
a wide range of reagents and protective group protocols
commonly used in oligosaccharide synthesis. The present
paper describes the preparation of a fluorine-labeled selenium-
based linker (compound 5, Scheme 1) and its use in solid-
phase synthesis of n-pentenyl glycosides and analysis of
resin-bound intermediates with gel-phase 19F NMR spec-
troscopy. In recent years, gel-phase 19F NMR spectroscopy
has been established as a simple, effective, and nondestruc-
tive method for gaining both quantitative and qualitative
information on reaction steps performed on solid phase.8
Synthesis of linker 5 started with lithiation of compound
1, followed by addition of elemental selenium to access the
corresponding selenide anion. This was used directly to
substitute iodo-alkyl derivative 26 to afford the selenoether
3 in excellent yield (97%) in a one-pot reaction (Scheme 1).
The phenol functionality of 3 was then alkylated with ethyl
bromoacetate using potassium carbonate as a base in the
presence of tetrabutylammonium iodide, which gave com-
pound 4 in 97% yield. Saponification of 4 with aqueous
LiOH provided the desired linker building block 5 in 94%
overall yield starting from 1. The carboxy functionality of 5
was subsequently attached to amino-functionalized ArgoGel
resin using standard peptide coupling conditions to give resin
6. Since the commercial resin also had some hydroxy
functionalities, the resin was capped with acetic anhydride
after completing the amide bond formation. Subsequent
Scheme 1. Synthesis of Selenide Linker Resin 7
cleavage of the silyl protective group with TBAF gave the
hydroxy-functionalized resin 7. To establish conditions for
glycosylations it was decided to investigate the glycosylation
of selenide linker 7 with three powerful and commonly
employed types of glycosyl donors that are activated by hard
Lewis acids: glycosyl trichloroacetimidates, glycosyl fluo-
rides and glycosyl sulfoxides (Scheme 2).9 The glycosyl
(4) (a) Mitchels, R.; Kato, M.; Heitz, W. Makromol. Chem. 1976, 177,
2311-2320. (b) Fujita, K.; Watanabe, K.; Oishi, A.; Ikeda, Y.; Taguchi,
Y. Synlett 1999, 1760-1762. (c) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao,
G.-Q.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1, 807-810. (d) Nicolaou, K.
C.; Fylaktakidou, K. C.; Mitchell, H. J.; van Delft, F. L.; Rodr´ıguez, R.
M.; Conley, S. R.; Jin, Z. Chem. Eur. J. 2000, 6, 3166-3185. (e) Nicolaou,
K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem., Int. Ed. 2000, 39,
734-739. (f) Nicolaou, K. C.; Cao, G.-Q.; Pfefferkorn, J. A. Angew. Chem.,
Int. Ed. 2000, 39, 739-743. (g) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker,
A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939-9953. (h) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.;
Roecker, A. J.; Barluenga, S.; Cao, G.-Q.; Affleck, R. L.; Lillig, J. E. J.
Am. Chem. Soc. 2000, 122, 9954-9967. (i) Nicolaou, K. C.; Pfefferkorn,
J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. J. Am.
Chem. Soc. 2000, 122, 9968-9976. (j) Horikawa, E.; Kodaka, M.;
Nakamura, Y.; Okuno, H.; Nakamura, K. Tetrahedron Lett. 2001, 42, 8337-
8339. (k) Qian, H.; Huang, X. Synlett 2001, 1913-1916. (l) Uehlin, L.;
Wirth, T. Org. Lett. 2001, 3, 2931-2933. (m) Huang, X.; Xu, W.
Tetrahedron Lett. 2002, 43, 5495-5497. (n) Fujita, K.; Hashimoto, S.; Oishi,
A.; Taguchi, Y. Tetrahedron Lett. 2003, 44, 3793-3795. (o) Huang, X.;
Sheng, S.-R. J. Comb. Chem. 2003, 5, 273-277. (p) Huang, X.; Xu, W.-
M. Org. Lett. 2003, 5, 4649-4652. (q) Nakamura, K.; Ohnishi, Y.;
Horikawa, E.; Konakahara, T.; Kodaka, M.; Okuno, H. Tetrahedron Lett.
2003, 44, 5445-5448. (r) Nicolaou, K. C.; Roecker, A. J.; Hughes, R.;
van Summeren, R.; Pfefferkorn, J. A.; Winssinger, N. Bioorg. Med. Chem.
2003, 11. (s) Sheng, S.-R.; Wang, X. C.; Liu, X. L.; Song, C. S. Synth.
Commun. 2003, 33, 2867-2872. (t) Sheng, S.-R.; Zhou, W.; Liu, X. L.;
Song, C. S. Synth. Commun. 2004, 34, 1011-1016.
Scheme 2. Synthesis of Galactosyl Donors 10-12
(5) (a) Nicolaou, K. C.; Mitchell, H. J.; Fylaktakidou, K. C.; Suzuki,
H.; Rodr´ıguez, R. M. Angew. Chem., Int. Ed. 2000, 39, 1089-1093. (b)
Nicolaou, K. C.; Winssinger, N.; Hughes, R.; Smethurst, C.; Cho, S. Y.
Angew. Chem., Int. Ed. 2000, 39, 1084-1088. (c) Russell, H. E.; Luke, R.
W. A.; Bradley, M. Tetrahedron Lett. 2000, 41, 5287-5290.
donors were prepared from the previously described thio-
galactoside donor 8,10a which is protected with fluorine-
labeled protective groups to allow analysis with gel-phase
19F NMR spectroscopy.8,10a-c Hydrolysis of the thiocresyl
(6) Nicolaou, K. C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem.
Commun. 1998, 1947-1948.
(7) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1974, 40, 947-949.
(8) Mogemark, M.; Gårdmo, F.; Tengel, T.; Kihlberg, J.; Elofsson, M.
Org. Biomol. Chem. 2004, 2, 1770-1776 and references therein.
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Org. Lett., Vol. 6, No. 26, 2004