J. Am. Chem. Soc. 1996, 118, 247-248
247
Stereoselective Synthesis of â-Mannopyranosides via
the Temporary Silicon Connection Method
Gilbert Stork* and James J. La Clair†
Department of Chemistry, Columbia UniVersity
Figure 1. Core pentasaccharide of N-linked glycoproteins.
New York, New York 10027
ReceiVed September 18, 1995
Increasing interest in the synthesis of biologically significant
carbohydrate glycosides and conjugates has led to the develop-
ment of ever more selective methods for the control of
stereochemistry at the anomeric center. The stereospecific
formation of â-mannopyranosides has proved particularly
difficult to achieve, however, in spite of considerable effort,
because the vicinal cis (axial) â-hydroxyl group blocks access
to the â-face.1 The presence of the â-mannopyranoside entity,
inter alia, in the core region of N-linked glycoproteins (cf. Figure
1) warrants significant attention toward its construction.
A general solution to this type of problem was introduced in
1983, with the demonstration that a carbon substituent could
be introduced, regio- and stereospecifically, in many ring
systems by using the temporary attachment of the desired
substituent to a stereochemistry-controlling hydroxyl within the
ring system.2 Internal transfer of the substituent by cyclization
cis to the controlling hydroxyl then allowed completion of the
process by removal of the temporary connector. Possible
choices for the latter are limited. We made use of a temporary
acetal link in a prostaglandin synthesis3 and a temporary silyl
ether connection in a method for the controlled introduction of
methyl groups.4 In these particular examples, the tethered
entities were cyclized by free-radical processes.
Figure 2.
So far as the synthesis of typical â-mannopyranosides, the
first applications of the temporary tethering concept were carried
out, independently, by Hindsgaul7 and us,8 using respectively
mixed acetals and silyl ether connectors. More recently, Ito
and Ogawa demonstrated the efficient use of p-methoxyben-
zylidene acetals.9
We now report our further exploration of the temporary silyl
ether route to â-mannopyranosides. As we had done previously,
we used the sulfoxide departing group method of Kahne10 to
attempt the formation of a variety of â-mannopyranoside-linked
disaccharides. In our initial sequence, we performed the
required thiophenyl to phenyl sulfoxide oxidation after initial
formation of the mixed silaketal. This was satisfactory when
â-mannoside formation involved connection of the second sugar
via its primary alcohol, but we found it, in general, much more
efficient to use the preformed mannose sulfoxide 3,11 because
we discovered that the mixed silaketals 4 could be produced
simply by the interaction of an equimolar mixture of the
mannose sulfoxide 3 and the sugar to be tethered with 1 equiv
of dimethyldichlorosilane, thus avoiding isolation of the sensitive
chlorodimethylsilyl ether intermediate (Scheme 1).12
In the carbohydrate area, the temporary connection method
was first applied in the acetal version to the stereospecific
synthesis of C-glycosides.5 We, in turn, explored the temporary
silyl ether version for the same purpose6 and found it especially
significant that the approach was successful even for the
synthesis of a â-C-mannopyranoside, thus obtained free from
its R-isomer (cf. 1 f 2, Figure 2).
Activation of the tethered species 4 was then carried out with
triflic anhydride in the presence of 2,6-di-tert-butylpyridine,
keeping the temperature at -100 °C during addition of the
anhydride to ensure complete stereoselectivity. Upon warming
these solutions to room temperature, the tethered species from
glucose derivatives 5,6 6,13 and 714 produced the desired
disaccharides 11, 12, and 13, free from their R-mannoside
anomers,15 in 92, 65, and 82% yields, respectively.16
† Current address: Department of Molecular Biology, The Scripps
Research Institute, La Jolla, CA 92037.
These results were encouraging, because they showed that
the temporary silicon connection was able to give the desired
(1) For a survey of the chemical synthesis of â-mannopyranosides, see:
(a) Gorin, P. A. J.; Perlin, A. S. Can. J. Chem. 1969, 39, 2474. (b) Betaneli,
V. I.; Ovchinnikov, M. V.; Backinowsky, L. V.; Kochetkov, N. K.
Carbohydr. Res. 1980, 84, 211, 225. (c) Paulsen, H.; Kutschker, W.;
Lockhoff, O. Chem. Ber. 1981, 114, 3102, 3233. (d) Srivastava, V. K.;
Schuerch, C. J. Org. Chem. 1981, 46, 1121. (e) Garegg, P. J.; Ossowski,
P. Acta Chem. Scand. 1983, B37, 229. (f) Rathmore, H.; From, A. H. L.;
Ahmed, K.; Fullerton, D. S. J. Med. Chem. 1986, 29, 1945. (g) Gunther,
W.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1990, 29, 1050. (h) Yamazaki,
N.; Eichenberger, E.; Curran, D. P. Tetrahedron Lett. 1994, 35, 6623. (i)
Brunckova, J.; Crich, D.; Yao, Q. Tetrahedron Lett. 1994, 35, 6619. (j)
Liu, K. C.; Danishefsky, S. J. J. Org. Chem. 1994, 59, 1892. (k)
Lichtenthaler, F. W.; Schneider Adams, Th.; Immel, S. J. Org. Chem. 1994,
59, 6735.
(7) (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 112, 9376.
(b) Barresi, F.; Hindsgaul, O. Synlett 1992, 795. (c) Barresi, F.; Hindsgaul,
O. Can. J. Chem. 1994, 72, 1447.
(8) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087. See also:
(a) Bols, M. Tetrahedron 1993, 49, 10049. (b) Bols, M. Acta Chem. Scand.
1993, 47, 829.
(9) (a) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765.
(b) Dan, A.; Ito, Y.; Ogawa, T. J. Org. Chem. 1995, 60, 4680.
(10) (a) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem.
Soc. 1989, 111, 6881. (b) Hamilton-Andreotti, A.; Kahne, D. J. Am. Chem.
Soc. 1993, 115, 3352. (c) Ragahvan, S.; Kahne, D. J. Am. Chem. Soc.
1993, 115, 1580. (d) Yan, L.; Taylor, C. M.; Kahne, D. J. Am. Chem. Soc.
1994, 116, 6853.
(11) Only one sulfoxide diastereomer was produced (in 89% yield) by
oxidation of the corresponding sulfide with m-CPBA. See ref 7 for the
synthesis of the sulfide precursor to 3.
(12) For example, a mixture of 1 equiv of imidazole, 0.5 equiv each of
DMAP, mannose sulfoxide 3, and â-methyl glucoside 6 (THF at -78 °C),
treated with 0.5 equiv of dichlorodimethylsilane, gave 84% of the
corresponding tethered species (cf. 4). Addition of 2 equiv of triflic
anhydride to the above in ether-methylene chloride (-100 °C) then gave
12 (65%, after flash chromatography). See supporting information for more
details. The success of this procedure derives from the slower silylation
of the 2-hydroxyl derivative of mannose sulfoxide 3 than of the free hydroxyl
of the glucose derivative in the cases we have examined. The exact reason
is not firmly established.
(2) Stork, G.; Mook, R., Jr.; Biller, S. A.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1983, 105, 3741.
(3) Stork, G.; Sher, P. M.; Chen, H. L. J. Am. Chem. Soc. 1986, 108,
6384.
(4) Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986, 108, 6826.
(5) (a) De Mesmaeker, A.; Hoffmann, P.; Ernst, B.; Hug, P.; Winkler,
T. Tetrahedron Lett. 1988, 29, 6585. (b) De Mesmaeker, A.; Hoffmann,
P.; Ernst, B. Tetrahedron Lett. 1989, 30, 57. (c) De Mesmaeker, A.;
Hoffmann, P.; Ernst, B.; Hug, P.; Winkler, T. Tetrahedron Lett. 1989, 30,
6307. (d) De Mesmaeker, A.; Hoffmann, P.; Winkler, T.; Waldner, A.
Synlett 1990, 201. (e) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.;
Mindt, T.; Hug, P.; Winkler, T. Synlett 1990, 687. (f) De Mesmaeker, A.;
Waldner, A.; Hoffmann, P.; Hug, P.; Winkler, T. Synlett 1992, 285. (g)
De Mesmaeker, A.; Waldner, A.; Hoffmann, P.; Winkler, T. Synlett 1994,
330.
(6) Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991, 113, 7054.
See also: (a) Myers, A. G.; Gin, D. Y.; Widdowson, K. L. J. Am. Chem.
Soc. 1991, 113, 9661. (b) Xin, Y. C.; Mallet, J.-M.; Sinay¨, P. J. Chem.
Soc., Chem. Commun. 1993, 864. (c) Chenede, A.; Perry, E.; Rekai, E.
D.; Sinay¨, P. Synlett 1994, 420.
(13) Methyl glucoside 6 was prepared from 3,4,6-tribenzylglucal using
the method of: Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661.
(14) Koto, S.; Morishima, R.; Kawahara, K.; Ishikawa, K.; Zen, S. Bull.
Chem. Soc. Jpn. 1982, 55, 631.
0002-7863/96/1518-0247$12.00/0 © 1996 American Chemical Society