J. Am. Chem. Soc. 2001, 123, 3379-3380
3379
Glycosyl Sulfonylcarbamates: New Glycosyl Donors
with Tunable Reactivity
Ronald J. Hinklin† and Laura L. Kiessling*,†,‡
Figure 1. Proposed formation of oxonium ion upon addition of an
electrophile.
Departments of Chemistry and Biochemistry
UniVersity of Wisconsin-Madison, Madison, Wisconsin 53706
ReceiVed October 26, 2000
The advent of the Koenigs-Knorr method of glycosylation
enabled the chemical synthesis of oligosaccharides.1 Since that
advance, the differences in regiochemistry and stereochemistry
of glycosyl linkages and variations in the stereoelectronic proper-
ties of glycosyl donors and acceptors have impelled the search
for milder and more selective procedures.2 Successes in this
pursuit have expanded the variety of complex, saccharide-
containing natural products accessible through chemical synthesis.
The method of choice for a given donor-acceptor pair, however,
depends on a number of variables. One such parameter is the
nature of the anomeric leaving group. A divergent synthetic
strategy to generate various glycosyl donors from a single
intermediate would facilitate the construction of different glyco-
sidic linkages. In search of such a donor, we explored the
glycosylation reactions of glycosyl sulfonylcarbamates.
Figure 2. General scheme for the synthesis and postsynthetic reaction
tuning of glycosyl sulfonylcarbamate donors.
We hypothesized that glycosyl sulfonylcarbamates could serve
as glycosyl donors with a unique feature: the reactivity of these
donors could be tuned by postsynthetic modification. Allyl3 and
phenyl4 glycosylcarbamates have previously been shown to act
as glycosyl donors. Likewise, we envisioned that treatment of
glycosyl sulfonylcarbamates with an electrophilic promoter would
result in a loss of CO2 and sulfonamide with production of a
reactive glycosyl donor (Figure 1).
Figure 3. Donors synthesized to investigate the glycosylation reactions
of glycosyl sulfonylcarbamates.
A unique feature of the sulfonylcarbamate group is that it can
be selectively altered by N-alkylation. We postulated that donors
of differing reactivity could be generated through alteration of
the characteristics of the resulting N-alkyl group.5 This approach
offers significant advantages over the current methods of reaction
tuning, which involve the independent syntheses of differently
functionalized glycosyl donors of varying reactivities.6
Figure 4. Acceptors used to determine the substrate specificity.
Glycosyl sulfonylcarbamates are readily synthesized from the
reaction of a sulfonyl isocyanate with the anomeric hydroxyl
group of a protected saccharide (Figure 2). The putative glycosyl
donors are formed in quantitative yield as a mixture of R and â
isomers. The resulting compounds can be purified by silica gel
chromatography, and are extremely stable; no decomposition is
observed for samples stored at room temperature for three months.
Although the two anomers can be separated, methods for
generating the R- or â-isomer preferentially were developed. The
â-anomer can be prepared by treatment of the starting material
with excess 1,4-diazabicyclo[2.2.2]octane (DABCO) in toluene
followed by addition of p-toluenesulfonyl isocyanate (TsNCO).
The resulting glycosyl p-toluenesulfonylcarbamate is obtained in
high selectivity (1:13 R: â ratio).4 When DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) is used as a base, the R-isomer is favored
(5:1 R: â). Since the â-isomer can be produced most efficiently,
it was used to explore the feasibility and scope of the proposed
glycosylation reaction.
Compound 1 was tested as a glycosyl donor (Figure 3). We
reasoned that 1 could be activated with Lewis acids to promote
glycosylation. The most effective promoter was found to be
trimethylsilyl triflate (TMSOTf). Treatment of 1 with TMSOTf
results in the production of a silylated intermediate; presumably
the trifluoromethanesulfonic acid that is generated activates this
intermediate for glycosylation. Using these conditions, a variety
of primary and secondary alcohols (Figure 4) were glycosylated
in high yields, including hindered hydroxyl groups (Table 1,
entries 8 and 9). As with typical glycosyl donors, however, the
yields of some reactions were lower. For example, phenols were
especially poor acceptors for glycosylation (entry 10). To optimize
the donor reactivity for less nucleophilic acceptors, donors with
alternative anomeric leaving groups were generated in a single
step.
The anomeric substituents that were employed vary in their
ability to serve as a leaving group. Because of the low pKa of the
sulfonylcarbamate group, we anticipated that N-alkylation of 1
could produce a variety of different donors.7 Backes et al.
demonstrated in reactions of related acylsulfonamides that the
electronic properties of an N-alkyl substituent could perturb the
ability of the sulfonamide to serve as a leaving group.5 Given
† Department of Chemistry.
‡ Department of Biochemistry
(1) Koenigs, W.; Knorr, E. Chem. Ber. 1901, 34, 957.
(2) For recent reviews, see: (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993,
93, 1503-1531. (b) Boons, G. J. Tetrahedron 1996, 52, 1095-1121. (c)
Whitfield, D. M.; Douglas, S. P. Glycoconjugate J. 1996, 13, 5-17. (d)
Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205. (e) Davis,
B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137-2160. (f) Seeberger, P. H.;
Haase, W. Chem. ReV. 2000, 100, 4349-4394.
(3) Kunz, H.; Zimmer, J. Tetrahedron Lett. 1993, 34, 2907-2910.
(4) Prata, C.; Mora, N.; Lacombe, J. M.; Maurizis, J. C.; Pucci, B.
Tetrahedron Lett. 1997, 38, 8859-8862.
(5) Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1996,
118, 3055-3056.
10.1021/ja005735i CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/20/2001
Hinklin
