(2 times the weight of donor)19 in CH2Cl2 in the presence or
absence of SrCO3.20 The representative O-ribosylations using
these conditions are summarized in Table 1. The reactions of
the primary alcohols 2a-e with tri-O-acyl riboside 1a or 1b at
0 °C provided the corresponding ꢀ-glycosides 3a-f exclusively
with greater than 85% yield within 1-5 min (entries 1-6). It
was realized that p-TolSOTf, which colors blue in CH2Cl2, could
be generated even at -78 °C21 and could also activate 1a and
1b at the same temperature without a noticeable decrease in
the reaction rate. Because chemical modifications of the
5-position of 5-deoxy-5-aminoribose in ribosaminouridine an-
tibiotics is important to improve in vitro and in vivo efficacy,
glycosylations of the acceptor 2e with the 5-TIPS-protected
thioribose 1c and 5-azido-5-deoxythioriboside 1d, whose 5-posi-
tions can easily be diversified after glycosylations, were
evaluated. Under the buffered conditions (condition B in Table
1), the azide and silyl groups in the ribosyl donors were intact
(entries 7 and 8). The primary and secondary donor alcohols
(i.e., alkanols, alkynols, and homoallylic alcohols)22 were
ribosylated with the donors 1a-d to furnish the ꢀ-glycosides
in greater than 80% yield; limited examples of the reactions of
the secondary alcohols (i.e., 2f) are shown in Table 1 (entries
19-21).22 However, primary and secondary allylic alcohols (i.e.,
5-phenylpent-1-en-3-ol) were not applicable to these conditions
due probably to their low nucleophilicity. Ribosylations of
propargyl alcohol with the ether-protected thioribosides 1e-g
(entries 9-11) provided a mixture of R/ꢀ glycosides (5-6.6/1)
in 75-90% yield. Thus, a synthetically useful level of R-se-
lectivity in O-ribosylations was observed by using the ether
protecting groups. Glycosylations of propargyl alcohol with the
acetonide protected thioribosides 1h-j (entries 12-14) provided
a 1:1.1 (R/ꢀ) mixture of the corresponding products regardless
of structure of the 5-position of 1h-j. As seen in muraymycins
(Figure 1), an alkylation is observed at the 2-position of the
aminoribose unit. To study the effect of the 3-O-acyl group in
the 2-O-methylated thioglycosides, glycosylations of propargyl
alcohol with 1k-n (entries 15-18) were examined. The 3-O-
acetyl group in 1k-n was effective in reversing the selectivity;
the reactions with 1k or 1l gave a 1:3 mixture of the R- and
ꢀ-ribosides. The 3-O-benzoyl-protected donors 1m or 1n
improved R/ꢀ-selectivity (R/ꢀ ) 1:5.5). These selectivities
observed at 0 °C were not dramatically enhanced by lowering
the reaction temperatures (i.e., -78 °C); the R/ꢀ selectivity was
increased to 1:6.5 for 1m. The glycosylations of 2f, a versatile
intermediate for the generation of ribosaminouridine libraries,
with 1m or 1n gave identical selectivities (R/ꢀ ) 1:5.5) observed
for the primary alcohol. Similarly, the reactions of 2f with the
3-O-acetate, 1k or 1l, provided an anomeric mixture (R/ꢀ )
1:2.5) of the glycosides (Scheme 2). Mechanistically, the ribosyl
carbenium ion generated by p-TolSOTf would first be stabilized
by the formation of an intimate ion pair23 with triflate ion and
undergoes a pseudo-5-membered ring formation when the 2-O-
acyl ribosyl donor is applied. These processes must proceed
prior to the glycosylation step. Although an anchimeric as-
SCHEME 1. Screening of a Promoter for 1 Using the
Immobilized Propargyl Alcohol on the Polymer Resin i
O-ribosylations of primary and secondary alcohols with a wide
variety of p-tolyl thioriboside donors and p-TolSOTf that would
be very useful to synthesize a library of ribosaminouridine
molecules.11
Because thioglycosides (1) can conveniently be synthesized
via acid-catalyzed thioglycosylations of 1-O-acetylglycoside and
(2) exhibit excellent chemical stabilities against acids and bases,
the anomeric thioethers have been widely utilized as a temporary
protecting group of anomeric positions as well as glycosyl
donors.12 However, a choice of promoter requires careful
consideration when using less electrophilic thioglycosides; in
some cases, no activation or very slow reaction rate was
observed using conventional thiophilic reagents.13 In order to
identify an effective thiophilic reagent for O-ribosylations, we
first screened thiophilic reagents using an anomeric mixture (R/ꢀ
) 1:6.6) of p-tolyltribenzoyl thioglycosides 1a and the im-
mobilized propargyl alcohol on the polymer resin i.14 As a result
of extensive reaction screenings, it was found that p-TolSOTf
in situ generated from p-TolSBr15 and AgOTf provided the ꢀ-O-
ribosylated product ii in near-quantitative yield within 15 min
at 0 °C;16 ii was characterized after cleavage from the polymer
resin with 20% TFA. Significantly, even in the presence of a
large excess of the promoters (>10 equiv), all functional groups
(acetal, alkyne, alkene, and BOM protecting group) were intact.
It is worth mentioning that the other conditions tested (i.e., NIS,
NIS/TfOH, NIS/AgOTf, and NIS/AgBF4)17 provided ii in
0-15% yields together with a significant amount of byproduct.18
To investigate how effectively p-TolSOTf can promote
glycosylations of a wide range of p-tolylthioribosides, we
synthesized the donor ribosides 1b-n, and the conditions
developed for an O-ribosylation on the polymer resin (Scheme
1) were applied to primary and secondary alcohols in solution.
All reactions were conducted with donor (2 equiv against
acceptor), p-TolSOTf (1 equiv against donor), and MS (4 Å)
(11) For ther potential glycosylations with ribose derivatives, see: (a) Garcia,
B. A.; Poole, J. A.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119, 7597. (b) Knapp,
S.; Shieh, W.-C. 1991, 32, 3627.
(12) (a) Ekelof, K.; Garegg, P. J.; Olsson, L.; Oscarson, S. Pure Appl. Chem.
1997, 69, 1847. (b) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52,
179.
(13) For an example of the nonsusceptible thioglycoside against NIS/TfOH,
see: Li, K.; Kurosu, M. Heterocycles 2008, 76, 455.
(14) Kurosu, M.; Biswas, K.; Crick, D. C. Org. Lett. 2007, 9, 1141.
(15) p-TolSBr was generated by mixing a 1:1 ratio of (p-TolS)2 and Br2 in
ClCH2CH2Cl, and this was stable over 1 month at rt.
(16) For a discussion of the utility of p-TolSCl/AgOTf for glycosylations
with the thiopyranosides, see: (a) Huang, X.; Huang, L.; Wang, H.; Ye, X-S.
Angew. Chem. Int. Ed 2004, 43, 5221.
(17) Kaeothip, S.; Pornsuriyasak, P.; Demchenko, A. V. Tetrahedron. Lett.
2008, 49, 1542.
(18) We also examined the effect of MeSOTf for this reaction. However,
trace amounts of the desired product were isolated; see: (a) Kurosu, M.; Kitagawa,
I. J. Carbohydr. Chem. 2006, 25, 427. (b) Dasgupta, F.; Garegg, P. J. Carbohydr.
Res. 1988, 177, C13.
(19) MS (4 Å) is not indispensable for these reactions. In order not to obtain
inconsistent results caused by adventitious water, two times the weight of MS
was added in all reactions.
(20) SrCO3 was applied as a buffer of the reactions. Addition of SrCO3 was
effective, especially in the reaction with the silyl group containing donors. 2,6-
Di-tert-butylpyridine was also effective, but the reaction rate was diminished.
(21) There is a short half-life (ca. 5-15 min) for p-TolSOTf at rt.
(22) For other examples of ribosylations with primary and secondary alcohols,
see the Supporting Information.
(23) Winstein, S.; Clippinger, E.; Fainberg, A. H.; Heck, R.; Robinson, G. C.
J. Am. Chem. Soc. 1956, 78, 328.
9768 J. Org. Chem. Vol. 73, No. 24, 2008