derivatives protected as silyl ethers and 3,5-O-acetals
(Table 1, 1aÀg, L-1b, andL-1f) by known or slightly modified
experimental procedures (see the Supporting Information).
With these compounds, a series of three-component compe-
tition glycosylations were run to assess the influence of silyl
protecting groups on glycosylation reactivity. In these experi-
ments, both a silylated thioarabinoside (donor A, 1.0 equiv)
and a nonsilylated armed or disarmed thioarabinoside
(donor B, 1.0 equiv) would be mixed in the same reaction
vessel in dry dichloromethane with a model acceptor arabi-
noside 3a13c or 3b14 (0.9 equiv), respectively. Upon addition
of the N-iodosuccinimide (NIS, 1.2 equiv)/trifluoromethane-
sulfonic acid (TfOH, 0.1 equiv) promoter system,15 the two
donors would then compete to couple with the acceptor to
form disaccharide products. The product ratio will reflect the
inherent reactivity of the donors. The results of these compe-
tition glycosylations are summarized in Table 1.
In the first instance, the competitive reaction between
the fully tert-butyldimethylsilyl (TBS) protected donor 1a
and the fully benzylated donor 2a16 with 5-OH acceptor 3a
gave (1f5)-linked disaccharide 4 as a mixture of anomers
(R/β = 1/1) in 85% yield (Table 1, entry 1). No coupling
product between 2a and 3a was detected under these
reaction conditions. More than 50% of the added 2a was
recovered after workup. Next, the glycosylation reaction
of the donors with a mixed protecting group pattern was
examined. Predominant activation of 3,5-di-O-TBS-2-O-Bz
protected 1b over 2a took place, giving 5a as the major
product along with a minor quantity of 5b (entry 2). So,
these results can be attributed to the greater anomeric
reactivity of the per- and disilylated donors 1a,b relative to
that of the per-benzylated armed donor 2a. Subsequently,
when compared with the less armed 2b having 3,5-dibenzyl-
2-Bz substituents, 1b and its 3,5-di-O-tert-butyldiphenylsilyl
(TBDPS) protected analogue 1c could be exclusively acti-
vated to glycosylate with 3a, to afford solely the disaccharides
5a and 5c with complete stereoselectivity in good yield,
respectively (entries 3À4). The mono-TBS masked substrates
1d,e were observed to be more reactive toward glycosylation
with 3a or 3b than the corresponding 3- or 5-O-Bn blocked
counterparts 2c,d (entries 5À6, respectively).
1f was compared with per-benzoylated 2e,13c a 1:1.9 mix-
ture of 8a and 8b18 was obtained (entry 8). Judging from
the results of both reactions, it is clear that the 3,5-silylene
acetal function remarkably decreases the donor reactivity,
rendering 1f even less reactive than the fully disarmed
donor 2e. The deactivation effect of an annulated 3,5-
acetal moiety was further demonstrated by the TIPDS-
protected 1g, which was confirmed to exhibit reactivity
that is between moderately armed (2b) and disarmed (2e)
donors (entries 9À10). The different glycosylation behav-
ior of 1f and 1g is probably due to the different torsional
strains induced by the respective 3,5-O-acetal groups in the
sugar rings. Compared with the TIPDS unit, the more
conformationally rigid DTBS group further limits forma-
tion of the corresponding arabinofuranosyl oxacarbenium
ion, thereby resulting in a decline in reactivity for 1f.
Similar observations were made in the L-arabinose series.
L-1B and L-1f were verified by the competition reactions to
be more and slightly less reactive than the corresponding
armed L-2b and disarmed L-2e (Table 1, entries 11À12).
The above silylated thioglycosyl donors may prove useful
for the synthesis of oligoarabinoses. Of particular promise
should be the 3,5-di-TBS/TBDPS (1b/c) and 3,5-DTBS (1f)
protected thioglycosides because of their exceedingly high
or low reactivity which widens the spectrum of furanosyl
donor reactivity. However, their abilities to ensure stereo-
selective construction of 1,2-trans glycosidic linkages via
neighboring group participation are equally important.
According to Scheme 1, eq 1, the coupling between 1b
and the armed 5-OH thioglycoside 11 proceeded smoothly
to furnish R-linked disaccharide thioglycoside 12 as the
only condensation product in good yield. It could undergo
chemoselective activation in the presence of 2a, reacting
with the hindered 1-adamantanol, to yield the correspond-
ing 1,2-trans glycoside 13 in 89% yield (eq 2).
Scheme 1. Selective Activation of 1b
We further sought to test the reactivity of thioglycosides
1f13c and 1g protected as cyclic 3,5-O-di-tert-butylsilylene
(DTBS) or 3,5-O-tetraisopropyldisiloxanylidene (TIPDS)
acetals. In previous work by Crich et al., a slow activation
for 3,5-acetalated p-tolyl thioglycoside and sulfoxide do-
nors was observed.17 Here, completely selective activation
was still retained in the three-component reaction of 1f, 2a,
and 3a. Only disaccharide 5b (R/β = 3/1), the coupling
product of 2a with 3a, was formed (Table 1, entry 7). When
It is now possible to perform one-pot glycosylations that
were previously not possible by the use of these super-
armed/disarmed glycosyl donors. Two such examples are
outlined in Scheme 2. It is worth pointing out that these
reactions were carried out as a true automated one-pot
glycosylation, as in both cases the three glycosylating
agents and the activating reagents are mixed simulta-
neously, and not added sequentially. Thus, on activation
(14) Wang, Z.-W.; Prudhomme, D. R.; Buck, J. R.; Park, M.; Rizzo,
C. J. J. Org. Chem. 2000, 65, 5969.
(15) NIS/TfOH has been screened as the appropriate activator for
discriminating the reactivity levels of the donor substrates. Other
activator systems, such as NIS, NIS/AgOTf, or DMTST, did not give
results as those of NIS/TfOH.
(16) Hiranuma, S.; Kajimoto, T.; Wong, C.-H. Tetrahedron. Lett.
1994, 35, 5257.
(17) Crich, D.; Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org.
(18) Kawabata, Y.; Kaneko, S.; Kusakabe, I.; Gama, Y. Carbohydr.
Res. 1995, 267, 39.
Chem. 2007, 72, 1553.
Org. Lett., Vol. XX, No. XX, XXXX
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