Scheme 1. General Glycosylation Mechanism
Figure 1. Thioglycosides Employed.
-60 °C with the combination of 1-benzenesulfinyl piperidine
(BSP, Figure 2)1b and trifluoromethanesulfonic anhydride,
In stark contrast the corresponding 4,6-O-benzylidene
glucosyl donors are R-selective.10 With the help of a series
of 2- or 3-deoxy and the corresponding deoxy fluoro gluco
and mannosyl donors, we have rationalized the glucose/
mannose stereoselectivity shift on the basis of the differing
O2-C2-C3-O3 torsional interactions as the covalent
triflates collapse to the ion pairs.11 In mannose, this torsion
angle is compressed as the oxacarbenium ion is formed,
whereas in glucose it is relaxed. Effectively, the formation
of the glucosyl oxacarbenium ion is less endothermic than
that of its mannosyl counterpart leading to a higher concen-
tration of ion pairs in glucose than in mannose.12
Figure 2. Coupling Reagents.
in the presence of the hindered base 2,4,6-tri-tert-butylpy-
rimidine (TTBP, Figure 2),16 to the corresponding glycosyl
triflates. The nucleophile was then added and the reaction
mixture was stirred for a further 2 h at -60 °C, before it
was quenched at that temperature, leading to the results
presented in Table 1.
A potential alternative explanation for the change in
selectivity between the glucose and mannose series invokes
hydrogen bonding between the OH group of the incoming
nucleophilic alcohol and O2 of the donor as the major
influence on reaction stereoselectivity, at least for the case
of the benzylidene acetal protected donors.13,14 As we now
describe, to address this issue we have investigated the
reaction of glucosyl and mannosyl triflates with C-nucleo-
philes, for which the possibility of hydrogen bonding does
not exist.
It is immediately apparent from the results presented in
Table 1 that the carbon nucleophiles follow the well-
established pattern of the alcohols, with the 4,6-O-ben-
zylidene protected mannosyl donors being ꢀ-selective, their
gluco counterparts R-selective, and the tetrabenzyl mannosyl
donor relatively unselective, ergo, there is no requirement
for hydrogen bonding to direct these systems.
Comparison of Table 1, entries 1 and 2 reveals that, not
unexpectedly, the more reactive allylstannane gives better
ꢀ-selectivity than the allylsilane in reactions with the
benzylidene protected mannosyl triflate. In the gluco-series
(Table 1, entries 7 and 8) complete R-selectivity is observed
regardless of the nature of the allylmetal employed. With
the trimethylsilyl enolethers as nucleophiles excellent ꢀ-
selectivity was again observed for the formation of ben-
zylidene protected mannosyl C-glycosides (Table 1, entries,
3,4, and 5), whereas the opposite selectivity was observed
for glucose (Table 1, entry 9). Interestingly, with the
pinacolone silyl enolether a minor amount of an R-O-glycosyl
enolether 8b was observed as byproduct in coupling to the
mannosyl donor 4 (Table 1, entry 3). With the corresponding
glucosyl donor 5, the R-enolether was formed in greater yield
than the correspoding C-glycoside (Table 1, entry 9).17 With
trimethylsiloxycyclohexene as nucleophile the major product
Thioglycosides 4-6 (Figure 1) were synthesized as
previously described15 and converted in dichloromethane at
(10) (a) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926–4930. (b)
Bousquet, E.; Khitri, M.; Lay, L.; Nicotra, F.; Panza, L.; Russo, G.
Carbohydr. Res. 1998, 311, 171–181.
(11) (a) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473–
8480. (b) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690.
(12) As discussed previously,11a,b this rationale is based on the computed
conformations of the 4,6-O-benzylidene-protected gluco- and mannopyra-
nosyl oxacarbenium ions as provided by Whitfield and co-workers: Nukada,
T.; Be´rces, A.; Whitfield, D. M. Carbohydr. Res. 2002, 337, 765–774.
(13) Hydrogen bonding between the acceptor OH and O3, but not O2,
of the benzylidene protected mannosyl donor has been invoked previously
on the basis of computations as one of several factors possibily affecting
stereoselectivity in these glycosylations. Likewise, computational work has
also raised the possibility of hydrogen bonding between the incoming
acceptor and the departing triflate, in an SNi-like manner as a possible
rationale for the R-selective glycosylations: (a) Reference 12. (b) Nukada,
T.; Be´rces, A.; Wang, L.; Zgierski, M. Z.; Whitfield, D. M. Carbohydr.
Res. 2005, 340, 841–852. (c) Ionescu, A. R.; Whitfield, D. M.; Zgierski,
M. Z.; Nukada, T. Carbohydr. Res. 2006, 341, 2912–2920. (d) Whitfield,
(16) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323–
326.
D. M.; Nukada, T. Carbohydr. Res. 2007, 342, 1291–1304
.
(17) Previous syntheses and applications of glycosyl enolethers, or vinyl
glycosides: (a) Chenault, H. K.; Castro, A.; Chafin, L. F.; Yang, Y. J. Org.
Chem. 1996, 61, 5024–5031. (b) Boons, G.-J.; Heskamp, B.; Hout, F.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2845–2847. (c) Boons, G.-J.; Isles,
S. J. Org. Chem. 1996, 61, 4262–4271. (d) Yuan, J.; Lindner, K.; Frauenrath,
H. J. Org. Chem. 2006, 71, 5457–5467. (e) Wang, P.; Haldar, P.; Wang,
Y.; Hu, H. J. Org. Chem. 2007, 72, 5870–5873.
(14) For previous discussions of the potential effects of donor-acceptor
hydrogen bonding in glycosylation reactions see: Be´rces, A.; Whitfield,
D. M.; Nukada, T.; do Santos, I.; Obuchoskwa, A.; Krepinsky, J. J. Can.
J. Chem. 2004, 82, 1157–1171
(15) (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348. (b) Dubois,
E.; Beau, J. M. Carbohydr. Res. 1992, 228, 103–120.
.
4732
Org. Lett., Vol. 10, No. 21, 2008