Chemistry Reference
In-Depth Information
glycosyl donor with a 2-nonparticipating group (often a
O
- benzyl) will usually
give the
-linked product in excess (due to the anomeric effect; please see Info
Box 1 in Chapter 2). Some trends can be observed - a sterically more hindered
acceptor will increase the
α
ratio, as will the use of some solvents and promot-
ers, whereas the temperature dependence is more uncertain. Mannosides can
often be obtained purely
α
/
β
- mannosides
can also be obtained in a more controlled way by using participating groups.
Galactosyl donors give usually better
α
-linked, but since this is a
trans
- linkage,
α
ratios than the corresponding glucosyl
donors, probably due to steric hindrance by the axial 4-
O
- protecting group to
α
/
β
β
- side
attack of the acceptor. Also, 6-
O
-acyl groups can participate to increase
- selectiv-
ity. Mainly because there is still a lack of a good general alternatives for the forma-
tion of
α
-
D
- glucosides and -galactosides (for example found as key epitopes
in histo-blood group B determinants, please see Figure 1.5) this is frequently
the approach taken: optimizing the reaction conditions and acceptor and
donor properties to get as good
α
ratio as possible and then separating the
obtained anomers (which is most often possible nowadays using silica gel high-
performance liquid chromatography (HPLC)) before continuing the synthesis with
the desired
α
/
β
α
-anomer. For the formation of the corresponding
α
- linked 2 -
acetamido glycosides,
-
D
-GalNAc (blood group A determinant,
please see Figure 1.5), the same approach is also generally employed. Most fre-
quently the azido group (N
3
) is then utilized as the 2- non - participating group. This
group can effi ciently be transformed into an acetamido group by reduction fol-
lowed by acetylation.
The drawbacks of this approach to 1,2-
cis
- glycosides are obvious - optimization
takes time, requires substantial amounts of the donors and acceptors, and the
selectivity obtained is rarely complete, so material is lost both during chromato-
graphy and due to the
α
-
D
- GlcNAc and
α
-anomer being formed. Consequently, there is a continu-
ous quest for new methodologies to construct 1,2-
cis
- linkages in a stereospecifi c
way [3] (please see also Info Box 2 ).
During glycosylations using halide donors with non- participating protecting
groups it was observed that added halide salts increased the ratio of
β
- product
formed and this fi nding was developed into a methodology called ' halide - assisted '
(or '
in situ
anomerization') glycosylations. In this approach no 'real' promoter is
added to the glycosylation reaction, only a halide salt, usually a tetraalkyl ammo-
nium bromide. The role of the halide salt is to establish a quick equilibrium
between the
α
-bromide of the donor, but not to remove the bromide as
a normal promoter does. This would give the undesired oxocarbenium intermedi-
ate and thereby loss of stereoselectivity. Of the two anomers, the
α
- and the
β
- bromide is by
far the most stable and in large excess, but under these conditions there is always
some
α
β
-bromide present as well. The rationale is now that the
α
- bromide is too
stable to react with the acceptor. The
-bromide, however, is highly reactive and
can be directly displaced by the acceptor to afford the
β
α
- linked glycoside (Figure
3.8). Once the (small amount of)
β
-bromide has reacted to give the product, new
β
-bromide will be formed due to the equilibrium and fi nally all the halide donor
has been turned into the desired
α
-product. This procedure utilizes easily available
