Page 80 - Academic Press Encyclopedia of Physical Science and Technology 3rd Organic Chemistry

P1: LLL/LLL P2: FJU Final Pages
Encyclopedia of Physical Science and Technology EN002C-80 May 25, 2001 20:18

388 Carbohydrates

tection of the hydroxyl groups) is not practical from the
synthetic point of view, because it is usually accompanied
by extensive isomerization and aromatization (including
the formation of furan derivatives).

4. Nucleophilic Attacks by Hydroxyl Groups
There are two types of hydroxyl groups in the acyclic
forms of monosaccharides: a primary hydroxyl group,
which is, by definition, always terminal, and a number of
secondary hydroxyl groups. In the cyclic forms of sugars,
there exists a third type, namely, the glycosidic hydroxyl
group attached to the anomeric carbon atom that forms
part of the hemiacetal group of aldoses, or the hemiac-
etal group of ketoses. All three types of hydroxyl group
are strong nucleophiles that can add to the carbonyl group
of acid anhydrides, to afford esters, or replace the leaving
groups of alkylating agents, to afford ethers. They can also
induce substitution reactions at the anomeric center of the
same or a different sugar, to afford anhydro derivatives or
SCHEME 12 Mechanism of hydrolysis of glycosides. disaccharides, respectively. Finally, they can add in pairs
to the carbonyl group of aldehydes and ketones, to gives
cyclic acetals.
Anomerization is the acid-catalyzed isomerization of
The hemiacetal hydroxyl groups of cyclic sugars are the
a group (OR) attached to the anomeric carbon atom of
most reactive of the three types of hydroxyl group. They
a cyclic saccharide derivative. The reaction is initiated
are followed in nucleophilicity by the reactivity of the ter-
by protonation of the OR group of the glycoside and is
minal primary hydroxyl groups. Because acyclic sugars do
followed by elimination of the alcohol group (ROH) to
not possess hemiacetal hydroxyl groups, their primary hy-
afford a carbocation. This then undergoes nucleophilic
droxyl groups are the most reactive hydroxyl groups in the
attack by an OR group (identical to the OR originally
molecule.Theleastreactivehydroxylgroupsinbothcyclic
presentintheglycoside).Ofthetwoanomerspossible,that
and acyclic sugars are the secondary hydroxyl groups.
having the bulkier axial group predominates (the anomeric
These may differ in reactivity, depending on whether they
effect).
are axially or equatorially oriented (eliminations are fa-
An important reaction of anomeric OR groups is their
vored by an antiperiplanar orientation) and according to
displacement by X groups to form glycosyl halides. The
whether the substituents are situated in a crowded environ-
latter are used in the Koenigs–Knorr method of glycosi-
ment. Thus, it is often possible to block a primary hydroxyl
dation, which involves the reaction of a glycosyl halide
group and leave the secondary hydroxyl groups free by
with an alcohol in the presence of a heavy-metal catalyst.
making use of the fact that, because secondary hydroxyl
Forexample,tetra-O-acetyl-α-D-glucopyranosylbromide
groups are in a more crowded environment, they might
reacts with methanol in the presence of silver carbonate
not react to any appreciable extent if mild reaction condi-
(which acts as an acid acceptor) to afford, in high yield,
tions and insufficient reagents are used. Stereo-chemical
methyl tetra-O-acetyl-β-D-glucopyranoside. The reaction
considerations also play important, and sometimes deci-
mechanism is presumed to involve an intermediate carbo-
sive, roles in determining the course of competing reac-
nium ion (see Scheme 13).
tions involving more than one hydroxyl group. For ex-
It should be noted that the direct replacement of a hemi-
ample, when methyl β-D-ribofuranoside, which possesses
acetal hydroxyl group by a halogen atom (without pro-
one primary and two secondary hydroxyl groups, reacts
with acetone, the 2,3-O-isopropylidene derivative is pref-
erentially formed by attack of the two cis-oriented sec-
ondary hydroxyl groups, despite the fact that a primary
hydroxyl group (which is trans-oriented) is available (see
Scheme 14). This is because, had the latter group reacted,
it would have produced a highly strained, six-membered
SCHEME 13 Mechanism of glycoside formation. 3,5-isopropylidene ring.