Peptide-Based Drug Design

Glycosylated Amino Acid Synthesis 193
RO
RO
OR
O
O
X
RO
RO
Ac
X = Br,Cl
O
OR
O
Ac
O
O
Oxocarbeniumion
RO RO
OR
O
O
O
Ac
Acyloxoniumion
Nu –
RO RO
RO RO
OR
O
Ac
O
O
OR
O
Nu
1,2-trans-Glycoside
O
O
Ac Nu
Orthoester
Fig. 3. Glycosidation pathways with a participating group in the 2-position.
pivaloyl group or a benzoyl group, which can delocalize the positive charge more
efficiently.
Glycosylation without a neighboring effect will result in the formation of both
1,2-trans as well as 1,2-cis glycosides. The in situ anomerization procedure is
the most common method for the synthesis of 1,2-cis glycosides. The soluble
catalyst facilitates the rapid interconversion between the �- and�-glycosyl
bromides via contact ion pairs (Fig. 4). The�-bromide is stabilized by the
anomeric effect, and the more reactive �-bromide is present only in low concentrations.
The higher reactivity of the �-bromide and the higher energy barrier for
attack on the �-bromide leads to the selective formation of the 1,2-cis glycoside
from the �-bromide. It is important to use a solvent of low polarity in order to
prevent the dissociation of the ion pairs with concomitant loss of stereoselectivity.
The most widely used approaches in the synthesis of the O-glycosylated
amino acids, Koenigs-Knorr, activation of anomeric acetate, trichloroacetimidate,
and thioglycosides will be explained in detail.
RO RO
OR
O
Y
1,2-trans
β−glycoside
Nu
Nu –
Slow
RO RO
OR
O
Y
X
RO RO
OR
OR
RO
RO
O
Y
RO
RO
O
Y
X
X
α−contaction-pair β−contaction-pair
X = Br or Cl; Y = BnO or N 3
OR
O
Y
X
Nu –
Fast
RO RO
OR
O
Y
Nu
1,2-cis
α−glycoside
Fig. 4. Glycosidation pathways with a nonparticipating group in the 2-position.