Peptide-Based Drug Design

194 Cudic and Burstein
3.2.1. Koenigs-Knorr Coupling
The Koenigs-Knorr method was, for a long time, the only available method
for glycosylation and still represents the most widely used procedure for the
synthesis of 1,2-trans glycosides in the chemistry of carbohydrate derivatives
(53). The�-glycosyl halide generated in the activation step (54) can be readily
further activated in the glycosylation step by promoters, i.e., heavy metal salts,
resulting in an irreversible glycosyl transfer to the acceptor. Insoluble silver salts,
such as Ag2CO3, as well as soluble ones, such as AgOTf and AgClO3, have been
employed in the synthesis of glycosides.
The Koenigs-Knorr method has been used for the formation of 1,2-trans
and 1,2-cis glycosidic bond. 1,2-trans-O-Linked glycosylated amino acids, �-D-
Glc-(1→O)-Ser (55), �-D-Gal-(1→O)-Hyl (56,57) (Fig. 5), �-D-Man-(1→O)-
Ser/Thr (58,59),and�-D-GlcNAc-(1→O)-Ser/Thr (60) are often prepared using
a participating group at C-2 of the glycosyl donor. In the case of GlcNAc, it
is desirable to replace the N-acetyl group with an electron-withdrawing group
like N-allyloxycarbonyl (Aloc) (61), N-trichloroethoxycarbonyl (Troc) (62–65),
or N-dithiasuccinoyl (Dts) (66,67) in order to decrease side product (oxazoline)
formation. 1,2-cis-O-Linked glycosylated amino acids, �-D-GlcNAc-(1→O)-
Ser/Thr, have been prepared by utilizing the nonparticipating azido group at C-2
of the GalNAc donor (68). Often, 1-bromo (69,70) (Fig. 6) and 1-chlorosugars
AcO
OAc OAc
O
AcO
Br
HO
HO
NHCbz
NHBoc
NHFmoc
a) Ag silicate
b) AgOTf
NHFmoc
CO 2 Allyl
CO 2 Bzl
OAc
AcO
O
AcO
O
AcO
OAc
OAc
OAc
O
AcO
O
NHCbz
NHBoc
NHFmoc
CO 2 Allyl
NHFmoc
CO 2 Bzl
Fig. 5. Synthesis of 1,2-trans glycosides using a participating group at C-2: for
example, synthesis of glycosylated hydroxylysine derivative (�-D-Gal-(1→O)-Hyl)
using (a) insoluble promoter-silver silicate (56); (b) soluble promoter-silver trifluoromethanesulfonate
(57).