Peptide-Based Drug Design

Glycosylated Amino Acid Synthesis 199
BzO
BzO
O
BzO
SEt
+
CH 2 -OH
Cbz-NH-CH-COOBn
DMTST
TMSOTf
(80%)
BzO
BzO
O
BzO
O CH2 -CH
COOBn
NH-Cbz
Fig. 10. Synthesis of �-D-Xyl-(1→O)-Ser derivative using thioglycoside derived
from xylose (85).
2. Add thiophenol (1.5 eq), followed by Lewis acid, BF3·Et2O (3 eq), and stir
overnight at room temperature.
3. Wash reaction mixture two times with saturated aqueous sodium bicarbonate
(NaHCO3) and then with water.
4. Combine filtrates, evaporate and purify by flash chromatography.
3.2.4.2. THIOGLYCOSIDE METHOD
1. Dissolve the glycosyl donor (1 eq) and acceptor (1 eq) in dichloromethane and stir
with activated molecular sieves (4 ˚A) under an inert atmosphere at room temperature
(see Note 2).
2. Add DMTST (1.5 eq) and stir overnight at room temperature (see Note 12).
3. At the same temperature add N,N-diisopropylethylamine (1.5 eq) to neutralize the
acid.
4. Filter reaction mixture over Celite and wash the Celite well with CH2Cl2.
5. Wash the organic filtrate with saturated aqueous NaHCO3.
6. Combine filtrates, evaporate and purify by flash chromatography.
3.3. N-Glycosylated Amino Acids
N-Glycosidic linkage is commonly formed between a glycosyl amine and
an activated aspartic acid derivative instead of glycosylation of asparagine
(Scheme 3). Therefore, the first step toward the synthesis of N-glycosylated
amino acids is the preparation of glycosyl amines. Two of the most commonly
used procedures for the synthesis of glycosyl amines include the reduction of
glycosyl azides and the treatment of reducing sugars with saturated ammonium
OR1 R O
1O NH
R1O 2
AcNH
R 1 = H or protecting group
+
R 2 HN
COOR 3
COOX
X = Activating group
R 2 ,R 3 = Protecting group
R1O R1O OR1 O H
N
AcNH
Scheme. 3. Formation of N-glycosidic linkage.
O
NH-R 2
N-glycosidic linkage
COOR 3