Y. Kakitsubata et al. / Tetrahedron Letters 57 (2016) 1154–1157
1155
1
OR2
O
Ph
R O
-O2C
HO
OR4
O
O
O
O
O
O
MeO2C
TBDMSO
AcHN
HO
HO
OH
OH
OPNB
O
O
N
H
N
H
3
O
R O
S
S
TrocHN
OAllyl
DS disaccharides
BzO
disaccharide building block 1
linker moiety
DS ligand conjugates, R1=R2=R3=R4= H or SO3
-
Figure 1. Designed disaccharide building block 1 and target DS ligand conjugates.
Ph
HO
HO
HO
HO
HO
HO
OH
O
O
OH
O
OH
O
a
b
c
O
OH
•HCl
OH
OAllyl
O
HO
NH
2
TrocHN
TrocHN
TrocHN
galactosamine hydrochloride
2
3
4
OAllyl
O
O
AcO
MsO
O
OH
O
OPNB
OPNB
OPNB
d, e
O
f, g, h
O
i
O
j, k
HO
HO
OH
O
O
O
O
O
O
OH
glucose
5
6
7
OAllyl
OAllyl
OAllyl
OPNB
O
OPNB
O
OPNB
O
OPNB
O
OAc
l
m, n
o
p
O
O
AcO
O
OH
10
O
OBz
11
OAc
OAc
AcO
OAc
OAc
pMP
pMP
8
9
OAllyl
OAllyl
OAllyl
OPNB
O
OPNB
O
OPNB
O
OPNB
O
q, r
HO
s, t
u, v
OH
MeO C
2
MeO
2
C
MPMO
TBDMSO
OBz
OH
OBz
TBDMSO
OBz
TBDMSO
OBz
1
2
13
14
15
+
Scheme 1. Syntheses of GalNAc 4 and IdoA 15. Reagents and conditions: (a) TrocCl, NaHCO
CH CN, 66% yield ( only, three steps); (d) H SO in acetone, 44% yield; (e) PNBBr, Ag O, MS 4A in Et
8-crown-6 in CH CN, reflux, 53% yield (three steps); (i) t-BuOK in t-BuOH/CH Cl (10:1 v/v), 40 °C; (j) TFA aq; (k) Ac
SnCl , MS 4A in CH Cl aq in MeOH, 0 °C; (n) p-MeO-PhCH(OMe) , CSA in CH CN, 67% yield (two steps); (o) BzCl in pyridine, 95% yield; (p) TFA,
NaBH CN, MS 4A in DMF, 72% yield; (q) TBDMSOTf, TEA, MS 4A in CH Cl , 92% yield (two steps); (s) TEMPO, NaHCO , KBr, NaOCl, H O in CH CN, 0 °C;
t) TMSCHN in MeOH, 0 °C, 95% yield (two steps); (u) Ir[(COD)(PMePh in THF; (v) H O, I in THF, 90% yield (two steps).
3
in H
2
O, 0 °C; (b) AllylOH, Dowex 50 W-X8 (H ), reflux; (c) PhCH(OMe)
2
2
, CSA in
3
a
3
2
4
2
O, 94% yield; (f) 60% AcOH aq, 40 °C; (g) MsCl in pyridine, 0 °C; (h) AcOK,
O in pyridine, 66% yield (three steps); (l) AllylOTMS,
1
2
2
2
4
2
2
, ꢀ18 °C, 86% yields; (m) NH
3
2
3
3
2
Cl
2
; (r) DDQ, H
]PF , H
2
O in CH
2
2
3
2
3
(
2
2
)
2
6
2
2
2
converted into monomesylate 6 via the selective removal of the
14 furnished 1-OH derivative 15, which is used as a glycosyl donor
after converting to an imidate.
5
6
6
,6-isopropylidene group, followed by 5,6-di-O-mesylation and
-O-acetylation. Epoxide 7 was synthesized from monomesylate
using t-BuOK as the base in a mixture of CH Cl /t-BuOH (1:10
2 2
With both the glycosyl donor and acceptor moieties in hand,
disaccharide building block 1 and trisaccharide intermediate 21
were synthesized (Scheme 2). After conversion of 1-OH derivative
15 to glycosyl imidate 16, the glycosylation of GalNTroc acceptor 4
with IdoA donor 16 was performed with TMSOTf, affording the
desired building block 1 in 69% yield. Stereochemistry of the
anomeric position was confirmed by NMR analysis; it was deter-
v/v). The PNB group could not be removed under this condition.
Epoxide 7 was converted into tetraacetate 8 after acidic hydrolysis
with TFA and acetylation. The anomeric position was then pro-
tected with an allyl group by glycosylation with (allyloxy)
trimethylsilane (AllylOTMS) in the presence of SnCl
4
. The de-O-
acetylation was performed with aqueous NH under mild basic
3
mined to be the
then converted to disaccharide donor 18 by the deprotection of
the allyl group, followed by the treatment with CCl CN. The glyco-
sylation of donor 18 with glucose 19, acting as the hydrophilic
reaction site to prepare the ligand conjugate for the immobilization
of disaccharide structure on the sensor chip of SPR biosensor,
afforded trisaccharide 20. Trisaccharide intermediate 2128 was
synthesized by the reduction of the NO group on PNB and Troc
2
group on GalNTroc moiety, followed by N-acetylation.
Next, the orthogonal deprotection, selective sulfation, and con-
jugation of linker 28 were investigated (Scheme 3). Selective cleav-
age of the benzylidene group at the 4,6-position on GalNAc was
a-anomer (d 5.28 ppm, br s). Disaccharide 1 was
conditions because the PNB group is unstable under strong basic
conditions such as MeONa. p-Methoxybenzylidenation of the
resulting compound afforded p-methoxybenzylidene 10. Benzoyla-
tion at the 2-position, followed by the reductive ring opening of the
3
27
p-methoxybenzylidene group with TFA and NaBH
-OH compound 12. After the silylation of the 4-OH group with
tert-butyldimethylsilyl triflate (TBDMSOTf) and triethylamine
TEA), the p-methoxybenzyl (MPM) group was removed with
,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), affording 6-OH
3
CN afforded
4
(
2
compound 13. Oxidation of the 6-position of 13 with (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) and NaOCl, followed by
methyl esterification with trimethylsilyldiazomethane afforded a
fully protected IdoA 14. Deprotection of the allyl group of IdoA
achieved with a combination of TfOH/Et
3
SiH, PhBCl
2
/Et
3
SiH, and
0
0
2
TFA/H O, affording 4 -OH compound 22, 6 -OH compound 23,