Chapter 6: Synthesis of Glycosyl Donors
I. Synthesis for the Glycosyl Donors of Normal Sugars
OH
O
HO
HO
HO
OAc
Ac2O
cat. c. H2SO4
or Ac2O, pyr.
O
AcO
AcO
OH
AcO
OAc
* Most of the peracetylated sugars are commercially available.
* Different conditions may lead to the formation peracetylated furanoses.
(i) Synthesis of glycosyl donors with acyl protecting groups
* acyl groups are deactivating groups and favor the formation of -glycosidic bond for
sugars with gluco- or galacto- configuration or -glycosidic bond for sugar with mannoconfiguration.
HBr
HOAc
O
(AcO)n
Br
O
O
(AcO)n
OAc
H2NNH2-HOAc
CCl3CN
base
(AcO)n
OH
HSR
Lewis acid
O
O
(AcO)n
O
CCl3
NH
(AcO)n
SR
{O}
O
(AcO)n
SR
O
(ii) Synthesis of glycosyl donors with alkyl protecting groups
* alkyl groups are activating groups and favor the formation of -glycosidic bond for
sugars with gluco-, galacto- or manno-configuration.
1
O
O
NaOMe
MeOH
(AcO)n
O
BnBr
NaH
(HO)n
SR
(BnO)n
SR
SR
NBS
acetone
O
(BnO)n
OH
(iii) Synthesis of -mannosides
* Both anomeric effect and neighboring group participation favor the formation of glycosidic bond
(a) Method 1: use of heterogeneous system
OR
O
RO
RO
RO
AgBr
Ag+
+
Br Ag
Ag+
OR
O
RO
RO
RO
(b) Method 2: use of 4,6-benzylidene group (pre-activation strategy)
Ph
OBn
O
O
O
R2N
BSP, Tf2O
TTBP, CH2Cl2
Ph
-50oC
OBn
O
O
O
R2 N
SPh
Ph
OBn
O
O
O
BnO
R'OH
Ph
O
O
R2N
OBn
O
O
OBn
O
OR'
OTf
BSP, Tf2O
TTBP, CH2Cl2
Ph
OBn
O
O
O
BnO
-50oC
SPh
R'OH
Ph
O
BnO
OR'
OTf
(J. Org. Chem. 2007, 72, 5183; J. Am. Chem. Soc. 1998, 120, 435; J. Carbohydr. Chem.
2002, 21, 667)
(c) Method 3: converting glucose into mannose
BnO
BnO
BnO
BnO
BnO
BnO
O
OR'
1) Ac2O, DMSO;
amine
2) NaBH4
BnO
BnO
BnO
OH
O
OR'
O
O
1) Ag(zeolite) Br
DCM
2) L-Selectride
OH
(Org. Lett. 2000, 2, 2939)
2
BnO
BnO
BnO
BnO
BnO
BnO
OH
O
O
O
OR'
II. Synthesis for the Glycosyl Donors of Unusual Sugars
* Normal sugars, such as glucose, galactose, and mannose, are commonly used as the
starting material.
* Two major issues: protective group manipulation stereoselective glycosylation
* Three types of modifications: deoxygenation, substitution with amino (azido) group,
and epimerization
Deoxygenation: using radical-based reagents (nBu3SnH) or hydride reducing agents
(LiAlH4)
Substitution with azido group: treating leaving groups with N3- nucleophile (SN2)
Epimerization: oxidation/reduction or SN2 with O-based nucleophile
Compatibility of glycosyl donors and reactions for unusual synthesis
Stability in
Stability in
hydride or
Glycosyl donor
Structures
epimerization
radical-mediated
conditions
deoxygenation
Stability in azido
group
substitution
O
Glycosyl Halide
Not stable
OP X
Not stable
Not stable
X = F, Cl or Br
O
Thioglycoside
Stable
OP SR
O
1-O-Acyl Sugar
OP O
Acyl
Could be stable
Not stable in
radical-mediated
deoxygenation
Not stable in
hydridemediated
deoxygenation
Stable
Could be stable
O
Ortho Ester
OO
Stable
Stable
Stable
Not stable
Not stable
Not stable
Not stable
Not stable
Not stable
Stable
Not stable in
radical-mediated
deoxygenation
Stable
Not stable
Not stable
Not stable
Not stable in
the presence of
Tf2O
Not Stable
Could be stable
R R'
1-O- and SCarbonate
Trichloroacetimi
date
O
OR
OP O
X
X = O or S
O
CCl3
OP O
N
4-Pentenyl
Glycoside
O
Phosphate
Derivatives
O
OP O
OP O
P
OR
OR
O
O
Sulfoxide
R
OP SR
O
3
1-O-Silylated
Glycoside
1,2-Anhydro
Sugar
1-Hydroxyl
Sugar
Glycal
O
OP OSiR3
Could be stable
Could be stable
Could be stable
Not stable
Not stable
Not stable
Not stable
Not stable
Not stable
Stable
Not stable
Stable
O
O
O
OP OH
O
(i) Representative methods for epimerization
Types of
Transformations
Oxidation/reduction
(Swern oxidation)
Examples of
Reagents
(1) (COCl)2,
DMSO, DIPEA
(2) NaBH4
SN2 substitution
(1) Tf2O
(2) (n-Bu)4N+NO2-
SN2 substitution
(1) Tf2O
(2) (nBu)4N+OAc(3) hydrolysis of
OAc
Comments
Vicinal protecting groups
(i.e. Bn) are essential for
the selectivity. However,
the selectivity may vary
among different sugars.
Others (i.e. Bz) may offer
lower or no selectivity
toward epimerization.
(n-Bu)4N+NO2- can be
soluble in CH2Cl2,
providing better results
than reagents like NaNO2.
In general, this method
offers stereospecific
epimerization.
(n-Bu)4N+OAc- can be
soluble in CH2Cl2,
providing better result than
reagent like KOAc or
CsOAc. In general, this
method offers
stereospecific
epimerization.
*Mechanism of Swern oxidation:
1) (COCl )2
DM SO
2) Et 3 N
H 3 CO
H
H 3 CO
O
OH
4
References
Tetrahedron Lett. 2001,
42, 7019-7023
Carbohydr. Res. 2001,
334, 195.
J. Am. Chem. Soc. 2001,
123, 1587
Org. Lett. 2002, 4, 355.
O
H3C
O
O
S
CH 3
H3C
S
CH 3
Cl
Cl
CH 3
O
O
S
O
O
CH 3
Cl
Cl
O
Cl
CH 3
O
O
CO
Cl
S
Cl
CH 3
Cl
Cl
H
Cl
CH 3
CH 3
S
O
H3 CO
H
S
CH 2
H
H3C
CH 3
O
H3 CO
H3 CO
OH
Et 3N
O
H3 CO
H
S
CH 3
H
H3 CO
S
H3C
CH 2
CH 3
O
* Stereoselectivity of keto reduction on six-membered ring
O
HO
LiAlH4
tBu
HO
tBu +
9
:
Stereoelectronic effect
H
H
O
path a
H
H
H
O
tBu
H
tBu
path b
H
H
5
tBu
1
S
CH 3
CO 2
* Thermodynamic stability of equatorial OH vs. axial OH cannot explain the 9/1 ratio
* Path a is favored by small nucleophile (LiAlH4, NaBH4, etc) since path b may
encounter higher electron density (→*).
* Path b is favored by large nucleophile (L-Selectride, Li+-HB(s-Bu)3-) due to less steric
hindrance from 1,3-diaxial groups.
In pyanose:
HO
OBn
O
O
O
NaBH4
MeOH
0oC
BnO
BnO
OBn
BnO
BnO
major
OMe
OMe
(Tetrahedron Lett. 2001, 42, 7019)
OBn
O
OBn
O
O
O
O
O
R
R
BnO
BnO
H
OMe
H
6
OMe
(ii) Representative methods for amino (azido) substitution
(Angew. Chem. Int. Ed. 2005, 44, 5188)
* Using N3- via SN2 substitution
Types of
Transformations
Reagents
One-pot
Two-step
Types of
Hydroxyl
Groups
Typical
Conditions
Notes
References
Complex
mixture may be
obtained,
difficult to
purify
J. Am. Chem.
Soc. 2001, 123,
998.
DPPA(or HN3),
PPh3 and
DEAD (or
DIAD)
-40º to 0ºC,
overnight
1º and 2º
(1) TsCl
(2) NaN3
(1) 0ºC to R.T.,
overnight
(2) 80ºC,
overnight
1º (2º
Can be used for
tosylate is
difficult to be selective azide
replaced with substitution
N3-)
J. Org. Chem.
2004, 69, 1513
1º and 2º
MsCl is cheaper
than Tf2O
J. Org. Chem.
2000, 65, 3811
1º and 2º
Most expedient
J. Org. Chem.
2004, 69, 1513
Two-step
(1) MsCl
(2) NaN3
Two-step
(1) Tf2O
(2) NaN3
(1) 0ºC to R.T.,
couple hours
(2) 120ºC,
overnight
(1) 0ºC, 0.5 hour
(2) R.T.,
overnight
* HN3 is highly toxic.
* Comparison with Mitsunobo reaction/Yamaguchi lactonization
COR
R1
O
DEAD,PPh3
RCO2H
OH
R1
R2
R2
CO2Et
CO2Et
CO2Et
EtO2C
N
N
H
O
H
O
H
N
N
CO2Et
RCO2-
R1
R2
N
CO2Et
PPh3
PPh3
R
N
O
H
CO2Et
CO2Et
HN
CO2Et
N
R1
R2
PPh3
O
H+ transfer
COR
O
HN
N
H
CO2Et
RCO2-
R1
R2
O
H
7
PPh3
R1
R2
P(O)Ph3
* Mechanism of DPPA, PPh3 and DEAD
O
CO2Et
EtO2C
O
N
P
P
N
CO2Et
N
Ph
Ph
P
CO2Et
Ph
N3
Ph
O
N
CO2Et
+ N3
N
Ph
N
Ph
PPh3
PPh3
R
O
H
O
O
CO2Et
P
Ph
N
Ph
CO2Et
P
H+ transfer
N
N
Ph
CO2Et
N
H
Ph
PPh3
O
R
O
R
N3
CO2Et
PPh3
H
O
P
CO2Et
N
Ph
N
H
Ph
R
CO2Et
O
H2O
work-up
CO2Et
P
Ph
OH
HN
N
H
Ph
N3
R
N3
(a) Examples
8
CO2Et
CO2Et
(iii) Representative methods for deoxygenation
Types of
Transformations
6-deoxy
4-deoxy
Reactions
3-deoxy
H3C
1) CS2, NaH
2) MeI
3) nBu3SnH, AIBN, reflux
BnOOMe
LiAlH4, THF
Ph
OMe
Ph
O
H
O
2-deoxy
O
O
O
TsO
AcO
AcO
AcO
Cl
4,6-dideoxy
HO
HO
O
H
O
O
TsO
LiAlH4, THF
Ph
O
OMe
O
Cl
O
+
ROH, H
O
O
HO
O
O
O
O
OR
H3C
HO
HO
OMe
9
J. Chem. Soc., Perkin
Trans. I, 1975, 1574
J. Am. Chem. Soc., 1983,
105, 4059
Preparative Carbohydrate
Chemistry, Hanessian, S.
Ed., Marcel Dekker, Inc.
1997, New York, p151
Tetrahedron Letter, 2001,
42, 6797
OMe
O
AcO
AcO
AcO
H2, Raney Ni, KOH
OMe
HO
Tetrahedron Letter, 2001,
42, 6797
OMe
O
Ph
2-deoxy
O
O
O
O
HO
Ph
OMe
O
1) CS2, NaH
2) MeI
3) nBu3SnH, AIBN, reflux
J. Org. Chem. 2004, 69,
1513
J. Chem. Soc., Perkin
Trans. I, 1975, 1574
J. Am. Chem. Soc., 1983,
105, 4059
Preparative Carbohydrate
Chemistry, Hanessian, S.
Ed., Marcel Dekker, Inc.
1997, New York, p151
O
O
O
HO
O
3-deoxy
BnOOMe
BnO
O
TsO
O
BnO
BnOOMe
O
O
TsO
O
HO
BnO
BnOOMe
O
BnO
HO
BnO
Ph
1) TsCl, py.
2) LiAlH4
O
HO
HO
BnO
References
O
HOOMe
J. Org. Chem. 1991, 56,
5468
Preparative Carbohydrate
Chemistry, Hanessian, S.
Ed., Marcel Dekker, Inc.
1997, New York, p105
(iv) Examples
Scheme 1.
O
AcO
SPh
O
O
95%
AcO
HO
O
HO
O
(1) NaOMe, MeOH
(2) Me2C(OMe)2, TsOH-H2O, acetone;
AcO
O
(1) Tf2O, py., CH2Cl2
(2) nBu4N+-AcO-
SPh
O
BzCl, DIPEA, DMAP, CH2Cl2
BzO
O
BnO
OH
(1) Tf2O, py., CH2Cl2
(2) NaN3, DMF.
SPh
SPh
HO
90%
O
BzO
N3
85%
BnO
91%
81%
NaOMe, MeOH
BnO
OAc
44%
BnO
(1) BnBr, NaH, TBAI, THF
(2) HOAc, TFA, H2O
HO
SPh
AcO
SPh
SPh
BnO
OH
Scheme 2
O
HO
HOHO
a
HOOMe
Methyl glucoside
Ph
95%
O
O
O
BnO
BnO
e
99%
OMe
f
BnO
HO
BnO
OMe
86%
HO
N3
O
BnO
BnO
BnO
OMe
N3 CH3
O
BnO
BnO
c
BnO
OMe
BnO
4
3
c
72%
BnOOMe
h
99%
g
OMe
5
BnO
OMe
11
78%
OH
O
N3
BnO
BnO
OMe
13
c
CH3 O
N3
BnO
BnOOMe
d
10
O
BnO
94%
BnOOMe
BnO
BnOOMe
9
O
N3
HO
BnO
12
HOCH
3 O
O
86%
BnO
N3
BnO
O
d
BnO
OMe
64%
8
78%
d
O
7
84%
H3C
O
2
c
BnO
6
80%
BnO
HO
BnO
c
BnOOMe
1
b
N3 N3
O
HO
HO
BnO
N3
N3
BnO
80%
O
BnOOMe
14
Conditions: (a) (1) PhCH(OMe)2, TsOH-H2O, DMF, (2) BnBr, NaH, TBAI, THF; (b)
BH3-Me3N, AlCl3, THF; (c) (1) Tf2O, py., CH2Cl2, (2) NaN3, DMF; (d) (COCl)2, DMSO,
DIPEA, (2) NaBH4, MeOH; (e) TsOH-H2O, MeOH; (f) (1) TsCl, py, (2) LiAlH4, THF;
(g) (1) MsCl, Et3N, CH2Cl2, (2) NaN3, DMF; (h) (1) TsCl, py, (2) NaN3, DMF.
Scheme 3.
Ac2O
cat. H2SO4
O
(BnO)n
O
(AcO)n
OMe
10
OAc
Scheme 4.
OAc
AcO
AcO
O
a
SPh
OAc
88%
Ph
O
O
O
BnO
OH
d
HO
BnO
SPh
78%
OBn
b
e
O
SPh
O
BnO
N3 CH
3
f
O
HO
BnO
OBn
SPh
OBn
26
CH3
SPh
BnO
OBn
O
SPh
OBn
23
13
g
77%
g
HO
CH3
O
SPh
BnO
OBn
28
24
52%
CH3
60%
c
N3
O
SPh
OBn
25
N3
SPh
OBn
N3
BnO
87%
HO
O
BnO
c
SPh
BnO
OBn
22
N3
AcO
O
BnO
18
80%
f
47%
AcO
O
BnO
SPh
SPh
c
74%
OBn
32%
N3
21
17
66%
h
O
HO
BnO
OBn
N3
OBn
20
CH3
OBn
c
81%
57%
O
N3
BnO
29
SPh
OBn
Conditions: (a) (1) NaOMe, MeOH, (2) PhCH(OMe)2, TsOH-H2O, DMF, (3) BnBr,
NaH, TBAI, THF; (b) BH3-Me3N, AlCl3, THF; (c) (1) MsCl, Et3N, DMAP, CH2Cl2, (2)
NaN3, DMF; (d) TsOH-H2O, MeOH/CH2Cl2; (e) (1) TsCl, py, (2) LiAlH4, THF; (f) (1)
Tf2O, py, CH2Cl2, (2) n-Bu4NOAc, CH2Cl2; (g) K2CO3, MeOH; (h) (1) TsCl, py, (2)
NaN3, DMF.
11
SPh
BnO
19
65%
HO
BnO
O
SPh
OBn
16
15
N3
N3
c
O
Scheme 5.
Ph
O
O
HO
O
O
SPh
BnO
d
CH3
HO CH
e
O
42%
OBn
SPh
67%
3
54%
SPh
OBn
29
68%
c
N3
HO
O
O
N3
BnO
SPh
31
30
N3
BnO
b
BnO
73%
OBn
N3
OH
a
O
SPh
BnO
SPh
BnO
OBn
OBn
25
OBn
24
28
Conditions: (a) TsOH-H2O, MeOH/CH2Cl2; (b) (1) Tf2O, py, CH2Cl2, (2) NaN3,
DMF; (c) (1) TsCl, py, (2) NaN3, DMF; (d) (1) TsCl, py, (2) LiAlH4, THF; (e) (1) MsCl,
Et3N, DMAP, CH2Cl2, (2) NaN3, DMF.
Scheme 6.
AcO
N3
N3
O
N3
O
a
OAc
26%
OAc
AcO
N3
N3
O
b
SPh
73%
BnO
N3
34
33
32
OBn
OAc
O
AcO
N3
c
SPh
OAc
35
SPh
OBn
OAc
73%
Ph
O
O
N3
O
d
SPh
OBn
90%
O
HO
N3
e
87%
37
f
N3
OBn
O
SPh
OBn
36
AcO
N3
SPh
OBn
38
78%
OBn
O
N3
SPh
OBn
39
Conditions: (a) PhSH, BF3-OEt2, CH2Cl2; (b) (1) NaOMe, MeOH, (2) BnBr, NaH, TBAI, THF; (c) (1)
NaOMe, MeOH, (2) PhCH(OMe)2, TsOH-H2O, DMF, (3) BnBr, NaH, TBAI, THF; (d) BH3-Me3N, AlCl3,
THF; (e) (1) Tf2O, py, CH2Cl2, (2) n-Bu4NOAc, CH2Cl2; (f) (1) Tf2O, py, CH2Cl2, (2) NaN3, DMF.
12