Regioselective benzylation of azido-containing monosaccharides

Article abstract of DOI:10.1055/s-2006-939681

A regioselective benzylation or p-methoxybenzylation of diols in azido-containing monosaccharide derivatives was reported, and the reaction was performed under the conventional reaction conditions (NaH/BnBr in DMF). The hydroxyl functionality adjacent to the azido group was benzylated selectively in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939681

LETTER
1217
Regioselective Benzylation of Azido-Containing Monosaccharides
R
egioselective Ben
i
zylatio
u
nof
A
zido-
-
ontainin
H
gMonosaccharid
u
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd #38,
Beijing 100083, P. R. of China
Fax +86(10)62014949; E-mail: xinshan@bjmu.edu.cn
Received 1 December 2005
tives under the conventional reaction conditions (NaH/
Abstract: A regioselective benzylation or p-methoxybenzylation
BnBr in DMF).
of diols in azido-containing monosaccharide derivatives was report-
ed, and the reaction was performed under the conventional reaction
conditions (NaH/BnBr in DMF). The hydroxyl functionality adja-
cent to the azido group was benzylated selectively in good yields.
Firstly, p-methylphenyl 2,3-dideoxy-2,3-diazido-1-thio-
b-D-mannopyranoside (1) was chosen to carry out the
benzylation reaction. When a solution of saccharide 1 in
DMF was treated with NaH (1.3 equiv) and BnBr (1.3
equiv),14 to our surprise, the 4-O-benzylated product was
gained as the major product in 71% isolated yield, the 6-
O-benzylated product and 4,6-O-dibenzylated product
were also collected as the minor products in 7% yield and
in 16% yield, respectively (Scheme 1).15 Like benzyl
group, p-methoxybenzyl (PMB) group is also a widely
used protective group. When thioglycoside 1 was treated
with p-methoxybenzyl chloride (PMBCl) under the same
conditions mentioned above, an excellent selectivity was
achieved, leading to the isolation of 4-O-substituted prod-
uct 1d in a yield of 77%, but no 6-O-substituted product
1e was detected (Table 1, entry 2).
Key words: selective benzylation, alkylation, azido-containing
monosaccharides, protection, hydroxyl group
Benzyl protection is one of the most frequently used
techniques for the protection of hydroxyl functionalities
in organic synthesis because benzyl protective group is
stable under acidic and basic conditions and is readily
removed by mild hydrogenolysis.1–3 Perbenzylation or
selective benzylation of primary, secondary, and even ter-
tiary alcohols is often applied to the preparation of syn-
thetic intermediates, especially to the synthesis of
saccharide building blocks and the assembly of oligosac-
charides.
OR2
N3
OH
Benzylation could be achieved by the reaction of alcohols
and benzyl halides in the presence of a base such as pow-
dered sodium hydroxide in anhydrous DMF at high tem-
perature,4 sodium hydride in anhydrous DMF at room
temperature,5 or a mild base (Ag2O) in THF using phase-
transfer catalysts.6 Benzylation could also be achieved by
the use of an acidic catalyst (trifluoromethanesulfonic
acid) with benzyl trichloroacetimidate as the reagent.7 A
method using PhCHN2 at –40 °C under near-neutral con-
ditions with HBF4 as catalyst was usually employed for
the protection of an alcohol, while leaving amino func-
tional groups unaffected.8 On the other hand, selective
benzylation could be difficult to achieve because so many
factors might contribute to the outcome of the reaction.
Limited methods were reported for selective benzylation
including the regioselective opening of O-benzylidene ac-
etals,9,10 selective activation by the formation of organotin
intermediates such as dibutylstannylene acetyls11 or tri-
butylstannyl ethers,12 and multistep strategy via tempo-
rary protective groups such as trityl13a or silyl ether13b
groups. There is a great demand for the selective benzyl-
ation of multihydroxyl compounds. In this letter, we wish
to report a selective O-benzylation or p-methoxybenzyl-
ation of some azido-containing monosaccharide deriva-
N3
O
BnBr (1.3 equiv)
NaH (1.3 equiv)
O
R1O
N3
HO
N3
STol
STol
1
1a R1 = Bn, R2 = H, 71.0%
1b R1 = H, R2 = Bn, 7.1%
1c R1 = Bn, R2 = Bn, 16.4%
Scheme 1 Selective benzylation of azido-containing mono-
saccharide
As illustrated in Table 1, when p-methylphenyl 2-deoxy-
2-azido-6-O-benzyl-1-thio-b-D-altropyranoside (2) was
employed to undergo benzylation reaction, the 3- and 4-
O-benzylated products 2a and 2b were obtained in 79%
and 5% yields, respectively, in the ratio of 16:1 (entry 3).
Similarly, the reaction of 2 with PMBCl gave, in 96% to-
tal yield, a separable mixture of 3-O-substituted, 4-O-sub-
stituted, and 3,4-O-disubstituted products 2d, 2e, and 2f,
in the ratio of 14.5:1 (2d:2e, entry 4). When azido-con-
taining O-glycoside 3 was treated with PMBCl in the
presence of NaH, the hydroxyl group adjacent to the azido
group was alkylated predominantly and good selectivity
(4-O-alkylated product 3a to 6-O-alkylated product 3b)
was also displayed (entry 5). As control experiments, non-
azido containing monosaccharides 4, 5, and 6 were sub-
jected to benzylation in the same manner as described in
Scheme 1, the regioselectivity of the two O-monobenzyl-
ated products was generally lost though monosaccharide
5 showed some moderate selectivity (entries 6–8). When
SYNLETT 2006, No. 8, pp 1217–1220
1
5.
0
5.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-939681; Art ID: W32405ST
© Georg Thieme Verlag Stuttgart · New York

1218
Q.-H. Fan et al.
LETTER
azido-containing thiogalactoside 7 underwent benzylation substrates with azido groups was also examined. Interest-
reaction, the 3-O-benzylated and 4-O-benzylated prod- ingly, the diols 11 and 12 bearing one azido group showed
ucts 7a and 7b were isolated in the ratio of 3:1 (entry 9). quite good regioselectivity and the hydroxyl group adja-
In contrast to thiogalactoside 7, the corresponding O-ga- cent to the azido group was benzylated as the major prod-
lactoside 8 exhibited much better regioselectivity (ratio uct (entries 13, 14). But for the benzylation of the diol 13
13.5:1) towards benzylation (entry 10). Thioglycoside 9, bearing two azido groups, the regioselectivity was
an anomeric isomer of 7, was benzylated to produce the completely lost (entry 15). It should be noted that the
two O-monosubstituted and one O-disubstituted products structures of all regioisomers were identified by their 1D
9a, 9b, and 9c in a total isolated yield of 93%, but the se- NMR, 2D correlated NMR spectroscopy, and further
lectivity was not good (entry 11). Likewise, the selectivity confirmed by their MS/HRMS or elemental analyses.
for benzylation of thioglycoside 10 was not good either
(entry 12). In addition, benzylation of some chain diol
Table 1 Selective Benzylation of Diols in Azido-Containing Monosaccharide Derivativesa
No. Diol
Product a
Product b
(yield, %)
Product c
(yield, %)
Total Ratio
yield of a/b
(%) or d/e
(yield, %)b
N3
N3
N3
O
N3
O
HO
HO
HO
BnO
HO
BnO
BnO
O
BnO
O
1
94
98
10:1
1:0
N3
STol
N3
STol
N3
STol
N3
STol
1a (71)
1
1b (7)
1c (16)
N3
O
N3
N3
O
N3
HO
HO
HO
PMBO
HO
PMBO
PMBO
PMBO
O
O
O
2
N3
STol
N3
STol
N3
STol
STol
N3
STol
1d (77)
1e (0)
1
1f (21)
N3
N3
BnO
BnO
N3
N
3O
BnO
HO
BnO
HO
BnO
BnO
O
O
STol
STol
3
96
96
92
16:1
STol
STol
OH
OBn
OH
OH
OBn
2b (5)
2a (79)
2
2c (12)
N3
N3
O
N3
N3
BnO
HO
BnO
HO
BnO
PMBO
BnO
O
O
O
PMBO
STol
STol
4
STol
14.5:1
8.6:1
OPMB
OH
OPMB
2d (80)
2
2e (5)
2f (11)
N3
N3
N3
O
N3
O
HO
HO
HO
PMBO
HO
PMBO
PMBO
O
PMBO
O
N3
N3
N3
5
N3
OMe
STol
OMe
OMe
OMe
3
3a (70)
3b (8)
3c (14)
BnO
BnO
HO
BnO
HO
HO
HO
O
O
BnO
O
OBn
O
BnO
BnO
4b (51)
Ph
STol
6
97
94
1:1.9
4.2:1
BnO
STol
BnO
STol
OBn
OBn
OBn
4a (27)
4c (19)
4
O
O
O
O
O
O
O
O
Ph
Ph
Ph
O
O
O
O
7
BnO
BnO
HO
HO
STol
STol
STol
OMe
STol
OMe
OH
OBn
OH
OBn
5
5a (65)
5b (15)
5c (14)
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
O
8
95
1.6:1
HO
HO
OMe
BnO
BnO
OMe
OH
OBn
OH
OBn
6
6a (49)
6b (30)
6c (16)
Synlett 2006, No. 8, 1217–1220 © Thieme Stuttgart · New York

LETTER
Regioselective Benzylation of Azido-Containing Monosaccharides
1219
Table 1 Selective Benzylation of Diols in Azido-Containing Monosaccharide Derivativesa (continued)
No. Diol
Product a
Product b
(yield, %)
Product c
(yield, %)
Total Ratio
yield of a/b
(%) or d/e
(yield, %)b
OBn
OBn
OBn
OBn
OBn
OH
OBn
OH
O
O
O
O
9
98
97
3:1
HO
STol
BnO
STol
OMe
HO
STol
OMe
BnO
STol
OMe
N3
N3
N3
N3
7b (21)
7a (64)
7
7c (13)
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OH
OBn
OH
OBn
O
O
O
O
10
13.5:1
BnO
HO
OMe
HO
BnO
N3
N3
N3
N3
8a (73)
8b (5)
8
8c (19)
OBn
OH
OH
OBn
OBn
O
O
O
O
11
93
2.3:1
BnO
HO
HO
9
BnO
N3
N3
N3
N3
STol
STol
STol
STol
9a (51)
9b (22)
9c (20)
OBn
OBn
OBn
OBn
O
O
BnO
HO
O
HO
HO
BnO
O
BnO
BnO
12
13
93
99
2:1
HO
N3
N3
N3
N3
STol
STol
STol
STol
10b (25)
10
10a (50)
10c (18)
N3
N3
N3
N3
OH
OBn
OH
OBn
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
7.1:1
OBn
OBn
OH
OH
OH
OBn
OBn
OBn
OBn
11b (11)
11c (6)
11
11a (82)
N3
N3
OH
N3
OH
N3
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OH
14
15
95
92
8.5:1
1:1.1
OBn
OBn
OBn
OBn
OBn
12a (72)
12b (8)
12
12c (15)
N3
OH
BnO
BnO
N3
N3
N3
OH
N
3OBn
BnO
BnO
BnO
BnO
N3
BnO
BnO
OBn
OH
OBn
N3
OH
N3
OBn
13b (40)
13a (36)
13
13c (16)
a All new compounds were characterized by their 1H NMR, 13C NMR, MS/HRMS or elemental analyses.
b Isolated yield.
Based on the experimental results depicted in Table 1, it high and this selective reaction can even be applied to
appears that for diols in azido-containing monosaccharide acyclic multihydroxyl compounds with azido groups. The
derivatives, the hydroxyl functionality adjacent to the azi- reaction can be operated just under the conventional
do group is usually more reactive towards O-benzylation benzylation conditions. This reaction may find wide ap-
or p-methoxybenzylation, and in many cases highly regi- plication in saccharide synthesis and selective protection
oselective benzylation can be realized (Table 1, entries 1– of other multihydroxyl molecules.
5, 10, 13, 14).
In summary, a selective O-benzylation (p-methoxy-
benzylation) of monosaccharide derivatives containing
azido groups has been disclosed. The hydroxyl function-
ality adjacent to the azido group can be benzylated pre-
dominantly. The regioselectivity in some cases is very
Acknowledgment
This work was financially supported by the National Natural
Science Foundation of China, ‘973’ grant from the Ministry of
Science and Technology of China, and ‘985’ program from the
Ministry of Education of China.
Synlett 2006, No. 8, 1217–1220 © Thieme Stuttgart · New York

1220
Q.-H. Fan et al.
LETTER
(15) General Experimental Procedure.
References and Notes
To a solution of p-methylphenyl 2,3-dideoxy-2,3-diazido-1-
thio-b-D-mannopyranoside (0.2 mmol) in anhyd DMF (4 mL)
was added NaH (1.3 equiv) at –15 °C, after stirring for 5 min
BnBr (1.3 equiv) was added, then the mixture was warmed
to r.t. for 30 min. The reaction mixture was quenched with
H2O and extracted with EtOAc. The organic layer was dried
over Na2SO4 and concentrated. The residue was purified by
column chromatography on silica gel (PE–EtOAc, 12:1 to
6:1) to afford products 1a (71%), 1b (7%) and 1c (16%).
Compound 1a: 1H NMR (500 MHz, CDCl3): d = 7.38–7.31
(m, 7 H), 7.13 (d, 2 H, J = 8.0 Hz), 4.85 (d, 1 H, J = 10.5 Hz,
-CH2Ph), 4.77 (d, 1 H, J = 1.5 Hz, H-1), 4.66 (d, 1 H,
J = 10.5 Hz, -CH2Ph), 4.09 (dd, 1 H, J = 1.5, 3.5 Hz, H-2),
3.90–3.86 (m, 2 H, H-4, H-6a), 3.76–3.74 (m, 2 H, H-3, H-
6b), 3.32–3.29 (m, 1 H, H-5), 2.34 (s, 3 H, -SPhCH3), 2.07
(d, 1 H, J = 7.0 Hz, 6-OH). 13C NMR (125 MHz, CDCl3):
d = 138.53, 136.97, 132.29, 130.01, 129.49, 128.58, 128.35,
128.27, 86.95, 80.54, 75.28, 73.72, 66.75, 64.83, 61.70,
21.10. MS (ESI-TOF): m/z = 444 [M + NH4]+, 449 [M +
Na]+. Anal. Calcd for C20H22N6O3S: C, 56.32; H, 5.20; N,
19.70. Found: C, 56.51; H, 5.38; N, 19.56.
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(14) The reaction conditions such as solvents, temperature, and
ratio of reagents were investigated. The optimized reaction
conditions: molar ratio of NaH/BnBr/substrates (1.3:1.3:1),
DMF as solvent, reaction temperature (–15 °C to r.t.).
Compound 1b: 1H NMR (500 MHz, CDCl3): d = 7.39–7.30
(m, 7 H), 7.10 (d, J = 8.5 Hz, 2 H), 4.74 (d, J = 1.5 Hz, 1 H),
4.58 (dd, J = 8.5, 14.5 Hz, 2 H), 4.03–3.99 (m, 2 H), 3.81
(dd, J = 5.0, 10.0 Hz, 1 H), 3.75 (dd, J = 7.0, 10.0 Hz, 1 H),
3.63 (dd, J = 4.0, 10.0 Hz, 1 H), 3.45–3.41 (m, 1 H), 3.21 (d,
J = 1.5 Hz, 1 H), 2.33 (s, 3 H). 13C NMR (125 MHz, CDCl3):
d = 138.69, 137.33, 132.74, 130.17, 129.90, 128.86, 128.40,
128.19, 87.33, 78.02, 74.24, 71.34, 69.93, 66.50, 64.41,
21.38. MS (ESI-TOF): m/z = 444 [M + NH4]+, 449 [M +
Na]+. Anal. Calcd for C20H22N6O3S: C, 56.32; H, 5.20; N,
19.70. Found: C, 56.11; H, 5.30; N, 19.51.
Compound 1c: 1H NMR (500 MHz, CDCl3): d = 7.43–7.41
(m, 2 H), 7.35–7.30 (m, 7 H), 7.26–7.24 (m, 2 H), 7.07 (d,
J = 8.5 Hz, 2 H), 4.79 (d, J = 12.0 Hz, 1 H), 4.73 (d, J = 1.5
Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.58–4.54 (m, 2 H), 4.73
(dd, J = 1.0, 3.5 Hz, 1 H), 3.85 (t, J = 10.0 Hz, 1 H), 3.73–
3.71 (m, 3 H), 3.43–3.39 (m, 1 H), 2.32 (s, 3 H). 13C NMR
(125 MHz, CDCl3): d = 138.12, 137.98, 137.02, 132.18,
129.89, 129.82, 128.45, 128.30, 128.28, 128.10, 127.89,
127.60, 86.84, 80.37, 75.06, 74.20, 73.54, 68.64, 66.90,
64.79, 21.05. MS (ESI): m/z = 516 [M]+. Anal. Calcd for
C27H28N6O3S: C, 62.77; H, 5.46; N, 16.27. Found: C, 62.70;
H, 5.40; N, 16.25.
Synlett 2006, No. 8, 1217–1220 © Thieme Stuttgart · New York