Selective reduction of azido groups in monosaccharides with triphenylphosphine

Article abstract of DOI:10.1055/s-2006-950430

The regioselective reduction of one azido group in glycopyranoside and mannitol derivatives containing two azido functions with triphenylphosphine is described. In cyclic substrates with two secondary azides, equatorial azides were reduced in good yields

Full text of DOI:10.1055/s-2006-950430

2464
LETTER
Selective Reduction of Azido Groups in Monosaccharides with Triphenyl-
phosphine
S
elective Reductio
i
n
of
A
z
n
ido Groups in Mon
L
osaccharides
w
i
ith Tri
,
phenylphosp
Q
hine iu-Hua Fan, Li-He Zhang, Xin-Shan Ye*
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 13 May 2006
diaxial epoxide-opening with sodium azide.23 The re-
Abstract: The regioselective reduction of one azido group in gly-
maining azido functionalities of 1a–8a were introduced
by SN2 displacement of triflate or tosylate with sodium
azide in DMF. The structures of substrates 1a–8a were
copyranoside and mannitol derivatives containing two azido func-
tions with triphenylphosphine is described. In cyclic substrates with
two secondary azides, equatorial azides were reduced in good yields
in preference to axial azides. Steric, but not electronic, factors identified by their 1D and 2D NMR spectra. Inspection of
the 1H NMR spectra of 1a–8a, especially their 3JH-H cou-
appear to determine the regiochemical outcome of the Staudinger
reduction.
pling constants revealed that all of them retained the typi-
cal 4C1 chair conformation of the D-hexopyranosides.
Key words: selective reduction, azido group, monosaccharides,
triphenylphosphine, functional-group manipulation
With these diazides in hand, we proceeded to examine
their reduction with triphenylphosphine. The reaction was
performed by simply stirring the diazides with a solution
Aminosugars are a group of structurally diverse sugars
of triphenylphosphine in anhydrous THF at 65 °C until the
with hydroxyl groups substituted by amino groups in a
reaction went to completion (monitored by TLC). The in-
common sugar scaffold, and have been shown to be close-
termediate formed was then treated with water. For ease
ly related to the biological activities of the aminosugar-
of purification, the primary amines obtained were acety-
containing antibiotics.1–5 Of the various procedures avail-
able for the synthesis of amines, the azide reduction plays
lated using acetic anhydride in pyridine (Table 1). When
the allo-type diazide 1a was reduced by triphenylphos-
phine, only the 2-amino product 1b was isolated in 97%
yield, no 3-amino product 1c was detected (Table 1, entry
1). Similarly, the thioglycoside 2a, an anomeric isomer of
1a, underwent the reduction providing regioisomers 2b
and 2c in a ratio of 11:1 in a total yield of 93% (Table 1,
entry 2). The corresponding O-glycoside 3a was subjected
an important role because the preparation of azides can be
achieved with good regio- and stereocontrol.6 Since the
subsequent reduction permits an easy introduction of an
amino functionality, azides have proven to be useful pre-
cursors for amines in chemical synthesis. A number of
reagents7 such as borohydrides,8 triphenylphosphine,9
benzyltriethylammonium tetrathiomolydate,10 hexa-
to the same reduction conditions resulting in good regio-
methyldisilathiane (HMDST),11 samarium(II) iodide,12
selectivity (15:1, Table 1, entry 3). Treatment of 2,4-
and iron(III) chloride/sodium iodide,13 have been em-
diazidogalactoside 4a with triphenylphosphine again
yielded the 2-amino product 4b in excellent selectivity
(4b/4c, 1:0, Table 1, entry 4). Based on the experimental
results, it appears that the type of D-hexopyranoside has a
ployed for this reduction. On the other hand, regioselec-
tive manipulation of multiple amines, which is important
in organic transformations and especially for amino
sugar-containing antibiotic modification, is very difficult
great influence on the outcome of the reduction. Thus, the
to access. There are only a very limited number of exam-
reduction of 2,3-diazidodideoxyallopyranosides and 2,4-
ples reported for the selective reduction of azides.10,14–17
diazidodideoxygalactopyranoside proceeded with good to
Our attempt to explore the possibility of regioselective
excellent regioselectivity regardless of the anomeric ste-
reduction of one azido group in monosaccharides contain-
reochemistry and the nature of the anomeric substituents.
ing two azido groups prompted us to initiate a systematic
The reduction of 2,6-diazidodideoxyglucopyranoside,
investigation of the Staudinger reaction18–20 using tri-
2,3-diazidodideoxygulopyranoside, and 2,3-diazidodide-
phenylphosphine as the reducing agent. The results are
oxymannopyranoside, on the other hand, showed moder-
disclosed herein.
ate or even poor selectivities (Table 1, entries 5–8). The
The sugar diazides 1a–8a21 (Table 1) were synthesized by equatorial azido groups were generally more susceptible
using standard protocols. The C-2 azido groups of 1a–7a to reduction. It seemed that, compared with b-pyrano-
were introduced by the use of diazotransfer methodology sides, a-pyranosides usually displayed better selectivities
starting from the corresponding glucosamine or galacto- toward reduction.
samine.22 The C-2 azido group of 8a was introduced by
The Staudinger reduction has been known for several de-
cades, and the main features of its mechanism have been
discussed.18–20 However, a literature survey reveals that
very little attention has been paid to the regioselective
reduction of azides based on the Staudinger reaction.
SYNLETT 2006, No. 15, pp 2464–2468
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950430; Art ID: W10006ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
9
.2
0
0
6

LETTER
Selective Reduction of Azido Groups in Monosaccharides with Triphenylphosphine
2465
Table 1 Regioselective Azide Reduction
Entry
1
Substrates
Theoretical products
Results
Total yield (%)
97
O
O
O
O
O
O
Ph
Ph
Ph
O
O
O
1b/1c (1:0)
(1b only)24
N3
AcHN
N3
N3
STol
N3
STol
NHAc STol
1c
1a
1b
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
O
O
2
3
4
5
2b/2c (11:1)
3b/3c (15:1)
93
98
88
98
STol
STol
STol
OMe
N3
NHAc
N3
N3
N3
NHAc
2c
2a
2b
O
O
O
Ph
Ph
O
O
O
O
O
O
OMe
OMe
N3
NHAc
STol
N3
N3
N3
NHAc
3c
OBn
3a
OBn
3b
OBn
N3
AcHN
BnO
N3
O
O
O
4b/4c (1:0)
(4b only)
BnO
BnO
N3
N3
AcHN
STol
STol
4a
4b
N3
4c
NHAc
N3
O
O
O
HO
HO
AcO
AcO
AcO
5b/5c (1:3.0)
6b/6c (4.1:1)
+
AcO
N3
STol
N3
AcHN
STol
STol
5a
6a
5b
5c
Ph
Ph
Ph
O
O
O
O
O
O
O
6
7
99
85
O
AcHN
6b
O
N3
STol
N3
N3
N3
STol
NHAc STol
6c
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
7b/7c (2.0:1)
STol
STol
N3
STol
NHAc
N3
N3
NHAc
N3
7a
7c
7b
7a
NHAc
O
O
O
N3
O
N3
O
Ph
Ph
Ph
O
O
N3
O
AcHN
8
9
8b/8c (2.6:1)
9b/9c (1:2.1)
88
93
O
N3
STol
STol
STol
OAc
8b
8a
H
8c
H
H
H
H
HO
BnO
H
AcO
BnO
AcO
BnO
N3
NHAc
N3
N3
OH
OAc
NHAc
OBn
OBn
OBn
N3
H
H
H
H
H
H
H
9a
9b
9c
H
H
H
H
H
BnO
BnO
BnO
BnO
BnO
N3
NHAc
N3
BnO
+
OBn
OBn
OBn
10
10b/10c (1:2)
96
OBn
OBn
OBn
NHAc
N3
N3
H
H
H
H
H
H
10b
10c
10a
Synlett 2006, No. 15, 2464–2468 © Thieme Stuttgart · New York

2466
Q. Li et al.
LETTER
Knouzi and co-workers reported that steric hindrance tronic factors played only a minor role in determining the
could potentially allow a selective azide reduction in the outcome of the reaction under these conditions. For 5a, al-
Staudinger reaction.16 On the other hand, Chapyshev pre- though the C-2 azido group is more electron-deficient
sumed that electron-deficiency caused the selective nu- than the C-6 azido group, as indicated by the chemical
cleophilic addition of triphenylphosphine to the g-azido shifts of the corresponding protons adjacent to the azido
group of 2,4,6-triazidopyridines.14 The Wong group dis- groups, the less sterically hindered primary azido on C-6
closed that azides could be reduced with good regioselec- was reduced preferentially. The observed reduction selec-
tivity in moderate yields by a modification of the tivity of 5a was consistent with the conclusion of Knouzi
Staudinger reaction using trimethylphosphine at low tem- and co-workers. However, by comparing some entries of
peratures. They thought electronic factors determined the Table 1, the lower regioselectivity obtained in 6a–8a with
selectivity for azide reduction, thus, the outcome of the re- respect to 1a–3a, cannot be substantially attributed to
action was predictable by 1H NMR analysis of the starting steric factors. For example, it is not obvious that 3-azido
material.15 Steric and stereoelectronic effects were also in 6a is less hindered than in 1a. Therefore, some factors
suggested by the Chang group for the regioselectivity of other than steric factors, such as stereoelectronic factors,
selective Staudinger reduction of tetra-azidoneamine us- related to the different configuration of the sugars, may
ing trimethylphosphine.17
also play an important role.
With regard to the reduction of diazide substrates men- In an attempt to further clarify the influence of electronic
tioned above, the observed regioselectivity seemed to factors on the regioselectivity of azide reduction using
have little to do with the electronic factors. In fact, the azi- triphenylphosphine, a series of monosaccharide 8a deriv-
do groups reduced preferentially in these cases were not atives were prepared and their reactions with triphen-
always the more electron-deficient azido group, as indi- ylphosphine and water were examined (Table 3).
cated by their downfield proton chemical shifts of the pro- Benzylidene, benzyl, and acetyl groups were chosen as
tons adjacent to the azido groups (Table 2), but the the protecting groups of hydroxyls in diazidomannopyra-
equatorial azido groups. This selectivity probably arose nosides. As displayed in Table 3, whether the O-substitu-
from an initial selective nucleophilic attack by a molecule ents are electron-donating or electron-withdrawing
of triphenylphosphine on the nitrogen terminus in the groups, similar regioselectivities (ratio ranging from
equatorial azido groups of 1a–8a leading to the formation 1.5:1–3.4:1) towards azide reduction were observed, indi-
of the corresponding phosphazide intermediates due to the cating various O-substituents have practically no effect on
rigidity of the hexopyranose ring. We reasoned that the the selectivity of reduction. It appeared that the exhibited
axial groups (H or STol) on the carbon, which are three regioselectivity in the reaction of 11a–16a was again con-
bonds apart from the axial azido groups, might destabilize sistent with the conclusion that electronic factors play a
the phosphazides via unfavorable 1,3-diaxial interactions, minor role in determining the outcome of the reduction.
thereby decelerating the formation of adducts between
This paper describes the regioselective reduction of one
triphenylphosphine and the axial azido groups. Obvious-
azido group in glycopyranoside and mannitol derivatives
ly, this effect was not a small one as it completely over-
containing two azido groups with triphenylphosphine. It
rides the electron-deficient directing effect of the
seems that steric hindrance plays a major role in determin-
Staudinger reduction, as shown in cases of the reduction
ing which azido group will be reduced predominantly.
of 1a–4a (Table 1). Our argument was supported by the
The steric discrimination in the Staudinger reaction using
triphenylphosphine is attributed to the bigger size of tri-
phenylphosphine, which should allow the selective reduc-
tion of suitably situated azido groups in the presence of
those less favorably sited. The disclosed methodology
may find applications in regioselective manipulation of
reactions of triphenylphosphine with diazides 9a and 10a.
Compounds 9a and 10a were prepared from 8a via de-
sulfidation with NBS followed by reduction and benzyla-
tion.21 Our choice of 9a and 10a as substrates was based
on the consideration that there was no axial/equatorial dis-
crimination between C-2 and C-3 azido groups in linear
multiple amines and modification of aminosugar-contain-
9a and 10a. Indeed, as seen in Table 1, compared to their
ing antibiotics.
parent compound 8a, the reduction selectivity was re-
versed: the azido group reduced preferentially was the less
Acknowledgment
hindered azido group on C-2. The experimental results
suggested that the regioselectivity for reduction of azides
1a–8a was mainly attributed to steric hindrance arising
This work was financially supported by the National Natural Sci-
ence Foundation of China, ‘973’ grant from the Ministry of Science
from the rigidity of the hexopyranose ring and that elec- and Technology of China, and Peking University.
Table 2 Chemical Shifts of ipso-Protons of Azides in Substrates 1a–8a
Azides
1a
2a
3a
4a
5a
6a
7a
8a
d CHN3 (ppm)a 4.02 (2)
3.31 (2)
4.30 (3)
3.47 (2)
4.20 (3)
4.14 (2)
3.99 (4)
3.86 (2)
3.56 (6)
4.51 (2)
4.02 (3)
3.83 (2)
4.05 (3)
4.10 (2)
3.90 (3)
4.28 (3)
a The number in parentheses is the carbon position attached to the azido group.
Synlett 2006, No. 15, 2464–2468 © Thieme Stuttgart · New York

LETTER
Selective Reduction of Azido Groups in Monosaccharides with Triphenylphosphine
2467
Table 3 The Substituent Effect on Regioselectivity of Azide Reductions
Substrates
Products
Ratio
Total yield (%)
88
N3
O
NHAc
O
N3
O
O
O
N3
O
O
AcHN
O
Ph
Ph
Ph
8b/8c (2.6:1)
O
STol
STol
STol
N3
8b
8c
8a
OH
OAc
OAc
N3
O
NHAc
O
N3
O
9b/9c (1.5:1)
93
86
94
93
92
97
HO
AcO
N3
AcO
AcHN
STol
STol
N3
STol
11b
11a
11c
OH
OH
OH
N3
N3
NHAc
O
12b/12c (2.7:1)a
13b/13c (3.4:1)
12b/12c (2.0:1)a
11b/11c (2.0:1)
11b/11c (1.7:1)
O
O
BnO
N3
BnO
BnO
N3
STol
STol
STol
STol
STol
AcHN
12b
12a
12c
OBn
OBn
OBn
N3
NHAc
O
N3
O
O
BnO
N3
BnO
AcHN
BnO
N3
STol
STol
STol
13b
13a
13c
OH
OH
OAc
N3
NHAc
O
N3
O
O
BnO
N3
BnO
AcHN
BnO
N3
STol
STol
STol
12b
12c
14a
OAc
OAc
OAc
N3
NHAc
O
N3
O
O
AcO
AcHN
AcO
AcO
N3
STol
STol
N3
11b
11b
15a
11c
OAc
N3
O
HO
N3
11c
16a
a For ease of purification, after acetylation of the reduced products with Ac2O/py, the two inseparable isomers were de-O-acetylated by MeONa/
MeOH to yield 12b and 12c as separable products.
(11) (a) Capperucci, A.; Degl’Innocenti, A.; Funicello, M.;
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Synlett 2006, No. 15, 2464–2468 © Thieme Stuttgart · New York

2468
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LETTER
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was dissolved in py (3.0 mL) and Ac2O (1.5 mL) was added
dropwise at 0 °C. The mixture was stirred for 6 h at r.t. and
the solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel (PE–
EtOAc, 3:1 to 2:1) yielding the title compound 1b (64.5 mg,
97%) as a colorless oil. 1H NMR (500 MHz, CDCl3): d =
7.52–7.50 (m, 2 H), 7.40–7.36 (m, 3 H), 7.33 (d, 2 H, J = 8.0
Hz), 7.11 (d, 2 H, J = 8.5 Hz), 6.20 (d, 1 H, J = 9.5 Hz), 5.59
(s, 1 H), 5.32 (d, 1 H, J = 6.0 Hz), 4.66–4.59 (m, 2 H), 4.35
(dd, 1 H, J = 5.5, 10.5 Hz), 4.23 (t, 1 H, J = 3.0 Hz), 3.87 (dd,
1 H, J = 3.0, 10.5 Hz), 3.78 (t, 1 H, J = 10.5 Hz), 2.32 (s, 3
H), 2.08 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 169.44,
137.86, 136.77, 132.01, 131.71, 129.90, 129.27, 128.34,
126.15, 102.05, 88.94, 78.37, 68.88, 59.93, 59.86, 48.93,
23.28, 21.04. HRMS: m/z calcd for C22H25N4O4S [M + H]+:
441.1591; found: 441.1595.
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1a (64.2 mg, 0.15 mmol) in anhyd THF (4.0 mL) was added
PPh3 (44.0 mg, 0.167 mmol, 1.1 equiv), and the mixture was
stirred at 65 °C for 8 h. Then H2O (2.0 mL) was added, and
the mixture was stirred at 65 °C for another 8 h. The reaction
mixture was concentrated to dryness. The resulting residue
Synlett 2006, No. 15, 2464–2468 © Thieme Stuttgart · New York