Towards glucosamine building blocks: Regioselective one-pot protection and deallylation procedures

Article abstract of DOI:10.1055/s-0030-1259001

Glucosamine building blocks have been prepared by an efficient regioselective one-pot protection approach. This synthetic route enabled the straightforward preparation of a glucosamine disaccharide in 73% yield. The system Pd(PPh₃)₄/

Full text of DOI:10.1055/s-0030-1259001

LETTER
2711
Towards Glucosamine Building Blocks: Regioselective One-Pot Protection
and Deallylation Procedures
G
lucosamine Bui
a
lding Block
m
s
u Enugala, Luísa C. R. Carvalho, M. Manuel B. Marques*
REQUIMTE/CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa,
2829-516 Caparica, Portugal
Fax +351(21)2948550; E-mail: mmbmarques@dq.fct.unl.pt
Received 3 August 2010
portance of these glycosides there is a need to develop a
highly efficient and regioselective protection methodolo-
gy.13 Among the several synthetic strategies developed for
the synthesis of carbohydrates and especially for the con-
Abstract: Glucosamine building blocks have been prepared by an
efficient regioselective one-pot protection approach. This synthetic
route enabled the straightforward preparation of a glucosamine dis-
accharide in 73% yield. The system Pd(PPh3)4/TES was investigat-
ed as an alternative procedure for anomeric allyl ether deprotection. struction of complex oligosaccharides, the most attractive
is a one-pot procedure.14 Recently, one-pot approaches for
Key words: glucosamine, regioselective protection, one-pot proce-
glycosylation strategies15 and for regioselective protec-
dure, allyl ether deallylation, palladium catalysis
tion of glucose monosaccharides have been reported.16,17
Over the past few years, our research interest has been fo-
cused on glycopeptide chemistry,18 particularly in glyco-
Carbohydrates are well known as important targets for
modern therapeutics.1,2 Among the biologically relevant
carbohydrates are the glycoconjugates possessing resi-
dues of 2-amino-2-deoxy-b-D-glucopyranosyl (D-glu-
cosamino) series. Some of the most representative
examples are: chitin (1), a linear homopolymer of 2-acet-
amido-D-glucosamine (GlcNAc) that is a naturally abun-
dant mucopolysaccharide, and heparin (2), a linear
sulfated polysaccharide consisting of alternating N-sulfat-
ed D-glucosamine and L-iduronic acid units which is the
major factor in several biological processes3 (Figure 1).
sides containing the glucosamine moiety. Despite the
work developed by Hung and co-workers on glucose
monosaccharides,19 we investigated a one-pot approach
for the construction of glucosamine building blocks, in or-
der to establish a more efficient and rapid methodology
towards glucosamine disaccharides. Herein, we report the
preliminary results on the synthesis of glucosamine build-
ing blocks via a one-pot regioselective protection ap-
proach. Such an approach allows the protection of the
hydroxy groups with suitable groups while avoiding mul-
tistep sequences, laborious workups, separations and pu-
rifications, and provides the control for a regioselective
glycosylation.
Indeed, the most important classes of glycoconjugates and
oligosaccharides are those incorporating glucosamine res-
idues.4–6 Thus, the development of synthetic methods to-
wards glycosides and oligosaccharides containing the
glucosamine moiety has been the focus of a significant
amount of research.7–11 The less explored preparation of
monomeric building blocks (glycosyl acceptors and do-
nors) usually requires multistep sequences and involves
several protecting-group manipulations.8,12 Given the im-
We envisaged that a properly N-protected glucosamine
fully silylated at O-3, O-4, and O-6 could be used as key
intermediate to achieve glucosamine building blocks, do-
nors and acceptors, with a different substitution pattern,
via a one-pot sequential procedure (Scheme 1). Moreover,
we planned to explore the possibility of including the
OH
O
OH
NHAc
NHAc
O
HO
O
HO
O
O
O
HO
O
HO
O
O
NHAc
NHAc
OH
OH
chitin (1)
–
OSO3
–
O
HO2C
OSO3
O
HO
–O3SHN
OH
O
O
O
–
O
HO
–O3SHN
OSO3
HO2C
O
O
O
HO2C
O
–O3SO
HO
O
–O3SO
OH
OH
O
OH
–O3SHN
heparin (2)
–O3SO
Figure 1 Some representative examples of glycoconjugates composed mainly of glucosamine blocks
SYNLETT 2010, No. 18, pp 2711–2716
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.10.2010
DOI: 10.1055/s-0030-1259001; Art ID: D21210ST
© Georg Thieme Verlag Stuttgart · New York

2712
R. Enugala et al.
LETTER
glycosylation as the last step of the one-pot synthetic se- cosamine we decided to use a benzyl ether as the perma-
quence.
nent protecting group. Thus, a solution of 3 in dry CH2Cl2
at –86 °C with 3 Å MS, was treated with benzaldehyde
and TMSOTf as catalyst. The reaction was monitored by
TLC,25 and after formation of the arylidene acetal, benzal-
dehyde, triethylsilane (TES), and TMSOTf were added.
The fully protected glucosamine 5 was formed and the se-
The synthesis started with the crucial choice of the pro-
tecting groups, for both the anomeric position and the
amine group. It has been reported that glycosylation of ag-
lycones with glycosyl donors bearing a 2-acetamido-2-
deoxy functionality is usually not viable.7,9,11 It is also
well demonstrated that the choice of protecting groups can
influence the reactivity of the glycosyl acceptor and con-
sequently the glycosylation step.19 Wong and co-
workers20 have confirmed that the reactivity of 2-amino
sugar acceptors can be suitably tuned by the N-protecting
group. To overcome these problems several N-protecting
groups have been developed.8,12 Indeed, it was reported
that N-trichloroethoxycarbonyl-protected (N-Troc) glu-
cosamine is 33.7-fold more reactive than the correspond-
ing N-phthaloyl-protected (N-Phth) glucosamine.
lective benzylidene acetal ring opening could be achieved
26,12
by sequential addition of TES, and BF3·OEt2.
Com-
pound 7 was purified and isolated in 60%.27 Alternatively,
compound 5 could be isolated in 71% yield by quenching
the reaction at stage ii. Similar reaction conditions were
carried out for thioglycoside 4. However, at stage i at –86
°C the reaction mixture became too viscous to allow stir-
ring, thus conditions were optimized at –20 °C for the next
stages (ii and iii). The compound 8 was purified and iso-
lated in 33% yield.27 Alternatively, fully protected com-
pound 6 could be isolated in 61% yield by quenching the
reaction at stage ii. This approach represents a straightfor-
ward route to the thioglycosides 6 and 8 that can be used
for oligosaccharides synthesis. Indeed, literature report24
for the synthesis of 8 involved additional protecting-group
manipulations such as the installation of a temporary
D-glucosamine
labile leaving group
R4O
O
R3O
R2O
OR1
TMSO
TMSO
TMSO
NHPG
O
donor
one-pot
OR1
NHPG
TMSO
TMSO
TMSO
R4O
HO
R2O
O
O
R
OR1
NHTroc
NHPG
one-pot
3 R = α-OAllyl
4 R = β-STol
free hydroxy group
acceptor
Scheme 1 Proposed strategy for the synthesis of glucosamine buil-
ding blocks
i), ii)
The use of allyl ether as a protecting group for the anomer-
ic position is of great importance in carbohydrate chemis-
try, due to its easy formation and stability under different
reaction conditions.21 Alternatively, thioglycosides are
widely used as glycosyl donors due to their easy prepara-
tion, stability and versatility, and S-p-methylphenyl
(STol) can be used directly for glycosylation.20 Therefore,
Troc group was used as the nitrogen protecting group,
while OAllyl and STol were used as protecting groups for
the anomeric position.
O
BnO
HO
BnO
iii)
Ph
O
O
O
BnO
R
R
NHTroc
NHTroc
5 R = α-OAllyl (71%)
6 R = β-STol (61%)
7 R = α-OAllyl (60%)
8 R = β-STol (33%)
7 + 9
1) 5, deallylation conditions
2) CCl3CN, Cs2CO3
TMSOTf (15 mol%),
CH2Cl2, 3 Å MS
15 min, –15 °C
Synthesis of the glucosamine building blocks started with
the preparation of the key intermediates 3 and 4. The syn-
thesis involved silylation of the known N-Troc allyl22,23
and N-Troc S-Tolyl glycosides20,24 in 88% and 70% yield,
respectively.
O
Ph
BnO
O
BnO
O
O
O
BnO
TrocHN
TrocHN
OAllyl
O
Ph
O
10 (73%)
O
The synthetic protocol consisted of a one-pot regioselec-
tive protection sequence catalyzed by trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf). The strategy
involved the following steps: (i) O-6 and O-4 protection
with an arylidene acetal; (ii) reductive arylmethylation of
O-3 to produce fully protected compounds 5 and 6; and
(iii) regioselective reductive opening of the benzylidene
group to produce 7 and 8 with a free O-4 position
(Scheme 2). To investigate this approach with glu-
BnO
TrocHN
O
CCl3
NH
9 (87%)
Scheme 2 Synthesis of a N-Troc glucosamine disaccharide via a
one-pot procedure for the monosaccharide’s preparation. Reagents
and conditions: i) PhCHO, TMSOTf, CH2Cl2, 3 Å MS, –86 °C; ii)
PhCHO, TES, TMSOTf; iii) TES, BF3·OEt2.
Synlett 2010, No. 18, 2711–2716 © Thieme Stuttgart · New York

LETTER
Glucosamine Building Blocks
2713
azide at C-2 to introduce the benzyl group at O-3, fol- underwent glycosylation promoted by NIS. This approach
lowed by Staudinger reaction to restore the amino group. has not been applied to the glucosamino moieties.
Such a multistep sequence involving many isolation and
purification procedures is avoided in the present route.
an iridium complex is usually performed with moderate to
Although the isomerization of the allyl group catalyzed by
The next step requires allyl ether cleavage in 5, but the high yields, the reaction is highly sensitive, and dependent
methods available are not compatible with a one-pot pro- on the control of the reaction conditions. Thus, alternative
cedure. In our first approach, the iridium complex28 was approaches to the isomerization of the anomeric allyl
used for the isomerization of 5, using the reported proto- group were also investigated. Preliminary studies were
col, followed by treatment with I2 to afford the deallylated performed with N-acetyl glucosamine derivative 11. After
compound. The free hydroxy group was treated with treatment of 11 with Pd(OAc)2, t-BuMe2SiH, and Et3N,40
Cs2CO3 and CCl3CN, affording the glycosyl trichloroace- the reduction product 12 was obtained in 85% yield.
timidate 9 in 87% yield. The initial plan involved a one-
pot glycosylation, as the last step of the procedure. How-
ever, the glycosylation did not proceed at all; probably
due to the conditions resulting from the previous step in
The system Pd(II)-TES has been reported for the reduc-
tion and isomerization41 of olefins under mild conditions.
We explored a similar system for the deallylation of 11
(Scheme 3, Table 1).42
the sequence. Thus, the glycosylation reaction was per-
Thus, to examine the Pd(0)/TES system for the isomeriza-
formed on isolated 7 and 9 under standard conditions to
tion of O-allyl glucosamine derivatives we first attempted
afford disaccharide 10 in 73% yield.27
the reaction of 11 with Pd(PPh3)4. Accordingly the condi-
Common deallylation methods consist of two-step proce-
dures, involving allyl isomerization to a labile prop-1-enyl
ether followed by hydrolytic cleavage. Deprotection of
tions were changed to TES and 5 mol% Pd(PPh3)4, and 13
was observed in 51% yield by 1H NMR (cis/trans = 2:0.1)
and isolated (after deallylation; Table 1, entry 1). The op-
the allyl group has been achieved using catalysts, such as
timized conditions for isomerization were achieved
iridium,29 (Ph3P)3RhCl,30 PdCl2/CuCl/O2,31 Pd/C,32 Ti(O-
through a series of experiments, consisting of sequential
i-Pr)4/BuMgCl,33 Pd(PPh3)/TsOH,34 CP2Zr,35 NaCNBH3/
changes of catalyst loading (Table 1). However, applying
TMSCl,36 t-BuLi,37 and NBS/hn.38 The use of vinyl glyco-
these conditions to N-Troc glucosamine derivative 5, re-
sides directly in the glycosylation was described by Wang
action being carried with 1 mol% of Pd(PPh3)4, only 32%
and co-workers.39 However, this methodology did not
of the isomerized product 15 was obtained (entry 2). A
better result was obtained when the 5 mol% of catalyst
was used, and the isomerized product 15 was observed by
avoid the use of the expensive iridium complex as catalyst
to afford the 1-propenyl glycoside intermediate, which
Table 1 Isomerization vs. Reduction of O-Allyl-Protected Glucosamine 11 and 5 in the Presence of Pd/TES System
Entry
1a
Compound
Pd(PPh3)4 (mol%) Solvent
Time (h)
24
Temp (°C)
r.t.
Products
Yield (%), cis/transc
11
5
CH2Cl2
CH2Cl2
CH2Cl2
THF
12
13
trace
51 (2:0.1)
2a
5
5
5
5
5
5
5
5
1
72
24
12
24
24
12
12
24
r.t.
r.t.
–5
r.t.
–5
r.t.
–5
r.t.
14
15
trace
32 (2:1)
3a
5
14
15
trace
48 (2:1)
4a
5
14
15
95
–
5a
20
20
20
20
30
CD2Cl2
CH2Cl2
CH2Cl2
CD2Cl2
CH2Cl2
14
15
20
50 (2:1)
6a
14
15
19
52 (2:1)
7b,d
8b,d
9a
14
15
20
40 (2:1)
14
15
86
trace
14
15
20
53 (2:1)
a TES addition to a mixture of catalyst and 5.
b Catalyst and TES (stirred for 30 min) followed by 5 addition.
c Isolated after deallylation, except in entries 5–7 (yield of 14 determined by 1H NMR).
d The reaction was monitored for 24 h; however, after 12 h no evolution was observed.
Synlett 2010, No. 18, 2711–2716 © Thieme Stuttgart · New York

2714
R. Enugala et al.
LETTER
The effect of order of reagents addition and temperature
was also investigated. In order to study how the order of
addition of reagents influences the reaction outcome, the
addition of 5 and TES was inverted. Thus, addition of 5 to
a mixture of 20 mol% Pd(PPh3)4 and TES at room temper-
ature afforded a lower yield of 15 (40%) and the reduced
compound 14 (20%) (entry 7). A similar result was ob-
tained when TES was added to a mixture of 20 mol%
Pd(PPh3)4 and 5 at room temperature, afforded 15 (50%)
and 14 (20%; entry 5).
O
O
Pd(OAc)2
Ph
O
t-BuMe2SiH⋅Et3N
BnO
12 (85%)
RHN
CH2Cl2 r.t., 24 h
O
11 R = Ac
5 R = Troc
Pd(PPh3)4 (5 mol%),
TES
CH2Cl2, r.t., 24 h
O
O
Ph
O
Ph
O
O
O
Several experiments were carried to investigate the influ-
ence of reaction temperature (entries 5 and 6; entries 7 and
8). The formation of 14 is enhanced if the mixture of Pd/
TES is allowed to stir previously at –5 °C for 30 minutes,
affording 14 with 86% yield (entry 7 vs. entry 8). Thus,
we observed that the combination of temperature and or-
der of addition of reagents play a major role in isomeriza-
tion vs. reduction.
BnO
BnO
+
RHN
RHN
O
O
12 R = Ac (trace)
14 R = Troc (trace)
13 R = Ac (51%)
15 R = Troc (48%)
I2
In summary, an efficient regioselective one-pot synthesis
of glucosamine building blocks was developed. Current-
ly, this approach is being applied to other glucosamine de-
rivatives. The Pd(PPh3)4/TES new isomerization method
described appears as an alternative to the costly and com-
monly used metal complexes. Despite the modest yield
obtained for the isomerized compound, it represents a step
forward in deallylation procedures. It is believed that ad-
vances on one-pot syntheses and allyl-deprotection proto-
cols are a valuable contribution to the improvement of the
synthetic efficiency in carbohydrate chemistry.
O
Ph
O
O
BnO
RHN
OH
16 R = Ac (quantitative)
17 R = Troc (quantitative)
Scheme 3 Isomerization of the allyl group catalyzed by Pd/TES
1H NMR in 48% yield and isolated (entry 3). Changing the
reaction solvent from CH2Cl2 to THF, gave almost exclu-
sively the reduction product (entry 4).
Encouraged by these initial results, we decided to monitor
the reaction by 1H NMR. Expecting to obtain a reduction
in reaction time, we carried out the first experiments using
20 mol% Pd(PPh3)4. Addition of TES to a mixture of 20
mol% Pd(PPh3)4 and 5 in CD2Cl2, at room temperature,
led to the isomerized product 15 in 50% yield and 14 in
20% (entry 5). The characteristic Hb multiplet of 5 could
be seen at d = 5.89 ppm, while in the isomerized product
15, the Hb signal appeared as a multiplet at d = 4.66 ppm.
Due to the presence of cis/trans isomers, the Hc proton
resonance appeared as a double doublets at d = 6.03 and
6.12 ppm (2:1; Scheme 4). The reduced compound 14
could also be observed under these conditions, as indicat-
ed by proton resonances for Hc at d = 3.41 and 3.64 ppm.
Acknowledgment
R. Enugala thanks Fundação para a Ciência e Tecnologia for a post-
doctoral fellowship (SFRH/BPD/42134/2007). This work was also
carried out in the framework of the project PTDC/SAU-IMU/
111806/2009. The authors would also like to thank Dr. Sérgio Filipe
for the helpful discussions.
References and Notes
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Further increase in the catalyst loading did not significant-
ly improve the yield of the isomerized product 15, but pro-
moted the formation of the reduction product 14 (entry 9).
O
O
Ph
Ph
O
BnO
Hb (1.55 ppm)
Ha (0.91 ppm )
TrocHN
O
O
TES (1.2 equiv)
14
O
Ph
O
Pd(Ph3)4 (20 mol%)
Hc (3.41 and 3.64 ppm)
BnO
+
Hb (5.89 ppm)
Ha (5.30 ppm)
Hc (3.99, 4.19 ppm)
CD2Cl2 (0.5 mL)
TrocHN
O
O
5
O
O
BnO
Hb (4.66 ppm)
TrocHN
15
O
Ha (1.55 ppm )
Hc (6.03, 6.12 ppm)
Scheme 4 1H NMR of reaction of 5 with 20 mol% Pd(PPh3)4-TES at r.t.
Synlett 2010, No. 18, 2711–2716 © Thieme Stuttgart · New York

LETTER
Glucosamine Building Blocks
2715
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69.8, 70.2, 71.9, 73.6, 74.4, 74.5, 80.1, 95.3, 96.8, 117.9,
127.6, 127.7, 128.4, 128.5, 133.3, 137.7, 138.2, 154.1.
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ArH), 5.11 (br s, 1 H, NH), 4.90 (d, 1 H, J = 9.7 Hz, H-1),
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J = 9.0 Hz, H-4), 3.52–3.50 (m, 1 H, H-5), 3.35 (dd, 1 H,
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25
Compound (10): colorless solid; mp 176–179 °C; [a]D
+43.3 (c 0.12, CHCl3). 1H NMR (400 MHz, CDCl3, 23 °C):
d = 7.49–7.26 (m, 20 H, ArH), 5.89–5.80 (m, 1 H,
CH2CH=CH2), 5.42 (s, 1 H, CHPh), 5.28–5.20 (m, 2 H,
CH2CH=CH2), 4.95–4.55 (m, 10 H, H-1, 2 × CH2Ph,
CH2Ph, 2 × CH2CCl3), 4.29 (d, 1 H, J = 12.1 Hz, CH2Ph),
4.13–3.95 (m, 5 H, CH2CH=CH2, H-2, H-1¢, H-3¢), 3.76–
3.44 (m, 6 H, H-6¢, H-2¢, H-4¢, H-3, H-5, H-6), 3.20–3.11 (m,
3 H, H-4, H-5¢, H-6¢). 13C NMR (100 MHz, CDCl3, 23 °C):
d = 54.6, 57.4, 65.4, 66.8, 68.4, 68.5, 70.2, 73.6, 73.9, 74.5,
76.5, 77.7, 78.0, 82.1, 95.4, 95.5, 96.7, 100.9, 101.1, 118.2,
126.0, 127.2, 127.8, 128.2, 128.3, 128.4, 129.0, 129.8,
133.2, 137.2, 137.7, 138.2, 138.9, 154.0, 154.1. HRMS
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(42) General Procedure for the Isomerization
To a solution of compound 5 or 11 (0.14 mmol) and Pd(PPh3)4
(8 mg, 5 mol%) in dry CH2Cl2 (3.2 mL) was added TES (27
mL, 0.17 mmol). After stirring for 24 h at r.t., the reaction
mixture was quenched with sat. aq solution of NaHCO3 (1
mL) and extracted with CH2Cl2. The organic layer was
washed with brine (1 mL), dried over Na2SO4, and
(27) Selected Spectroscopic Data
Compound (7): white solid; mp 63–65 °C; [a]D25 +58.8 (c
0.5, CHCl3). 1H NMR (400 MHz, CDCl3, 23 °C): d = 7.49–
7.26 (m, 10 H, ArH), 5.90 (m, 1 H, CH2CH=CH2), 5.23 (d, 1
H, J = 17.4 Hz, CH2CH=CH2), 5.24 (d, 1 H, J = 10.1 Hz,
CH2CH=CH2), 5.16 (d, 1 H, J = 9.7 Hz, NH), 4.80–4.70 (m,
3 H, H-1, CH2CCl3), 4.67–4.54 (m, 4 H, CH2Ph), 4.17 (m, 1
H, CH2CH=CH2), 4.01–3.98 (m, 2 H, H-2, CH2CH=CH2),
3.70–3.60 (m, 5 H, H-4, H-5, H-6a, H-6b, H-3), 2.66 (br s, 1
Synlett 2010, No. 18, 2711–2716 © Thieme Stuttgart · New York

2716
R. Enugala et al.
LETTER
concentrated under reduced pressure.
Selected Spectroscopic Data
4.25 (m, 2 H, H-5, H-6), 3.84–3.74 (m, 4 H, H-3, H-2, H-4,
H-6), 1.91 (s, 3 H, COCH3), 1.54 (d, J = 6.9 Hz, 3 H,
CH=CHCH3). 13C NMR (100 MHz, CDCl3, 23 °C): d = 10.5,
23.2, 52.4, 63.4, 69.7, 68.8, 74.0, 75.4, 82.7, 98.1, 101.2,
104.8, 125.9, 127.6, 127.8, 128.1, 128.2, 128.4, 128.9,
137.2, 138.3, 141.5, 169.9. HRMS–FAB: m/z calcd for
C25H29NO6Na: 462.1887; found: 462.1658.
Compound (13): 1H NMR (400 MHz, CDCl3, 23 °C): d =
7.52–7.28 (m, 10 H, ArH), 6.01 (d, 1 H, J = 4.4 Hz,
CH=CHCH3), 5.59 (s, 1 H, CHPh), 5.25 (d, 1 H, J = 9.3 Hz,
NH), 5.04 (d, 1 H, J = 3.6 Hz, H-1), 4.95–4.90 (m, 1 H,
CH2Ph), 4.67–4.59 (m, 2 H, CH2Ph, CH=CHCH3), 4.34–
Synlett 2010, No. 18, 2711–2716 © Thieme Stuttgart · New York

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