Selective derivatization of d-galactose towards a practical synthesis of C-6 l-fucose analogues

Article abstract of DOI:10.1016/j.tetlet.2012.08.127

Starting from d-galactose, a convenient protocol is described for the synthesis of l-fucose C-6 analogue, 2,3,4,5-tetra-O-acetyl-5-(1,3-dithiolan-2- yl)-l-galactopyranose, in an overall yield of 40% after 6 steps, making use of stable intermediates. A chemoselective protection/deprotection strategy was studied using TBDMS and TBDPS silyl ethers for protection of d-galactose primary hydroxyl group.

Full text of DOI:10.1016/j.tetlet.2012.08.127

Tetrahedron Letters 53 (2012) 6633–6636
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective derivatization of D-galactose towards a practical synthesis of C-6
L-fucose analogues
⇑
Rui C. Pinto, Marta M. Andrade, Maria Teresa Barros
REQUIMTE, CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2012
Revised 2 August 2012
Accepted 29 August 2012
Available online 13 September 2012
Starting from
2,3,4,5-tetra-O-acetyl-5-(1,3-dithiolan-2-yl)-
making use of stable intermediates. A chemoselective protection/deprotection strategy was studied using
TBDMS and TBDPS silyl ethers for protection of -galactose primary hydroxyl group.
Ó 2012 Elsevier Ltd. All rights reserved.
D
-galactose, a convenient protocol is described for the synthesis of
L-fucose C-6 analogue,
L-galactopyranose, in an overall yield of 40% after 6 steps,
D
Keywords:
L
-Fucose analogues
Selective derivatization
Silyl ether cleavage
a
-
L
-Fucose is often a terminal monosaccharide in N- and
strategy consists in masking the aldose as a dithioacetal, com-
monly diethyl dithioacetal, and to proceed with the oxidation of
the primary hydroxyl group to the desired aldehyde, Scheme 1.
Diethyl dithioacetals are easily obtained by reaction of the sugar
with malodorous and highly volatile ethanethiol in strong acidic
medium.18 A better alternative is the formation of ethylene dithio-
acetals by reacting the aldose with ethan-1,2-dithiol, with the
advantage of being less volatile, thus facilitating preparative proce-
O-linked glycoconjugates that takes part in important cell–cell
interactions and cell migration.1 As such, it often serves as an
important molecular recognition element in various physiological
and pathological processes, including cancer metastasis,2 immune
responses3 and neuronal development.4,5 This biological relevance
has recently stimulated major interest in the synthesis of
a-L-fucose analogues that have been successfully applied in
chemical strategies for monitoring glycan and glycan-protein
dures, yielding D
-galactose ethylene dithioacetal (1).19 The primary
interactions.6–13
hydroxyl group of 1 was protected as a tert-butyldimethylsilyl
(TBDMS) or tert-butyldiphenylsilyl (TBDPS) ether, whilst the sec-
ondary hydroxyl groups were protected as acetyl (4, 6) or benzoyl
(7, 9) esters or benzyl ethers (10, 12), Scheme 2. These silyl ethers
were easily obtained through standard scalable protocols in overall
good yields, together with small amounts of peracetylated,
a-L-Fucose analogues can be easily synthesized from L-galact-
ose.11 However, it is far more interesting and sustainable to devel-
op synthetic strategies from readily accessible and cheaper
D
-galactose.14 There are a few methods reported in the literature
for the conversion of D-galactose into L-fucose. Flowers’ strategy
is lengthy and provides an overall yield of 15%.15 The method de-
scribed by Vogel and co-workers makes use of expensive reagents
and sticky intermediates,16 whilst Roy’s approach makes use of
crystalline intermediates, with an overall conversion of 34% from
S
OAc
OAc
O
S
OAc
D
-galactose diethyl dithioacetal.17 A recent method described by
OAc
Maeda et al. converts D-galactose into a C-6 azide fucopyranose
in 11 steps and a overall yield of 23%.14 Thus, it is of great and cur-
rent interest to develop new direct and handy procedures for the
CHO
H
CH2OR
H
conversion of
means of stable intermediates and with overall good yields.11
In order to convert -galactose into C-6 derived -fucose ana-
logues, it is necessary to transform the reducing end of the aldose
and to oxidize the primary OH group at C-6. The most convenient
D-galactose into valuable L-fucose analogues by
RO
H
H
OH
RO
H
H
HO
HO
OR
OR
H
OR
OR
H
O
D
L
RO
OH
HO
RO
D
-galactose
S
S
O
⇑
Corresponding author. Tel.: +351 212948361; fax: +351 212948550.
E-mail address: mtb@fct.unl.pt (M.T. Barros).
Scheme 1. Retrosynthetic analysis of fucopyranose C-6 analogue.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.127

6634
R. C. Pinto et al. / Tetrahedron Letters 53 (2012) 6633–6636
OR OR OR OR
OR OR
S
S
TBDMSO
RO
+
S
S
OR OR
5: R = Ac, 6%
8: R = Bz, 18%
4: R = Ac, 89%
7: R = Bz, 80%
OR OR
S
TBDMSCl, Py,
then Ac2O or
BzCl
TBDPSCl, Py,
then Ac2O or
BzCl
TBDPSO
S
1,2-
OR OR
OH
ethanedithiol,
HCl 37%, 0°C
6: R = Ac, 92%
9: R = Bz, 93%
HO
HO
-galactose
OH OH
S
O
HO
TBDPSCl,
Py
99%
NaH,
DMF,
S
68%
HO OH
OH OH
1
OH OH
S
OBn OBn S
BnBr, 0°C
D
TBDPSO
TBDPSO
S
S
86%
TBDMSCl,
Py
OH OH
3
OBnOBn
96%
OH OH
OH OH
12
NaH,
DMF,
BnBr, 0°C
S
OBnOBn S
OBn OBn S
TBDMSO
TBDMSO
BnO
+
S
S
S
OBn OBn
10, 74%
OBn OBn
11, 20%
2
Scheme 2. Selective derivatization of D-galactose.
perbenzoylated and perbenzylated by-products (5, 8 and 11,
respectively).
Deprotection of TBDMS ether 4 was tested using TBAF (Table 1,
entry 1).20 It was observed that an increase in the amount of TBAF
results in lower yields of the desired alcohol 13 and consequently
the following substrates were treated with only 1 equiv of TBAF.
Such a protocol provided low chemical yields, for acetylated
substrates 4 and 6 (Table 1, entries 1 and 2) and benzoylated sub-
strates 7 and 9 (Table 1, entries 3 and 4). Moreover, when TBDPS
ether 6 was treated with 1 equiv of TBAF, the yield again decreased
with the increased reaction time, from 46% (1 h) to 19% (4.5 h)
(Table 1, entry 2). However, this method delivered excellent con-
version of benzylated silyl substrates 10 and 12 into the desired
Deprotection of the C-6 silyl ethers was carried out using three
different methods, in order to optimize chemical yields: TBAF in
THF, hydrogenolysis using Pd/C and iodine in methanol. Deprotec-
tion yields and reaction conditions are summarized in Table 1. In
order to demonstrate the compatibility of the dithiolane function
towards these desilylation protocols, we have previously tested
substrates 5, 8 and 11, for each protocol. Full recovery of the initial
sugar was observed in all cases, proving that the dithiolane ring is
stable under these conditions.
Table 1
Selective deprotection of silane ethers
Method
A, B or C
OR2 OR2
S
OR2 OR2 S
R1O
HO
S
S
OR2 OR2
OR2 OR2
4: R1 = TBDMS, R2 = Ac
6: R1 = TBDPS, R2 = Ac
7: R1 = TBDMS, R2 = Bz
9: R1 = TBDPS, R2 = Bz
10: R1 = TBDMS, R2 = Bn
12: R1 = TBDPS, R2 = Bn
13: R2 = Ac
14: R2 = Bz
15: R2 = Bn
Entry
1
Substrate
Product
Method
(A) TBAF, THF
(B) H2, 10% Pd/C
(C) I2, MeOH
73% (24 h, 1 equiv I2)
81% (8 h, 2.5 equiv I2)
88% (15 h, 2.5 equiv I2)
100% (4.5 h, 5 equiv I2)
88% (4.5 h, 10 equiv I2)
4
55% (1 h, 1 equiv. TBAF)
34% (1 h, 2 equiv TBAF)
78% (17 h) + 19% 4
82% (24 h)
13
46% (1 h)
27% (3 h)
19% (4.5 h)
b
a
2
3
6
7
—
—
61% (20 h) + 38% 7
86% (26 h) + 12% 7
89% (48 h)
25% (96 h) + 74% 9
60% (1 h) + 17% 10
92% (2 h)
b
48% (1 h)
—
14
15
b
4
5
9
10
38% (22 h)
73% (1 h)
—
—
a
a
6
12
99% (5 h)
—
50% (24 h) + 30% 12
a
Initial substrate fully recovered after 48 h.
Initial substrate fully recovered after 72 h.
b

R. C. Pinto et al. / Tetrahedron Letters 53 (2012) 6633–6636
6635
alcohol 15 (Table 1, entries 5 and 6). The limited conversions of
TBAF, THF,
0°C, 5h
OBn OBn S
OBn OBn S
acetyl and benzoyl derivatives may be related to the inconvenient
migration of acetyl and benzoyl groups, due to the presence of the
strong basic fluoride ion.21–23
TBDPSO
HO
S
S
99%
OBn OBn
12
OBn OBn
15
Sajiki et al. have reported the cleavage of silyl ethers by hydrog-
enolysis using 10% Pd/C as being a chemoselective procedure
which is dependent on the solvent used. The authors found that
using methanol as the solvent there was a selective cleavage of
TBDMS and triethylsilyl (TES) over TPDPS and triisopropylsilyl
(TIPS) ethers.24,25 In addition to these chemoselectivity features,
this method offers several practical advantages, including practical
simplicity and lack of aqueous work-up.26 In this context, we have
subjected the silylated substrates to hydrogenolysis in methanol
using 10% Pd/C. We have not only observed selectivity in hydrog-
enolysis towards TBDMS silyl ethers, as reported by Ikawa
et al.,24 but also a dependency of the secondary alcohol protecting
groups. Acetylated TBDMS ether 4 was cleaved in 82% to yield the
corresponding alcohol (Table 1, entry 1), whilst benzoylated and
benzylated TBDMS ethers 7 and 10 were unreactive under this pro-
tocol (Table 1, entries 3 and 5). Such observation may be attributed
to chemical hindrance of the silyl ether caused by bulky benzoyl
and benzyl groups. To the best of our knowledge there are no
reports of such selectivity in recent literature, although steric con-
straints were reported by Rokach and co-workers in the deprotec-
tion of a bicyclic prostaglandin synthon.26
Finally, we have tested the cleavage of silyl ethers with I2 in
methanol at room temperature. This method has been described
in the literature as straightforward for deprotection of TBDMS
and our group have previously reported the chemoselectivity of
this protocol towards the deprotection of TBDMS in the presence
of TBDPS,27,28 the latter being readily cleaved under refluxing
methanol with Br2.29,30 Many authors have successfully applied
this procedure, but the amount of I2 used is variable among the
methods described. Therefore, we have varied the amount of io-
dine in the deprotection of 4 (Table 1, entry 1) concluding that
the use of 5 equiv of I2 is the most adequate. This optimized proto-
col was applied to the remaining substrates to provide overall good
deprotection yields of TBDMS ethers (Table 1, entries 3 and 5). Ben-
zylated TBDMS ether 10 was converted in 60% yield into alcohol 15
after 1 h, whilst the benzoylated derivative 7 was converted into
the same extent only after 20 h. TBDPS ethers were also cleaved
by means of this protocol, although they took longer (Table 1, en-
tries 4 and 6). This observation finds agreement with previous re-
ports in the literature claiming a kinetic selectivity of TBDMS over
TBDPS for this protocol.31 On the other hand, benzylated silyl
ethers 10 and 12 reacted much faster than benzoylated ones, 7
and 9, making this protocol suitable for rapid deprotection of silyl
ethers in benzylated substrates.
(COCl)2,
DMSO, CH2Cl2,
-78°C, then Et3N
86%
4 bar H2, 10% Pd/C,
MeSO3H,
MeOH/EtOAc 15:1, 48h,
then Ac2O, py, 6h
OBn OBn S
S
S
OAc
OAc
O
O
S
OAc
82%
OAc
OBn OBn
17
Scheme 3. Conversion of alcohol 15 into
16
L
-fucose C-6 analogue 17.
methanesulfonic acid, for 48 h. The unprotected
was immediately acetylated without purification to yield the
desired -fucose C-6 analogue 17 in 82% yield as the
b-anomer.
Dithioacetals are versatile intermediates in the synthesis for
masking and converting the carbonyl moiety.31 This protecting
group allows numerous synthetic transformations, including
reduction of carbonyl group to methylene, the interchange of car-
bonyl groups with adjacent methylene groups.31
L-fucopyranosyl
L
This procedure takes advantage of stable and easily handled,
intermediates to achieve an overall conversion of 40% from com-
mercially available and cheap D-galactose to L-fucopyranose deriv-
ative 17, offering an accessible and cheaper alternative to the
synthetic strategies currently described in the literature. Moreover,
we present a systematic study on the selective deprotection of silyl
ethers under three different conditions. We describe an interesting
and unpredicted selectivity for cleavage of TBDMS ethers by cata-
lytic hydrogenolysis for acetylated substrates. In other hand, iodine
mediated cleavage of silyl ethers proved to be a reliable and selec-
tive method for the deprotection of TBDMS as an alternative to
fluoride catalysed protocols that promote acetyl and benzoyl
groups migration.
Acknowledgments
This work was supported by Fundação para a Ciência e a Tecn-
ologia, grant PEst-C/EQB/LA0006/2011. The NMR spectrometers
are part of the National NMR Network (RNRMN) and are funded
by Fundação para a Ciência e a Tecnologia (FCT). Rui C. Pinto is
grateful to Fundação para a Ciência e a Tecnologia for his Grant
SFRH/BD/38204/2007.
An overview of the results summarized in Table 1 indicates
preferable methods for the deprotection of silyl ethers depending
on the secondary hydroxyl protecting groups. In this sense, the
cleavage of TBDMS in the presence of acetyl groups is more effec-
tive through hydrogenolysis whilst in the presence of benzoyl
groups iodine is more suitable. Instead, the cleavage of both
TBDMS and TBDPS in the presence of benzyl ethers proceeds pref-
erably by reaction with TBAF.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.127.
After the selective cleavage of silyl ethers, primary alcohols 13,
14 and 15 were submitted to Swern oxidation conditions to yield
the corresponding aldehydes, Scheme 3.
Although, the consumption of alcohols 13 and 14 was observed
by TLC, we were unable to isolate the desired aldehydes after puri-
fication and to confirm their structure. On the other hand, aldehyde
16 was isolated in excellent yield (86%), after purification by flash
chromatography with silica gel, Scheme 3.
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