3-Butenyloxycarbonyl as a new hydroxyl protecting group in carbohydrate synthesis

Article abstract of DOI:10.1016/j.tetlet.2016.05.078

3-Butenyloxycarbonyl (Bloc) has been identified as a new hydroxyl protecting group, which can be introduced under mild conditions in high yields and selectively removed by OsO₄/NaIO₄/2,6-lutidine in CH₃CN-H₂O wi

Full text of DOI:10.1016/j.tetlet.2016.05.078

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
3-Butenyloxycarbonyl as a new hydroxyl protecting group in
carbohydrate synthesis
y
y
⇑
Nana Zeng , Youhong Niu , Xin-Shan Ye
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Butenyloxycarbonyl (Bloc) has been identified as a new hydroxyl protecting group, which can be intro-
duced under mild conditions in high yields and selectively removed by OsO4/NaIO4/2,6-lutidine in
CH3CN–H2O without affecting most commonly-used protecting groups. Moreover, this new protecting
group is inert under glycosylation conditions.
Received 22 April 2016
Revised 18 May 2016
Accepted 20 May 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
3-Butenyloxycarbonyl
Protecting group
Orthogonality
Oxidative cleavage
Protecting groups play important roles in the synthesis of com-
plex compounds. It is especially true for the chemical synthesis of
carbohydrates,1 which contain a large number of same functional
groups, and they must be differentiated to achieve chemoselectiv-
ity and regioselectivity. The protection and deprotection of hydro-
xyl groups are still major manipulations in oligosaccharide
synthesis. Therefore, the development of new protecting groups
which can be employed in orthogonal protection strategy,2 known
as an effective protocol for the oligosaccharide assembly, is still in
demand in carbohydrate chemistry. The ideal orthogonal protect-
ing groups should be easily introduced and inert under common
reaction conditions, and can be removed selectively without caus-
ing any other undesired transformations. Besides being described
in the book,3 some new protecting groups showing good orthogo-
nality have been reported in the last two decades, these include
ether groups such as PPB,4 2-arylallyl,5 POMB,6 4-trifluoromethyl-
benzenepropargyl,7 4-(tert-butyldiphenylsiloxy)-3-fluorobenzyl,8
DMPBn,9 and Msem groups,10 ester groups such as 2-(allyloxy)phe-
nyl acetyl,11 AMPA,12 AZMB,13 NPAc,14 MPMDB, and AzDMB,15 and
carbonate groups such as CPEOC16 and Msc17. Given the growing
interest in the synthesis of oligosaccharides and their biological
studies, it is still in demand to find orthogonal protecting groups
for reducing the number of building blocks or synthetic intermedi-
ates required in oligosaccharide construction.
the ozonolysis of alkene and beta-elimination of acrolein in buffer
solution. Inspired by this work, we envisaged that 3-butenyloxy-
carbonyl (Bloc) group, in which the carbonic ester is even a better
leaving group than the ether, could serve as a new protecting group
which can be selectively removed by oxidative cleavage
(Scheme 1). The removal of this group may include an initial
OsO4-catalyzed dihydroxylation of the double bond in 1, followed
by periodate oxidation of the resulting glycerol derivative 2 to
provide the aldehyde 3 which could undergo the intramolecular
elimination under basic conditions to release the free hydroxyl
group-containing compound 4. Based on this assumption, herein
we report our investigation on introduction of 3-butenyloxycar-
bonyl (Bloc) protecting group and its orthogonality with most
commonly-used protecting groups in sugar building blocks.
Having this idea in mind, we started to find suitable conditions
for the introduction of 3-butenyloxycarbonyl (Bloc) group. After
careful screening of bases, solvents, and additives, it was found
that the protection of 6-OH in glycoside 5a with BlocCl was
achieved using TMEDA as a base in CH2Cl2 at 0 °C in 93% yield
(Table 1).19 The use of other bases such as triethylamine and pyr-
idine led to lower yields (83% and 88% respectively). The optimized
conditions were then applied to other different carbohydrate
building blocks, and it was shown that the introduction of this pro-
tecting group was accomplished in excellent yields regardless of
primary or secondary hydroxyl groups (Table 1). Furthermore,
the reaction conditions were compatible with a variety of other
protecting functionalities such as ketal, benzyl ether, silyl ether,
ester, and benzylidene groups.
Koide and co-workers18 reported that the 3-butenyl masked flu-
orophore can specifically detect ozone in turn-on manner through
⇑
Corresponding author. Tel.: +86 10 8280 5736; fax: +86 10 8280 2724.
E-mail address: xinshan@bjmu.edu.cn (X.-S. Ye).
After finishing the introduction of Bloc, we then proceeded to
optimize the conditions for deprotection of Bloc20 and test the
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2016.05.078
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zeng, N.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.078

2
N. Zeng et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 2
O
Optimization of deprotection conditions of Bloc
RO
O
1
OsO4
OH
O
ROH
H
OH
O
BnO
OMe
7a
O
4
O
+ CO2
PMBO
BnO
O
O
PMBO
BnO
+H+
O
OH
BnO
8a
OMe
RO
O
O
2
RO
O
O
Entry Deprotection conditions
Yield
(%)
NaIO4
O
-H+
1
2
3
4
5
RuCl3 (0.1 equiv), NaIO4 (3.0 equiv), CH3CN/H2O (4:1), rt,
24 h
OsO4 (0.1 equiv), NaIO4 (3.0 equiv), NMO, THF/H2O (1:1), rt, 72
0
RO
O
O
3
Scheme 1. Removal of 3-butenyloxycarbonyl group via oxidative cleavage.
8 h
OsO4 (0.1 equiv), PhI(OAc)2 (3.0 equiv), 2,6-lutidine, THF, rt, 60
5 h
OsO4 (0.1 equiv), NaIO4 (3.0 equiv), 2,6-lutidine, dioxane/
H2O (3:1), rt, 7 h
OsO4 (0.1 equiv), NaIO4 (3.0 equiv), 2,6-lutidine, CH3CN/H2O 93
(4:1), rt, 4 h
88
Table 1
Introduction of the Bloc groupa
O
O
TMEDA
O
OR
Cl
O
O
O
O
HO
CH2Cl2, 0 oC to r.t.
OR
Table 3
Orthogonality of the Bloc group with common protecting groups
Entry
1
Substrate
Product
Yield (%)
O
O
O
O
OH
OBloc
O
RO
O
OR
O
OR
O
OH
O
HO
O
O
O
O
O
B
O
RO
OMe
OMe
A
5a
6a
R = AcCl
6b R = o-NO2Bn
R = AcCl
93
90
5b R = o-NO2Bn
Entry
1
Substrate
Aa (yield)
B (yield)
OH
OBloc
O
RO
O
O
O
O
RO
OBloc
OBloc
OH
O
BnO
BnO
O
O
BnO
OMe
BnO
O
OMe
O
O
2
HO
ClAcO
ClAcO
OMe
7a
R = PMB
OMe
OMe
8a
95
90
92
R = PMB
17b (89%)
6a
5a (90%)
7b R = Ac
7c R = Bz
8b R = Ac
8c R = Bz
O
O
O
OBloc
OH
OBloc
O
O
O
Ph
LevO
O
Ph
LevO
O
O
O
O
O
O
O
O
2
o-NO2BnO
OMe
o-NO2BnO
HO
OMe
OMe
3
4
HO
BlocO
90
OMe
OMe
6b
17c (96%)
5b (92%)
9
10
OH
OBloc
OBloc
OR
O
OR
O
O
PMBO
HO
O
PMBO
BnO
O
BlocO
BnO
HO
BnO
BnO
3
4
5
BnO
OMe
(93%)
BnO
BnO
OMe
BnO
BnO
OMe
BnO
OMe
OMe
18d
8a
(97%)
7a
12a
98
97
88
R = TBDPS
11a
R = TBDPS
11b R = Trt
11c R = Piv
12b R = Trt
12c R = Piv
Ph
LevO
Ph
LevO
Ph
O
O
O
O
O
O
O
O
O
HO
HO
(95%)
BlocO
OMe
BlocO
OMe
OMe
HO
OBloc
O
19e
9
10
Ph
Ph
(96%)
O
AllO
O
AllO
O
O
O
89
5
6
OTBDPS
OTBDPS
OH
OMe
OH
OMe
O
BlocO
BnO
O
O
BlocO
BnO
HO
13
BnO
14
BnO
BnO
BnO
OMe
OMe
OMe
11a (90%)
20f (89%)
OBloc
O
BnO
BnO
NapO
BnO
BnO
NapO
12a
O
91
OTrt
OH
OTrt
OMe
OMe
O
O
BlocO
BnO
O
BlocO
BnO
HO
BnO
15
16
6
7
BnO
BnO
OMe
BnO
OMe
OMe
20g (92%)
12b
a
11b (85%)
General conditions: sugar substrate (1.0 equiv), 3-butenyl chloroformate
(1.5 equiv), TMEDA (1.5 equiv), CH2Cl2, 0 °C to rt, 3 h.
OBloc
O
OH
BnO
OBloc
BnO
BnO
BnO
O
BnO
O
BnO
HO
NapO
NapO
OMe
OMe
15 (88%)
OMe
21h (86%)
16
orthogonality of the Bloc group against some common protecting
groups. As shown in Table 2, the deprotection of compound 8a
was performed. It was found that the deprotection of Bloc group
can be realized to provide 7a in 93% isolated yield under the con-
ditions of OsO4, NaIO4, and 2,6-lutidine in CH3CN–H2O. Using the
optimized conditions, we began to survey the compatibility of
deprotection conditions with other protecting groups.
We first investigated the orthogonality of Bloc group against the
commonly-used protecting groups which can be removed by base.
For example, chloroacetyl group is even sensitive to NaHCO3 in
methanol. However, when the monosaccharide building block 6a
was treated with OsO4, NaIO4, and 2,6-lutidine, the product 5a
was isolated in 90% yield and no deprotection product of
chloroacetyl group was observed (Table 3, entry 1). Similarly, when
a
General conditions: substrate (1.0 equiv), OsO4 (0.1 equiv), NaIO4 (3.0 equiv),
2,6-lutidine (2.0 equiv), CH3CN/H2O (4:1), rt, 3–7 h.
b
Reaction conditions: 6a, saturated NaHCO3, MeOH/H2O (V/V = 5:1), THF, rt, 6 h.
Reaction conditions: 6b, UV irradiation, CH3CN, 1 h.
c
d
Reaction conditions: 8a, trifluoroacetic acid, CH2Cl2, ꢀ20 °C, 30 min.
e
Reaction conditions: 10, hydrazine acetate, THF/MeOH (V/V = 10:1), rt, 1 h.
f Reaction conditions: 12a, tetrabutylammonium fluoride, acetic acid, THF, rt, 5 h.
g
Reaction conditions: 12b, trifluoroacetic acid, CH2Cl2, ꢀ20 °C, 10 min.
h
Reaction conditions: 16, DDQ, CH3CN/MeOH (V/V = 10:1), rt, 5 h.
building block 10 was treated in the same conditions, compound 9
was afforded in a high yield with the Lev group intact (entry 4). The
PMB group is known to be oxidant-labile. Interestingly, this
protecting group can still survive under the oxidative deprotection
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N. Zeng et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
O
conditions of Bloc group (entry 3). When building block 12a was
subjected to the standard conditions for removal of the Bloc group,
compound 11a was obtained in 90% yield while TBDPS group was
not cleaved (entry 5). For building blocks 6b, 12b, and 16, the Bloc
group was selectively removed in 85–92% yields without affecting
the o-NO2Bn, Trt, Nap groups (entries 2, 6, 7). On the other hand,
the Bloc group can survive when the chloroacetyl, o-NO2Bn, PMB,
Lev, TBDPS, Trt, and Nap groups are cleaved with the appropriate
reagents and conditions, and in all cases, the Bloc group-bearing
products are furnished in excellent yields. These results indicated
that the Bloc group is orthogonal to the protecting groups
mentioned above.
OBn
O
OH
O
Ph2SO, Tf2O
O
BnO
BnO
O
STol
BnO
CH2Cl2, -78 o
80%
C
N3
BnO
OMe
24
4a
O
OBn
O
O
O
O
OsO4, NaIO4, 2,6-lutidine
CH3CN, H2O, r.t.
88%
BnO
O
BnO
N3
BnO
BnO
OMe
25
OBn
O
HO
O
BnO
O
BnO
N3
BnO
BnO
OMe
26
We then further checked the orthogonality of Bloc group with
other groups such as allyl, alloc, acetyl, benzoyl, and pivaloyl
groups. The Bloc group which contains carbonate unit should be
unstable to strong basic conditions like other carbonate groups
and acyl groups.3 However, the Bloc group could be selectively
deprotected under oxidation conditions in the presence of acetyl,
benzoyl, and pivaloyl protecting groups (8b, 8c, 12c) in high yields
(Table 4). It is noteworthy that no acyl group migration (entries
1–3), which usually happens in the presence of base such as
pyridine, was observed under basic conditions. Bloc, allyl, and alloc
groups all contain the double bond so that the allyl and alloc
groups would be damaged when the deprotection of Bloc group
was carried out using the standard removal conditions. However,
it was found that the Bloc group was not affected when the
deprotection of allyl or alloc groups was performed in the presence
of Pd(PPh3)4 (entries 4–5).21
Having investigated the introduction and removal of the Bloc
protecting group and its orthogonality with commonly-used pro-
tecting groups, we further examined the compatibility of Bloc
group with the conditions of glycosylation reactions. A thiogly-
coside was chosen as the glycosyl donor to perform the glycosyla-
tion by pre-activation strategy22 which is widely-used in
oligosaccharide synthesis. As depicted in Scheme 2, promoted by
Ph2SO–Tf2O,23 the reaction of methyl glycoside 4a with thiogly-
coside 24 stereoselectively furnished disaccharide 25 in 80% yield,
proving that the Bloc protecting group can withstand the glycosy-
lation conditions. Finally, the Bloc group in 25 was smoothly
removed to generate disaccharide 26 in 88% yield, showing that
Scheme 2. Bloc as a protecting group in glycosylation.
the benzyl and azido groups can tolerate the deprotection
conditions.
In conclusion, 3-butenyloxycarbonyl (Bloc) group as a new and
useful protecting group for hydroxyl functionality in carbohydrate
chemistry has been identified. This Bloc group can be conveniently
attached to primary and secondary hydroxyl functionalities, and
selectively removed under mild conditions. Furthermore, the Bloc
group is orthogonal to the commonly-used protecting groups such
as silyl, Trt, PMB, chloroacetyl, o-NO2Bn, Nap, and Lev groups, and
it can be selectively deprotected prior to the protecting groups
which are removed by strong base. In addition, it was proven that
the Bloc group is inert under the glycosylation conditions.
Although this new group is liable to strong basic conditions and
not compatible with some protecting groups, and the deprotection
conditions are not perfect, we believe this new protecting group
will find applications in complex oligosaccharide synthesis.
Acknowledgments
This work was financially supported by the Grants
(2012CB822100, 2013CB910700) from the Ministry of Science
and Technology of China, and the National Natural Science
Foundation of China (Grant Nos. 21232002, 81473084).
Supplementary data
Table 4
Supplementary data (experimental procedures, characteriza-
tion of compounds, and copies of NMR spectra) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2016.05.078.
Compatibility of the Bloc group with ester, allyl, and alloc groups
Entry
1
Substrate
Product
Yield (%)
89
OBloc
OH
O
O
AcO
BnO
AcO
BnO
BnO
BnO
OMe
OMe
References and notes
7ba
8b
OBloc
OH
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