Regioselective removal of the anomeric O-benzyl from differentially protected carbohydrates

Article abstract of DOI:10.1016/j.tetlet.2011.09.130

A mild, regioselective deprotection of the anomeric O-benzyl from multi-functionally protected carbohydrates via catalytic transfer hydrogenation is described. The protocol is tolerant of O-benzyl and O-benzylidene protections at non-anomeric positions, g

Full text of DOI:10.1016/j.tetlet.2011.09.130

Tetrahedron Letters 52 (2011) 6587–6590
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Tetrahedron Letters
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Regioselective removal of the anomeric O-benzyl from differentially
protected carbohydrates
⇑
Nigel Kevin Jalsa
Department of Chemistry, The University of the West Indies, St. Augustine, Trinidad and Tobago
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, regioselective deprotection of the anomeric O-benzyl from multi-functionally protected carbohy-
drates via catalytic transfer hydrogenation is described. The protocol is tolerant of O-benzyl and
O-benzylidene protections at non-anomeric positions, groups which are normally labile under typical
hydrogenolysis conditions.
Received 1 September 2011
Revised 27 September 2011
Accepted 28 September 2011
Available online 5 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Catalytic transfer hydrogenation
Protecting groups
Carbohydrates
Benzyl
Anomeric position
Carbohydrates are well known to have significant biological
functions.1 Owing to their polyfunctional (polyhydroxylated) nat-
ure, judicious choice of protecting group strategy is paramount at
the undertaking of any complex oligosaccharide synthesis.2
One of the most critical positions in glycoside synthesis is the
anomeric centre3; and consequently, a suitable protection is
required for this position. At present, such groups fall into two broad
categories: (1) those installed early in the synthetic scheme and
which require deprotection prior to appending a suitable activating
group to facilitate glycoside synthesis, such as p-methoxyphenyl,4 p-
nitrophenyl,5 TMSEt,6 allyl,7 and most recently N,O-dimethylhydr-
oxylamine;8 or (2) those that are employed as latent activating
groups facilitating eventual glycoside synthesis themselves, such
as n-pentenyl glycosides,9 thioglycosides,10 and sulfoxides.11 The
traditional approaches may require preliminary multi-step manipu-
lation of the molecule and/or may not be compatible particularly in
complex oligosaccharide synthesis.
The O-benzyl ether is among the most popular groups used to
protect the non-anomeric hydroxylic positions of carbohydrates
for a variety of reasons:12 (1) their ease of installation and removal,
(2) they are very robust and stable, (3) not prone to migration un-
like the commonly used esters and silyls, and (4) compared to most
other protecting groups, their greater electron-donating nature
allows the activation of both the glycosyl donor and acceptor for
glycoside bond formation.3,13 The O-Bn group may be introduced
utilizing a variety of systems, the specific method dependent on
the tolerance of the other protecting groups present toward acidic
or basic conditions.12 In addition, several methods have been
developed for the selective removal of benzyl groups from non-
anomeric positions in multi-benzylated substrates.14 Despite these
advantages, it has not been considered as a viable anomeric
protecting group owing to the fact that its controlled regioselective
removal has not been achieved in diversely-protected carbohy-
drates.15 The most commonly used high-yielding deprotection
conditions, hydrogenolysis employing Pd/C/H2, will remove other
benzyls as well as the popular and highly functional benzylidene
groups,16 while the less popular, strong Lewis acid methods,12,17
will cleave glycoside bonds and other common protecting
groups.18
Catalytic transfer hydrogenation (CTH)19 has been widely
employed in both carbohydrate-based and other benzyl deprotec-
tion strategies, utilizing a range of donors such as ammonium
formate,20 formic acid,21 and cyclohexene.22 CTH has advantages
over conventional hydrogenation in that it is technically simpler
and presents a reduced risk of explosion. Deprotection of a
non-anomeric O-Bn has been achieved in the presence of a six-
membered O-benzylidene ring; under conventional hydrogenoly-
sis conditions utilizing a Raney nickel catalyst.23 However, with
substrates possessing five-membered benzylidene acetals, selec-
tive deprotection of a benzyl group was not possible.23 Despite
these advancements, minimal studies have been carried out for
the regioselective removal of a benzyl group in multi-functional
systems using CTH.20a,24
Bieg and Szeja described the regioselective hydrogenolysis of the
anomeric O-Bn from a variety of per-O-benzylated monosaccharides
⇑
Corresponding author. Tel.: +1 (868) 6626013; fax: +1 (868) 6453771.
E-mail address: nigel.jalsa@sta.uwi.edu
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.130

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N. K. Jalsa / Tetrahedron Letters 52 (2011) 6587–6590
Table 1
Selective removal of the anomeric O-benzyl27
Pd/Al2O3, NH4HCO2
O
O
OBn
OH
RO
MeOH, rt
RO
Entry
1
Substrate
Time (h)
Productsa (yield%)
O
O
BnO
BnO
BnO
BnO
OH
OBn
OBn
10
10
OBn
1a
OBn
1b [71%]
OH
O
O
OBn
OBn
2
3
4
OBn
OBn
OBn
OBn
2a
2b [72%]
BnO
BnO
BnO
BnO
BnO
BnO
O
O
BnO
O
O
O
O
BnO
OBn
OH
OBn
8
6
BnO
BnO
OBn
OBn
OBn
3a
3b [79%]
BnO
BnO
O
O
BnO
BnO
BnO
BnO
OBn
NHAc
4a
OH
NHAc
4b [81%]
BnO
BnO
O
N
Ac
5a
O
BnO
BnO
BnO
BnO
OBn
Bn
OH
5
4
N
Ac
Bn
[80%]
5b
AcO
OBn
AcO
AcO
OBn
O
O
AcO
6
7
2
3
OBn
OBn
OH
BnO
BnO
6a
6b
[89%]
AcO
AcO
AcO
O
O
AcO
OH
OBn
7b [90%]
BnO
BnO
OBn
7a
OAc
OAc
OBn
O
OBn
O
OBn
8
9
2
8
OH
OBn
AcO
Ph
AcO
Ph
OBn
8a
8b [90%]
O
O
O
O
O
O
OBn
OH
BnO
BnO
OBn
OBn
9a
9b [70%]
Ph
Ph
Ph
O
O
O
O
O
O
10
11
7
O
O
O
BnO
BnO
OH
BnO
BnO
10c
OBn
10b [68%]
OBn
OH
OBn
BnO
OBn
10a
[7%]
OBn
O
O
BnO
3
O
BnO
11b
O
OH
[59%]
11a
Ph
OBn
OH
O
O
O
O
12
0.5
O
O
OBn
OBn
12b
[73%]
Ph
12a
Ph
a
Isolated yields.
and disaccharides, utilizing Pd on the atypical solid support, Al2O3,
with NH4HCO2 as the hydrogen source.15b To date, this valuable con-
tribution remains the only report of the successful removal of the
anomeric O-Bn of various substrates, in the presence of an inter-
glycosidic bond as well as other O-benzyl groups. However, the
development of this protocol, and the demonstration of its compat-
ibility with other, typically hydrogenolysis-labile protecting groups,
has not been explored. As a consequence, the anomeric O-Bn protec-
tion is not significantly employed in oligosaccharide syntheses. To
the best of our knowledge, this Letter is the first to report findings
that the Pd/Al2O3/NH4HCO2 system favors the regioselective
removal of the anomeric O-benzyl group in the presence of other
benzyl, acetate and most significantly, five-membered and six-
membered benzylidene groups; in good yield.
The Pd/C system has been shown to result in greater rates of
hydrogenolysis than that of Pd/Al2O3 albeit in non-carbohydrate
systems.25 This is presumably due to the lower surface area that
exists with the alumina solid support.26 This catalyst, as part of a

N. K. Jalsa / Tetrahedron Letters 52 (2011) 6587–6590
6589
Table 2
13C NMR comparison of reactant to products
Reactant
C-1 (ppm)
Product
C-1 (ppm)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
95.4 (
98.3 (
103.2 (b)
a
a
), 103.2 (b)
), 102.6 (b)
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
10c
91.4 (
91.8 (
91.3 (
92.1 (
a
a
a
a
), 97.7 (b)
), 97.7 (b)
), 97.3 (b)
)
99.3 (
99.0 (
a
a
)
), 99.7 (
a)
92.7, 93.9, 94.1
99.9 (b)
93.2 (
91.3 (
91.7 (
92.2 (
92.5 (
98.7 (
98.2 (
92.1 (
a
a
a
a
a
a
a
a
), 93.5 (b)
), 97.5 (b)
), 97.6 (b)
), 97.8 (b)
), 96.5 (a)
)
95.7 (
96.1 (
96.6 (
97.6 (
a
a
a
a
), 102.3 (b)
), 102.7 (b)
), 103.1 (b)
), 101.2 (
a)
11a
12a
96.2 (
96.3 (
a
a
-exo), 96.1 (
-endo), 96.8 (
a
a
-endo)
-exo)
11b
12b
)
-endo), 92.3 (b-endo), 92.1 (a-exo), 93.0 (b-exo)
controllable CTH system presented the most promising approach
for the selective removal of an anomeric O-benzyl in multi-
functional substrates. Ammonium formate was selected as the
hydrogen donor due to its ease of handling, less toxic byproducts
relative to cyclohexene and lower acidity relative to formic acid,
an important factor when the substrate contained the acid-labile
benzylidene. In order to establish the scope of this system, a set
of diversely protected carbohydrate substrates was synthesized;
with benzyl, acetate, and benzylidene groups in various positions
and configurations (Table 1).
For the per-O-benzylated substrates (entries 1–3), the anomeric
O-benzyl was selectively removed in good yield, as expected.15b
Those derivatives which had combinations of N- and O-benzyls
and acetates (entries 4–8) underwent faster selective anomeric
O-benzyl removal than the per-O-benzylated substrates. Interest-
ingly, those possessing O-acetates (entries 6–8) experienced the
fastest average reaction times of all the types of substrates exam-
ined, suggesting a role for the electron-rich O-Ac groups in adsorb-
ing to the alumina catalytic surface.
Most gratifyingly, results obtained with both the 1,3-dioxane
and 1,3-dioxolane28 benzylidene-protected derivatives indicated
that regioselective removal of the anomeric O-Bn could be
achieved. For entries 9, 10, and 12, the major product was that with
only the anomeric hydroxyl free. With the 4,6-O-benzylidene
galactopyranoside derivative, 10a, minor amounts of the derivative
bearing a free 2-OH was isolated, 10c.22c Only the S-4,6-O-benzyl-
idene derivative underwent deprotection of the 2-OBn; its R coun-
terpart, with its phenyl ring in the sterically unfavored axial
position, gave exclusively the product with a free anomeric
hydroxyl.
The results obtained with the rhamnopyranoside derivatives,
(entries 11 and 12) deserve special attention. A 1:1 diastereomeric
mixture of exo- and endo-2,3-O-benzylidene rhamnopyranosides,
11a, both underwent ring opening to yield exclusively the deriva-
tive bearing a 2-OH and 3-OBn. This appears to be the first example
where: (1) a benzylidene ring is opened to yield a free OH on car-
bon and an O-Bn on the other, under palladium-catalyzed hydrog-
enolysis conditions29 and (2) where both exo- and endo-isomers
undergo the same exclusive stereoselective ring opening. They nor-
mally yield complementary ring-opened products.30 In the latter
case, Pastore and coworkers have also reported an occurrence of
both the exo- and endo-2,3-O-benzylidene mannopyranosides
yielding the 3-OH derivative when subjected to BH3ÁTHF/Cu(OTf)2
mediated ring-opening.31 With a diastereomeric mixture of exo-
and endo-3,4-O-benzylidene derivatives, 12a, the desired product
bearing a free anomeric hydroxyl was obtained in good yield. The
preservation of the trans-3,4-O-benzylidene rings was arguably
the most significant result obtained: these trans fused five-
membered bicyclic systems are among the most thermodynami-
cally unstable of the O-benzylidene rings, due to the significant
torsional strain that exists.32 Their retention is an indication of
the versatility and applicability of this regioselective CTH process.
Prolonged reaction times resulted in cleavage of the various
O-benzylidene rings (whether five- or six-membered) as well as
further debenzylations. Similarly, performing the reaction on the
O-benzylidene protected substrates, but using the typical Pd/C cat-
alyst instead, resulted in complex mixtures of debenzylated and
benzylidene-deprotected products; the desired free-anomeric
product being isolable only in minimal yield. This suggests that
the role of the solid support is critical in allowing isolation of the
product, with only the anomeric hydroxyl free, in practical yield.
As reported in other non-carbohydrate systems,25,26 it is likely that
the lower surface area presented by the alumina facilitates a rela-
tively slower, more controlled reaction, which allows the isolation
of the desired product in good yield.
Of diagnostic interest, 13C NMR analysis illustrated a useful rela-
tionship for suggesting the nature of the protecting group
removed: deprotection of the anomeric O-Bn resulted in an aver-
age upfield shift of 5 ppm for C-1 (the anomeric carbon) for both
anomers (Table 2). Where a 2-OH resulted (10c and 11b), a down-
field shift of around 2 ppm for C-1 was observed.
In summary, we have developed a mild method for the regiose-
lective removal of an anomeric O-benzyl from an array of carbohy-
drate derivatives containing the commonly employed benzyl and
benzylidene protecting groups in various configurations and con-
formations. Conventional wisdom dictates that the benzyl group
is a permanent protecting group, only suitable for non-anomeric
positions and to be removed generally at the end of a multi-step
synthesis.18b These results, in conjunction with those for the vari-
ous per-O-benzylated substrates,15b challenge that assumption.
They suggest that the O-Bn be considered as a stable, easily intro-
duced and robust anomeric protecting group, whose removal to
generate a hemiacetal prior to glycosyl donor formation, is com-
patible with benzyl and benzylidene groups, which are known to
be labile under typical hydrogenolysis conditions (Pd/C/H2). This
system utilizes a non-commonly used, but readily available solid
support (Al2O3) for the Pd catalyst and has several benefits: (1)
does not require an inert atmosphere, (2) minimizes hazards
associated with an open, continuous source of H2, (3) simple
non-aqueous work-up, and (4) proceeds in good yield with rela-
tively short reaction times at room temperature. It is envisioned
that the utilization of an anomeric O-Bn-based protection strategy
could significantly shorten reaction sequences and allow access to
complex oligosaccharides via a facile route.
Acknowledgments
The author is grateful to Dr. Lebert Grierson for invaluable
advice and discussions. Many thanks to Mr. Franklyn Julien and
Mr. Faisal Mohammed for the provision of high resolution mass

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N. K. Jalsa / Tetrahedron Letters 52 (2011) 6587–6590
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spectral data. This work was supported by The University of the
West Indies, St. Augustine.
Supplementary data
18. (a) Tanaka, N.; Ogawa, I.; Yoshigase, S.; Nokami, J. Carbohydr. Res. 2008, 343,
2675–2679; (b) Takano, Y.; Habiro, M.; Someya, M.; Hojo, H.; Nakahara, Y.
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Organic Synthesis; Wiley-Interscience: New York, NY, 2001.
Supplementary data (NMR data and spectra data) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.09.130.
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27. General Procedure for removal of the anomeric O-Bn: The carbohydrate
derivative (0.5 mmol) was stirred in MeOH (20 mL) for 10 min. 10% Pd/Al2O3
(0.5 g) was then added, followed by NH4HCO2 (7.5 mmol) and the mixture
stirred at room temperature. Upon completion, the mixture was filtered
through Celite and the residue was washed with MeOH (2 Â 50 mL) and then
CH2Cl2 (2 Â 100 mL). The filtrate and washings were combined, and the
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chromatography to yield the pure products.
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