Reverse orthogonal strategy for oligosaccharide synthesis

Article abstract of DOI:10.1039/c1cc13409d

Herein, we report the invention of a novel expeditious concept for oligosaccharide synthesis. Unlike the classic orthogonal strategy based on leaving groups, the reverse approach is based on orthogonal protecting groups, herein p-methoxybenzyl and 4-pentenoyl, which allows for efficient oligosaccharide assembly in the reverse direction.

Full text of DOI:10.1039/c1cc13409d

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Reverse orthogonal strategy for oligosaccharide synthesiswzy
Kohki Fujikawa, N. Vijaya Ganesh, Yih Horng Tan, Keith J. Stine and
Alexei V. Demchenko*
Received 9th June 2011, Accepted 16th August 2011
DOI: 10.1039/c1cc13409d
Herein, we report the invention of a novel expeditious concept for
oligosaccharide synthesis. Unlike the classic orthogonal strategy
based on leaving groups, the reverse approach is based on orthogonal
protecting groups, herein p-methoxybenzyl and 4-pentenoyl, which
allows for efficient oligosaccharide assembly in the reverse direction.
implies the use of two orthogonal leaving groups (LGa
and LGb) and requires a pair of orthogonal activators:
A (activates LGa selectively) and B (activates LGb, but
not LGa, Scheme 1b). Theoretically, the orthogonal strategy
allows for unlimited number of reiterations of leaving groups.
In practice, however, the efficiency of glycosylations declines
rapidly with the increase of the bulk of glycosyl donor:
di(85%) -tri(72%) -tetra(66%).9 In our related study,
STaz/SEt activation yielded the following decline in yields
di(98%) -tri(93%) -tetra(77%) -penta(59%).11 Resultantly,
this drawback precludes extending the orthogonal-like assembly
and is often practical for the synthesis of relatively small oligo-
saccharides.12,13
It is already appreciated that a chemical or enzymatic synthesis1
could lead to natural oligosaccharides or glycoconjugates for
study of their composition,2 conformation,3 interaction with
other molecules,4 and determining their biological roles.5 Also,
only the synthetic approach can provide unnatural mimetics
that are often of interest due to their therapeutic and diagnostic
potential.6 However, even with significant progress in the
recent years, chemical synthesis of oligosaccharides remains
cumbersome.
Herein we report a reverse orthogonal strategy that combines
advantages of the linear (monosaccharide donor and high
yields at each step) and orthogonal (no protecting group mani-
pulations required) approaches. As opposed to the Ogawa’s
orthogonal strategy based on orthogonal leaving group, we
base our approach on the orthogonal protecting groups
(PGa and PGb, Scheme 1c). This reverse approach would
According to the conventional (linear) oligosaccharide
synthesis, disaccharides obtained as a result of the first glyco-
sylation step are typically converted into the second-generation
glycosyl acceptor via liberation of a specific hydroxyl. This
requires the formal additional synthetic step that is often asso-
ciated with isolation and purification of the glycosyl acceptor.
The latter is then allowed to react with a glycosyl donor,
resulting in the formation of a trisaccharide (Scheme 1a). The
deprotection–glycosylation steps are then reiterated to yield
larger saccharides. Because the reactive monosaccharide glycosyl
donor is used at every step, the yields of glycosylations typically
remain high.7 However, the requirement to perform additional
deprotection steps between glycosylations is the major conceptual
disadvantage of the conventional approach.
Many modern strategies that help to streamline oligo-
saccharide assembly by minimizing or even eliminating
protecting/leaving group manipulations between coupling
steps are based either on chemoselective or on selective activations
of leaving groups.8 Amongst these, Ogawa’s orthogonal con-
cept is arguably the most advantageous.9,10 This technique
Department of Chemistry and Biochemistry, University of
Missouri–St. Louis, One University Boulevard, St. Louis, Missouri
63121, USA. E-mail: demchenkoa@umsl.edu
w This article is part of the ChemComm ‘Glycochemistry and
glycobiology’ web themed issue
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for the synthesis of all new
compounds. See DOI: 10.1039/c1cc13409d
y This work was supported by awards from NIGMS (GM090254 and
GM077170)
Scheme 1 (a) Conventional linear synthesis involving separate
glycosylation and deprotection steps. (b) Ogawa’s leaving group-based
orthogonal strategy. (c) New reverse orthogonal concept based on
orthogonal protecting groups.
c
10602 Chem. Commun., 2011, 47, 10602–10604
This journal is The Royal Society of Chemistry 2011

allow for oligosaccharide assembly in the opposite direction to
that of the leaving group-based approaches. The oligosaccharide
will be elongated in a similar manner to that of the linear
approach, but the reverse orthogonal strategy will significantly
shorten the synthesis by combining the deprotection and
glycosylation steps.
Table 1 Establishment of protecting groups and the reaction condi-
tions for the reverse orthogonal strategy
The successful execution of the reverse strategy will require
at least two orthogonal protecting groups (PGa and PGb) that
will be removed during the glycosylation and in principle the
couplings can be executed with only one type of a leaving
group. A concept of orthogonal protecting groups is known,
but it refers to orthogonally removable protecting groups;14–17
for example, benzyl and benzoyl are orthogonal protecting
groups. A glycosyl acceptor-based orthogonal approach has
also been developed, but it the term ‘‘orthogonal’’ used therein
refers to differentiation of carbonyl vs. hydroxyl glycosyl
acceptors.18 A few concepts for protecting group-based glyco-
sylations are known, and undoubtedly served as a powerful
motivation for studies described here. Kochetkov demon-
strated that triphenylmethyl (trityl) ethers can be glycosylated
directly with orthoesters, thiocyanates or thioglycosides.19,20
Approaches involving ‘‘glycodesilylation’’ of TMS or TBDMS-
protected glycosyl acceptors have also been developed.21–24
None of these glycosylations, however, could be extended to
the multi-step oligosaccharide synthesis due to the lack of the
second (orthogonal) protecting group.
Entry Donora Acceptor Promoterb
Product (yield)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1ae
1be
1c
2a
2b
2c
2c
2c
2d
2d
2c
2c
NIS/TfOH
3a (11%)
SnCl4/EtSH,c NIS 3a (50%)
SnCl4/EtSH,c NIS 3a (>80%)d
TMSI, NIS/TfOH 3a (>80%)d
NIS/TfOH
3a (o5%)d
3a (>80%)d
3b (81%)
NIS/TfOH/H2Oc
NIS/TfOH/H2Oc
SnCl4/EtSH, NIS
TMSI/AgOTf
3c (o5%)d,f
3c (85%)
1d
a
In all preliminary reactions donor and acceptor were used in
b
equimolar amounts. All reactions were performed in the presence
c
of molec. sieves (3 or 4 A). The use of water or EtSH (1 equiv.) was
d
found to improve the yield. Estimated by TLC. Donor was added
e
f
upon complete deprotection of the acceptor. Pentenoyl group of the
donor was removed instead.
presence of NIS/TfOH as shown in entry 5, whereas pentenoyl
can be easily removed followed by glycosylation of the liber-
ated hydroxyl (entry 6). To prove the concept, we obtained
6-O-pMB glycosyl donor 1b and glycosidated it with glycosyl
acceptor 2d equipped with pentenoyl. The highest yield of
disaccharide 3b (81%, entry 7) was achieved if the donor 1b
was used in excess or, alternatively, if it was added upon
deprotection of 2d. Although the mechanistic rationale is still
to be understood, the use of water (1 equiv.) was found
necessary to maintain high yields of this reaction.
For the purpose of establishing a compatible pair of orthogonal
protecting groups, we began screening a series of differently
protected glycosyl acceptors. As the starting point, per-
benzoylated S-ethyl glycoside 1a was chosen as the glycosyl
donor. Initial coupling of 1a with 6-O-TBDMS-protected
acceptor 2a in the presence of a powerful promoter system
for thioglycoside activation NIS/Tf OH was very disappointing,
and the resulting disaccharide 3a was isolated in a very modest
yield of 11% (entry 1, Table 1). Our attempts to improve this
result were unsuccessful, therefore, we began screening other
temporary protecting groups. Encouragingly, Boc-protected
glycosyl acceptor 2b could be glycosylated with 1a in the
presence of SnCl4/EtSH, followed by the addition of NIS much
more efficiently. However, still a rather average yield of 50%
could be achieved (entry 2). Further screening of the compatible
protecting groups showed that 6-O-p-methoxybenzyl (pMB)
acceptor 2c could be glycosylated with 1a in the presence of
either SnCl4/EtSH25 followed by the addition of NIS (entry 3),
or TMSI,26 followed by the addition of NIS/Tf OH (entry 4).
In both reactions, disaccharide 3a was cleanly generated
with yields exceeding 80%. Conversely, NIS/TfOH-promoted
glycosylation of 2c with 1a was rather inefficient, and only
traces of disaccharide 3a were obtained (entry 5). Further search
of suitable protecting groups revealed that 6-O-pentenoyl (Pent)
acceptor 2d can be efficiently glycosylated with 1a in the presence
of NIS/Tf OH. Improved yield of 3a, exceeding 80% could be
achieved if water (1.0 equiv.) was added to the reaction (entry 6).
Although O-(pent-4-enoyl) moiety has been investigated as the
anomeric leaving group27–29 and as a precursor for the synthesis
of sugar-based macrocycles,30,31 its use as a temporary protecting
group of carbohydrates32 is still uncommon.
With the intention of determining the reaction conditions
for the second-stage orthogonal activation, we obtained 6-O-
pentenoyl glycosyl donor 1c. Disappointingly its coupling with
6-O-pMB acceptor 2c in the presence of SnCl4/EtSH and NIS
was inefficient due to the rapid hydrolysis of pentenoyl group
(entry 8). This was resolved by using a similar building block
1d equipped with the SBox leaving group. Its glycosidation
with the pMB acceptor 2c was carried out in the presence of
TMSI and AgOTf and the resulting disaccharide 3c was
obtained in 85% yield (entry 9).
Having established the entirely orthogonal activation con-
ditions, we turned our attention to the synthesis of a simple
oligosaccharide sequence via alternating reverse orthogonal
activation steps. Herein, a slight excess of the glycosyl donor
was used in each step. First, disaccharide 3b was obtained from
1b and 2d in 81% as depicted in Scheme 2. The disaccharide 3b
was then glycosylated with SBox donor 1d equipped with an
O-pentenoyl group. The resulting trisaccharide 4 was obtained
in 82% yield and then reacted with 1b to afford tetrasaccharide
5 in 71% yield. Finally, tetrasaccharide 5 was coupled with 1d
and the resulting pentasaccharide 6 was isolated in 75% yield.
To expand the scope of the strategy developed we decided to
investigate the glycosylation of secondary glycosyl acceptors.
For this purpose we obtained glycosyl acceptors 7a and 7b
equipped with 4-O-pentenoyl and 4-O-pMB groups respectively.
In our opinion, the latter two reactions created the basis for
the first step of orthogonal activation: pMB is stable in the
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10602–10604 10603

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Scheme 2 Four-step synthesis of pentasaccharide 6 via the reverse
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The utility of the concept has been demonstrated by a
rapid assembly of pentasaccharide 6. It should be noted that
consistent yields in the range of 70–80% could be achieved
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c
10604 Chem. Commun., 2011, 47, 10602–10604
This journal is The Royal Society of Chemistry 2011