Hybrid solution/solid-phase synthesis of oligosaccharides by using trichloroacetyl isocyanate as sequestration-enabling reagent of sugar alcohols

Article abstract of DOI:10.1002/anie.200462422

(Chemical Equation Presented) An excess of glycosyl acceptor is used in the solution-phase synthesis of oligosaccharides and any unconverted acceptor is removed by using trichloroacetyl isocyanate. A levulinoyl (Lev) ester group is then used as a masked tag in the following "resin-capture-release" purification strategy (see scheme).

Full text of DOI:10.1002/anie.200462422

Communications
Carbohydrate Chemistry
appears to be the convergent solution-phase approach by
coupling tri- or tetrasaccharide building blocks.[6]
Hybrid Solution/Solid-Phase Synthesis of
Hence the search for innovative and practical methods
based on recent synthetic techniques is actively pursued.
Notable is the tag-assisted solution-phase strategy developed
by Hindsgaul and co-workers,[7] Pozgay,[8] and Ito and co-
workers[9] in which a suitable group (tag) installed in one of
the reactants serves to selectively remove the coupled product
from the complex reaction mixture. An oligosaccharide
Oligosaccharides by Using Trichloroacetyl
Isocyanate as Sequestration-Enabling Reagent of
Sugar Alcohols
Alessandro Dondoni,* Alberto Marra,* and
Alessandro Massi*
synthesis centered on the use of a highly fluorinated tag was
[10]
reported by Inazu and co-workers
following an earlier
In recent years there has been a steady increase in interest in
glycoscience with particular emphasis toward programs at the
chemistry/biology interface. Current studies are mainly
directed toward the understanding at molecular level of the
key role exerted by glycoconjugate-derived oligosaccharides
in beneficial or detrimental events that occur in living
organisms.[1] In most, if not all, of these studies, organic
synthesis is required to provide meaningful quantities of
native oligosaccharides and their analogues in a pure state
with well-defined structures to be used as biological, bio-
chemical, and biophysical probes. Pure oligosaccharides are
very difficult to access from natural sources owing to the
complexity and microheterogeneity of glycosylated proteins[2]
and their instability to many isolation procedures. Enormous
progress has been made in the area of oligosaccharide
synthesis especially in the last decade, and a plethora of
synthetic methods in either the solution or solid phase have
been reported.[3,4] However both techniques present their
own limitations. For instance, solution-phase reactions
require a laborious workup and time-consuming product
isolation by chromatography after each glycosidation trail.
On the other hand, the solid-phase approach does not entail
the above problems and lends itself to automation, however,
the polymer-bound substrate suffers an attenuated reactivity
for entropic and steric reasons, and monitoring the progress of
the reaction and estimating the yield of coupled product by
TLC or standard NMR and MS analyses is more difficult. A
number of sophisticated analytical methods have therefore
been developed as a result.[5] Another serious concern in the
solid-phase approach is the need for robust linkers that
tolerate various reaction conditions but can be easily cleaved
to retrieve the product without affecting its functionalities,
especially the labile and stereomutable O-glycosidic bond.
Even in the face of spectacular advances in the field of
automated solid-phase synthesis of oligosaccharides up to
nine-member constructs,[4l] the main way to access complex
oligosaccharides that feature a great structural diversity still
approach by Curran et al. based on the fluorous-tag
method[11] which, however, was quite limited in scope. We
envisaged a novel approach to oligosaccharide synthesis
based on a solid-supported sequestering or scavenging
technique,[12] which involves executing the reaction in solution
in the presence of an excess of one reactant and then
removing the residue with a polymer-bound reagent. This
approach is referred to as polymer-assisted solution-phase
(PASP) synthesis and offers all the advantages associated with
solution-phase chemistry and those which are intrinsic to
classical solid-phase techniques, such as the use of a large
excess of one reagent to drive the reaction to completion
followed by a simple filtration step for the isolation of the
product. Quite surprisingly there are few examples of the
PASP technique applied to oligosaccharide synthesis, and
unfortunately the reported methods are not free of substantial
shortcomings. In one instance Kirschning et al. reported a
route that was limited to the preparation of 2-deoxy-
glycoconjugates,[13] while Ley and co-workers developed a
method that operated only with primary sugar alcohols as
acceptors.[14] Herein we report our own strategy in which the
coupling of the sugar is carried out by the use of a twofold
excess of a primary or secondary sugar alcohol. Once the
reaction is completed, as shown by the total consumption of
the glycosyl donor, the unreacted acceptor is selectively
derivatized by trichloroacetyl isocyanate, which is a powerful
detecting reagent of alcohols and is widely employed as an
analytical tool in NMR spectroscopy.[15] The resultant tri-
chloroacetyl urethane is removed from the solution mixture
by a suitable solid-supported base. The free sugar alcohol is
recovered from the sequestered material and reused as an
acceptor in a subsequent glycosylation cycle.
Before developing our method, we made several (unsuc-
cessful) attempts to sequester the model secondary sugar
alcohol 9 (Scheme 2) with commercially available polymer-
supported reagents such as PS-benzenesulfonyl chloride
(PS = polystyrene), PS-phenylisocyanate, and the dichloro-
triazine developed by Masala and Taddei.[16] Discouraging
results were also obtained in an attempt to modify the capture
strategy of 9 by the use of tetrafluorophthalic anhydride as a
sequestration-enabling reagent (SER).[17] This anhydride
failed to provide the expected ester (see Supporting Infor-
mation). To develop an efficient strategy for sequestering
both primary and secondary sugar alcohols in a PASP
synthesis of oligosaccharides, our study commenced by
examining the capture–release sequence of the primary
sugar alcohol 1 using trichloroacetyl isocyanate (2, TAI) as
the hitherto unemployed SER.[18] Thus treatment of 1 with 2
[*] Prof. A. Dondoni, Prof. A. Marra, Dr. A. Massi
Laboratorio di Chimica Organica
Dipartimento di Chimica
Universitꢀ di Ferrara
Via L. Borsari 46, 44100 Ferrara (Italy)
Fax : (+39)0532-291-167
E-mail: adn@dns.unife.it
mra@dns.unife.it
msslsn@dns.unife.it
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462422
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(ratio 1:2) under neutral conditions afforded the sugar
urethane 3 almost instantaneously as shown by TLC analysis
(Scheme 1, derivatization step). Then, the reaction mixture
was quenched with a large excess of MeOH that transformed
Scheme 2. Other representative sugar alcohols and a hemiacetal sub-
jected to the derivatization–sequestering–release (DSR) sequence.
Note compounds 12–15 were recovered as deacylated derivatives.
Bz=benzoyl, Lev=levulinoyl (4-oxopentanoyl).
easily formed by the hydrolysis of a large variety of activated
glycosyl donors.
With an efficient solid-phase sequestering methodology of
sugar alcohols in hand, the solution-phase synthesis of various
disaccharides and their isolation was conducted as outlined in
Table 1. Once the glycosidation of the donor was completed
in the presence of a twofold excess of acceptor, filtration of
the reaction mixture was followed by aqueous workup and
evaporation of the solvent to afford the target disaccharide
along with the unconverted acceptor and other carbohydrate-
containing byproducts. This reaction mixture was essentially
free of impurities arising from the glycosyl donor-activation
system. In fact, the accurate choice of anomeric leaving
groups (thioethyl, pentenyl, phosphates, and phosphites; see
Table 1 and Scheme 5) and the relevant promoters (Cu(OTf)2
(OTf = trifluoromethanesulfonate), MeOTf, NIS (N-iodosuc-
cinimide), TMSOTf (TMS = trimethylsilyl), BF3·OEt2) led to
byproducts that could be removed by filtration, evaporation,
or by aqueous workup.[21] Only in the case of succinimide,
which formed in the NIS activation system, did removal of
this byproduct take place in the next step upon treatment of
the reaction mixture with polymer-supported BEMP (5). The
unconverted acceptor was scavenged and recovered by the
above DSR sequence, and the desired disaccharide was
isolated as a mixture of anomers. Excellent yields and high
purities were registered for all crude products 18, 19, 21, and
23 obtained in this way. The purities estimated in the 1H NMR
spectra were confirmed by means of chromatographic puri-
fication, which also allowed the identification of the residual
(4–5%) sugar carbamates 26 and 27 byproducts (Scheme 3).
The yields of the two analytically pure products 18 and 19
were much higher than those obtained when equimolar
amounts of reaction partners were used in the same solution-
phase synthesis, thus substantiating the effectiveness of the
glycosidation reaction under the conditions employed. Never-
theless, we observed that our improved glycosidation con-
Scheme 1. Use of trichloroacetyl isocyanate (2, TAI) as a new seques-
tration-enabling reagent (SER). Also shown are other polymer-sup-
ported bases (6–8) tested in the sequestering step. Bn=benzyl.[19]
unconverted TAI 2 into methyl urethane 4. The exclusion of
water in this operation is recommended to avoid the decom-
position of 2 into trichloroacetamide whose removal would
require purification by column chromatography. The solid-
phase sequestering of 3 and 4 was carried out using the highly
basic, non-nucleophilic polymer-supported BEMP (2-tert-
butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-dia-
zaphosphorine on polystyrene, 5) to give urethanes bound to
the polymer as ion pairs.[19] Filtration of the resin and
subsequent treatment with KOH in MeOH followed by
neutral aqueous workup released the starting sugar alcohol 1
in high yield (95%) and purity (95%).
The wide scope of this derivatization–sequestering–
release (DSR) sequence was demonstrated by successful
application to primary and secondary sugar alcohols 9—15,
which feature diverse protecting groups of the hydroxy group
(Scheme 2). In all cases the starting compound or a partially
deprotected derivative was recovered in high yield (95%) and
purity (> 95%) with unaltered anomeric configuration. Note
that the methodology was compatible with the presence of the
NHAc group (see compound 10) which allowed N-acetyl
amino sugars to be included as substrates in the TAI-
mediated capture–release sequence.[20] Efficient sequestering
of the sugar hemiacetal 16 was also demonstrated, although in
this case the polymer-bound product decomposed under the
strongly basic conditions of the release step. Nevertheless, a
means for removing hemiacetal side products from glycosi-
dation mixtures is a useful tool, as these compounds may be
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Table 1: Application of the proposed methodology to the synthesis of disaccharides.
Glycosidation
Yield [%] Purity [%][a] Isolated
yield [%][b] a/b excess
acceptor [%]
Ratio Recovered
quant.
95
95
96 (83)[c] 1:2
92
98
91 (59)[c] 1:1
95
92
95
95
87
96
0:1
0:1
97
92
quant.
94[d]
80[d]
73
1:3
98[e]
[a] From 1H NMR analysis. [b] After column chromatography on silica gel. [c] Yield of isolated disaccharide when the glycosidation reaction is carried out with an
equimolar ratio of donor and acceptor. [d] Disaccharide 25 was obtained in 88% yield with 90% purity using TMSOTf (trimethylsilyl trifluoromethanesulfonate)
as the promoter under the same reaction conditions. [e] Acceptor recovered as deacylated derivative.
isolation of its contaminants—the carbamate 28, glycosyl
fluoride 29, and trehaloses 30—by chromatography
(Scheme 3). Evidently, the side products 29 and 30 arise
from the initial decomposition of the phosphite-activated
donor 24. To overcome this limitation, we refined the
proposed methodology by considering a second cycle of
purification for disaccharide 25 which exploits the benefits of
both a tag-assisted and a “resin-capture–release” purification
strategy.[22] The key element in this improved protocol was the
levulinoyl (4-oxopentanoyl) ester group which serves as a
hidden tag (Scheme 4) and was earlier installed on the
glycosyl acceptor 12. Thus, the crude disaccharide 25, which
results from the first TAI-based purification sequence (80%
Scheme 3. Sugar byproducts formed during the glycosidations de-
scribed in Table 1.
purity, Table 1), was treated with polymer-supported borohy-
dride 31 to unveil the C2 hydroxy group.[23] Instead, the g-
hydroxyester 32 was obtained as a single product. This
product was derivatized with TAI (2), trapped as an activated
ditions did not always protect the donor from its partial
degradation, thus giving unsatisfactory results especially in
terms of purity of the isolated target glycoconjugate. This was
the case with disaccharide 25, which was obtained in good
yield (94%) but with quite low purity (80%), as confirmed by
polymer intermediate onto PS-BEMP, and finally, after
washing to remove soluble byproducts 28–30, was released
in solution by means of KOH in MeOH (Scheme 4). This new
hybrid solution/solid-phase approach afforded the disacchar-
ide 33 in 70% overall yield (starting from 24) and with 95%
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Scheme 4. Use of the levulinoyl group as a hidden tag in the “resin-
capture–release” purification strategy.
Scheme 5. Synthesis of a trisaccharide; chromatographic purification
not required.
purity (determined by chromatography and 1H NMR
spectroscopy).
As a demonstration of the power of our strategy, the
assembly of trisaccharide 37 was conducted by iterative
glycosidation (Scheme 5). Efficiency relied on the nontrivial
task to select reaction partners with suitable hydroxy group
protection and anomeric activation to ensure good reactivity
and stereo- and chemoselectivity in each cycle. Thus, under
methyl triflate activation, the 2-benzoyl-directed b glycosida-
tion of thioethyl galactoside 34 with an excess of primary
alcohol 13 followed by derivatization with TAI (2) and
sequestration of the urethane with PS-BEMP (5) afforded b-
d-(1,6)-disaccharide 35. This crude compound under O-
pentenyl activation by NIS–TMSOTf was subjected to
glycosidation by the sugar alcohol 14, which bears the
levulinoyl ester group at C2. The trisaccharide 36 obtained
was isolated by workup of the reaction mixture with the
standard TAI-based sequestering technique. The crude tri-
saccharide 36 was finally purified by reduction of the
levulinate carbonyl group using the polymer-supported bor-
ohydride 31 followed by sequestration with the DSR
sequence as described in Scheme 4. The benzoyl- and
levulinoyl-free trisaccharide 37 was isolated in 42% yield
and 95% purity according to NMR spectral analysis. In two
separate experiments, the coupled products 35 and 36 were
isolated (89 and 55% yield, respectively) by column chroma-
tography and were duly characterized by NMR spectroscopy,
thus confirming the formation of the b-d-glycosidic linkage in
both solution-phase glycosidations.
Overall, the efforts made herein were directed to find
conditions that would allow an automated synthesis of
oligosaccharides by the merging of the polymer-support
technology with solution-phase chemistry. The results
obtained so far are quite promising and indicate that this
goal can be pursued. The effectiveness of TAI as a new SER
for scavenging both primary and secondary sugar alcohols and
the exploitation of the levulinoyl group as a hidden tag for
hybrid solution/solid-phase synthesis represent the major
novelties and key operations in this new strategy. However,
more research is required to provide examples that allow the
scope of this strategy to be extended to the synthesis of more-
complex oligosaccharides than those described above. This
work is currently underway in our laboratory.
Received: October 25, 2004
Revised: December 10, 2004
Published online: February 3, 2005
Keywords: chemoselectivity · glycosylation ·
.
solid-phase synthesis · synthetic methods
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