Iterative, orthogonal strategy for oligosaccharide synthesis based on the regioselective glycosylation of polyol acceptors with partially unprotected n-pentenyl-orthoesters: Further evidence for reciprocal donor acceptor selectivity (RDAS)

Article abstract of DOI:10.1039/b507468a

An efficient iterative, orthogonal protocol based on the regioselective glycosyl coupling of D-mannose polyols with, partially unprotected, n-pentenyl orthoester donors permits the synthesis of linear and branched oligosaccharides with minimal protecting

Full text of DOI:10.1039/b507468a

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COMMUNICATION
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Iterative, orthogonal strategy for oligosaccharide synthesis based on the
regioselective glycosylation of polyol acceptors with partially
unprotected n-pentenyl-orthoesters: further evidence for reciprocal
donor acceptor selectivity (RDAS)
J. Cristo´bal Lo´pez,*a Attila Agocs,a Clara Uriel,a Ana M. Go´meza and Bert Fraser-Reidb
Received (in Cambridge, UK) 27th May 2005, Accepted 22nd August 2005
First published as an Advance Article on the web 14th September 2005
DOI: 10.1039/b507468a
branched saccharides (e.g. 7) by sequential manipulation of the
orthogonal protecting groups in 3 followed by glycosylation with
different donors e.g. 1 and 6. In this communication we disclose
the implementation of the strategies postulated in Scheme 1,
which have resulted in the preparation of linear penta- and
hexasaccharides as well as a branched trisaccharide.
An efficient iterative, orthogonal protocol based on the
regioselective glycosyl coupling of D-mannose polyols with,
partially unprotected, n-pentenyl orthoester donors permits the
synthesis of linear and branched oligosaccharides with minimal
protecting group tampering.
Oligosaccharide synthesis, commonly recognized as a difficult
task,1,2 is usually complicated by the cumbersome protection–
deprotection steps required to expose only one hydroxyl group (in
the glycosyl acceptor) to the glycosyl donor in the glycosidation
event.2 This issue, however, has recently been eased by refinements
in the area of regioselective glycosyl couplings.3,4 Thus, in some
processes a diol acceptor can be exposed to a glycosyl donor to
yield a single disaccharide, which could be further coupled with an
additional glycosyl donor to produce a trisaccharide.5 During the
last few years our research groups have been interested in the
development of regioselective glycosidation protocols which would
obviate tedious protection–deprotection steps.6,7
For our studies we chose n-pentenyl orthoester (NPOE) 8 (to
represent 1), and disaccharide 10 (to represent 3), the latter being
readily obtained by glycosidating methyl glucoside 9 with NPOE 8
(Scheme 2a). Compound 10, which already bears two orthogonal
protecting groups, was transformed into triols 11 and 12
(Scheme 2b).
The synthesis of the first linear oligosaccharide involved
iterative glycosylations of triol 11, and polyol acceptors derived
therefrom, with diol donor NPOE 8 (Scheme 3). Accordingly,
glycosylation of 11, with diol donor 8 (1 equiv.)10 took
place smoothly by treatment with NBS (1.5 equiv) and
There are, however, scarce examples of glycosylations in which
the glycosyl donor has itself one or more free hydroxyl groups.8,9
In this context, we have recently turned our attention to
glycosylation strategies of glycosyl donors with free hydroxyl
groups in regioselective glycosylations of polyol acceptors, which
will result in a reduced number of protection–deprotection steps
and would simplify the preparation of the monosaccharides
required for glycosyl assembly. Such a process would demand an
exquisite regioselectivity to avoid not only the formation of cross-
glycosylated isomers but also that of saccharides resulting from
self-coupling of the glycosyl donor.
Along these lines, we have been interested in the viability of the
strategy outlined in Scheme 1. Glycosidation of triol acceptor (2)
with a glycosyl diol donor (1) could lead, provided that some
regiochemical control can be exerted, to a single disaccharide (3)
(Scheme 1a). Subsequent unveiling of an additional hydroxyl
group at the non-reducing end of compound 3, and iteration of
the process could eventually lead to oligosaccharides, e.g. 4
(Scheme 1b). The protocol could be extended to the preparation of
isomeric linear saccharides (e.g. 5) if a second (orthogonal)
protecting group had been present in glycosyl donor 1 (Scheme 1c).
And finally, the strategy could be also of use in the preparation of
aInstituto de Qu´ımica Orga´nica General, (CSIC), Juan de la Cierva 3,
28006, Madrid, Spain. E-mail: clopez@iqog.csic.es; Fax: +34 915644853
bNatural Products and Glycotechnology Research Institute Inc. (NPG),
595f Weathersfield Road, Pittsboro, NC 27312, USA
Scheme 1 Synthesis of linear and branched saccharides.
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Scheme 2 Synthesis of building blocks for oligosaccharides.
Scheme 5 Synthesis of branched trimannan 28.
completely regioselective to give trisaccharide 26 (60% yield)
(Scheme 5). Removal of the silyl protecting group from 26 exposed
the 2,4,6-triol 27 in 75% yield, which underwent iterative
glycosylation with NPOE 8, completely regioselective, to furnish
trimannan 28 in 30% yield.11–13
Several features of these strategies deserve further comment. We
have chosen acyl and silyl substituents as orthogonal protecting
groups because of their mild removal conditions. The success of
the strategy is entirely based on the use of NPOEs as
glycosyl donors: first because of their exquisite regioselectivity
towards D-mannose 2,3,4- and 3,4,6-triols, and second because of
their potential as masked 2-O-benzoyl acceptors. This regioselec-
tivity was not met with armed glycosyl donors. Thus, an armed
thiophenyl glycosyl donor reacted with 12 to give a complex reaction
mixture consisting of at least 4 different tri- and tetrasaccharides.
The NPOE results therefore prove the value of the reciprocal
donor acceptor selectivity (RDAS) concept.5
Scheme 3 Synthesis of linear saccharide 19.
BF3?Et2O (0.3 equiv.) in dichloromethane in the presence of
molecular sieves (4 s) at 230 uC, and yielded trisaccharide 13
(55%) as the only observed coupling product. Deprotection of the
tert-butyl diphenylsilyl group (TBDPS) yielded pentaol 14 in 85%
yield. In the second iteration, glycosylation of 14 with 8 under our
standard conditions, furnished tetrasaccharide 15 in 50% yield, and
again as the only coupled product observed, and desilylation
afforded tetrasaccharide 16, bearing seven free hydroxyl groups. A
third iteration (55% and 70%, respectively), resulted in the
formation of pentasaccharide 18 bearing nine free hydroxyl
groups. Glycosidation with diol donor 8 then gave hexasaccharide
19 in 30% yield.
The glycosylations described herein take place with unprece-
dented regioselectivity, as exemplified in Scheme 3 where NPOE 8
has to choose between nine free hydroxyl groups in the glycosyl
acceptor 18 (cross-coupling) plus two of its own (self-coupling). No
other regioisomers10 were observed in the glycosylation processes.
The reaction sequences were stopped with compounds 19 and 24
since product yields were below 10% due undoubtedly to poor
solubility of the polyol substrates.
The synthesis of the second linear saccharide followed a similar
plan starting with 2,3,4-mannose triol 12. Glycosylation with 8
occurred with complete regioselectivity at O3 to give trisaccharide
20 in 50% yield (Scheme 4), debenzoylation of which yielded
pentaol 21 in 60% yield. A second iteration of coupling (40%) and
debenzoylation (55%) allowed the formation of tetrasaccharide 23
bearing seven free hydroxyl groups. Glycosylation with donor 8
then gave the single pentasaccharide 24 (25% yield).
The strategy disclosed in this communication permits access to
biologically important D-mannose derivatives with a O-3, or O-6
substitution pattern, and to trimannan derivative 28.14 Although
some of the glycosyl couplings described in this paper proceed only
with moderate yields, this protocol illustrates that ‘‘less-reactive’’
hydroxyl groups can remain unprotected throughout synthetic
sequences for oligosaccharides, thus avoiding the need for fully
protected monomers and the final deprotection step.
Next, the value of the strategy for the formation of branched
saccharides was tested. Glycosylation of 12 with NPOE 25 was
In summary we have reported an iterative orthogonal strategy
for oligosaccharide synthesis which permits an efficient entry into
linear or branched oligomannan-derivatives by coupling of
partially unprotected n-pentenyl orthoesters with mannose-derived
triols.
This research was supported with funds from the Direccio´n
General de Ensen˜anza Superior (Grant: PPQ2003-00396). A. A.
thanks the Ministerio de Ciencia y Tecnolog´ıa for financial
support. C. U. thanks the CSIC for financial support. B. F. R. is
Scheme 4 Synthesis of saccharide 24.
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grateful to the National Science Foundation (CHE-0236946) and
the Mizutani Foundation of Japan for partial support of this
work.
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