A new, general method for the synthesis of carbasugar-sugar pseudodisaccharides

Article abstract of DOI:10.1021/ol901960y

A general synthetic methodology for the synthesis of sugar-carbasugar pseudodisaccharides is described. The methodology is based on the cycloaddition of pyran-2-ones to vinylated sugars and the subsequent manipulation of the cycloadducts to construct the

Full text of DOI:10.1021/ol901960y

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5182-5184
A New, General Method for the
Synthesis of Carbasugar-Sugar
Pseudodisaccharides
Kamyar Afarinkia,*,† Mohamed Haji Abdullahi,† and Ian J. Scowen‡
Institute of Cancer Therapeutics and Analytical Center, UniVersity of Bradford,
Richmond Road, Bradford, BD7 1DP, United Kingdom
k.afarinkia@bradford.ac.uk
Received September 10, 2009
ABSTRACT
A general synthetic methodology for the synthesis of sugar-carbasugar pseudodisaccharides is described. The methodology is based on the
cycloaddition of pyran-2-ones to vinylated sugars and the subsequent manipulation of the cycloadducts to construct the carbasugar component
of the pseudodisaccharide.
Synthetic and naturally occurring oligosaccharides containing
carbasugars have a plethora of biological activities and have
significant applications in biological and medicinal chemis-
try.1
rides that avoids both disadvantages. Building on the
methodology we have previously developed for the efficient
synthesis of individual carbasugars, we demonstrate a new,
general method for the asymmetric construction of a carba-
sugar unit on a free hydroxyl function of a “true” saccharide
(Scheme 1) and show its application to the synthesis of a
novel pseudodisaccharide.
As a result, a good number of synthetic methodologies
are available for their synthesis.1,2 The vast majority of these
methods involve synthesis of the carbasugar as a distinct
moiety, followed by its coupling to the “true” sugar.
However, although quite valid, the obvious disadvantages
of this approach are the excessive reliance on functional
group protection protocols and an inherent inelegance of
using two different chiral sources (one involved in the genesis
of carbasugar and one in the form of “true” sugar). Here,
we report on a method for the synthesis of pseudodisaccha-
Scheme 1. General Method for the Synthesis of
Pseudodisaccharides
† Institute of Cancer Therapeutics.
‡ Analytical Center.
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Following on from pioneering work by Posner,3 we and
others have previously reported extensively on the ver-
satility of the Diels-Alder cycloadditions of 2(H)-pyran-
2-ones,4-6 2(H)-pyridones,7 and 2(H)-oxazin-2-ones8 and
Biomol. Chem. 2005, 162–171
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10.1021/ol901960y CCC: $40.75
Published on Web 10/13/2009
 2009 American Chemical Society

their application in synthesis.6,9,10 These heterocycles un-
dergo efficient cycloadditions as the diene component to
afford functionally rich, bridged bicyclic lactone cycload-
ducts. Halogen-substituted pyran-2-ones are particularly
interesting and useful since they undergo cycloadditions with
a very wide range of dienophiles of different electron
demand, albeit with modest regio- and stereocontrol.5
However, significantly improved regio- and stereoselectivity
is observed if the pyran-2-one substituent electronically
complements that of the dienophile.3 We have also demon-
strated that manipulation of these cycloadducts affords a rapid
synthetic access to heavily substituted six-membered rings
and, in particular, individual carba- and azasugar moieties.
On the basis of this earlier work, we envisaged that
cycloadditions of a suitably substituted pyran-2-one to a
vinylated sugar would be an advantageous means of access-
ing pseudodisaccharides. First, the Diels-Alder cycloadducts
are functionally rich and, as we have already demonstrated,
are ideal springboards for the synthesis of the carbasugar
component of a pseudodisaccharide. In addition, cycload-
ditions can benefit from the induction of chirality by the
enantiopure dienophile to afford the required pseudodisac-
charides as single enantiomers.
Scheme 2. Cycloaddition of 2-Carbomethoxy-2(H)-pyran-2-one
to 1,2:5,6-Di-O-isopropylideneglucofuranose
unreacted pyrone. Following chromatographic separation on
silica gel, the endo configuration for cycloadducts 3a and
3b and the exo configuration for cycloadduct 3c were
established by analysis of the coupling constants in the 400
We prepared vinylated glucofuranose 111 from the corre-
sponding glucofuranose in 88% yield, via a palladium-
catalyzed trans-etherification. Cycloaddition with commer-
cially available 2-carbomethoxy-2(H)-pyran-2-one 2 was
carried out in a sealed tube in methylene chloride at 65 °C
over 7 days using 2 equiv of the dienophile (Scheme 2).
Analysis of the crude reaction mixture by NMR revealed it
to contain a mixture of three cycloadducts in the ratio of
3.4(3a):2.0(3b):0.1(3c) as well as a small quantity of
1
MHz H NMR in accordance to the extensive literature
precedent.3a,5c
At this stage, the absolute configuration of the minor endo
cycloadduct 3b was established unequivocally by X-ray
crystallography as (1R,5R) (see Supporting Information). The
major endo cycloadduct 3a was an oil; however, as can be
seen later, the absolute configuration of this isomer was
established retrospectively as (1S,5S) on the basis of X-ray
crystallography on a derivative (Scheme 3). To rationalize
this modest diastereofacial selectivity, we must assume that
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K.; Bahar, A.; Neuss, J. Synlett 2003, 2341–2344. (d) Afarinkia, K.;
Scheme 3. Transformation of Cycloadduct 3a to
Pseudodisaccharide 8
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Org. Lett., Vol. 11, No. 22, 2009
5183

the approach of the pyrone diene to the vinyl ether is
controlled by the steric bulk of the sugar’s 5′,6′-O-isopro-
pylidene substituent, rather than the 1′,2′-O-isopropylidene
substituent. This is presumably because the former can exert
more steric hindrance due to possible rotation about the
C4′-C5′ bond (Figure 1).
starting from the other diastereofacial endo isomer 3b
(Scheme 4).
Scheme 4. Transformation of Cycloadduct 3b to
Pseudodisaccharide 12
Figure 1. Origins of diastereofacial selectivity.
In summary, we have provided an example of a new
method for the synthesis of carbasugar-“true” sugar pseudo-
disaccharides. In this method, a free hydroxyl function of a
“true” sugar is derivatized to afford an attached carbasugar.
Stereoselective transformations allow the synthesis of a range
of configurations at the newly constructed carbasugar moiety.
We are now in the process of further exemplification of the
method and its application to the synthesis of a range of
naturally occurring and biologically significant pseudo-
oligosaccharides.
Treatment of the major endo isomer 3a with lithium
allyloxide, freshly prepared by addition of butyllithium to
allylalcohol, resulted in transesterification to afford diester
4. One-pot deallylation/decarboxylation of 4 by treatment
with Pd(OAc)2 afforded unsaturated ester 5.12 At this stage,
the structure of compound 5 was confirmed by X-ray
crystallography. Since compound 5 had originated from 3a,
it was now possible to confirm the absolute configuration of
3a as (1S,5R).
Acknowledgment. We thank EPSRC (M.H.A.), Yorkshire
Cancer Research (K.A.), and Yorkshire Enterprise Fellow-
ships (K.A.) for financial support.
Treatment of compound 5 with DIBAL-H then afforded
allylic alcohol 6. Stepwise deprotection of acetonide in 6
led to the formation of 7 and then fully deprotected 8. A
similar approach was adapted to prepare compound 12,
Supporting Information Available: Experimental pro-
cedures and full characterizations of all new compunds. X-ray
crystallography data for 3b in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
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R. L.; Kobayashi, T.; Okano, T.; Tsugawa, N. J. Org. Chem. 1995, 60,
4617–4628.
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