Synthesis of pseudo-oligosaccharides by a sequence of yne-ene cross metathesis and Diels-Alder reaction

Article abstract of DOI:10.1039/a903208h

Various pseudo oligosaccharides were prepared by a combination of selective yne-ene cross metathesis and Diels-Alder reaction from readily available monosaccharide building blocks.

Full text of DOI:10.1039/a903208h

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Synthesis of pseudo-oligosaccharides by a sequence of yne-ene cross metathesis
and Diels–Alder reaction
Stephan C. Schürer and Siegfried Blechert*
Institut für Organische Chemie, Sekr. C3, Technische Universität Berlin, Straße des 17. Juni 135, D-10623 Berlin,
Germany. E-mail: sibl@wap0105.chem.tu-berlin.de
Received (in Liverpool, UK) 21st April 1999, Accepted 17th May 1999
Various pseudo oligosaccharides were prepared by a combi-
nation of selective yne-ene cross metathesis and Diels–Alder
reaction from readily available monosaccharide building
blocks.
allyl- and 1-O-propargyl-glyco- and -galacto-pyranosides af-
forded pseudo-oligosaccharides 3 and 4 in high yields.‡
A problem of all cross metathesis reactions that has not been
solved as yet is the formation of E/Z mixtures,3 usually resulting
in stereoisomeric mixtures after subsequent transformations.
Although the described Diels–Alder reaction proceeds with
excellent regioselectivity, diastereomeric mixtures are obtained,
due to the incorporation of E/Z mixtures of the carbohydrate-
substituted 1,3-dienes. The diastereomers refer to the relative
configuration of the cyclohexene substituents. However, this
disadvantage can be overcome by equilibration into the
thermodynamically more stable trans-configuration using
NaOMe in MeOH–THF with simultaneous cleavage of any
acetate protective groups (Scheme 2).
This equilibration–deprotection strategy has been success-
fully applied to the preparation of compounds 8–10, where
acetyl- and benzyl-protected b-d-glyco- and b-d-galacto-
pyranosides with glycosidic and nonglycosidic linkage of the
respective carbohydrate residue have been employed.
In addition to the described Lewis acid catalysed Diels–Alder
reactions of 1,3-dienes we focused on aza-Diels–Alder trans-
formations, since these would provide access to biologically
interesting pipecolic acid derivatives substituted by two varia-
ble carbohydrates (Scheme 3).
Oligosaccharides have been implicated as key participants in a
number of biological processes including signal transduction
and a wide range of recognition events.1 Because of this
tremendous biological importance, carbohydrates have aroused
much interest in synthetic and medicinal chemistry.2
During recent years the number of applications of olefin
metathesis as a very mild and competitive synthetic method3 has
been considerably increased, due to the availability of well-
defined catalysts, in particular Grubbs’ well-established ruthe-
nium initiator Cl2(PCy3)2RuNCHPh (Ru, Cy = cyclohexyl).4
However, olefin metathesis has rarely been used in carbohy-
drate chemistry. Most applications are ring closing metatheses
(RCM) for the synthesis of monosaccharide derivatives5 and
few examples exist for ring opening metathesis polymerisation
(ROMP) involving carbohydrates.6 A very recent publication
describes the homodimerisation of a number of olefinated
pyranosides.7 Selective cross metatheses employing mono-
saccharide building blocks have not been studied, apart from
some isolated examples.8,9 Nonetheless, the selective cross
coupling of monosaccharide building blocks is very intriguing
since the diversity of accessible carbohydrate derivatives is
much higher compared to simple homodimerisation.
As dienophiles we employed N-trichloroethylidene toluene-
p-sulfonamide and ethyl (4-tolylsulfonylimino)acetate. Similar
A selective cross metathesis between a terminal alkyne and a
terminal alkene yielding 1,3-disubstituted butadienes has been
found recently in our laboratory.9 These 1,3-dienes, formed by
yne-ene cross metathesis, represent attractive starting materials
for subsequent Diels–Alder reactions (Scheme 1).
O
CH3
OAc
AcO
O
O
AcO
OAc
However, little is known about Diels–Alder transformations
of nonactivated acyclic 1,3-dienes,10 which are regarded as poor
substrates for Diels–Alder reactions. As there were no examples
of Diels–Alder reactions incorporating carbohydrate-substi-
tuted 1,3-butadienes, we started investigations on yne-ene cross
metatheses of monosaccharide building blocks and subsequent
Diels–Alder transformations, providing an easy and very
flexible access towards pseudo-oligosaccharides.
Introducing acetylated 1-O-allyl- and 1-O-propargyl-glyco-
pyranoside as the alkene and alkyne components to yne-ene
cross metathesis followed by MeAlCl2-catalysed Diels–Alder
reaction with methyl vinyl ketone yielded compounds 1 and 2,
respectively (Fig. 1).†
OAc
OAc
1 Metathesis yield = 60%
Diels–Alder yield = 70%
O
O
CH3
OBn
AcO
AcO
O
OAc
2 Metathesis yield = 51%
Diels–Alder yield = 86%
O
OAc
O
CH3
AcO
AcO
OAc
O
O
O
AcO
A number of allyl- and propargyl-substituted carbohydrate
building blocks was then prepared and introduced to yne-ene
cross metathesis followed by Diels–Alder transformation
according to Scheme 2. The combination of acetylated 1-O-
OAc
O
O
3 Metathesis yield = 58%
Diels–Alder yield = 96%
Ac
OAc
O
AcO
Ru
R1
R1
R1
R2
Acc
R2
O
CH3
R2
+
+
AcO
AcO
OAc
OAc
O
O
AcO
OAc
Acc
X
R1
R2
X
OAc
4 Metathesis yield = 65%
Diels–Alder yield = 94%
Scheme 1
Fig. 1 Yields of 1–4.
Chem. Commun., 1999, 1203–1204
1203

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OAc
In conclusion, we have developed a general sequence of
selective yne-ene cross metathesis, Diels–Alder transformation
and equilibration–deprotection for the synthesis of various
biologically interesting carbohydrate derivatives. The combina-
tion of different monosaccharide building blocks and dieno-
philes has been demonstrated and should potentially give rise to
a large number of pseudo-oligosaccharides of the types
presented. Further investigations to explore the scope of the
described reactions are now in progress.
OBn
O
O
BnO
O
AcO
AcO
+
O
O
Bn
OBn
OAc
6
5
i,ii
O
OAc
O
AcO
AcO
OBn
O
We are thankful to the Fonds der Chemischen Industrie for
financial support and to Priv. Doz. Dr J. Jakupovic for NMR
characterisation of some of the presented compounds.
O
O
BnO
OAc
7
O
Bn
OBn
iii
O
OH
O
Notes and references
HO
HO
OBn
O
O
O
BnO
† Yne-ene cross metathesis: 5 mol% of Ru was added to a solution of 0.5
mmol of alkyne and 1.5–2.0 equiv. of alkene in CH2Cl2 (0.2 M
concentration). After 12 h stirring another 5 mol% of Ru was added. After
an additional 18 h the product was purified by column chromatography.
MeAlCl2-catalysed Diels–Alder reaction: To a solution of 100 mmol of
1,3-diene and 20 equiv. of methyl vinyl ketone in 3 ml of CH2Cl2 and 1 ml
of toluene, MeAlCl2 (3 equiv.) was added at 278 °C. The reaction was
stirred for 24 h at 235 °C and then quenched at 278 °C by addition of 10
equiv. of Et3N and 1 ml of MeOH, followed by filtration through silica gel,
concentration, and purification by column chromatography.
OH
O
8 68% (step i), 76% (steps ii,iii)
Bn
OBn
O
OR
O
O
RO
O
R
O
BnO
O
OMe
BnO
OBn
Equilibration and deprotection: The cycloadducts were stirred with 0.02
M NaOMe in MeOH–THF (1+1, v/v) at 0.01 M concentration for 12 h and
then neutralised by addition of weakly acidic ion exchange resin, followed
by filtration and purification by column chromatography.
OR
9 R = Bn, 67% (step i), 91% (steps ii,iii)
10 R = H, 57% (step i), 54% (steps ii,iii)
High pressure aza-Diels–Alder reaction: A solution of 100 mmol of
1,3-diene and 1.5–2.0 equiv. of dienophile (0.2 M concentration) in CH2Cl2
was heated in a Teflon tube to 70–75 °C under 12 kbar pressure for 40 h. The
product was purified by column chromatography.
Scheme 2 Reagents and conditions: i, Ru (10%), CH2Cl2; ii, methyl vinyl
ketone, MeAlCl2, CH2Cl2–PhMe, 235 °C; iii, NaOMe, MeOH–THF.
‡ All prepared pseudo-oligosaccharides have been characterised by 1H
NMR, 13C NMR, FAB-MS and IR spectroscopy. Additional 2D NMR
spectra (COSY, HMQC, TOCSY, HMBC) have been obtained.
OR
O
O
O
O
RO
BnO
BnO
O
OMe
R
11
OR
OBn
1 For references see: R. A. Dwek, Chem. Rev. 1996, 96, 683; R. Roy, in
Carbohydrate Chemistry, ed. G. J. Boons, Chapman and Hall, UK,
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Trans. 1, 1998, 371; M. Schuster and S. Blechert, Angew. Chem., 1997,
109, 2124; Angew. Chem., Int. Ed. Engl., 1997, 36, 2036.
R'
12 kbar, 70 °C
CH2Cl2
NTs
R'
Ts
N
OR
O
O
O
O
RO
BnO
BnO
O
R
OMe
OR
OBn
12 R = Bn, R′ = CO2Et, 55%
13 R = Ac, R′ = CCl3, 57%
CO2Et
N
4 P. Schwab, M. B. France, J. W. Ziller and R. H. Grubbs, Angew. Chem.,
1995, 107, 2179; Angew. Chem., Int. Ed. Engl., 1995, 34, 2039.
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Strehler and J. Eustache, Tetrahedron Lett., 1999, 40, 853; D. J. Holt,
W. D. Barker, P. R. Jenkins, D. L. Davies, S. Garrat, J. Fawcett, D. R.
Russel and S. Ghosh, Angew. Chem., 1998, 110, 3486; Angew. Chem.
Int. Ed., 1998, 37, 3298; H. S. Overkleeft, P. Bruggeman, U. K. Pandit,
Tetrahedron Lett., 1998, 39, 3869; H. Ovaa, M. A. Leeuwenburgh, H. S.
Overkleeft, G. A. van der Marel and J. H. van Boom, Tetrahedron Lett.,
1998, 39, 3025; A. Fürstner and T. Müller, J. Org. Chem., 1998, 63, 424;
F. E. Ziegler and Y. Wang, J. Org. Chem., 1998, 63, 426.
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Fraser and R. H. Grubbs, Macromolecules, 1995, 28, 7248; K. H.
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OAc
Ts
O
AcO
AcO
OBn
O
O
O
BnO
OAc
O
14 61%
Bn
OBn
CCl3
N
AcO
Ts
O
AcO
AcO
OAc
OAc
O
O
O
OAc
AcO
OAc
15 61%
Scheme 3
to the Diels–Alder reactions described above, acetyl- and
benzyl-protected b-d-glyco- and b-d-galacto-pyranosides with
glycosidic and nonglycosidic linkages have been introduced to
aza-Diels–Alder transformations, which were found to proceed
with moderate to reasonable yield and excellent regioselectivity
under 12 kbar pressure at 70 °C in CH2Cl2 to yield pseudo-
oligosaccharides 12–15.
9 R. Stragies, M. Schuster and S. Blechert, Angew. Chem., 1997, 109,
2628; Angew. Chem., Int. Ed. Engl., 1997, 36, 2518.
10 W. R. Roush and D. A. Barda, J. Am. Chem. Soc., 1997, 119, 7402.
Communication 9/03208H
1204
Chem. Commun., 1999, 1203–1204