A highly convergent synthesis of a branched C-trisaccharide employing a double SmI2-promoted C-glycosylation

Article abstract of DOI:10.1039/b007117j

The branched C-trisaccharide analogue of α-D-Man-(1→3)-[α-D-Man-(1→6)]-D-Man has been synthesised by the SmI₂-mediated coupling of two mannosyl pyridyl sulfone units to a monosaccharide dialdehyde. This approach represents a highly convergent s

Full text of DOI:10.1039/b007117j

A highly convergent synthesis of a branched C-trisaccharide employing a
double SmI2-promoted C-glycosylation
Lise Munch Mikkelsen,a Sussie Lerche Krintel,a Jesús Jiménez-Barberob and Troels Skrydstrup*a
a Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark.
E-mail: ts@kemi.aau.dk; Fax: +45 8619 6199
b Instituto de Química Orgánica,CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain
Received (in Liverpool, UK) 29th August 2000, Accepted 10th October 2000
First published as an Advance Article on the web 9th November 2000
The branched C-trisaccharide analogue of a-
D
-Man-
(1?3)-[a-
D
-Man-(1?6)]-
D
-Man has been synthesised by the
SmI2-mediated coupling of two mannosyl pyridyl sulfone
units to a monosaccharide dialdehyde. This approach
represents a highly convergent synthesis of a C-oligo-
saccharide.
C-Disaccharides, in which the interglycosidic linkage has been
replaced by a methylene group, have proved to be valuable tools
for studying conformational preferences of their parent O-
glycosides both in solution and protein bound, as well as
providing important insight into the mechanism of glycoside
cleaving enzymes (glycosidases) owing to the inability of C-
disaccharides to undergo hydrolysis.1 Many synthetic ap-
proaches to these analogues have therefore been devised, but
have mainly been restricted to disaccharides and not higher
oligomers thereof owing to the synthetic challenge in preparing
such compounds.2,3 In previous reports, we have shown that
reductive samariation of glycosyl pyridyl sulfones in the
presence of a C-formyl branched sugar is a viable approach for
the stereoselective construction of C-disaccharides.4,5 The
synthetic approach to these sugar mimics employs intact
carbohydrate units as both C-glycosyl donors and acceptors,
which are complementary to approaches exploited in standard
O-glycoside synthesis. This suggested the possibility of apply-
ing this procedure for the construction of branched C-
oligosaccharides as well, by a multiple C-glycosylation step of
a carbohydrate unit containing more than one C-formyl chain.
In this communication, we report on the success of this goal in
the highly convergent construction of the C-glycoside analogue
Fig. 1
of the core region, a-
D
-Man-(1?3)-[a-
D
-Man-(1?6)]- -Man,
D
of the asparagine-linked oligosaccharides.
The synthetic approach to the branched C-trisaccharide 1 is
illustrated in Fig. 1, comprising of the direct double coupling of
dialdehyde 3 with two equivalents of the configurationally
stable anomeric samarium species 2, which in turn may easily
be prepared via the in situ reduction of the anomeric pyridyl
sulfone.4,5 Subsequent radical-based deoxygenation of the two
hydroxy groups formed would then complete this short
synthesis of the protected C-trisaccharide.
We began the synthesis of the branched C-trisaccharide with
the construction of the dideoxymannosyl unit 9 containing the
C3 and C6 formyl groups via the stepwise introduction of two
alkene groups at the denoted positions, as illustrated in Scheme
1.† Regioselective opening of the easily available epoxide 4 (5
steps from 1,6-anhydroglucose6) with excess vinylmagnesium
bromide7 and subsequent dibenzylation afforded the alkene 5 in
42% yield. In order to introduce the second alkene group at C-6,
we took advantage of a recent report by Clark et al. in their
synthetic approach to the marine polycyclic ethers of the
brevetoxin and ciguatoxin family.8 Hence, methanolysis of 5
led to the opening of the anhydro-ring affording only the methyl
a-mannoside 6, which could easily be transformed to the
corresponding triflate by treatment with Tf2O–2,6-lutidine.
Alkynylation with the lithium anion of TMSacetylene in THF–
HMPA then afforded the C6-alkyne branched sugar 7 (53%, 2
Scheme 1 Reagents and conditions: i, 3 equiv. of CH2CHMgBr, THF,
60 °C; ii, NaH, BnBr, DMF, 42% (2 steps); iii, conc. HCl in MeOH, reflux,
56%; iv, Tf2O, 2,6-lutidine, CH2Cl2, 240 °C; v, Me3SiCCLi, THF–HMPA,
278 °C to 20 °C, 53% (2 steps); vi, Bu4NF, THF, 20 °C; vii, H2, Lindlar’s
catalyst, quinoline, EtOAc, 20 °C, 77% (2 steps); viii, O3, CH2Cl2–MeOH,
278 °C, then Ph3P, 77%.
DOI: 10.1039/b007117j
Chem. Commun., 2000, 2319–2320
This journal is © The Royal Society of Chemistry 2000
2319

We thank the Danish National Science Foundation (THOR
programme), The University of Aarhus, and the Carlsberg
Foundation for generous financial support.
Notes and references
† We initially attempted several routes to introduce simultaneously the two
alkene units into the easily available methyl 2,4-di-O-benzyl-a-D-man-
nopyranoside, although this synthetic pathway was unrewarding.
‡ Selected data for 13: (400 MHz, C6D6) dH 5.53 (dd, 1H, J 6.0, 3.0 Hz,
H3A), 5.48 (dd, 1H, J 8.8, 3.6 Hz, H3B), 5.45 (dd, 1H, J 8.8, 7.6 Hz, H4B),
5.38 (dd, 1H, J 3.6, 3.2 Hz, H2B), 5.28 (dd, 1H, J 6.4, 3.0 Hz, H2A), 5.25 (dd,
1H, J 2.4, 1.6 Hz, H2), 5.23 (dd, 1H, J 10.4, 9.2 Hz, H4), 5.17 (dd, 1H, J 6.0,
4.8 Hz, H4A), 4.72 (dd, 1H, J 11.6, 7.2 Hz, H6aA), 4.64 (d, 1H, J 1.6 Hz, H1),
4.48 (dd, 1H, J 12.0, 7.2 Hz, H6aB), 4.16 (ddd, 1H, J 7.6, 6.4, 4.8 Hz, H1A),
4.04 (dd, 1H, J 12.0, 2.8 Hz, H6bB), 4.00 (m, 2H, H5A, H6bA), 3.95 (ddd, 1H,
J 10.4, 3.6, 3.2 Hz, H1B), 3.89 (ddd, 1H, J 7.6, 7.2, 2.8 Hz, H5B), 3.69 (ddd,
1H, J 9.2, 9.2, 2.8 Hz, H5), 2.96 (s, 3H, OMe), 2.54 (m, 1H, H3); HR-MS
(ES) calcd for C41H58O24 (M + Na): 957.3215, found 957.3216.
§ The stereochemistry at C1 for both of the non-reducing sugars in 13 was
assigned to the a-configuration, based on the similar coupling patterns
observed for the H1A and H1B protons compared to those observed in the C-
Scheme 2 Reagents and conditions: i, 4.7 equiv. of 10, 10 equiv. of SmI2,
THF, 20 °C; ii, 25 equiv. of (Imid)2CS, CH3CN, reflux, 67% (2 steps); iii,
4 equiv. of F5C6OH, 5.2 equiv. of Ph3SnH, AIBN (cat.), toluene, 90 °C,
53%; iv, Pd/C, H2, MeOH–AcOH; v, Ac2O, DMAP (cat.), pyridine.
disaccharides of a-D-Man-(1?3)-D-Man and a-D-Man-(1?6)-D-Man. In
addition, all previous reactions performed with the mannosyl pyridyl
sulfone 10 have led only to the formation of a-C-mannosides.
1 A. Wei, K. M. Boy and Y. Kishi, J. Am. Chem. Soc., 1995, 117, 9432;
J.-F. Espinosa, F. J. Cañada, J. L. Asensio, H. Dietrich, M. Martín-
Lomas, R. R. Schmidt and J. Jiménez-Barbero, Angew. Chem., Int. Ed.
Engl., 1996, 35, 303; J.-F. Espinosa, F. J. Cañada, J. L. Asensio, M.
Martin-Pastor, H. Dietrich, M. Martín-Lomas, R. R. Schmidt and J.
Jiménez-Barbero, J. Am. Chem. Soc., 1996, 118, 10862; J.-F. Espinosa,
H. Dietrich, M. Martín-Lomas, R. R. Schmidt and J. Jiménez-Barbero,
Tetrahedron. Lett., 1996, 37, 1467; J.-F. Espinosa, E. Montero, A. Vian,
J. L. Garcia, H. Dietrich, M. Martín-Lomas, R. R. Schmidt, A. Imberty,
F. J. Cañada and J. Jiménez-Barbero, J. Am. Chem. Soc., 1998, 120, 1309;
R. Ravishankar, A. Surolia, M. Vijayan, S. Lim and Y. Kishi, J. Am.
Chem. Soc., 1998, 120, 11297; J. F. Espinosa, M. Bruix, O. Jarreton, T.
Skrydstrup, J.-M. Beau and J. Jiménez-Barbero, Chem. Eur. J., 1999, 5,
442; J. L. Asensio, J.-F. Espinosa, H. Dietrich, F. J. Cañada, R. R.
Schmidt, M. Martín-Lomas, S. André, H.-J. Gabius and J. Jiménez-
Barbero, J. Am. Chem. Soc., 1998, 120, 1309.
2 M. H. D. Postema, C-Glycoside Synthesis, CRC Press, Boca Raton, FL,
1995; D. E. Levy and C. Tang, The Chemistry of C-Glycosides, Pergamon
Press, Exeter, 1995; G. Casiraghi, F. Zanardi, G. Rassu and P. Spanu,
Chem. Rev., 1995, 95, 1677. See also, C. Pasquarello, S. Picasso, R.
Demange, M. Malissard, E. G. Berger and P. Vogel, J. Org. Chem., 2000,
65, 4251, and references therein.
3 For examples of the synthesis of C-oligosaccharides, T. Haneda, P. G.
Goekjian, S. H. Kim and Y. Kishi, J. Org. Chem., 1992, 57, 490; A. Wei,
A. Haudrechy, C. Audin, H.-S. Jun, N. Haudrechy-Bretel and Y. Kishi,
J. Org. Chem., 1995, 60, 2160; D. P. Sunderlin and R. W. Armstrong,
J. Org. Chem., 1997, 62, 5267; A. Dondoni, M. Kleban, H. Zuurmond
and A. Marra, Tetrahedron Lett., 1998, 39, 7991; Y.-C. Xin, Y.-M.
Zhang, J.-M. Mallet, C. P. J. Glaudemans and P. Sinaÿ, Eur. J. Org.
Chem., 1999, 471; A. Dondoni, M. Mizuno and A. Marra, Tetrahedron
Lett., 2000, 41, 6657.
steps), which was first desilylated and then hydrogenated with
Lindlar’s catalyst providing the dialkene 8 in 77% yield (2
steps). Finally, ozonolysis led to the required dialdehyde 9.
The key coupling step of the dialdehyde with the mannosyl
pyridyl sulfone 10 was achieved by quickly adding a 0.1 M
solution of SmI2 (10 equiv.) to a mixture of 9 with excess 10
(4.7 equiv.) at 20 °C leading to the immediate consumption of
both reagents (Scheme 2).4,5 Subsequent work-up led to a
complex mixture of diastereomers, which was immediately
subjected to a surplus of thiocarbonyldiimidazole (25 equiv.) in
refluxing acetonitrile. A quick reaction was observed as
monitored by TLC analysis leading to the introduction of a
single thiocarbonylimidazole unit, which was most likely to
occur at the sterically less encumbered carbon adjacent to C6.
However, the slow evaporation of the solvent under heating
finally led to the formation of a second more polar product at the
expense of the first, which was identified as compound 11 as a
mixture of diastereomers containing two functionalised alcohol
groups (67% yield, 2 steps). The slow removal of the solvent is
necessary for the successful introduction of the second
thicarbonylimidazole moiety as previously observed in similar
cases for the functionalisation of sterically hindered secondary
alcohols.4
Finally, radical-based deoxygenation employing our estab-
lished procedure with the F5C6OH–Ph3SnH–AIBN combina-
tion in hot toluene4 completed this short synthesis of the desired
branched C-trisaccharide 12, obtained as a single stereoisomer
in 53% yield. Further characterisation of 12 was made by its
conversion to the decaacetate 13 easily prepared by a two-step
protocol involving catalytic hydrogenation and peracetyla-
tion.‡,§
In conclusion, we have successfully applied the SmI2
promoted C-glycosylation procedure to the expedient and
convergent synthesis of a branched C-trisaccharide related to
the core structure of the asparagine-linked oligosaccharides.
Work can now commence in studying its conformational
behaviour in comparison to its parent O-glycoside, the in-
vestigation of which will be reported in due course.
4 (a) O. Jarreton, T. Skrydstrup and J.-M. Beau, Chem. Commun., 1996,
1661; (b) L. Andersen, L. M. Mikkelsen, J.-M. Beau and T. Skrydstrup,
Synlett, 1998, 1393; (c) O. Jarreton, T. Skrydstrup, J.-F. Espinosa, J.
Jiménez-Barbero and J.-M. Beau, Chem. Eur. J., 1999, 5, 430; (d) S. L.
Krintel, J. Jiménez-Barbero and T. Skrydstrup, Tetrahedron Lett., 1999,
40, 7565.
5 For a recent review, T. Skrydstrup and J.-M. Beau, in Advances in Free
Radical Chemistry, ed. S. Z. Zard, Jai Press, Stamford, 1999, vol. 2,
p. 89.
6 J. Dolezalová, T. Trnka and M. Cerny, Collect. Czech. Chem. Commun.,
1982, 47, 2415.
7 T. Inghardt and T. Frejd, Synthesis, 1990, 285.
8 J. S. Clark and O. Hamelin, Angew. Chem., Int. Ed., 2000, 39, 372.
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