Selective radical synthesis of β-C-disaccharides

Article abstract of DOI:10.1016/S0040-4039(01)01533-7

Several β-C-disaccharides have been selectively synthesized by radical cyclization of two temporarily tethered functionalized monosaccharides. In this process, intramolecular addition of a carbohydrate-derived radical onto an anomeric exomethylene group,

Full text of DOI:10.1016/S0040-4039(01)01533-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7269–7272
Selective radical synthesis of b-C-disaccharides
Boris Vauzeilles† and Pierre Sinay¨*
De´partement de Chimie, UMR CNRS 8642, Ecole Normale Supe´rieure, 24 rue Lhomond, 75231 Paris Cedex 05, France
Received 31 July 2001; accepted 21 August 2001
Abstract—Several b-C-disaccharides have been selectively synthesized by radical cyclization of two temporarily tethered
functionalized monosaccharides. In this process, intramolecular addition of a carbohydrate-derived radical onto an anomeric
exomethylene group, followed by axial hydrogen addition, resulted in b stereochemistry. © 2001 Published by Elsevier Science
Ltd.
C-Di and oligosaccharides are defined as close counter-
parts of natural di- or oligosaccharides in which the
interglycosidic oxygen atom has been replaced by a
methylene group or a substituted methylene group,
such as hydroxymethylene. These non-natural mimetics,
together with the easily available synthetic thiooligosac-
charides,1 should conserve the global geometry of the
natural structure,2 but contain a glycosidic linkage
resistant to enzymatic cleavage. They are thus well
qualified as stable potential surrogates of biologically
active oligosaccharides or, more generally, as attractive
new tools in glycobiology.
cess,6 which parallels the one observed in the inter-
molecular version.7
Hydrogen abstraction by anomeric radicals is known to
selectively occur axially.8 This suggests that addition of
a
carbohydrate-derived radical onto an anomeric
exomethylene group (‘exoglycal’), followed by preferred
axial hydrogen abstraction by the generated anomeric
radical, should lead to the desired b-stereochemistry, as
shown in Fig. 1. Although intermolecular nucleophilic
radical addition onto an enol ether is not favored,
several examples of successful intramolecular trapping
of this type have been reported.9 We would like to
report on the materialization of this so-called reversed
strategy.
The first report on the chemical preparation of a C-di-
saccharide appeared in 1983,3 and a great deal of
attention has since then been devoted to their synthe-
sis.4 We have developed5 over the years an entry to
C-disaccharides based on a 8 or 9 endo-trig radical
cyclization from two tethered monosaccharides. In this
process, the critical carbonꢀcarbon bond formation
resulted from the initial attack of an anomeric radical
onto a non-anomeric exomethylene double bond. An
a-selectivity has generally been observed in this pro-
The previously reported 1-exomethylene gluco and
galacto saccharides 510 and 611 were alternatively syn-
thesized from the known benzylated orthoesters 112 and
2,13 as shown in Scheme 1. Mild aqueous acetic acid
selective opening of the orthoester function,14 followed
by PCC oxydation15 of the resulting hemiacetal, gave
the corresponding lactones 3 and 4.16 Chimioselective17
Figure 1.
Keywords: radicals; cyclization; carbohydrate mimetics; stereocontrol.
* Corresponding author. Tel.: +33-1-44-32-33-90; fax: +33-1-44-32-33-97; e-mail: Pierre.Sinay@ens.fr
† Current address: Universite´ Paris-Sud, Laboratoire de Synthe`se de Biomole´cules, UMR CNRS 8614, Institut de Chimie Mole´culaire, F-91405
Orsay Cedex, France.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01533-7

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B. Vauzeilles, P. Sinay¨ / Tetrahedron Letters 42 (2001) 7269–7272
O
O
O
O
O
O
a,b
c,d
BnO
R2
BnO
R2
BnO
R2
OMe
OAc
OH
R1
R1
R1
OBn
OBn
OBn
1 R1=OBn, R2=H
2 R1=H, R2=OBn
3 R1=OBn, R2=H
4 R1=H, R2=OBn
5 R1=OBn, R2=H
6 R1=H, R2=OBn
,
Scheme 1. Reagents and conditions: (a) AcOH, H2O, 20°C (1), or AcOH, H2O, pyridine, 20°C (2); (b) PCC, 4 A mol. sieves,
CH2Cl2, 20°C; (c) Tebbe’s reagent (1.05 equiv.), THF/pyridine 5/1, −40°C“20°C; (d) MeONa, MeOH, 20°C (5, 52% from 1), or
K2CO3, MeOH, 20°C (6, 33% from 2).
Tebbe methylenation18 of the carbonyl function of the
lactone, followed by deacetylation, afforded a new
approach to the ‘exoglycals’ 5 and 6. In these two
compounds, the secondary hydroxyl group will be used
for the anchoring to another saccharide and the cyclic
enol ether as a radical acceptor.
In a typical experiment (see Scheme 3), the radical
donor 11 was connected to the radical acceptor 5
through a silaketal tether, following the procedure pre-
viously developed by us.5 Tributyltinhydride mediated
8-endo-trig radical cyclization of compound 12 gave,
after detethering of the non isolated intermediate 13,
the protected C-disaccharide 14 in 37% overall yield
(from starting materials 5 and 11). A clear-cut 1H
NMR analysis was achieved on the peracetate 16,25
obtained after hydrogenolysis to compound 15, fol-
lowed by peracetylation. Two asymmetric centers have
been created in the condensation. The b stereochemistry
is the one expected based on the previous premises. The
stereochemistry of the other stereogenic center was not
unexpected as it is known26 that equatorial substituents
adjacent to the radical center favor equatorial addition
of cyclohexyl and non-anomeric hexopyranosyl radicals
(Fig. 1). The C-laminaribioside 15 is of potential bio-
logical interest as it mimics the repeating disaccharide
Alkyl iodides are frequently used for radical carbon–
carbon coupling reactions and, being easily and selec-
tively prepared from saccharides,19 we have selected
them as progenitors of the radical donors. In our
strategy, the iodosugars should also bear a free
hydroxyl group for temporary attachment to the previ-
ously prepared exoglycals. The iodide 920 was easily
prepared from the known21 secondary alcohol 7,
through the iodide 8,22 as shown in the self-explanatory
Scheme 2. The other selected known iodide was 11,
selectively synthesized from the known diol 10,23
according to Samuelsson et al.24
O
OMe
OBn
O
OMe
OBn
O
OMe
OBn
TBSO
TBSO
HO
HO
b
a
I
I
OBn
OBn
OBn
7
8
9
O
OMe
OH
O
OMe
OH
c
O
O
O
Ph
Ph
O
OH
I
10
11
Scheme 2. Reagents and conditions: (a) PPh3, I2, imidazole, toluene, reflux, 82%; (b) CSA, MeOH, 20°C, 94%; (c) PPh3, I2,
imidazole, toluene, 70°C, 68%.
Ph
O
O
O
OMe
OH
O
I
O
BnO
BnO
a,b,c
O
Ph
O
O
O
Si
I
OBn
OMe
11
12
R3O
R5O
13 R1,R2=SiMe2, R3=Bn, R4,R5=CHPh
14 R1=R2=H, R3=Bn, R4,R5=CHPh
15 R1=R2=R3=R4=R5=H
R4O
O
R3O
e
d
O
f
g
R3O
OMe
16 R1=R2=R3=R4=R5=Ac
OR1
OR2
Scheme 3. Reagents and conditions: (a) BuLi, THF; (b) Me2SiCl2; (c) 5, DMAP, THF; (d) Bu3SnH, AIBN, syringe-pump 17 h,
toluene, reflux; (e) TBAF, THF, 37% from 11; (f) H2, Pd/C, MeOH; (g) Ac2O, pyridine, 99% from 14.

B. Vauzeilles, P. Sinay¨ / Tetrahedron Letters 42 (2001) 7269–7272
7271
R2O
R2O
R4O
R3O
R2O
R2O
OR1
O
OMe
OR2
O
O
O
R2O
OMe
R2O
OR1
OR1
OR1
OR2
17 R1=H, R2=Bn
19 R1=R2=Ac
18 R1=H, R2=Bn, R3,R4=CHPh
20 R1=R2=R3=R4=Ac
a, b
a, b
Scheme 4. Reagents and conditions: (a) H2, Pd/C, MeOH; (b) Ac2O, pyridine, 78% from 17 and 90% from 18.
R2O
R2O
R2O
R2O
OR2
O
OR2
O
O
SePh
OH
R1O
O
R1O
O
a-e
BnO
BnO
OR2
OR2
OR2
OR2
R2O
R2O
OBn
OR1
OR1
21
22a R1=H, R2=Bn
23a R1=R2=Ac
22b R1=H, R2=Bn
23b R1=R2=Ac
f, g
f, g
Scheme 5. Reagents and conditions: (a) BuLi, THF; (b) Me2SiCl2; (c) 5, DMAP, THF; (d) Bu3SnH, AIBN, syringe-pump 17 h,
toluene, reflux; (e) TBAF, THF, 44% from 21 (22a/22bꢀ1); (f) H2, Pd/C, MeOH; (g) Ac2O, pyridine, 99% (from 22a or 22b).
unit of fungal b-(1“3)-glucans, which have antitumoral
and immunomodulating properties.
3. Rouzaud, D.; Sinay¨, P. J. Chem. Soc., Chem. Commun.
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4. For recent chapters on the stereoselective synthesis of
C-disaccharides, see: (a) Vogel, P.; Ferrito, R.; Kraehen-
buehl, K.; Baudat, A. In Carbohydrate Mimics; Chapleur,
Y., Ed.; Stereoselective Synthesis of C-Disaccharides,
Aza-C-Disaccharides and C-Glycosides of Carbapyran-
oses Using the ‘Naked Sugars’ Wiley-VCH: Weinheim,
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Vauzeilles B.; Skrydstrup, T. In Glycoscience: Chemistry
and Chemical Biology; Fraser-Reid, B.; Tatsuta, K.;
Thiem, J., Eds. C-Glycosyl compounds as stable analogs
of natural oligosaccharides and glycosyl amino acids.
Springer: Heidelberg, 2001; Vol. 3, pp. 2679–2724. For
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Org. Chem. 2000, 65, 4251–4260; (e) Postema, M. H. D.;
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2000, 65, 6061–6068; (f) Zhu, Y. H.; Vogel, P. Synlett
2001, 79–81.
5. (a) Xin, Y. C.; Mallet, J. M.; Sinay¨, P. J. Chem. Soc.,
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D.; Mallet, J.-M.; Sinay¨, P. Synlett 1993, 522–524; (c)
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hedron: Asymmetry 1994, 5, 2593–2608; (e) Rubinstenn,
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let, J.-M.; Petitou, M.; Sinay¨, P. Bull. Soc. Chim. Fr.
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Following the same methodology, connection of com-
pounds 5 and 9 afforded the C-cellobioside derivative
17 (17% overall yield), while the temporary tethering of
saccharides 6 and 11 led to a protected C-mimic 18 of
Gal-b-(1“3)-Glc (24% overall yield) (Scheme 4). The
structure was again easily assigned after conversion into
the peracetates 1927 and 20,28 respectively.
Finally, the exoglucal 5 was used to synthesize C-tre-
haloses. After tethering with the known29,5a phenyl
Se-glycoside 21, followed by cyclization and desilyla-
tion, an equimolar mixture of two C-disaccharides 22a
and 22b was obtained, in 44% overall yield (Scheme 5).
After separation, hydrogenolysis and acetylation, these
two compounds have been identified as known30 a,b-C-
trehalose 23a and b,b-C-trehalose31 23b. We believe the
loss of selectivity in this case is due to non-selective
trapping of initial radical by the double bond, the
H-abstraction by newly generated anomeric radical
being probably as selective as in the former examples.
This result is consistent with the absence of selectivity
observed in another 8-endo-trig cyclization with the
same radical precursor.5a
In conclusion, whereas our original procedure5 often
delivered a-C-disaccharides, this reversed version pre-
dictably provides b-C-disaccharides and enlarges the
synthetic potential of the tether approach.
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6
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6
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6
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=
J2%,3% 10.0 Hz, H-2%); 4.90 (dd, 1H, J1,2 7.0; J2,3 10.0 Hz,
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1
20. Selected data for 9: [h]2D0 +107 (c 0.97, CHCl3). H NMR
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(400 MHz, CDCl3) 7.60–7.30 (m, 10H, H arom.), 4.90
and 4.70 (2d, 2H, J 12.0 Hz, OCH6 2Ph), 4.78 and 4.65 (2d,
2H, J 11.5 Hz, OCH2Ph), 4.64 (d, 1H, J1,2 4.0 Hz, H-1),
6