Synthesis of new α- and β-gem-difluoromethylene C-glycosides in the galactose and glucose series

Article abstract of DOI:10.1016/S0040-4039(01)01144-3

A synthesis of gem-difluoromethylene C-glycopyranosides was efficiently achieved via a Reformatsky reaction on an aldehyde and subsequent intramolecular cyclization involving either the opening of an epoxide or an oxymercuration.

Full text of DOI:10.1016/S0040-4039(01)01144-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5879–5882
Synthesis of new a- and b-gem-difluoromethylene C-glycosides
in the galactose and glucose series
Ste´phane Marcotte, Franc¸ois D’Hooge, Sathunuru Ramadas, Christian Feasson, Xavier Pannecoucke
and Jean-Charles Quirion*
Laboratoire d’He´te´rochimie Organique associe´ au CNRS, IRCOF, INSA et Universite´ de Rouen, Rue Tesnie`re,
76821 Mont Saint-Aignan cedex, France
Received 17 May 2001; accepted 26 June 2001
Abstract—A synthesis of gem-difluoromethylene C-glycopyranosides was efficiently achieved via a Reformatsky reaction on an
aldehyde and subsequent intramolecular cyclization involving either the opening of an epoxide or an oxymercuration. © 2001
Published by Elsevier Science Ltd.
The importance of carbohydrate moiety in cellular and
molecular recognition processes has stimulated intense
research interest in the synthesis of modified glycocon-
jugates. C-Glycosides are synthetic compounds of con-
siderable importance and numerous methods have been
explored for their synthesis.1,2 However, replacement of
the anomeric oxygen by a methylene group may induce
differences in biological functions of these hydrolyti-
cally stable derivatives. For this reason, using a
difluoromethylene group in place of the anomeric oxy-
gen bond is becoming a promising avenue for the
preparation of new glycoconjugate derivatives.3,4
Indeed, this tetrahedral and electronegative unit is con-
sidered as bioisosteric and isoplanar to oxygen.5 How-
ever, a general synthesis of gem-difluoromethylene
C-glycosides applicable to the most often encountered
carbohydrates is still to discover. In this paper, we
present preliminary results in glucose and galactose
series related to previous studies dealing with the reac-
tivity of ethyl bromodifluoroacetate zinc reagent.6 We
reasoned that gem-difluoroesters 2 would be valuable
starting materials for the preparation of the corre-
sponding amino acids 1 which can be regarded as
analogues of O-glycoserine or O-glycothreonine
(Scheme 1).
In a first attempt, we considered the nucleophilic attack
of the ethyl bromodifluoroacetate zinc reagent on an
oxonium ion generated from the corresponding func-
tionalized carbohydrate but all our attempts failed
whatever the conditions.
Scheme 1.
Keywords: carbohydrates; fluorine; glycosides.
* Corresponding author. Tel.: 33(0)235522920; fax: 33(0)235522959; e-mail: quirion@insa-rouen.fr
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01144-3

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S. Marcotte et al. / Tetrahedron Letters 42 (2001) 5879–5882
We then turned our attention to a synthetic pathway
involving the nucleophilic attack of the same reagent on
aldehydes 4 derived from the corresponding carbohy-
drates 5. The resulting olefinic alcohols 3 could then be
cyclized to furnish desired products.
Disappointed by the absence of stereoselectivity, we
then performed the cyclization using an intramolecular
oxymercuration. Examples of such a reaction have been
previously described in glucose series11 and for the
preparation of an azasugar.12 When applied to com-
pounds 7a and 7b this method provided single isomers
9a and 9b, respectively (Scheme 3). NMR studies and
Synthesis of aldehyde 6 starting from methyl-D-glu-
coside in six steps has been previously described by
Vasella.7 The method involved a fragmentation of a
6-bromo derivative. With aldehyde 6 in hand, we then
studied the attack of the ethyl bromodifluoroacetate in
the presence of activated Zn dust (Scheme 2).
especially NOESY experiments clearly indicated an L-
idose configuration for the two products. The conver-
sion of the alcohol(s) 10a13 and 10b was accomplished by
the slow addition of an oxygenated solution of NaBH4
to a solution of the organomercurial compound at 0°C
in the presence of a rapid stream of oxygen.14
We obtained a 1:1 diastereomeric mixture of epimeric
compounds 7a and 7b. We tried to enhance the
stereoselectivity by making the zinc reagent at lower
temperature8 or by using difluoroenoxysilane9 but this
method failed (despite also the addition of a Lewis acid
such as BF3·OEt2). The aldehyde was in each case
totally recovered. We also tried the Reformatsky-type
reaction using SmI2.10 Addition proceeds well (yield
40%) but there was no improvement in the stereoselec-
tivity (1:1 ratio). However, these compounds gave us an
access to both a- and b-difluoromethylene C-glycosides.
Fortunately 7a and 7b were easily separated by chro-
matography on silica gel. At this stage of our study, we
were able to consider the cyclization step. We envisaged
two different procedures for this purpose. The first one
involved the formation of an epoxide (Scheme 3).
We then transposed this strategy to the galactose series
(Scheme 4). Aldehyde 15 was prepared as follows.
Methyl -galactoside 11 was selectively protected as an
D
acetal, then the two remaining hydroxyl groups were
benzylated in 60% yield for the two steps. A regioselec-
tive reduction15 of protected compound 12 (LAH,
AlCl3) furnished alcohol 13 in 95% yield. Mesylation of
the primary alcohol followed by bromination afforded
derivative 14 which was submitted to fragmentation in
the presence of activated Zn dust. Key aldehyde 15 was
then obtained in 77% yield from 13.
Reaction of this aldehyde with zinc ethyl bromodi-
fluoroacetate led to the formation of a 1:1 mixture of
separable alcohols 16a and 16b which were submitted
to oxymercuration reaction to furnish diastereoselec-
tively isomers 17a and 17b, respectively (Scheme 5).
NMR studies unambiguously demonstrated that the
resulting products possessed the correct C-5 galactose
configuration.
Treatment of the two ethylenic compounds 7a and 7b
with mCPBA gave a 1:1 mixture of C-5 epimeric epox-
ides. We were unable to improve the diastereoselectivity
whatever the conditions of epoxide formation. Cycliza-
tion was performed in acidic conditions (CSA, CH2Cl2)
affording 8a and 8b as two 1:1 mixtures of C-5 epimeric
compounds.
As was previously observed,11 the stereochemistry of
these intramolecular oxymercurations is highly depen-
Scheme 2. Reagents and conditions: BrCF2COOEt, Zn dust, THF, 60°C, 64%.
Scheme 3. Reagents and conditions: (a) mCPBA, then CSA, CH2Cl2, 71% (8a), 63% (8b); (b) Hg(OTFA)2, THF; (c) NaHCO3,
then KBr, 85% (9a), 79% (9b); (d) NaBH4, O2, DMF, 0°C, 50% (10a), 46% (10b).

S. Marcotte et al. / Tetrahedron Letters 42 (2001) 5879–5882
5881
Scheme 4. Reagents and conditions: (a) PhCHO, ZnCl2; (b) BnBr, NaH, DMF, 60% from 11; (c) LiAlH4, AlCl3, ether, CH2Cl2,
95%; (d) MsCl, NEt3, CH2Cl2; (e) LiBr, butan-2-one, 95% from 13; (f) Zn, CeCl3, MeOH, 81%.
Scheme 5. Reagents and conditions: (a) BrCF2COOEt, Zn dust, THF, 60°C, 98%; (b) Hg(OTFA)2, THF; (c) NaHCO3, then KBr,
95% (17a), 72% (17b, 4:1 mixture of C-5 epimers).
dent on the C-4 configuration. The influence of an
oxygen on this position has been well studied and
explained.16 It proceeds via an intramolecular attack
on a p complex; the conformer where the oxygen is
in the plane of the double bond is favored (Fig. 1).
Thereby, the internal nucleophile is constrained to
attack on the Re face for 17a or on the Si face for
9a.
methylene C-glycosides has been developed.
A
diastereoselective ring formation via an intramolecular
oxymercuration was the key step. Currently, experi-
ments are underway to prepare compound 1. Our
present work deals with functional transformation of
the carboxylic ester to obtain the desired amino acids.
We are also studying new methods of cyclization to
avoid the use of mercury salts and the application of
this strategy to other biologically interesting carbo-
hydrates.
In conclusion, an access to the a- and b-gem-difluoro-
Figure 1. Favored p complex and intramolecular attack in the glucose and galactose series.

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S. Marcotte et al. / Tetrahedron Letters 42 (2001) 5879–5882
10. Yoshida, M.; Suzuki, D.; Iyoda, M. J. Chem. Soc.,
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