Straightforward preparation of functionalized α-CF 2-galactosides through an oxygen to carbon acyl migration

Article abstract of DOI:10.1002/chem.201100183

A privileged Glycon! A radical-addition Meerwein-Ponndorf-Verley (MPV) reduction sequence provides access to functionalized α-CF ₂-galactosides (see scheme). Introduction of a CF₂Br group in the pseudo-anomeric position aided the transfer of an aglycon chain from O-2 to C-1′ through an intramolecular addition-reduction sequence, which involved a Br-Li exchange. This methodology gives access to a wide range of fluorinated C-glycosidic analogues of glycoconjugates.

Full text of DOI:10.1002/chem.201100183

DOI: 10.1002/chem.201100183
Straightforward Preparation of Functionalized a-CF2-Galactosides through
an Oxygen to Carbon Acyl Migration
Sophie Colombel,[a] Morgane Sanselme,[b] Eric Leclerc,*[a] Jean-Charles Quirion,[a] and
Xavier Pannecoucke[a]
A high number of O-glycoconjugates of therapeutic inter-
est feature an a-galactose or 2-deoxy-2-acetamido-a-galac-
tose unit in their structure, often serving as the link between
the aglycon and the glycosidic parts.[1] For example, this
motif is found in tumor-associated antigens, antifreeze glyco-
proteins (AFGP) or in immunoregulative a-galactosylcera-
mides. This last family of glycosphingolipids (agelasphins)
exhibit strong in vivo activities against infectious diseases
and tumor metastases, which were found to be related to
their immunoregulative properties.[2–4]
metastatic activity than the parent O-glycosidic molecule.
Although there was no evidence that this enhancement of
bioactivity was due to the hydrolytic stability of this ana-
logue, the relevance of testing C-glycosidic surrogates of O-
glycoconjugate-based drugs was thus established.[6]
Our group has been investigating for many years the syn-
thesis of fluorinated C-glycosides, in which the glycosidic
link is replaced by a CF2 moiety.[7] The electronic properties
of this group were expected to impart improved mimicking
abilities to these surrogates, relative to classical C-glyco-
sides. The incorporation of fluorine atoms into drug candi-
dates has become more and more frequent in the past two
or three decades.[8] The unique properties of the fluorine
atom undoubtedly account for this trend, because its intro-
duction into a biologically active molecule might allow alter-
ations of crucial biological functions within limited structur-
al modifications.[9] The synthesis of CF2-glycopyranosides,
which combine the hydrolytic stability of C-glycosidic carbo-
hydrate analogues with these properties, was pioneered by
Motherwell and co-workers and further investigated by
other groups.[10] Our team aimed to provide methodologies
that applied this synthesis to several carbohydrate series
(glucose, mannose, and galactose) and for any pseudo-
anomeric center configuration (a or b). In this context, dis-
closing an efficient methodology for the synthesis of CF2 an-
alogues of a-galactosides was thus a very attractive chal-
lenge due to the many applications one could think of for
these surrogates. To the best of our knowledge, the only re-
ported example of such an analogue is an aryl-a-CF2-d-gal-
actoside, a compound that was therefore not suitable for the
preparation of functionalized a-galactoconjugate mime-
tics.[10k]
Our approach relies on the introduction of a fluorinated
moiety that would feature an appropriate functional group
to introduce the desired side chain (Scheme 1). A sequence
involving a radical addition to galactal 1 followed by a ste-
reoselective reduction of the resulting 2-oxogalactoside was
envisioned to provide such an intermediate. If the efficiency
of the radical addition was previously established, disclosing
a stereoselective reduction reaction and an efficient func-
tionalization methodology were still issues to be addres-
sed.[7d] Herein, we are pleased to report a solution to both
problems due to a new reduction method that enables the
preparation of fluorinated a-C-galactosides through an orig-
inal reductive acyl-chain transfer from O-2 to C-1’. This last
In 2004, the Franck group reported the synthesis of the
CH2 analogue of the a-galactosylceramide KRN 7000.[5] Be-
sides the remarkable synthetic achievement of this work, the
results obtained in terms of immunostimulation were
groundbreaking: a-CH2-GalCer displayed a 1000-fold more
potent antimalaria activity and a 100-fold more potent anti-
[a] S. Colombel, Dr. E. Leclerc, Prof. Dr. J.-C. Quirion,
Prof. Dr. X. Pannecoucke
UMR6014 & FR3038-IRCOF, CNRS
Universitꢀ et INSA de Rouen, 1 rue Tesniꢁre
76821 Mont Saint-Aignan Cedex (France)
Fax : (+33)2-35-52-29-59
E-mail: eric.leclerc@insa-rouen.fr
[b] M. Sanselme
UPRES EA 3233, Universitꢀ de Rouen
1 rue Tesniꢁre, 76821 Mont Saint-Aignan Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100183.
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Chem. Eur. J. 2011, 17, 5238 – 5241

COMMUNICATION
Scheme 1. Our approach to functionalized a-CF2-galactosides. Bn=
benzyl; Y=Br, CO2Et.
synthetic modification provides a convergent and elegant
method for the preparation of analogues of a-galactose-de-
rived glycoconjugates.
Scheme 3. Meerwein–Ponndorf–Verley reduction of 2–4.
The radical addition of BrCF2CO2Et and CF2Br2 to 2-ben-
zyloxyglucal and 2-benzyloxygalactal provided 2-oxoglyco-
sides with interesting a selectivity (Scheme 2).[7d,11] The hy-
dride-mediated reduction of the glucose derivatives led to
especially in the case of 3 (Scheme 3). Due the moderate
stability of 3 on silica gel, when this compound undergoes
chromatography immediately after the radical addition, a
disappointing 41% yield is observed (Scheme 2). On the
other hand, if the crude material is directly engaged in a
MPV reduction, compound 9 is obtained in an appreciable
53% yield over two steps from galactal 1 (Scheme 3). A
slight decrease in yield was observed when the reaction was
performed on a larger scale (41% starting from 2 g of galac-
tal).
The analytical data clearly indicated that 6 and 9 were
diastereomers and therefore that 9 was the desired a-CF2-d-
galactoside. The saponification of ethyl esters 5 and 7 and
isopropyl esters 8 and 10 led to carboxylic acids with differ-
ent NMR data, to give the same conclusion. An X-ray dif-
fraction study on 9 eventually confirmed the C-2 configura-
tion.[13] To our surprise, and unlike the results obtained by
Jimꢀnez-Barbero and Vogel for a fully deprotected a-CF2-
galactoside, this benzylated derivative crystallized under a
1C4 chair conformation.[10k] The conformational flexibility of
this compound in solution was however demonstrated by
the sole H-3/H-5 NOESY correlation. This NMR data is
Scheme 2. Radical addition onto 2-benzyloxygalactal 1 and sodium boro-
hydride reduction of the resulting 2-oxogalactosides. Methods:
A) BrCF2CO2Et or CF2Br2, BEt3, DMF, air; B) EtOC(S)SCFHCO2Et, di-
lauroyl peroxide (DLP), 1,2-dichloroethane (DCE)/tBuOH, reflux. See
ref. [7d].
the expected a-CF2-d-glucoside, however, their galactose
counterparts 2–4 behaved differently. A reversal of diaste-
1
reoselectivity occurred through a major C4 conformation, to
give the a-CF2-d-talloside analogues 5–7 (Scheme 2). Since
the use of other hydrides (diisobutylaluminium hydride
(DIBAH), L-Selectride, Et3BHLi, and so forth) led to the
same stereoselectivity, we reasoned that the diastereoselec-
tivity issue we met with kinetically-controlled reductions
could be tackled under thermodynamic control. A reversible
hydride transfer would indeed favor the most stable diaste-
reomer, which was not expected to be compound 5 because
of the possibility of a strong 1,3-diaxial interaction between
the C-3 and C-5 substituents. The Meerwein–Ponndorf–
Verley (MPV) reduction is a well-known hydride-transfer
reaction for the reversible reduction of aldehydes and ke-
tones and was therefore chosen to challenge this assump-
1
4
indeed only compatible with a S3-skew-boat or a C1-chair
conformation and the 1C4-chair conformation is therefore
exclusive only in the solid state.
Having in hand several fluorinated a-C-galactosides, the
next step was to explore further synthetic modifications that
would enable future preparations of a-GalCer analogues.
The CF2Br group of 9 appeared suitable to introduce agly-
con moieties through a Br/Li exchange, followed by a nucle-
ophilic addition on the appropriate electrophile. However,
we were worried about the thermal stability of the corre-
sponding CF2Li compound due to its carbenoid nature. This
prediction was confirmed by the poor results obtained from
many attempts to perform a Br/Li exchange on 11, followed
by an intermolecular addition (Scheme 4). Low and irrepro-
ducible yields of addition products 12 were indeed obtained
when the CF2Li compound was allowed to react with Gar-
nerꢃs aldehyde. On the other hand, a trapping of the lithium
species with an internal electrophile attached to O-2 ap-
tion.[12] To our delight, the classical Al
ACTHNUTRGNEU(NG OiPr)3-mediated re-
action was extremely efficient and cleanly delivered CF2-gly-
cosides 8–10 from 2–4 (Scheme 3). Moreover, these condi-
tions were compatible with a direct reduction of the crude
compound obtained from the radical addition, which was
not the case with sodium borohydride. The two-step proce-
dure allowed us to significantly improve the global yields,
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5239

E. Leclerc et al.
coconjugate analogues because it would allow the introduc-
tion of various aglycon moieties in the pseudo-anomeric po-
sition through a simple, mild, and convergent process. The
synthesis of difluorinated a-C-galactosylceramides and a
thorough conformational study of a-CF2-galactosides are
currently under investigation. Results in these areas will be
reported in due course.
Experimental Section
Representative procedure for the reductive acyl chain transfer: nBuLi
(1.53m in hexane, 0.337 mL, 0.52 mmol) was added dropwise to a solution
of acetate 13 (0.260 g, 0.43 mmol; obtained by acetylation of 9 using
Ac2O/NEt3/cat. 4-dimethylaminopyridine (DMAP)) in THF (5 mL) at
À788C under an argon atmosphere. The mixture was stirred for 1 h at
À788C then quenched with 1m HCl (5 mL) and extracted with EtOAc
(3ꢄ10 mL). The combined organic layers were washed with water
(10 mL) and brine (10 mL), dried over Na2SO4, and evaporated. Chroma-
tography on a flash purification system (3–30% EtOAc in cyclohexane)
gave intermediate 14 as a colorless oil (0.171 g, 75%). The two diastereo-
mers could not be separated at this stage. NaBH4 (0.019 g, 0.50 mmol)
was added to a solution of 14 (0.171 g, 0.32 mmol) in MeOH (5 mL) at
08C. The mixture was stirred for 3 h at 08C, at which point TLC monitor-
ing showed complete conversion of 14 (eluent: cyclohexane/EtOAc
70:30). The mixture was then warmed up to RT, quenched with sat.
NH4Cl and extracted with EtOAc (3ꢄ10 mL). The combined organic
layers were washed with brine (10 mL), dried over Na2SO4, and evaporat-
ed. Chromatography on a flash purification system (7–60% EtOAc in cy-
clohexane) gave 15 as a colorless oil (0.098 g, 58%).
Scheme 4. Br/Li exchange and intramolecular trapping with an electro-
phile. Boc=tert-butoxycarbonyl.
peared as a method of choice to circumvent the potential
problem of stability. To challenge this intramolecular strat-
egy, acetate 13 was thus prepared from 9 by using a standard
acetylation procedure (Ac2O/NEt3). We were pleased to see
that a Br/Li exchange on 13 indeed resulted in the immedi-
ate trapping of the lithium species by the neighboring ace-
tate to afford the stable hemiketal species 14 in 75%
yield.[14] A reduction of this intermediate provided the alco-
hol 15 in 68% yield and the global transformation can be
analyzed as a formal addition of the lithiated anion of 9 to
acetaldehyde. This reductive migration of an ester from O-2
to C-1’ appeared to be a good approach to O-glycoconjugate
analogues, if a highly functionalized ester was introduced at
the 2-position of 9. Ester 16 was thus prepared from 9 and
from the corresponding d-serine-derived acid (through an
N,N’-diisopropylcarbodiimide (DIPC)-mediated coupling,
85% yield) to challenge this hypothesis. To our delight, a
Br/Li exchange with nBuLi at À788C provided hemiketal 17
in 57% yield, which could be reduced to the desired a-C-
galactoside 18 in 57% yield. If the intermolecular trapping
of the lithiated anion at low temperature can still be investi-
gated, this last intramolecular strategy appears much more
preferable for the synthesis of highly functionalized glyco-
conjugate analogues. The high chemical and configurational
stability of a-aminoesters and acids compared with a-amino-
aldehydes is indeed appreciable for the preparation of the
aglyconic moiety.
Acknowledgements
Prof. Dr. A. Vasella is deeply acknowledged for his fruitful suggestions
regarding the reduction reaction. We also thank the Agence Nationale de
la Recherche (ANR) for a PhD grant to S.C. and for funding, and the
Rꢀgion Haute-Normandie (CRUNCH network) for funding.
Keywords: fluorine
· glycoconjugates · organolithium ·
radical reactions · reduction
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Straightforward Preparation of Functionalized a-CF2-Galactosides
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Received: January 18, 2011
Published online: April 11, 2011
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