Addition of difluoromethyl radicals to glycals: A new route to α-CF2-D-glycosides

Article abstract of DOI:10.1021/ol070835f

The synthesis of synthetically useful α-CF₂ glycosides by radical addition of ethyl bromodifluoroacetate onto 2-benzyloxyglycals Is described. The methodology provides an access to α-O-glycoside mimics and, potentially, to valuable α-O-glycocon

Full text of DOI:10.1021/ol070835f

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2477-2480
Addition of Difluoromethyl Radicals to
Glycals: A New Route to
r
-CF2- -Glycosides
D
Benjamin Moreno, Cindy Quehen, Maureen Rose-He´le`ne, Eric Leclerc,* and
Jean-Charles Quirion
Laboratoire d’He´te´rochimie Organique, UMR 6014 CNRS, IRCOF, INSA et UniVersite´
de Rouen, 1 rue Tesnie`re, 76821 Mont Saint-Aignan Cedex, France
eric.leclerc@insa-rouen.fr
Received April 9, 2007
ABSTRACT
The synthesis of synthetically useful
r-CF2-glycosides by radical addition of ethyl bromodifluoroacetate onto 2-benzyloxyglycals is described.
The methodology provides an access to
r
-O-glycoside mimics and, potentially, to valuable -O-glycoconjugate analogues.
r
Among the different classes of biomolecules, O-glycocon-
jugates have acquired an increasing importance in the field
of drug discovery in recent years. Their involvement in many
recognition processes, such as the immune response, un-
doubtly accounts for this trend.1 For example, KRN 7000,
an R-galactosylceramide (R-GalCer) structurally close to
natural O-glycolipids called agelasphins, exhibits a strong
immunostimulatory activity and shows a high in vivo activity
toward a wide range of diseases.2-5 However, a major
drawback of O-glycosides and O-glycoconjugates as drug
development candidates resides in the low metabolic stability
of the anomeric bond that erodes the bioavailability of
carbohydrate-based drugs. As a consequence, the synthesis
of nonhydrolyzable analogues such as CH2-glycopyranosides
has been investigated intensively, but unfortunately has
scarcely ever been applied to valuable targets.6 On the other
hand, the O T CF2 transposition offers an interesting
alternative to standard C-glycosides as it could potentially
provide closer surrogates of carbohydrates thanks to the
electronic properties of the CF2 moiety.7 Several groups have
thus focused on the synthesis of CF2-glycopyranosides as
new glycomimetics.8 The next step would be of course to
produce CF2-analogues of potent O-glycoconjugates such as
R-galactosylceramides. This project has become a major goal,
(1) (a) Essentials of Carbohydrate Chemistry and Biochemistry, 2nd ed.;
Lindshorst, T. K., Ed.; Wiley-VCH: Weinheim, Germany, 2002. (b)
Carbohydrate-Based Drug DiscoVery; Wong, C.-H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003.
(2) Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Tetrahedron 1994,
50, 2771.
(3) (a) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa,
E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.; Fukushima, H. J. Med. Chem.
1995, 38, 2176. (b) Giaccone, G.; Punt, C. J. A.; Ando, Y.; Ruijter, R.;
Nishi, N.; Peters, M.; von Blomberg, B. M. E.; Scheper, R. J.; van der
Vliet, H. J. J.; van den Eertwegh, A. J. M.; Roelvink, M.; Beijnen, J.;
Zwierzina, H.; Pinedo, H. M. Clin. Cancer Res. 2002, 8, 3702.
(4) (a) Grubor-Bauk, B.; Simmons, A.; Mayrhofer, G.; Speck, P. G. J.
Immunol. 2003, 170, 1430. (b) Nieuwenhuis, E. E.; Matsumoto, T.; Exley,
M.; Schleipman, R. A.; Glickman, J.; Bailey, D. T.; Corazza, N.; Colgan,
S. P.; Onderdonk, A. B.; Blumberg, R. S. Nat. Med. 2002, 8, 588. (c) Hong,
S.; Wilson, M. T.; Serizawa, I.; Wu, L.; Singh, N.; Naidenko, O. V.; Miura,
T.; Haba, T.; Scherer, D. C.; Wei, J.; Kronenberg, M.; Koezuka, Y.; Van
Kaer, L. Nat. Med. 2001, 7, 1052.
(6) For a review on C-glycoside synthesis, see: (a) Skrydstrup, T.;
Vauzeilles, B.; Beau, J. M. C-Oligosaccharide Synthesis. In Glycoscience:
Chemistry and Chemical Biology; Fraser Reid, B., Tatstuta, K., Thiem, J.,
Eds.; Springer: Heidelberg, Germany, 2001; Vol. 3, pp 2679. For this
application of a CH2-glyconjugate analogue, see: (b) Yang, G.; Schmieg,
J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int. Ed. 2004, 39, 3818. (c)
Schmieg, J.; Yang, G.; Franck, R. W.; Tsuji, M. J. Exp. Med. 2003, 198,
1631.
(7) For potent nonhydrolyzable CF2-analogues of bioactive molecules,
see: (a) Burke, T. R., Jr.; Lee, K. Acc. Chem. Res. 2003, 36, 426. (b) Burke,
T. R., Jr.; Smyth, M. S.; Otaka, A.; Nomizu, M.; Roller, P. P.; Wolf, G.;
Case, R.; Shoelson, S. E. Biochemistry 1994, 33, 6490. (c) Blackburn, G.
M.; Jakeman, D. L.; Ivory, A. J.; Williamson, M. P. Bioorg. Med. Chem.
Lett. 1994, 4, 2573 and references cited therein.
(5) The mechanism of action, based on a cytokine release by NKT cells,
has been identified: Kronenberg, M. Annu. ReV. Immunol. 2005, 23, 877.
10.1021/ol070835f CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/27/2007

following the publication of the outstanding biological results
obtained with the CH2 analogue of KRN 7000.6b For such a
purpose, the development of a new synthetic access to CF2-
glycopyranoside intermediates was needed and had to fulfill
two major requirements.
First, the method had to lead stereoselectively to difluo-
romethylated analogues of R-glycosides. In the second place,
the R-CF2-glycoside obtained by such a reaction should
feature appropriate functional groups in order to serve as a
useful intermediate in the synthesis of R-GalCer analogues.
Among the efficient CF2-glycoside syntheses that have been
developed, some methods have provided solutions only to
either one problem or the other.8b,e We wish to present herein
a new reaction for the addition of difluoromethyl radicals to
glycals that leads stereoselectively to synthetically useful
R-CF2-glycosides.
Sodium dithionite in MeCN/H2O or AIBN in refluxing
benzene was not effective for this less reactive precursor.
We then turned our attention to triethylborane and several
attempts were made with benzylated D-glucal 3 as the starting
material. The use of polar solvents appeared crucial as a low
but significant conversion was observed in THF whereas only
traces of product could be identified when reactions were
performed in dichloromethane and toluene (Table 1). A faster
Table 1. Triethylborane-Mediated Addition of BrCF2CO2Et to
D-Glucal 3
The addition of difluoromethyl radicals onto standard
glycals has already been studied and exhibits a well-defined
regioselectivity.9 The addition takes place exclusively at the
C-2 carbon and is therefore not suitable for CF2-glycoside
synthesis. However, we reasoned that the introduction of an
alkoxy substituent at the C-2 position should direct the
addition to the less hindered C-1 carbon (Scheme 1).
entry
solvent
yield (%)
1
2
3
4
5
6
CH2Cl2
toluene
THF
THF/H2O
DMF
traces
traces
11
21
28
51a
DMF
a 5 equiv of BrCF2CO2Et and 3 equiv of BEt3 were used.
Scheme 1. Synthesis of R-CF2-Glycosides from
2-Alkoxyglycals
reaction occurred in DMF allowing the isolation of 2-keto-
hexopyranoside 4 in 28% yield but a large amount of starting
material was again recovered (Table 1, entry 5).
The formation of the 2-ketohexopyranoside 4 can be
explained by a fragmentation of the radical resulting from
•
the addition of CF2CO2Et, thanks to the departure of a
stabilized tolyl radical. This particular pathway is of course
not applicable to acetylated D-glucal 2, which moreover
underwent no addition process of any type under these
conditions. The need for a polar solvent is in agreement with
the general behavior of fluoroalkyl radicals. Indeed, addition
During the early stages of this work, the group of
Miethchen reported the sodium dithionite-mediated addition
of bromochlorodifluoromethane to 2, affording almost ex-
clusively the corresponding R-CF2-glucoside analogue 1 (Y
) Cl) but with a low conversion.8e,f Moreover, a fluorinated
synthon allowing easier functionalization than CF2Cl was
required for our purposes. The ester function of ethyl
bromodifluoroacetate, an accessible and easy-to-handle
fluorinated synthon, already proved suitable for further
synthetic elaboration.8h Several initiators were tested in order
to perform this addition of BrCF2CO2Et to glycals 2 or 3.10
•
reactions of electronegative radicals such as CF2CO2Et to
electron-rich double bonds give rise to polar transition states
that are usually stabilized in polar media.11 The reaction was
eventually driven to completion by using a longer reaction
time and an excess of triethylborane. Performing several
additions of BrCF2CO2Et and BEt3 proved to be particularly
efficient and 2-ketohexopyranoside 4 could be isolated in
51% yield (Table 1, entry 6). The addition of •CF2CO2Et to
double bonds from a stable and easily available bromodi-
fluoroacetate is noteworthy since the few reported examples
of such reactions involve the use of the less common iodide
or require the painstaking synthesis of the corresponding
selenide.12 The two diastereomers 4a and 4b were present
(8) (a) Houlton, J. S.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.;
Williams, D. J.; Slawin, A. M. Z. Tetrahedron 1993, 49, 8087. (b) Herpin,
T. F.; Motherwell, W. B.; Weibel, J.-M. Chem. Commun. 1997, 923. (c)
Brigaud, T.; Lefebvre, O.; Plantier-Royon, R.; Portella, C. Tetrahedron Lett.
1996, 37, 6115. (d) Berber, H.; Brigaud, T.; Lefebvre, O.; Plantier-Royon,
R.; Portella, C. Chem. Eur. J. 2001, 7, 903. (e) Wegert, A.; Miethchen, R.;
Hein, M.; Reinke, H. Synthesis 2005, 1850. (f) Wegert, A.; Hein, M.; Reinke,
H.; Hoffmann, N.; Miethchen, R. Carbohydr. Res. 2006, 341, 2641. (g)
Cuenca, A. B.; D’Hooge, F.; Gouge, V.; Castelot-Deliencourt, G.; Oulyadi,
H.; Leclerc, E.; Jubault, P.; Pannecoucke, X.; Quirion, J.-C. Synlett 2005,
2627. (h) Karche, N. P.; Pierry, C.; Poulain, F.; Oulyadi, H.; Leclerc, E.;
Pannecoucke, X.; Quirion, J.-C. Synlett 2007, 123. (i) Tony, K. A.; Denton,
R. W.; Dilhas, A.; Jime´nez-Barbero, J.; Mootoo, D. R. Org. Lett. 2007, 9,
1441.
(10) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron 2004,
60, 8411.
(11) Dolbier, W. R., Jr. Chem. ReV. 1996, 96, 1557.
(12) (a) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 5125. (b)
Iseki, K.; Asada, D.; Takahashi, M.; Nagai, T.; Kobayashi, Y. Tetrahedron
Lett. 1994, 35, 7399. (c) Xiao, F.; Wu, F.; Shen, Y.; Zhou, L. J. Fluorine
Chem. 2005, 126, 63. (d) Murakami, S.; Ishii, H.; Fuchigami, T. J. Fluorine
Chem. 2004, 125, 609.
(9) (a) Miethchen, R.; Hein, M.; Reinke, H. Eur. J. Org. Chem. 1998,
919. (b) Wegert, A.; Reinke, H.; Miethchen, R. Carbohydr. Res. 2004, 339,
1833.
2478
Org. Lett., Vol. 9, No. 13, 2007

Scheme 2. Addition of Difluoromethyl Radicals to 2-Benzyloxy-D-glycals
in a 3:1 ratio in the crude mixture as measured by 19F NMR
and 12 obtained in the galactose series was, in contrast, more
puzzling. HOESY experiments showed no significant cor-
relations between fluorine atoms and protons, and the
and were separated by column chromatography (Scheme 2).
The same procedure was succesfully applied to D-galactal
5. The reaction proceeded this time with complete stereo-
selectivity. Indeed, 2-ketohexopyranoside 6 was present as
a single diastereomer in the crude mixture (19F NMR) and
could be isolated in 59% yield. A clean and fast addition of
dibromodifluoromethane was also performed and afforded
2-oxogalactoside 7 as the sole reaction product according to
TLC and NMR analysis of the crude mixture. However, and
despite a complete conversion of 5, compound 7 was isolated
in a disappointing 41% yield probably due to the modest
stability of this compound (Scheme 2).
A reduction step was then necessary to obtain the desired
CF2-glycosides and to assess their relative configurations.
A first reduction of compound 4a under standard conditions
(NaBH4 in MeOH at room temperature) afforded a mixture
of the desired CF2-glycoside 9 along with a significant
amount of diol 8. The use of a 3-fold excess of sodium
borohydride allowed the exclusive formation of 8 in 68%
yield (Scheme 3). The selective reduction of the ketone
moiety was eventually achieved by performing the reduction
at -78 °C. Compounds 9, 10, 11, and 12 were obtained from
4a, 4b, 6, and 7 in fair yields and with complete diastereo-
selectivity. In each case, only one diastereomer could be
detected in the 19F NMR spectrum of the crude mixture
(Scheme 3).
1
coupling constants which could be extracted from the H
spectra were hardly compatible with a classical 4C1 confor-
1
mation. A closer examination of the H spectrum of 11
revealed that the H1-H2, H2-H3, and H3-H4 coupling
constants were consistent with an axial-axial-equatorial
disposition for H1-H2-H3. The R-D-taloside configuration
(1C4 conformation) was therefore assigned to compound 11.
The same configuration and conformation was attributed to
1
12 due to similar H NMR data.15 The presence of the free
hydroxy group in 11 provided an opportunity to perform
substitution reactions with inversion of configuration at C-2
and thus obtain the desired R-D-galactoside analogues.
Unfortunately, the Mitsunobu-type reactions we attempted
only left unreacted starting material. Similarly, substitution
Scheme 3. Synthesis of R-CF2-Glucosides and Talosides
The R-D-glucoside configuration of 8 and 9 was proved
thanks to HOESY and NOESY experiments performed on
compound 8. Despite diaxial coupling constants slightly
lower than expected (3Jax-ax ) 7-8 Hz), a NOE correlation
between H2 and H4 and hOe correlations of the CF2 moiety
with H3 and H5 unambiguously proved this configuration
4
and the C1 conformation of both compounds (Figure 1).
Moreover, an X-ray diffraction study performed on crystal-
line compound 9 later confirmed this configuration and
conformation.13 On the other hand, the assignment of a â-D-
mannoside configuration to 10 was unmistakable thanks to
the measurement of the different coupling constants.14 The
determination of the relative configuration of compounds 11
(13) CCDC-641689 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 9, No. 13, 2007
2479

hemiketal was directly subjected to a Horner-Wadsworth-
Emmons reaction with triethyl phosphonoacetate to afford
14 in 76% overall yield. Homogeneous hydrogenation
allowed the isolation of CF2-glycoside 15 in 81% yield
(Scheme 4).
Scheme 4. Side-Chain Elongation
Figure 1. Configurations and conformations of the R-CF2-
glycosides.
reactions of the triflate derived from 11 did not afford the
desired R-D-galactoside.
The discrepancy between the favored conformations of the
glucose derivative 9 and of the galactose derivative 11
prompted us to take a closer look at their precursors 4a and
6 through epimerization studies. It was found that, under
slightly basic conditions, the glucose derivative 4a could be
converted to a 4:1 mixture of 4b and 4a whereas galactose
derivative 6 was either left unchanged or degraded under
basic conditions (Scheme 2). It was deduced from these
results that the conformations of 4a and 6 were also
dissimilar. The strong steric repulsions induced by the CF2-
CO2Et group were certainly dramatically increased in the
galactose series and give rise to these unusual conforma-
tions.16
In conclusion, we have reported an original methodology
for the preparation of synthetically useful R-CF2-glycosides
based on the radical addition of BrCF2CO2Et or CF2Br2 to
glycals. The presence of the ester function in the final
compounds allows further synthetic elaboration toward the
preparation of O-glycoconjugate analogues. The ketone
function in compounds 4, 6, and 7 is also valuable for the
synthesis of 2-deoxy-2-aminoglycoside analogues via reduc-
tive amination reactions. These two research areas, along
with the scope and limitations of this radical addition
reaction, are currently under investigation.
Finally, the relevance of the ester function for C-C bond
formation was illustrated by the synthesis of compound 15
through an olefination/hydrogenation sequence inspired from
syntheses of CH2-analogues of glycosylserine.17 The ester
function of MOM-protected 13 was reduced and the resulting
Acknowledgment. We thank the Ministe`re de l’Education
Nationale, de l’Enseignement Supe´rieur et de la Recherche
for a postdoctoral grant to B.M. We also thank Dr. Hassan
Oulyadi and Pedro Lameiras (LRMN, UMR 6014, Mont
Saint-Aignan, France) for the HOESY experiments.
(14) The stereoselective reduction of R- and â-2-keto-D-arabino-hex-
opyranosides is well documented: (a) Lichtenthaler, F. W.; Lergenmu¨ller,
M.; Peters, S.; Varga, Z. Tetrahedron: Asymmetry 2003, 14, 727. (b)
Lichtenthaler, F. W.; Lergenmu¨ller, M.; Schwidetzky, S. Eur. J. Org. Chem.
2003, 3094.
(15) A similar stereochemical outcome for the reduction of other
2-oxogalactosides has been described: Cipolla, L.; La Ferla, B.; Lay, L.;
Peri, F.; Nicotra, F. Tetrahedron: Asymmetry 2000, 11, 295.
(16) A similar situation was already observed with another methodology.
See ref 8h.
Supporting Information Available: Complete experi-
mental details and compound characterization data, as well
1
as copies of H, 19F, and 13C spectra, NOESY and HOESY
spectra for 8, and a CIF file for the X-ray diffraction study
of 9. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) (a) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J. J.
Am. Chem. Soc. 1997, 119, 9897. (b) Bertozzi, C. R.; Hoeprich, P. D., Jr.;
Bednarski, M. D. J. Org. Chem. 1992, 57, 6092.
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