the pseudoanomeric substituent.6,7 Given the electronegativity
properties of fluorine, such structures may function as closer
mimetics of O-glycosides, compared to the unsubstituted
methylene analogues.6,8 In this context, the CF2 moiety has
been considered an electronic isostere of oxygen. However,
the generality of this tenet has been questioned, and it has
been suggested that the CHF group may be a closer isopolar
substitute for oxygen.9,10 Fluorine substitution on the pseudo-
anomeric carbon substituent could also have a pronounced
influence on the conformational behavior about the intersac-
charide torsions.11 This situation is analogous to distortion
of the natural conformation of the sugar residue in nucleo-
sides by introduction of a 2-fluoro substituent.12 Thus,
C-glycosides with one or two fluorine substituents on the
pseudoanomeric carbon are potentially useful mechanistic
probes for interrogation of carbohydrate recognition. Herein
we describe the synthesis of such fluorinated â-C-galacto-
sides.
An obvious strategy for C-glycosides such as 3 and 4 is
the reaction of alcohol and keto derivatives with fluorinating
agents.13 Although several methodologies to synthesize these
precursors have been developed,1 the fluorination of such
highly substituted substrates can be problematic. A conver-
gent approach in which fluorine is introduced in simpler
precursors is potentially more general, and in this context,
we envisaged a variation of our previously reported C-
glycoside synthesis.14 Accordingly, a fluorinated C-glycoside
such as 10 may be obtained from the stereoselective
hydroboration-oxidation of the C1-substituted galactal 9
(Scheme 1). The latter is expected from the thioacetal-enol
Scheme 1
ether 8, via an oxocarbenium ion cyclization. Precursors such
as 8 could be assembled in a convergent fashion through an
esterification-methylenation sequence starting from the
1-thio-1,2-O-isopropylidene alcohol 5 and different mono-
or difluoroacids 6. Because the original methodology was
applied to systems which did not contain an electronegative
substituent in the eventual pseudoglycosidic position, there
was some concern that the presence of one or more fluorine
substituents in this location could have deleterious effects
at different stages in the synthetic sequence, in particular,
on the oxocarbenium ion cyclization (i.e., 8 f 9).15 A second
issue that had to be addressed was synthesis of more complex
examples of the fluorinated acid precursors 6.
Acid precursors 6, for several biologically interesting
C-glycolipids,16 C-disaccharides,17,18 and benzylic C-glyco-
sides19 were required (Table 1). The monofluoride acid
precursors were used as a mixture of enantiomeric or
diastereomeric fluorides, with the anticipation that the
corresponding epimeric fluoro-C-glycosides would be chro-
matographically separable. 2-Fluorohexanoic acid 6a20 was
prepared from the mesylate derivative of the methyl ester
following a known procedure, and R-fluorophenylacetic acid
6e21 was commercially available. Initial attempts to prepare
carbohydrate-derived fluorides 6c and 6d following variations
of the procedure used for 6a led to complex mixtures. In an
alternative approach, 6c was obtained by reaction of aldehyde
1122 with the sodium salt of triethyl 2-fluoro-2-phospho-
(4) For an example where O- and C-glycosides bind in different
conformations with respect to the intersaccharide torsions: Espinosa, J. F.;
Montero, E.; Vian, A.; Garc´ıa, J. L.; Dietrich, H.; Schmidt, R. R.; Mart´ın-
Lomas, M.; Imberty, A.; Can˜ada, F. J.; Jime´nez-Barbero, J. J. Am. Chem.
Soc. 1998, 120, 1309-1318.
(5) Gabius, H.-J. Pharm. Res. 1998, 15, 23-30. Dam, T. K.; Brewer, C.
F. Chem. ReV. 2002, 102, 387-429.
(6) For examples of difluoromethylene-linked C-furanosides: Herpin,
T. F.; Motherwell, W. B.; Tozer, M. J. Tetrahedron: Asymmetry 1994, 5,
2269-2282. Herpin, T. F.; Motherwell, W. B.; Weibel, J.-M. J. Chem. Soc.,
Chem. Commun. 1997, 923-924.
(7) For reviews on fluorinated carbohydrates: Card, P. J. J Carbohydr.
Chem. 1985, 4, 451-487. Fluorinated Carbohydrates, Chemical and
Biochemical Aspects; Taylor, N. F., Ed.; ACS Symp. Ser. 374; American
Chemical Society: Washington, DC, 1996. Plantier-Royon, R.; Portella,
C. Carbohydr. Res. 2000, 327, 119-146.
(14) Khan, N.; Cheng, X.; Mootoo, D. R. J. Am. Chem. Soc. 1999, 121,
4918-4919. Cheng, X.; Khan, N.; Mootoo, D. R. J. Org. Chem. 2000, 65,
2544-2547.
(8) For discussions on fluorinated compounds in medicinal chemistry:
Welch, J. T.; Eswaraksrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley: New York, 1991. Organofluorine Chemistry: Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum: New York, 1994. Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symp. Ser. 639;
American Chemical Society: Washington, DC, 1996. Bo¨hm, H.-J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander, U.; Stahl,
M. ChemBioChem. 2004, 5, 637-643.
(9) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619-8683.
(10) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin
Trans. I 1984, 1119-1125. Thatcher, G. R. J.; Campbell, A. S. J. Org.
Chem. 1993, 58, 2272-2281. Nieschalk, J.; O’Hagan, D. J. Chem. Soc.,
Chem. Commun. 1995, 719-720.
(11) The preferred gauche conformation in 2-fluoroethyl residues attached
to electronegative substituents is well documented. For recent examples:
Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. J. Fluorine
Chem. 2003, 119, 9-13. Briggs, C. R. S.; O’Hagan, D.; Rzepa, H. S.;
Slawin, A. M. Z. J. Fluorine Chem. 2004, 125, 19-25.
(12) Meier, C.; Knispel, T.; Marquez, V. E.; Siddiqui, M. A.; De Clercq,
E.; Balzarini, J. J. Med. Chem. 1999, 42, 1615-1624.
(13) Hudlicky, M. Org. React. 1988, 35, 513-637. Singh, R. P.; Shreeve,
J. M. Synthesis 2002, 2561-2578.
(15) For an example of deactivation of enol ethers with one or two
fluorines on the adjacent carbon: Matsumura, Y.; Asai, T.; Shimada, T.;
Nakayama, T.; Urushihara, M.; Morizawa, Y.; Yasuda, A.; Yamamoto, T.;
Fujitani, B.; Hosoki, K. Chem. Pharm. Bull. 1995, 43, 353-355. Chang,
C. S.; Negishi, M.; Nakano, T.; Morizawa, Y.; Matsumura, Y.; Ichikawa,
A. Prostaglandins 1997, 53, 83-90.
(16) Yang, G.; Franck, R. W.; Bittman, R.; Samadder, P.; Arthur, G.
Org. Lett. 2001, 3, 197-200. Yang, G.; Franck, R. W.; Byun, H.-S.;
Bittman, R.; Samadder, P.; Arthur, G. Org. Lett. 1999, 1, 2149-2151. Yang,
G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int Ed. 2004, 43,
3818-3822. Dondoni, A.; Perrone, D.; Turturici, E. J. Org. Chem. 1999,
64, 5557-5564. Cipolla, L.; Nicotra, F.; Vismara, E.; Guerrini, M.
Tetrahedron 1997, 53, 6163-6170.
(17) Hiruma, K.; Kajimoto, T.; Weitz-Schmidt, G.; Ollmann, I.; Wong,
C.-H. J. Am. Chem. Soc. 1996, 118, 9265-9270. Shibata, K.; Hiruma, K.;
Kanie, O.; Wong, C.-H. J. Org. Chem. 2000, 65, 2393-2398.
(18) Denton, R. W.; Cheng, X.; Tony, K. A.; Dilhas, A.; Herna´ndez, J.
J.; Canales, A.; Jime´nez-Barbero, J.; Mootoo, D. R. Eur. J. Org. Chem.
2007, 645-654.
(19) Schmidt, R. R.; Dietrich, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 1328-1329.
(20) Focella, A.; Bizzarro, F.; Exon, C. Synth. Commun. 1991, 21, 2165-
2170.
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