Synthesis of Nucleoside 3′-Phosphate Analogues
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of
â,â-Disubstituted-R,R-difluorophosphonates 1
binding interactions between the modified nucleotide and its
target or, in the case of oligonucleotides, a lower stability of
the RNA/MON duplex.6
A possible response to this undesirable behavior may be the
replacement of the C3′ oxygen atom by a difluoromethylene
(CF2) moiety. In addition to potentially bringing a solution to
the above conformational problem, the presence of the fluorine
atoms increases both the structural and electronic similarities
between the phosphonate and the parent phosphate groups:
Blackburn’s seminal contributions in that field have been
corroborated by many studies.7,8 Despite this, 3′- or 5′-
phosphonodifluoromethylnucleosides have only received scant
attention due to the problems and difficulties associated with
their preparation. Thus, notwithstanding the many potential
advantages of these compounds, only 5′-phosphononodifluo-
romethylnucleosides have been prepared by Usman and co-
workers,9 and a dinucleotide analogue has been generated from
the monomer.
Until recently, difluorophosphonates, featuring geminal dis-
ubstitution on the carbon atom â to the phosphorus atom, could
not be synthesized, due to important limitations from the then-
available methodologies.10 We and others have published
solutions that allow the preparation of difluorophosphonates with
this particular substitution pattern.11 Thus, addition of phos-
phonyl (and phosphonothioyl) radicals 3 onto gem-disubstituted
difluoroalkenes 2 followed by hydrogen quenching, or genera-
tion of tertiary alcohols from ketones 5 and lithiated species 6
followed by deoxygenation of the resultant adduct 4, now
provide the two established strategies allowing access to â,â-
disubstituted difluorophosphonates 1 (routes A and B, Scheme
1).
To the best of our knowledge however, these methodologies
have been applied only to the preparation of one L-phospho-
threonine analogue.11e We now report herein our own work,
based on the dual approach depicted in Scheme 1, which has
resulted in the preparation of all five fully protected C3′-
phosphonodifluoromethyl analogues 7b, 8b, 9b, 10b, and 11b
of nucleoside 3′-phosphates, as well as the completely depro-
tected disodium difluorophosphonates 7c, 8c, and 9c (Figure
1).
(5) (a) Jones, G. H.; Albrechts, H. P.; Damodaran, N. P.; Moffatt, J. G. J. Am.
Chem. Soc. 1970, 92, 5510-5511. (b) Albrechts, H. P.; Jones, G. H.;
Moffatt, J. G. J. Am. Chem. Soc. 1970, 92, 5511-5513. (c) Morr, M.; Ernst,
L.; Grotjahn, L. Z. Naturforsch. 1983, 38b, 1665-1668. (d) Albrechts, H.
P.; Jones, G. H.; Moffatt, J. G. Tetrahedron, 1984, 40, 79-85. (e) Morr,
M.; Ernst, L.; Schomburg, D. Liebigs Ann. Chem. 1991, 615-631. (f) Serra,
C.; Dewynter, G.; Montero, J.-L.; Imbach, J.-L. Tetrahedron 1994, 50,
8427-8444. (g) Lau, W. Y.; Zhang, L.; Wang, J.; Cheng, D.; Zhao, K.
Tetrahedron Lett. 1996, 37, 4297-4300. (h) Yokimatsu, T.; Sada, T.;
Shimizu, T.; Shibuya, S. Tetrahedron Lett. 1998, 39, 6299-6302. (i)
Yokimatsu, T.; Shimizu, T.; Sada, T.; Shibuya, S. Heterocycles 1999, 50,
21-25. (j) An, H.; Wang, T.; Maier, M. A.; Manoharan, M.; Ross, B. S.;
Cook, P. D. J. Org. Chem. 2001, 66, 2789-2801.
Retrosynthetic Analysis. Retrosynthetic analysis of both
routes highlights the crucial issue of stereochemical control when
constructing (route A, radical addition approach) or introducing
(route B, anion addition approach) the phosphonodifluoromethyl
unit.
(6) (a) Guschlbauer, W.; Jankowski, K. Nucleic Acids Res. 1991, 6, 521-529.
(b) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag: New
York, Berlin, Heidelberg, Tokyo, 1984. (c) Plaveg, J.; Garg, N.; Chatto-
padhyaya, J. Chem. Commun. 1993, 1011-1013.
(7) (a) Blackburn, G. M.; England, D. A.; Kolmann, F. J. Chem. Soc., Chem.
Commun. 1981, 930-932. (b) Blackburn, G. M.; Kent, D. E.; Kolkmann,
F. J. Chem. Soc., Chem. Commun. 1981, 1188-1190. (c) McKenna, C.
E.; Shen, P.-D. J. Org. Chem. 1981, 46, 4573-4576. (d) Blackburn, G.
M.; Kent, D. E. J. Chem. Soc., Perkin Trans 1 1986, 913-917. (e) Phillion,
D. P.; Cleary, D. G. J. Org. Chem. 1992, 57, 2763-2764. (f) Burke, T. R.,
Jr.; Kole, H. K.; Roller, P. P. Biochem. Biophys. Res. Commun. 1994, 204,
129-134. (g) Halazy, S.; Ehrhard, A.; Eggenspiller, A.; Berges-Gross, V.;
Danzin, C. Tetrahedron 1996, 52, 177-184. (h) Higashimoto, Y.; Saito,
S.; Tong, X.-H.; Hong, A.; Sakaguchi, K.; Appella, E.; Anderson, C. W.
J. Biol. Chem. 2000, 275, 23199-23203.
(A) Radical Addition Approach. The sequence of events
in this synthetic route was expected to lead to either the desired
analogue, possessing the phosphonodifluoromethyl moiety on
the R face of the furanose, or the undesired one (with the same
unit on the other face) depending on the initial substrate (Scheme
2). Inasmuch as the base would exert an undesired directing
effect in the quenching of radical 13, thereby positioning the
phosphate group mimic on the â-face and delivering adduct 14,
we decided to start from carefully chosen protected furanoses,
construct the phosphonodifluoromethyl functional group first,
and, finally, bring in the different bases.12 Thus the well-known
steric hindrance generated by an isopropylidene protecting group
in the 1,2 positions of the furanose was expected to mainly
furnish the desired stereoisomer 17 upon hydrogen atom capture
by radical 16. Data from the literature and from these labora-
tories support this assumption.13
(8) It has also been suggested that the R-monofluorophosphonates give, at least
in some cases, superior results to R,R-difluorination in phosphonate mimics
of biological phosphates. See (a) Chambers, R. D.; Jaouhari, R.; O’Hagan,
D. Tetrahedron 1989, 45, 5101-5108. (b) Chambers, R. D.; O’Hagan, D.;
Lamont, R. B.; Jain, S. C. J. Chem. Soc., Chem. Commun. 1990, 1053-
1054. (c) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J. A. K.
Tetrahedron 1996, 52, 165-176. (d) Berkowitz, D. B.; Bose, M.;
Pfannenstiel, T. J.; Doukov, T. J. Org. Chem. 2000, 65, 4498-4508. (e)
Berkowitz, D. B.; Bose, M. J. Fluorine Chem. 2001, 112, 13-33.
(9) (a) Matulic-Adamic, J.; Usman, N. Tetrahedron Lett. 1994, 35, 3227-
3230. (b) Matulic-Adamic, J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995,
60, 2563-2569.
(10) For example, the lithium salt of dialkyl difluoromethylphosphonates does
not react with secondary halides or triflates. See Obayashi, M.; Ito, E.;
Kondo, K. Tetrahedron Lett. 1982, 23, 2323-2326.
(11) (a) Piettre, S. R. Tetrahedron Lett. 1996, 37, 2233-2236. (b) Herpin, T.
F.; Houlton, J. S.; Motherwell, W. B.; Roberts, B. P.; Weibel, J.-M. J.
Chem. Soc., Chem. Commun. 1996, 613-614. (c) Herpin, T. F.; Motherwell,
W. B.; Roberts, B. P.; Roland, S.; Weibel, J.-M. Tetrahedron 1997, 53,
15085-15100. (d) Kovensky, J.; McNeil, M.; Sinay¨, P. J. Org. Chem. 1999,
64, 6202-6205. (e) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemaker,
R. K. J. Org. Chem. 1996, 61, 4666-4675.
(B) Anion Addition Approach. Here again, addition of the
lithium salt 6 of difluoromethylphosphonate to nucleoside
(12) See for instance, (a) Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1992,
33, 3101-3104. (b) Serafinowski, P. J.; Barnes, C. L. Synthesis 1997, 225-
228.
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J. AM. CHEM. SOC. VOL. 124, NO. 49, 2002 14669