followed by hydrogenation,7b,11 transition metal-mediated
(RO)2P(O)CHF-C(sp2) bond formation,12 and SET-induced
addition of the (RO)2P(O)CHF radical to alkenes.13
Given our conVergent triflate displacement approaches to
both the CH2- and CF2-phosphonates,8,14 we were particularly
interested in developing a related route to the CHF-
phosphonates. To be sure, displacement reactions with dialkyl
lithiofluoromethylphosphonates [(RO)2P(O)CHFLi] had been
reported,15 but both in our hands and elsewhere, these
reagents have proved difficult to handle.16 In one elegant
solution to this problem, Savignac and co-workers report the
transient in situ generation and subsequent displacement
reactions of (RO)2P(O)CF(TMS)Li. Careful, base-mediated
desilylation is then required to release the targeted monof-
luorinated phosphonate product.17
We report a complementary approach here, wherein a
phenylsulfonyl group is used to stabilize that R-fluorometh-
ylphosphonate anion. McCarthy had reported the in situ
generation of (RO)2P(O)CF(SO2Ph)Li and its condensation
reactions with carbonyl compounds to give R-fluorovinyl
sulfones.18,19 Whereas McCarthy normally generates this
anion in situ from PhSO2CH2Li and diethyl chlorophosphate,
we have found it much more convenient to begin with
(RO)2P(O)CHF(SO2Ph) (8). Appell has described a conve-
nient synthesis of this phosphonate that is amenable to scale-
up.20
Figure 1. R-Monofluoroalkylphosphonate analogues of biological
phosphates (the phosphate counterpart of these mimics is listed in
parentheses).
reaction coordinate of PI-specific phospholipase C and
inhibits this enzyme. The latter is a good pseudo-substrate
for glycerol 3-phosphate dehydrogenase. Compound 4 rep-
resents one member of an intriguing class of R-monofluori-
nated nucleoside phosphonates7d and may be of interest from
an anti-sense point of view.
We recently completed a “fluorinated phosphonate scan”
of the well-defined phosphate binding pocket of G6PDH.8
Interestingly, in terms of Km, both the best phosphonate
pseudo-substrate (5; 7S stereochemistry) and the phosphonate
with the lowest affinity (7R diastereomer) are of the
R-monofluorinated variety. Stereochemical dependencies
such as these have also been observed by O’Hagan.7c Thus,
at least in some active sites, the additional stereocenter
present in this class of phosphate mimics may be used to
fine-tune their binding.
Pleasingly, deprotonation of 8 at low temperature, followed
by addition of a primary alkyl iodide or triflate, leads to
efficient displacement upon removal of the cold bath (Table
1). To evaluate the counterion dependence of this displace-
ment, several bases were examined, with the isopropylidene-
protected glyceryl triflate (9c) serving as the model electro-
phile. KHMDS provided the best results, with lower yields
being obtained with LiHMDS, NaHMDS, LDA, and
Schwesinger’s P1-t-Bu phosphazene base (MeCNpKBH+
)
(12) Zhang, X.; Qiu, W.; Burton, D. J. Tetrahedron Lett. 1999, 2681-
2684.
(13) Zhang, X.; Qiu, W.; Burton, D. J. J. Fluorine Chem. 1998, 89, 39-
49.
(14) (a) Berkowitz, D. B.; Bhuniya, D.; Peris, G. Tetrahedron Lett. 1999,
40, 1869-1872. (b) Berkowitz, D. B.; Sloss, D. G. J. Org. Chem. 1995,
60, 7047-7050. (c) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J.
Org. Chem. 1993, 58, 6174-6176.
(15) Blackburn, G. M.; Parratt, M. J. J. Chem. Soc., Perkin Trans. I 1986,
1425-1430.
(16) For a discussion of the problems associated with generating and
alkylating the anion of dialkyl fluoromethylphosphonates, see: Hamilton,
C. J.; Roberts, S. M. J. Chem. Soc., Perkin Trans. I 1999, 1051-1056.
(17) Waschbu¨sch, R.; Carran, J.; Savignac, P. J. Chem. Soc., Perkin
Trans. I 1997, 1135-1138.
With growing interest in this class of phosphate mimics,
there has been significant interest in synthetic methods for
accessing (R-monofluoroalkyl)phosphonates. Current ap-
proaches include electrophilic fluorination [Selectfluor, FN-
(SO2Ph)2],7d,9 nucleophilic fluorination (DAST),8,10 HWE- or
Peterson-olefination entries into R-fluorovinylphosphonates,
(8) Berkowitz, D. B.; Bose, M. B.; Pfannenstiel, T. J.; Doukov, T. J.
Org. Chem. 2000, 65, 4498-4508.
(9) (a) Iorga, B.; Eymery, F.; Savignac, P. Synthesis 2000, 576-580.
(b) Taylor, S. D.; Dinaut, A. N.; Thadani, A. T.; Huang, Z. Tetrahedron
Lett. 1996, 37, 8089-8092. (c) Lal, G. S. J. Org. Chem. 1993, 58, 2791-
2796. (d) Differding, E.; Duthaler, R. O.; Krieger, A.; Ru¨egg, G. M.; Schmit,
C. Synlett 1991, 385-396.
(10) (a) Benayoud, F.; deMendonca, D. J. Digits, C. A.; Moniz, G. A.;
Sanders, T. C.; Hammond, G. B. J. Org. Chem. 1996, 61, 5159-5164. (b)
Yokumatsu, T.; Yamagishi, T.; Matsumoto; K.; Shibuya, S. Tetrahedron
1996, 52, 11725-11738. (c) Blackburn, G. M.; Kent, D. E. J. Chem. Soc.,
Perkin Trans. I 1986, 913-917.
(11) (a) Waschbu¨sch, R.; Carran, J.; Savignac, P. Tetrahedron 1996, 52,
14199-14216. (b) Keeney, A.; Nieschalk, J.; O’Hagan, D. J. Fluorine
Chem. 1996, 80, 59-62. (c) Blackburn, G. M.; Rashid, A. J. Chem. Soc.,
Chem. Commun. 1988, 317-319. (d) Blackburn, G. M.; Parratt, M. J. J.
Chem. Soc., Chem. Commun. 1986, 1417-1424.
(18) (a) McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. Org. Synth.
1993, 72, 216-224. (b) McCarthy, J. R.; Matthews, D. P.; Stemerick, D.
M.; Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J.
Am. Chem. Soc. 1991, 113, 7439-7440. (c) McCarthy, J. R.; Matthews,
D. P.; Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T. Tetrahedron Lett.
1990, 31, 5449-5452.
(19) We are aware of only an isolated report in which McCarthy’s reagent
was used for nucleophilic displacement reactions. Note that these authors
used only simple alkyl halides and reported being unable to reductively
cleave the sulfonyl group without P-C cleavage. Koizumi, T.; Hagi, T.;
Horie, Y.; Takeuchi, Y. Chem. Pharm. Bull. 1987, 35, 3959-3962.
(20) Appell, R. Synth. Commun. 1995, 25, 3583-3587.
(21) Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Peters,
E.-M.; Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed. Engl. 1993,
32, 1361-1363.
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Org. Lett., Vol. 3, No. 13, 2001