electron-withdrawing effect of the difluoromethylene group
adjacent to the site of oxidation.
single moiety. Most importantly, this compound has been
dialkylated sequentially (LDA/MeI) in excellent yields.16
The synthesis and fluorination of 4 is shown in Scheme
2. The sequence starts with the well-known chiral pyro-
Electrophilic fluorination using so-called “N-F” reagents
has grown in popularity and application in recent years as a
method for the selective fluorination of activated aromatics,
alkenes, and enolates.8 We envision electrophilic fluorination
of a pyroglutamate-derived lactam enolate as a means to
synthesize fluoroglutamic acids substituted in the 4-position
while completely avoiding the problematic RuO4 oxidation.
Despite increased use of these reagents, reports of elec-
trophilic N-F difluorinations in the literature are few in
number. Recently, success was reported in the difluorination
of benzylic phosphonates, nitriles, sulfonates, and tetrazoles.9
Such reactions appear to be dependent on the acidity of the
hydrogens being replaced,10 which must be great enough to
enable formation of the required R-fluoro carbanion inter-
mediate. According to this argument, the fact that the
carbanions in these benzylic substrates are stabilized by
resonance with unsaturated functionality on either side
probably plays a role in the success of their difluorination.
An early study supports such an acidity argument and reports
low yields for the difluorination of relatively less acidic alkyl
amides and esters.11 Indeed, all examples of electrophilic
N-F difluorinations of amide enolates we have found in the
literature involve compounds with additional unsaturated
functionality in the â-position relative to the amide carbo-
nyl.12 In apparent contrast to this generalization is another
report of the successful electrophilic N-F difluorination of
an unactivated lactone.13 While the R-CH protons of an ester
are more acidic than an amide,14 this result was nonetheless
encouraging in the context of the present work.
Scheme 2
glutaminol 5 obtained in two steps from L-glutamic acid
using the method of Pickering et al.17 Protection and ring
closure was accomplished with 2,2-dimethoxypropane (DMP)
using a modification of the procedure of Allen et al.18 Lactam
4 was treated with 1.1 equiv of LDA followed by 1.3 equiv
of NFSi at -78 °C to give a mixture of monofluorinated
diastereomers in a 1.2:1.0 ratio and 59% total yield. The
mixture was subjected to the same fluorination conditions a
second time, and the difluorinated product 6 was obtained
in 71% yield.
The conversion of compound 6 to L-4,4-difluoroglutamic
acid 8 is outlined in Scheme 3.19 It was anticipated that this
A series of monocyclic compounds corresponding to 3
with various combinations of protecting groups (R, R′) was
synthesized, and NFSi-mediated difluorination was attempted
using a wide variety of strong bases and reaction conditions.
Unfortunately, these attempts to access 2 were also unsuc-
cessful (Scheme 1, path B) and the reaction conditions used
resulted primarily in monofluorinated products.15
Scheme 3
Ultimately, the bicyclic lactam 4 was focused on as a
difluorination substrate. This compound is attractive because
it is easily available in chirally pure form and has both its
nitrogen and oxygen atoms protected simultaneously by a
(5) (a) Hudlicky, M. J. Fluorine Chem. 1993, 60, 193-210. (b) Hart, B.
P.; Coward, J. K. Tetradedron Lett. 1993, 34, 4917-4920.
(6) (a) Sufrin, J. R.; Balasubramanian, T. M.; Vora, C. M.; Marshall, G.
R. Int. J. Peptide Protein Res. 1982, 20, 438-442. (b) Demange, L.; Menez,
A.; Dugave, C. Tetrahedron Lett. 1998, 39, 1169-1172.
(7) Hart, B. P. Ph.D. Thesis, The University of Michigan, 1995.
(8) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737-
1755.
(9) (a) Taylor, S. D.; Kotoris, C. C.; Dinaut, A. N.; Chen, M.-J.;
Tetrahedron 1998, 54, 1691-1714. (b) Kotoris, C. C.; Chen, M.-J.; Taylor,
S. D. J. Org. Chem. 1998, 63, 8052-8057.
(10) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619-8683.
(11) Differding, E.; Ruegg, G. M.; Lang, R. W. Tetrahedron Lett. 1991,
32, 1779-1782.
might be carried out in only two steps via RuO4-mediated
oxidation of the cyclic ether of 6 to a lactone followed by
acid hydrolysis. Unfortunately, treatment of 6 with RuO4 led
to the undesired, but not unprecedented,20 hydroxylation of
the chiral bridgehead CH carbon. Therefore, the difluorinated
bicyclic lactam was cleanly deprotected with acetic acid in
(16) Davies, S. G.; Doisneau, G. J.-M.; Prodger, J. C.; Sanganee, H. J.
Tetrahedron Lett. 1994, 35, 2369-2372.
(17) Pickering, L.; Malhi, B. S.; Coe, P. L.; Walker, R. T. Nucleosides
Nucleotides 1994, 13, 1493-1506.
(12) (a) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. J. Chem. Soc.,
Chem. Commun. 1994, 3, 343-344 (b) Resnati, G.; DesMarteau, D. D. J.
Org. Chem. 1992, 57, 4281-4284 (c) Davis, F. A.; Han, W.; Murphy, C.
K. J. Org. Chem. 1995, 60, 4730-4737.
(18) Allen, N. E.; Boyd, D. B.; Campbell, J. B.; Deeter, J. B.; Elzey, T.
K.; Foster, B. J.; Hatfield, L. D.; Hobbs, J. N.; Hornback, W. J.; Hunden,
D. C.; Jones, N. D.; Kinnick, M. D.; Morin, J. M.; Munroe, J. E.;
Swartzendruber, J. K.; Vogt, D. G. Tetrahedron 1989, 45, 1905-1928.
(19) The (2R) enantiomer, D-4,4-difluoroglutamic acid, should be
accessible via this route starting with D-glutamic acid.
(20) Yoshifuji, S.; Arakawa, Y.; Nitta, Y. Chem. Pharm. Bull. 1985,
33, 5042-5047.
(13) Nakano, T.; Makino, M.; Morizawa, Y.; Matsumura, Y. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1019-1021.
(14) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327-4331.
(15) Konas, D. W.; Coward, J. K. Manuscript in preparation.
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