ORGANIC
LETTERS
2006
Vol. 8, No. 16
3429-3431
Facile Dephosphonylation of
-Ketophosphonic Acids: Mechanistic
Studies
â
Michael J. Hawkins, Eugene T. Powell, Gregory C. Leo, Diane A. Gauthier,
Michael N. Greco,* and Bruce Maryanoff
Research & Early DeVelopment, Johnson & Johnson Pharmaceutical Research &
DeVelopment, Spring House, PennsylVania 19477-0776
Received March 2, 2006 (Revised Manuscript Received June 16, 2006)
ABSTRACT
We have found that
is dependent on the electronic nature of the substituent on the carbon atom
the process. 31P NMR studies were used to probe the mechanism for the process.
â-ketophosphonic acids can undergo facile dephosphonylation under fairly mild conditions. The rate of dephosphonylation
r
to phosphorus, with electron-withdrawing groups accelerating
The phosphonate functionality has played an important role
in organic chemistry, especially through the Horner-
Wadsworth-Emmons olefination reaction, which has been
used extensively to construct the carbon framework of
diverse synthetic targets.1-2 Phosphonates and phosphonic
acids have also been important in the bioorganic arena. In
fact, there are several therapeutic agents that contain the
phosphonate moiety as a critical pharmacophore.3 With
certain antiviral nucleosides, replacement of a phosphate by
a phosphonate has provided analogues that are resistant to
dephosphorylation, thereby paving the way for drugs against
human immunodeficiency virus (HIV), hepatitis B virus, and
cytomegalovirus.4
decarboxylation of â-ketocarboxylic acids, the spontaneous
dephosphonylation of â-ketophosphonic acids is quite rare.
A literature search revealed just a single report of dephos-
phonylation of a â-ketophosphonic acid.6 Specifically, Kluger
found that the monosodium salt of acetonylphosphonic acid
thermally decomposes on melting around 150 °C to produce
acetone and sodium metaphosphate.6 A related base-catalyzed
dephosphonylation of diethyl â-ketophosphonate derivatives
containing electrophilic keto groups has also been reported.7
To shed light on this area, we have examined the dephos-
phonylation of structural analogues of 1 with respect to
stereoelectronic influences. In addition, we conducted 31P
(5) (a) de Garavilla, L.; Greco, M. N.; Sukumar, N.; Chen, Z.; Pineda,
A. O.; Mathews, F. S.; Di Cera, E.; Giardino, E. C.; Wells, G. I.; Haertlein,
B. J.; Kaufman, J. A.; Corcoran, T. J.; Derian, C. K.; Eckardt, A. J.;
Damiano, B. P.; Andrade-Gordon, P.; Maryanoff, B. E. J. Biol. Chem. 2005,
280, 18001. (b) Greco, M. N.; Hawkins, M. J.; Powell, E. T.; Almond, H.
R., Jr.; Corcoran, T. W.; de Garavilla, L.; Kauffman, J. A.; Recacha, R.;
Chattopadhyay, D.; Andrade-Gordon, P.; Maryanoff, B. E. J. Am. Chem.
Soc. 2002, 124, 3810.
We have been interested in interfering with the serine
proteases cathepsin G and chymase, which are involved in
inflammatory processes. Our research effort led us to a novel
class of inhibitors that contain a key â-ketophosphonic acid
group.5 In particular, we identified and biologically charac-
terized potent, dual cathepsin G/chymase inhibitor 1.5b During
our studies, we noticed that 1 has a tendency to dephospho-
nylate to 2 under fairly mild conditions. In contrast to the
(6) Kluger, R. J. Org. Chem. 1973, 38, 2721. For an isolated case, see:
Denmark, S. E.; Marlin, J. E. J. Org. Chem. 1991, 56, 1003.
(7) (a) Piettre, S. G.; Girol, C.; Schelcher, C. G. Tetrahedron Lett. 1996,
37, 4711. (b) Thenappan, A.; Burton, D. J. J. Org. Chem. 1991, 56, 273.
(c) Thenappan, A.; Burton, D. J. Tetrahedron Lett. 1989, 30, 6113. (d)
Thenappan, A.; Burton, D. J. Tetrahedron Lett. 1989, 30, 3641. (e) Among
the possibilities in Table 1, Horner-Emmons elimination is least likely
because related substrates have been shown to be thermally stable. See:
Phillion, D. P.; Cleary, D. G. J. Org. Chem. 1992, 57, 2763.
(1) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(2) Wiemer, D. P. Tetrahedron 1997, 53, 16609.
(3) Fields, S. C. Tetrahedron 1999, 55, 12237.
(4) Hwang, J.; Choi, J. Drugs Future 2004, 29, 163.
10.1021/ol060519l CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/04/2006