J. Am. Chem. Soc. 2001, 123, 7457-7458
7457
Simple phosphonoformate diesters are relatively stable toward
neutral or mildly acidic hydrolysis; e.g., hydrolysis of 2 (R ) R′
Chemoselectivity in Metal Cation Mediated
Hydrolysis of a Phosphonoformate Diester
) Et) at pH 7.0 proceeds with k ) 5.8 × 10-8 s-1 4b
,
although
basic hydrolysis occurs rapidly at C-O.4d Here, we describe the
first metal-mediated hydrolyses of phosphonoformates, as well
as rate accelerations in the acidic hydrolyses of DMPF mediated
by Zr(IV), Hf(IV), Th(IV), and Ce(IV) cations. Remarkably, we
observe unprecedented chemoselectivity in these reactions.
Reactions were initiated by combining 10 mM DMPF14,15 with
25 mM ZrCl4, HfCl4, Ce(NH4)2(NO3)6, or Th(NO3)4‚4H2O at 25
°C in D2O (0.5 M NaClO4) that contained pyrazine as a 1H NMR
integration standard. Solution pD values were established by the
natural hydrolysis of the metal cations: Zr(IV), 1.7; Hf(IV) 2.2;
Robert A. Moss* and Hugo Morales-Rojas
Department of Chemistry, Rutgers
The State UniVersity of New Jersey
New Brunswick, New Jersey 08903
ReceiVed December 4, 2000
ReVised Manuscript ReceiVed May 30, 2001
The phosphonoformate trianion, “foscarnet” (PFA, 1), is an
antiviral agent active against herpes simplex virus (HSV) and
AIDS-related human cytomegalovirus.1 However, PFA is trian-
ionic at physiological pH,2 resulting in poor membrane perme-
ability and low bioavailability. Therefore, PFA mono-, di-, and
triesters are of current interest as PFA prodrugs.3-5
1
Ce(IV), 1.9; Th(IV) 3.1. The reactions were monitored by H
and 31P NMR, with products identified by NMR spiking experi-
ments using authentic materials.15
With Zr(IV) and Hf(IV), DMPF hydrolyses proceeded mainly
with P-OMe cleavage to C-monoester 5 (Scheme 1, branch A).
Rather less C-OMe cleavage to P-monoester 6 occurred (branch
B). The 5:6 product distributions were 79:21 from Zr(IV) and
90:10 from Hf(IV), after 15, 30, or 60 min of reaction.16 The
reaction kinetics were readily followed by 1H NMR, monitoring
the growth of singlets for MeOD at δ 3.33 and 5 at δ 3.79
(characteristically, no CH3O-P coupling was observed for C-ester
5). Rate constants and product distributions appear in Table 1.
Quite different behavior is observed in reactions of DMPF with
Th(IV) or Ce(IV). Th(IV) affords only C-OMe scission to
P-monoester 6 (which is stable to Th(IV) for 5 days) (Scheme 1,
Monoanionic PFA diesters (2) display anti-viral activity in PFA
prodrug studies,3,6 and have exhibited catalytically selective
C-ester cleavage reactions with aminocyclodextrins.4b The parent
PFA diester, dimethyl phosphonoformate (3, DMPF), bears some
resemblance to dimethyl phosphate (4, DMP). Although DMP is
notoriously resistant to hydrolysis,7 enormous rate enhancements
are obtainable in metal cation mediated hydrolyses. For example,
1
branch B). In the H NMR spectrum, MeOD and 6 (δ 3.74, d,
JP-H )11.7 Hz) grow in; P-OMe cleavage to 5 is not competitive.
Ce(IV) cleavage of DMPF begins similarly with C-OMe scission;
P-monoester 6 is formed transiently, along with MeOD.17 About
10% of C-monoester 5 is also produced by competitive P-OMe
cleavage. Monoester 6, however, is unstable to Ce(IV), which
subsequently converts it to methyl phosphate 7 (31P δ 3.07, q,
JP-H ) 10.8 Hz) by oxidative decarboxylation and C-P cleavage.
Rate constants and product distributions appear in Table 1.
With Zr(IV) or Hf(IV), P-monoester 6 is decarboxylatively
cleaved to methyl D-phosphonate 8 (31P δ 9.03, t, JP-D ) 97
Hz).18 Rate constants for 8 f 9 (measured by MeOD release)
were 2.4 × 10-4 or 2.1 × 10-4 s-1 with Zr(IV) or Hf(IV),
respectively; P-OMe cleavages of 8 by these metal cations
occurred at about half the P-OMe cleavage rate of DMPF.
C-monoester 5 hydrolyzed very slowly with Zr(IV) or Hf(IV),
affording only PFA (1) (31P δ 4.2) after ∼3 days. With Ce(IV),
5 was converted to phosphate ion (31P δ 2.1) by net hydrolysis
and oxidative decarboxylation. Finally, although Th(IV)-mediated
hydrolysis of DMPF does not yield 5, this monoester does slowly
release MeOD upon reaction with Th(IV) in D2O. 31P NMR
spectroscopy in the presence of tartrate reveals the formation of
PFA (1) from this reaction.
10
Ce(IV),8 Co(III)-cyclen,9 and Cp2MoCl2 provide 108-1011
hydrolytic rate accelerations. Other highly charged metal cations
such as Zr(IV), Hf(IV), and Th(IV), while not very reactive toward
DMP, greatly speed the hydrolyses of more reactive phosphodiest-
ers.8c,11-13 Might we also expect accelerations in the metal cation
mediated hydrolysis of DMPF?
(1) Physicians Desk Reference; Medical Economics Co., Montvale, NJ,
2000; pp 600-603. See also: Obert, B. Pharmacol. Ther. 1989, 40, 213.
(2) The pKa values of PFA (µ ) 0.1) are 0.78, 3.61, and 7.57: Song, B.;
Chen, D.; Bastian, M.; Martin, R. B.; Sigel, H. HelV. Chim. Acta 1994, 77,
1738.
(3) Noren, J. O.; Helgstrand, E.; Johansson, N. G.; Misiorny, A.; Stening,
G. J. Med. Chem. 1983, 26, 264.
(4) (a) Ferguson, C. G.; Gorin, B. I.; Thatcher, G. R. J. J. Org. Chem.
2000, 65, 1218. (b) Ferguson, C. G.; Thatcher, G. R. J. Org. Lett. 1999, 1,
829. (c) Krol, E. S.; Thatcher, G. R. J. J. Chem. Soc., Perkin Trans. 2 1993,
793. (d) Krol, E. S.; Davis, J. M.; Thatcher, G. R. J. Chem. Commun. 1991,
118. (e) Thatcher, G. R. J.; Krol, E. S.; Cameron, D. R. J. Chem. Soc., Perkin
Trans. 2 1994, 683.
(5) (a) Mitchell, A. G.; Nicholls, D.; Irwin, W. J.; Freeman, S. J. Chem.
Soc., Perkin Trans. 2 1992, 1145. (b) Mitchell, A. G.; Nicholls, D.; Walker,
I.; Irwin, W. J.; Freeman, S. J. Chem. Soc., Perkin Trans. 2 1991, 1297.
(6) Gorin, B. I.; Ferguson, C. G.; Thatcher, G. R. J. Tetrahedron Lett. 1997,
38, 2791.
Kinetics data are summarized in Table 1, and products are
displayed in Scheme 1. As a basis for comparison, the acid-
(7) khydrol ) 1.6 × 10-13 s-1 at pH 7, 25 °C for C-O hydrolysis; P-O
cleavage is ∼2 orders of magnitude slower: Wolfenden, R.; Ridgeway, C.;
Young, G. J. Am. Chem. Soc. 1998, 120, 833.
(14) NaDMPF was prepared by the NaI demethylation of commercial
trimethyl phosphonoformate (refluxing acetone, 2 h): mp 179-181 °C. Anal.
(C, H). 1H NMR (δ, D2O) 3.71 (s, 3H), 3.58 (d, JP-H ) 11.1 Hz, 3H). 31P
(8) (a) Moss, R. A.; Ragunathan, K. G. Chem. Commun. 1998, 1871. (b)
Moss, R. A.; Morales-Rojas, H. Org. Lett. 1999, 1, 1791. (c) Moss, R. A.;
Ragunathan, K. G. Langmuir 1999, 15, 107.
(9) Kim, J. H.; Chin, J. J. Am. Chem. Soc. 1992, 114, 9792.
(10) Kuo, L. Y.; Barnes, L. A. Inorg. Chem. 1999, 38, 814.
(11) (a) Moss, R. A.; Zhang, J.; Ragunathan, K. G. Tetrahedron Lett. 1998,
39, 1529. (b) Stulz, E.; Leumann, C. Chem. Commun. 1999, 239. (c) Ott, R.;
Kra¨mer, R. Angew. Chem., Int. Ed. Engl. 1998, 37, 1957.
(12) Moss, R. A.; Zhang, J.; Bracken, K. Chem. Commun. 1997, 1639.
(13) (a) Williams, N. H.; Takasaki, B.; Wall, M.; Chin, J. Acc. Chem. Res.
1999, 32, 485. (b) Blasko, A.; Bruice, T. C. Acc. Chem. Res. 1999, 32, 475.
(c) Kra¨mer, R. Coord. Chem. ReV. 1999, 182, 243. (d) Roigk, A.; Hettich,
R.; Schneider, H.-J. Inorg. Chem. 1998, 37, 751 (e) Molenveld, P.; Engbersen,
J. F. J.; Reinhoudt, D. N. Chem. Soc. ReV. 2000, 29, 75.
1
NMR (δ, D2O) -2.6 (s, H-decoupled).
(15) For 31P NMR studies, M(IV) was first “removed” by chelation with
EDTA to prevent line broadening. Reaction aliquots were then examined at
various time intervals. The 31P NMR chemical shifts varied slightly in the
presence of the different metal cations.
(16) (a) 31P NMR chemical shifts (δ, D2O, 1H-decoupled): 5, -5.2; 6,
6.9; 3, -2.5. (b) A labeling experiment conducted in 47% 18O-H2O with
DMPF (P-O13CH3)) and Hf(IV), monitored by 31P and 13C NMR,8b gave 5
with stoichiometric 18O-incorporation and 13CH316OH (only); i.e., P-O-Me
cleavage by Hf(IV) and (presumably) Zr(IV) occurred only by P-O scission.
(17) Precipitation occurred after ∼1000 s; the rate constant is therefore
estimated from the initial rate.
(18) About 10% of PFA (1) also forms from 6.
10.1021/ja004156a CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001