J . Org. Chem. 1999, 64, 2847-2851
2847
P h osp h od iester Alk yla tion w ith a Qu in on e Meth id e
Qibing Zhou and Kenneth D. Turnbull*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701
Received December 3, 1998
Despite the wide array of studies involving DNA alkylation and cleavage with quinone methide
generating compounds, there have been no reports on the alkylation of phosphodiesters with quinone
methides. We have investigated the reaction of dialkyl phosphates with a p-quinone methide in
order to determine the potential for alkylation to produce trialkyphosphates. These studies have
revealed that a phosphodiester can be alkylated with a p-quinone methide when promoted by a
Brønsted acid. The role of the Brønsted acid is to sufficiently activate the p-quinone methide to
allow phosphodiester addition to occur. The alkyl substituents of the phosphodiester have been
found to effect the reactivity of the dialkyl phosphate under the reaction conditions examined.
Equilibrium conversions up to 83% trialkyl phosphate formation have been achieved.
In tr od u ction
Sch em e 1
Quinone methides are common reactive intermediates
1
,2
in a variety of bioactive compounds. Their potential as
bioreductive alkylators of DNA is well established.3
Numerous investigations of nucleic acid base alkylations
4
,5
with o-quinone methides and fewer with p-quinone
methides6 have been reported. However, to our knowl-
edge there are no studies of quinone methide alkylation
of the most abundant nucleophilic functional group of
DNA: phosphodiesters. This is likely due to the relative
weak nucleophilicity of phosphodiesters and known dif-
ficulty in directing alkylation to this functional group in
nucleic acid polymers (Scheme 1).8-10 In developing a
research program around the application of quinone
,7
(
1) Peter, M. G. Angew. Chem., Int. Ed. Engl. 1989, 28, 555-570.
methides to drug design, drug delivery, and biomolecular
labeling, we have investigated the reactivity of a p-
quinone methide with mildly nucleophilic phosphodi-
esters as models for nucleic acid polymers. We have found
that phosphodiester alkylation with this p-quinone me-
thide is possible when promoted by a Brønsted acid.
(2) For reviews on quinone methides, see: (a) Wan, P.; Barker, B.;
Diao, L.; Fischer, M.; Shi, Y.; Yang, C. Can. J . Chem. 1996, 74, 465-
75. (b) Volod’kin, A. A.; Ershov, V. V. Russ. Chem. Rev. 1988, 57,
36-349. (c) Gr u¨ nanger, P. in Methoden der Organisch Chemie; Muller,
E., Bayer, O., Eds.; Thieme G. Verlag: Stuttgart, 1979; Houben-Weyl,
Vol. VII/3b, pp 395-521. (d) Wagner, H. U.; Gompper, R. In The
Chemistry of Quinonoid Compound; Patai, S., Ed.; J ohn Wiley & Sons;
New York, 1974; Vol. 1, pp 1145-1178. (e) Turner, A. B. Quart. Rev.
4
3
1
965, 18, 347-360.
3) (a) Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249-
80. (b) Moore, H. W. Science 1977, 197, 527-532.
4) Many nucleic acid base alkylation products by o-quinone me-
(
Resu lts
2
(
We initially investigated the alkylation of quinone
methide 1 with tetrabutylammonium dibenzyl phosphate
thide derivatives have been characterized: (a) Ouyang, A.; Skibo, E.
B. J . Org. Chem. 1998, 63, 1893-1900. (b) Marques M. M.; Beland, F.
A. Carcinogenesis 1997, 18, 1949-1954. (c) Angle, S. R.; Rainer, J . D.;
Woytowicz, C. J . Org. Chem. 1997, 62, 5884-5892. (d) Rokita, S. E.;
Yang, J .; Pande, P.; Greenberg, W. A. J . Org. Chem. 1997, 62, 3010-
(8) An elegant aziridinium derivative has been reported to selec-
tively alkylate the DNA phosphodiester backbone: (a) Skibo, E. B.;
Schulz, W. G. J . Med. Chem. 1993, 36, 3050-3055. (b) Schulz, W. G.;
Nieman, R. A.; Skibo, E. B. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
11854-11858. (c) Skibo, E. B.; Islam, I.; Schulz, W. G.; Zhou, R.; Bess,
L.; Boruah, R. SYNLETT 1996, 297-309. (d) Skibo, E. B.; Xing, C.
Biochemistry 1998, 37, 15199-15213.
(9) Two examples of attempts at DNA phosphodiester alkylation and
later retrations: (a) Gohil, R. N.; Roth, A. C.; Day. R. A. Arch. Biochem.
Biophys. 1974, 165, 297-312. (b) Bhat, G.; Roth, A. C.; Day, R. A.
Biopolymers 1977, 16, 1713-1724. (c) Koole, L. H.; van Genderen, M.
H. P.; Buck, H. M. J . Am. Chem. Soc. 1987, 109, 3916-3921. (d) Buck,
H. M.; Moody, H. M.; Quaedflieg, P. J . L. M.; Koole, L. H.; van
Genderen, M. H. P.; Smit, L.; J urriaans, S.; Geelen, J . L. M. C.;
Goudsmit, J . Science 1990, 250, 125-126.
(10) A few synthetic methods have been developed to convert dialkyl
phosphate salts into trialkyl phosphates: (a) Ayukawa, H.; Ohuch, S.;
Ishikawa, M.; Hata, T. Chem. Lett. 1995, 81. (b) Meier, C.; Habel, L.
W.; Balzarini, J .; Clercq, E. D. Liebigs. Ann. 1995, 2203-2208. (c)
Neumann, J .-M.; Herv e´ , M.; Debouzy, J .-C.; Guerra, F. I.; Gouyette,
C.; Dupraz, B. Huynh-Dinh, T. J . Am. Chem. Soc. 1989, 111, 4270-
4277.
3
012. (e) Angle, S. R.; Yang, W. J . Org. Chem. 1992, 57, 1092-1097.
(
(
(
f) Angle, S. R.; Yang, W. J . Am. Chem. Soc. 1990, 112, 4524-4528.
g) Egholm, M.; Koch, T. H. J . Am. Chem. Soc. 1989, 111, 8291-8293.
h) Tomasz, M.; Chowdary, D.; Lipman, R.; Shimotakahara, S.; Veiro,
D.; Walker, V.; Verdine, G. L. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,
702-6706.
5) Examples of compounds proposed to alkylate and/or cleave DNA
6
(
through quinone methide intermediates include: (a) Zheng, Q.; Rokita,
S. E. J . Org. Chem. 1996, 61, 9080-9081. (b) Taatjes, D.; Gaudiano,
G.; Resing, K.; Koch, T. H. J . Med. Chem. 1996, 39, 4135-4138. (c)
Mayalarp, S. P.; Hargreaves, R. H. J .; Butler, J .; O’Hare, C. C.; Hartley,
J . A. J . Med. Chem. 1996,39, 531-537. (d) Chatterjee, M.; Rokita, S.
E. J . Am. Chem. Soc. 1994, 116, 1690-1697. (e) Boruah, R. C.; Skibo,
E. B. J . Med. Chem. 1994, 37, 1625-1631. (f) Nicolau, K. C.; Dai, W.-
M. J . Am. Chem. Soc. 1992, 114, 8908-8921.
(
6) Lewis, M. K.; Yoerg, D. G.; Bolton, J . L.; Thompson, J . A. Chem.
Res. Toxicol. 1996, 9, 1368-1374.
7) For an example of a p-quinone methide forming analogue of CC-
065 with potential DNA alkylating abilities, see: Boger, D. L.; Nishi,
T.; Teegarden, B. R. J . Org. Chem. 1994, 59, 4943-4949.
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0.1021/jo9823745 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999