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J . Org. Chem. 2000, 65, 5615-5622
5615
Zin c-Med ia ted Ch a in Exten sion of â-Keto P h osp h on a tes
Christopher A. Verbicky and Charles K. Zercher*
Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824
ckz@christa.unh.edu
Received March 9, 2000
A variety of â-keto phosphonates can be converted to γ-keto phosphonates through reaction with
ethyl(iodomethyl)zinc. The presence of R-alkyl substituents, Lewis basic functionality, and modestly
acidic NH-protons are accommodated in substrates of this reaction. Chain extension of â-keto
phosphonates that contained olefinic functionality proceeded more quickly than cyclopropanation;
however, it was not possible to effect the chain extension to the exclusion of cyclopropane formation.
A primary reason for this imperfect chemoselectivity appears to be the slow chain extension of
â-keto phosphonates. Nevertheless, the simplicity, the scope, and efficiency of this method serve to
make it an attractive alternative to the established methods for γ-keto phosphonate formation.
In tr od u ction
of matrix-metalloprotease (MMP-2) and kininogenase,
respectively. The γ-keto phosphonic acids are represented
in compounds such as 6, which is an inhibitor of 5-alanine
levulinic acid dehydratase, an early enzyme on the
tetrapyrrole biosynthetic pathway.8 Another amino acid
derived γ-keto phosphonate 7 was identified as a tight
binding inhibitor of D-alanine:D-alanine ligase, an es-
sential enzyme in bacterial wall synthesis.9 Facile reduc-
tion of the carbonyl within the γ-keto phosphonate
provides easy access to biologically relevant γ-hydroxy
phosphonates.3,10
The phosphonate moiety plays many roles in organic
chemistry.1 Most often employed with respect to its anion-
stabilizing ability, the phosphonate unit is applied fre-
quently to the functionalization and manipulation of the
carbon skeleton. Moreover, the diverse ways in which the
phosphonate group can be removed, like elimination of
an oxaphosphatane or reduction with dissolving metals,
have made the phosphonate group an essential function-
ality to organic chemists.
In addition to its synthetic utility, the phosphonate
unit has been recognized as an attractive isosteric
replacement for the biologically relevant phosphate moi-
ety and as a transition state analogue for mimicking
hydrolysis reactions. A wide range of biologically active
phosphonate-containing compounds have been identified,
including compounds which are active as anti-viral,
insecticides, anti-acidosis agents, and antibiotics.2
One particular subset of phosphonates that have been
demonstrated to have diverse biological activity is the
γ-keto phosphonates. Molecules of this type possess
diverse biological activity ranging from herbicides and
fungicides (1)3 to antihypertensive agents (2).4 Compound
3 has been proposed as a treatment for osteoporosis,5
while compounds 46 and 57 exhibit activity as inhibitors
Synthetic approaches to γ-keto phosphonates have
been varied. The first method (eq 1) designed for the
formation of γ-keto phosphonates involved the addition
of silyl phosphites to R,â-unsaturated carbonyls.11 The
lack of specific reaction conditions and unreported prod-
uct ratios led other research groups to study this reaction
in greater detail.2d,12 Competition between 1,2- and 1,4-
addition pathways were observed, yet the 1,4 addition
pathway could be optimized when reactions were per-
formed at 180 °C in a sealed tube. The utility of this
general strategy for the preparation of γ-keto phosphon-
ates and their derivatives was enhanced when it was
reported that the addition of catalytic or stoichiometric
(6) Kluender, H. C. E.; Benz, G. H. H. H.; Brittelli, D. R.; Bullock,
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M. C.; Wolanin, D. J .; Wilhelm, S. M. US Pat. Appl. US 95-539409
951106; Chem. Abstr. 1998, 129, 161412.
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GB1887 940831; Chem. Abstr. 1995, 123, 257409.
(8) (a) Patchett, A. A.; Thornberry, N. A.; Bull, H. G.; Taub, D.;
Wilson, K. E. BCPC Monogr. 1989, 42 (Prospects Amino Acid Biosynth.
Inhib. Crop Prot. Pharm. Chem.), 109-118. (b) Chakravarty, P. K.;
Greenlee, W. J .; Parson, W. H.; Patchett, A. A.; Combs, P.; Roth, A.;
Busch, R. D.; Mellin, T. N. J . Med. Chem. 1989, 32, 1886.
(9) Appleton, D.; Duguid, A. B.; Lee, S.-K.; Ha, Y.-J .; Ha, H.-J .;
Leeper, F. J . J . Chem. Soc., Perkin Trans. 1 1998, 89.
(10) (a) Mori, I.; Kimura, Y.; Nakano, T.; Matsunaga, S.; Iwasaki,
G.; Ogawa, A.; Hayakawa, K. Tetrahedron Lett. 1997, 38, 3543. (b)
Crooks, S. L.; Robinson, M. B.; Koerner, J . F.; J ohnson, R. L. J . Med.
Chem. 1986, 29, 1988. (c) Mori, I.; Iwasaki, G.; Kimura, Y.; Matunaga,
S.; Ogawa, A.; Nakano, T.; Buser, H.-P.; Hatano, M.; Tada, S.;
Hayakawa, K. J . Am. Chem. Soc. 1995, 117, 4411.
(1) (a) Hilderbrand, R. L. The Role of Phosphonates in Living
Systems; CRC Press: Boca Raton, 1983. (b) Engel, R. Synthesis of
Carbon-Phosphorous Bonds; CRC Press: Boca Raton, 1988. (c) Wiemer,
D. F. Tetrahedron 1997, 53, 16609.
(2) (a) McClure, C. K.; Mishra, P. K.; Grote, C. W. J . Org. Chem.
1997, 62, 2437. (b) Mori, I.; Iwasaki, G.; Hayakawa, K. Yuki Gosei
Kagaku Kyokaishi 1996, 56, 514. (c) Chakravarty, P. K.; Combs, P.;
Toth, A.; Greenlee, W. J . Tetrahedron Lett. 1987, 28, 611. (d) Evans,
D. A.; Hurst, K. M.; Takacs, J . M. J . Am. Chem. Soc. 1978, 100, 3467.
(e) Collomb, D.; Chantegrel, B.; Deshayes, C. Tetrahedron 1996, 52,
10455.
(3) Mori, I.; Iwasaki, G.; Scheidegger, A.; Koizumi, S.; Hayakawa,
K.; Mano, J . PCT Int. Appl. WO 92-J P485 920417; Chem. Abstr. 1993,
118, 124547.
(4) Karanewsky, D. S.; Dejneka, T. Eur. Pat. Appl. EP 87-104477
870326, 1987; US Appl. 844635, 1986; Chem. Abstr. 1988, 109,
129685.
(11) Birum, G. H.; Richardson, G. A. US Patent 3 113 139, 1963;
Chem. Abstr. 1964, 60, 5551d.
(12) Liotta, D.; Sunay, U.; Ginsberg, S. J . Org. Chem. 1982, 47, 2229.
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10.1021/jo000343f CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000