,
2004, 14(3), 93–93
New synthesis and fungicidal activity of a phosphinic analogue of glycine
a
b
a
a
b
Yurii N. Zhukov, Nelli A. Vavilova, Tat’yana I. Osipova, Elena N. Khurs, Vitalii G. Dzhavakhiya and
a
Radii M. Khomutov*
a
V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
b
Research Institute of Phytopathology, Russian Academy of Agricultural Sciences, 143050 Golitsyno, Moscow Region,
DOI: 10.1070/MC2004v014n03ABEH001864
Aminomethylphosphinic acid, which was found to exhibit fungicidal activity, was synthesised in one step by the interaction of
formaldoxime and sodium hypophosphite with HCl.
1
-Aminoalkylphosphinic acids are of interest as biologically
OH
H
active isosteres of natural amino acids and as synthetic pre-
cursors of other organophosphorus analogues of amino acids.1
Correspondingly, aminomethylphosphinic acid 1 can be con-
sidered an analogue of glycine, which is a metabolic precursor
of a number of biologically active compounds: creatine (N-methyl-
guanidoacetic acid), glutathione, and porphyrins. It was found
that a phosphinic analogue of creatine can be the substrate of
H N
P
N
H3PO2
2
,2
H2C
OH
O
1
Scheme 1
analogue 1. We studied the effect of acid 1 on the growth of
practically important phytopathogenic fungi and found that ana-
logue 1 exhibited specific activity towards Pyricularia oryzae, a
pathogen of rice. Procedures used for the cultivation of fungi
and the evaluation of the effects of substances on the germina-
tion of conidia and mycelium and on pigmentation were
described previously.12 In in vitro experiments, the effects of
analogue 1 were studied in both a standard agar medium and a
medium containing only inorganic salts, glucose, thiamine, and
biotine (a minimum medium) to reveal competition of the
analogue with the amino acids of the medium. This procedure
does not exclude a correlation between the activity under these
conditions and in vivo. Acid 1 suppressed the growth of
mycelium in a minimum medium (EC50 50 µg cm ) and only
slightly affected the germination of conidia. In a standard
medium, the effect was weaker by an order of magnitude. Thus,
acid 1, similarly to glycine, can penetrate into a pathogen and
compete with glycine in cell methabolism; this is responsible
for the fungitoxicity of compound 1.
3
creatine kinase, which is an important enzyme of muscular
contraction; thus, such analogues are promising for the regula-
tion of cell metabolism. Acid 1 suitably protected at the amino
group and the phosphorus-containing moiety is a starting
compound in the synthesis of aminoalkylphosphinic acids by
alkylation.4
†
Compound 1 was prepared using several procedures; one of
them was the amination of inaccessible chloromethylphosphinic
acid. The reaction of 1,2,5-tribenzhydrylhexahydro-s-triazine
with H PO resulted in N-substituted compound 1, which was
converted into acid 1 in a total yield of 6%. The use of the
5
3
2
6
–
3
ethyl ester of diethoxymethylphosphinic acid in place of H PO
3
2
7
significantly increased the yield of compound 1. The interac-
tion of another phosphorus-containing synthon, the bis(trimethyl-
silyl) ester of ethoxycarbonylphosphinic acid, with N-(bromo-
methyl)phthalimide followed by the hydrolysis of the resulting
phthalimide derivative also resulted in an analogue of com-
8
pound 1. Thus, the currently available procedures for the pre-
paration of amino acid 1 include the syntheses of both amine
and phosphorus components and are multistage processes.
A general procedure for the preparation of 1-aminoalkyl-
phosphinic acids by the interaction of oximes with anhydrous
This work was supported by the Russian Foundation for
Basic Research (grant no. 03-04-48949) and by the Presidential
Programme for Leading Russian Scientific Schools (grant no.
1800.2003.4).
9
,10
H PO is well known.
We studied this reaction and found
3
2
that strong acids catalyse the reaction and water-free conditions
are not critical for the reaction. This allowed us to exclude the
1
2
3
4
5
6
7
J. G. Dingwall, Abstr. III Int. Conf. Chem. and Biotech. Biol. Active
Natural Prods, Sofia, Bulgaria, 1986, vol. 1, p. 87.
G. L. Rowley, A. L. Greenleaf and G. L. Kenyon, J. Am. Chem. Soc.,
1971, 93, 5542.
preparation and use of anhydrous H PO , which is dangerous
3
2
compound, especially at elevated temperatures. This practically
resulted in a single-step procedure for the synthesis of amino
acid 1 in ~25% yield. In this procedure, an aqueous solution of
NaH PO and formaldoxime (from aqueous formaldehyde and
2
2
P. P. McCleery and B. Tuck, J. Chem. Soc., Perkin Trans. 1, 1989,
hydroxylamine) was added to hot HCl in alcohol, and the pro-
duct was separated by ion-exchange chromatography (Scheme 1).
Some 1-aminoalkylphosphinic acids exhibit antibacterial
activity2 and inhibit the growth of leukemia cells L1210.11
However, there is no published data on the biological activity of
1
319.
A. D. E. Toy and E. H. Uning, US Patent, 3160632, 1964 (Chem.
Abstr., 1965, 62, 4053).
E. K. Baylis, C. D. Campbell and J. G. Dingwall, J. Chem. Soc., Perkin
Trans. 1, 1984, 2845.
J. G. Dingwall, J. Ehrenfreund and R. G. Hall, Tetrahedron, 1989, 45,
†
NH OH·HCl (7 g, 0.1 mol) and NaHCO (7.5 g, 0.09 mol) were alter-
2
3
3
783.
nately added to an 8% aqueous formaldehyde solution (40 ml, 0.1 mol)
with stirring to maintain pH 4–5. Next, the reaction mixture was stirred
for 2 h; NaH PO ·H O (21.2 g, 0.2 mol) was added, and resulted mix-
8
9
D. Grobelny, Synth. Commun., 1989, 19, 1177.
R. M. Khomutov and T. I. Osipova, Izv. Akad. Nauk SSSR, Ser. Khim.,
2
2
2
1
978, 1951 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1978, 27, 1722).
ture was added to stirring 20% HCl (40 ml, 0.22 mol of HCl) in 50 ml of
MeOH at reflux. The mixture was refluxed for 30 min, cooled, and
evaporated in a vacuum. The residue was dissolved in 15 ml of water,
1
0 Yu. N. Zhukov, A. R. Khomutov, T. I. Osipova and R. M. Khomutov,
Izv. Akad. Nauk SSSR, Ser. Khim., 1999, 1360 (Russ. Chem. Bull.,
1
999, 48, 1348).
+
and the product was separated on Dowex 50x8 resin (H form); 15%
11 R. M. Khomutov, Yu. N. Zhukov, A. R. Khomutov, E. N. Khurs, D. L.
aqueous isopropanol was used as an eluent. Fractions containing com-
pound 1 were vacuum evaporated to dryness; the residue was vacuum
Kramer, J. T. Miller and K. V. Porter, Bioorg. Khim., 2000, 26, 718
(
Russ. J. Bioorg. Chem., 2000, 26, 647).
dried over P O5 to obtain compound 1 (2.4 g, 25%), mp 259–263 °C
2
12 R. M. Khomutov, E. N. Khurs, V. G. Dzhavakhiya, T. M. Voinova and
6
7
8
(
decomp.) [lit., 254–256 °C; 258–260 °C; 272–276 °C (decomp.)].
R 0.55 (Pr OH–25% NH OH–H O, 7:1:2). H NMR (400 MHz, D O)
B. S. Ermolinskii, Bioorg. Khim., 1987, 13, 1422 (in Russian).
i
1
f
4
2
2
d: 2.88 (dd, 2CH, CH , J 11 Hz, J 1.9 Hz), 6.99 (dt, 1H, PH, J 540 Hz,
2
J 1.8 Hz).
Received: 19th November 2003; Com. 03/2190
–
93 –
Zhukov, Yurii N.
