Chiral phosphorus dithio acids derived from (1S,2S,3S,5R)-(+)- isopinocampheol. Synthesis and fungicidal activity

Full text of DOI:10.1007/s11172-012-0336-7

Russian Chemical Bulletin, International Edition, Vol. 61, No. 12, pp. 2370—2371, December, 2012
2370
Chiral phosphorus dithio acids derived from
(1S,2S,3S,5R)ꢀ(+)ꢀisopinocampheol. Synthesis and fungicidal activity
I. S. Nizamov,a,b L. A. Al´metkina,a G. T. Gabdullina,a R. R. Shamilov,a A. V. Sofronov,a
L. E. Nikitina,v S. A. Lisovskaya,g N. I. Glushko,g and R. A. Cherkasova
aPrivolzhskii Kazan Federal University,
18 ul. Kremlevskaya, 420008 Kazan, Russian Federation.
Fax: +7 (843) 292 7418. Eꢀmail: isnizamov@mail.ru
bA. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Scientific Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253
cKazan State Medical University,
49 ul. Butlerova, 420012 Kazan, Russian Federation.
Fax: +7 (843) 236 0393
dKazan Scientific Research Institute of Epidemiology and Microbiology,
67 ul. Bol´shaya Krasnaya, 420015 Kazan, Russian Federation.
Fax: +7 (843) 236 6741
Recent growth within promising trend in organophosꢀ
phorus chemistry dealing with optically active dithiophosꢀ
phoric and dithiophosphonic acids, as well as dithiophosꢀ
phoryl derivatives of naturally occurring compounds, can
lead to new generation of biologically active compounds
of selective action, including veterinary agents.1 The
known methods for the synthesis of dithio phosphoric acids
by the reaction of tetraphosphorus decasulfide2 and dithioꢀ
phosphonic acids or by the reaction of 2,4ꢀdiorganylꢀ
1,3,2,4ꢀdithiadiphosphetane 2,4ꢀdisulfides with alcohols
did not allow one to obtain Pꢀchiral dithio acids despite
the presence of nonidentical substituents at the stereogenꢀ
ic phosphorus atom in the molecules of dithiophosphonic
acids due to the averaging the sulfur atoms in the triad
S=P—SH. An alternative approach to chiral thio acids of
tetracoordinated phosphorus atom can be the synthesis of
compounds with the asymmetric centers in the Oꢀorganyl
substituents. In our opinion, such compounds can be obꢀ
tained by the reaction of tetraphosphorus decasulfide or
1,3,2,4ꢀdithiadiphosphetane 2,4ꢀdisulfides with chiral alꢀ
cohols, including the natural ones, among which optically
active monoterpenols are the most available. Taking into
account the tendency of terpenes to skeletal rearrangeꢀ
ments,3,4 we initially decided to find out whether the optiꢀ
cal activity would be preserved in the products of thioꢀ
phosphorylation of enantiopure bicyclic monoterpenols
and evaluate their biological activity. We found out
that the reaction of tetraphosphorus decasulfide 1 with
(1S,2S,3S,5R)ꢀ(+)ꢀisopinocampheol (2) led to O,O´ꢀbisꢀ
[(1S,2S,3S,5R)ꢀ2,6,6ꢀtrimethylbicyclo[3.1.1]heptꢀ3ꢀyl]ꢀ
dithiophosphoric acid (3), which was characterized by the
angle of optical rotation []22 +35.0, c 1.0, C6H6
D
(cf. the optical angle of terpenol 2: []22 +35.1, c 20,
D
EtOH).5
Scheme 1
The 31P NMR spectrum of dithiophosphate 3 exhibits
a singlet signal at P 85.1 in region indicative of dithioꢀ
phosphoric acids.6 The reaction of terpenol 2 with 2,4ꢀbisꢀ
(4ꢀphenoxyphenyl)ꢀ1,3,2,4ꢀdithiadiphosphetane 2,4ꢀdiꢀ
sulfide (4) gave rise to Oꢀ[(1S,2S,3S,5R)ꢀ2,6,6ꢀtrimethylꢀ
bicyclo[3.1.1]heptꢀ3ꢀyl]ꢀPꢀ(4ꢀphenoxyphenyl)dithiophosꢀ
phonic acid (5) (Scheme 2), P 83.4.
We found out that acid 3 had fungicidal effect on the
microscopic fungi Candida albicans, Aspergillus fumigatus,
and Epidermophiton flocosum in the concentration of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2347—2348, December, 2012.
1066ꢀ5285/12/6112ꢀ2370 © 2012 Springer Science+Business Media, Inc.

Chiral phosphorus dithioacids
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 12, December, 2012
2371
Scheme 2
((CH3)2Csgem); 1089 m ((P)O—C); 973 v.s, v.br ((OC—C));
772 s ((PO2as,s)); 676 v.s ((P=S)); 521 m ((P—S)). 1H NMR
(CDCl3), : 0.96 and 1.23 (both s, 12 H, 2 Me2C(6)); 1.21 (d, 6 H,
2 C(8)H3, 3JH,H = 7.5 Hz); 1.97 (m, 4 H, 2 C(7)H2); 2.24 (m, 2 H,
2 C(2)H); 2.38 (m, 4 H, C(4)H2); 2.05 (m, 2 H, C(5)H); 2.62
(m, 2 H, C(1)H); 4.96 (m, 1 H, 2 P—OC(3)H). Found (%):
C, 59.98; H, 8.33; P, 7.58; S, 15.73. C20H35O2PS2. Calculatꢀ
ed (%): C, 59.67; H, 8.76; P, 7.69; S, 15.93.
(+)ꢀOꢀ[(1S,2S,3S,5R)ꢀ2,6,6ꢀTrimethylbicyclo[3.1.1]heptꢀ
3ꢀyl]ꢀPꢀ(4ꢀphenoxyphenyl)dithiophosphonic acid (5) was obtained
similarly from terpenol 2 (0.3 g, 2.0 mmol) and disulfide 4 (0.5 g,
1.0 mmol). The reaction conditions: benzene (15 mL), 50 C,
Ar = 4ꢀPhOC6H4
20
1 h. The yield was 0.8 g (99%), Rf 0.34 (hexane), nD 1.5820;
[]22D +50.7, c 1.0, C6H6. IR (KBr, pellet), cm–1: 3090 w, 3069
w, 3036 w ((=C—H, Ar)); 2912 v.s, v.br ((CH3as,s), (CH2as,s),
(CH)); 2571 w ((S—Hfree)); 2442 w ((S—Hbond)); 1584 v.s,
1488 v.s ((C=C), Ar); 1455 m ( (CH3as)); 1386 m, 1369 m
((CH3)2Csgem); 980 s ((P)O—C); 944 s ((OC—C)); 679 s
((P=S)); 528 m ((P—S)). 1H NMR (CDCl3), : 1.06 and 1.32
(both s, 6 H, Me2C(6)); 1.28 (d, 3 H, C(8)H3); 1.94 (m, 2 H,
C(7)H2); 2.05 (m, 1 H, C(5)H); 2.33 (m, 1 H, C(2)H); 2.46 (m,
2 H, C(4)H2); 2.77 (m, 1 H, C(1)H); 5.27 (m, 1 H, P—OC(3)H);
7.10 (m, 2 H, CPh(2)H, CPh(6)H); 7.43 (m, 5 H, CPh(3)H,
CPh(4)H, CPh(5)H, CC H (3)H, CC H (5)H); 8.01 (d, 2 H,
40 mg mL–1 in liquid culture medium. During the growth
process of the fungi strains in the culture medium conꢀ
taining acid 3, morphoꢀphysiological changes took place
in the cells. Some sites of the cell surface of fungi Candida
albicans underwent deformation, the invagination was obꢀ
served, which resulted in the change of the normal shape
of the cells. The cell organelles in the cytoplasmic matrix
migrated to the cell center, moving away from the damꢀ
aged cytoderm, that caused a delay of the phase of the
increase in the number of microorganisms.
6
6
4
CC H (2)H and CC H (6)H4, JP,H = 14.6 Hz). Found (%): C,
3
4
6
4
63.635; H, 6.26; P, 7.58; S, 15.53. C22H27O2PS2. Calculated (%):
IR spectra were recorded on a Bruker Vector 22 Fourierꢀ
spectrometer (400—4000 cm–1) for neat films or suspensions in
Nujol between KBr plates. 31P NMR spectra were recorded on
a Bruker Avanceꢀ400 spectrometer (161.98 MHz, in solutions in
C, 63.13; H, 6.50; P, 7.40; S, 15.32.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 11ꢀ03ꢀ00264ꢀa).
1
C6H6, external standard 85% aqueous H3PO4). H NMR specꢀ
tra were recorded on a Bruker Avanceꢀ600 spectrometer
(600 MHz, in solutions in CDCl3, using signal for the residual
protons of the deuterated solvent as a reference). The angle of
the planeꢀpolarized light was determined on a Perkin—Elmer
instruments 341 polarimeter ( 589 nm, sodiumꢀhalogen lamp,
the pathway of a quartz cuvette 55 mm). The minimal inhibitory
concentration of compounds toward fungi was evaluated using
a photoelectrocolorimeter ( 530 nm).
(+)ꢀO,O´ꢀBis[(1S,2S,3S,5R)ꢀ2,6,6ꢀtrimethylbicyclo[3.1.1]ꢀ
heptꢀ3ꢀyl]dithiophosphoric acid (3). Sulfide 1 (0.9 g, 2.2 mmol)
was added in portions to a stirred solution of terpenol 2 (2.5 g,
16.2 mmol) in anhydrous benzene (20 mL) at 20 C under dry
argon. The mixture was heated for 2 h at 50 C with stirring.
After cooling to 20 C, the mixture was filtered. The solvent was
evaporated from the filtrate in vacuo (0.5 Torr) at 40 C over 1 h
and at 0.02 Torr and 40 C over another 1 h. Acid 3 (1.8 g, 55%)
was thus obtained, which was purified by column chromatoꢀ
graphy (silica gel 0.060—0.200 m, eluent benzene), Rf 0.45
(hexane), nD20 1.5230. IR (KBr, liquid film), cm–1: 2987 s, 2911
v.br (CH3as,s), CH2as,s), CH)); 2583 w.br (S—Hfree)); 2403
w.br ((S—Hbond)); 1471 s, 1452 s ((CH3as)); 1385 m, 1368 m
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Received July 23, 2012;
in revised form November 16, 2012