Synthesis of hydrophospohoryl derivatives of the antifungal antibiotic pimaricin by the Kabachnik-Fields reaction

Article abstract of DOI:10.1007/s11176-008-2021-y

Reactions of the polyene macrolide antibiotic pimaricin with aromatic aldehydes and hypophosphorous acid are shown to afford pimaricin hydrophosphoryl derivatives. Physicochemical and biological properties of these compounds are explored. Biological studi

Full text of DOI:10.1007/s11176-008-2021-y

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 2, pp. 305 312.
Pleiades Publishing, Ltd., 2008.
Synthesis of Hydrophospohoryl Derivatives
of the Antifungal Antibiotic Pimaricin
by the Kabachnik Fields Reaction*
V. V. Belakhova, Yu. D. Sheninb, and B. I. Ioninc
a Schulich Faculty of Chemistry, Technion Israel Institute of Technology,
Haifa 32000, Israel
e-mail: chvalery@techunix.technion.ac.il
b Russian Research Institute of Plant Protection,
sh. Podbel’skogo 3, Saint-Petersburg, 196608 Russia
c St. Petersburg Technological Institute,
Moscovskii pr. 26, St. Petersburg, 198020, Russia
e-mail: borisionin@mail.ru.
Received February 12, 2008
Abstract Reactions of the polyene macrolide antibiotic pimaricin with aromatic aldehydes and hypo-
phosphorous acid are shown to afford pimaricin hydrophosphoryl derivatives. Physicochemical and biological
properties of these compounds are explored. Biological studies indicated that the pimaricin hydrophosphoryl
derivatives are low toxic agents possessing a high antifungal activity.
DOI: 10.1134/S1070363208020217
Polyene macrolide antibiotics constitute an abun-
dant group of natural compounds that embarrasses
over 200 preparations revealing activity toward yeast,
yeast-like, and filamentous fungi of both saprophytic
and pathogenic species [1 4]. Perspectives of medical
application of polyene macrolide antibiotics were
enhanced after revealing their antiviral activity [5 8],
activity toward parasitic Protozoa [9 11], and potential
use as antitumor agents [12 14]. They are particularly
useful for treatment of fungal diseases complicating
AIDS [15 18]. On the other hand, the polyene macro-
lide antibiotics used in medical practice do not satisfy
completely requirements of clinical physicians due to
restricted efficiency, in part, inapplicability for treat-
ment of certain forms of deep mycoses [19 21].
Medical application of these antifungal preparations
is also hindered by their high toxicity [22 25], instab-
ility on storage [26 30], poor solubility in water
[1 4], and reduced sensitivity to these antibiotics of
fungal microorganisms [31 34]. Therefore, search for
new derivatives of polyene macrolide antibiotics
possessing improved medical and biological proper-
ties is being continued.
ricin derivatives has been described in the literature:
esters [37 40], N-acyl [41, 42] and N-glycosyl deri-
vatives [43], enamine and amidine derivatives [44], a
mides [45], trimethylsilyl derivatives [46], N,N-di-
alkyl derivatives [47], and water-soluble salts and
complexes [48 50]. There is no published data con-
cerning synthesis of phosphorus-containing deriva-
tives of this antifungal antibiotic.
Continuing studies on the synthesis of semisyn-
thetic derivatives of polyene macrolide antibiotics
[51 63] we explored reactions of pimaricin with
aromatic aldehydes and hypophosphorous acid and
studied antifungal activity of the obtained derivatives.
We showed that pimaricin reacts with aromatic
aldehydes and hypophosphorous acid to form hydro-
phosphoryl derivatives of the antibiotic. The studied
reaction can be considered as a specific version of the
Kabachnik Fields reaction [64, 65] whose synthetic
performance has been considered in detail in [66, 67].
In the first step of the process, the primary amino
group of the pimaricin carbohydrate fragment is added
to the carbonyl group of the aromatic aldehyde to
form an azomethine intermediate. In the second step,
hypophosphorous acid reacts at the C=N bond of the
azomethine fragment to afford hydrophoshoryl
pimaricin derivatives I VII.
As the object for investigation we took tetraene
macrolide antibiotic pimaricin A widely used for
treatment of mycoses [1, 35, 36]. A series of pima-
*
The text was submitted by authors in English.
305

306
BELAKHOV et al.
R = OH (I), MeO (II), NO2 (III), Me2N (IV), F (V), Cl (VI), Br (VII).
1
For the phosphorylation we applied hypophos-
and 3407 3429 cm , that attest presence of P H and
N H bonds, respectively. The absorption bands of the
phorous acid, a mild phosphorylating agent [66, 68].
The following aromatic aldehydes were used in this
work: 4-hydroxybenzaldehyde, 4-methoxybenzalde-
hyde, 4-nitrobenzaldehyde,4- (dimethylamino)benz-
aldehyde, 4-fluorobenzaldehyde, 4-chlorobenzalde-
hyde, and 4-bromobenzaldehyde.
1
P=O group are fixed at 1232 1247 cm and those of
phenyl substituents, at 1573 1584 cm .
1
The following specific adsorption indices were
registered in the UV spectra of pimaricin derivatives
I VII (E ): 710 713, 1100 1108, 1020 1027, at
1%
1 cm
the bond lengths 290, 303, and 318 nm, respectively,
characteristic of a tetraene conjugated system [35];
phenyl absorption maxima were also detected at 257
263 nm.
Pimaricin derivatives I VII are white or cream-
colored solid crystalline compounds having no sharp
melting point and decomposing on heating. Com-
pounds I VII are readily soluble in DMSO and DMF,
moderately soluble in MeOH, EtOH, and water, in-
soluble in chloroform, higher alcohols, ethers, di-
oxane, benzene, and hexane.
EXPERIMENTAL
Pimaricin produced by Sigma (USA) by means of
microbiological synthesis with the producing agent
Streptomyces chattanoogensis was used throughout
the study. Organic solvents were purified before use,
according to known procedures [71].
The structure of these derivatives was confirmed
1
using H, 13C, and 31P NMR, as well as IR and UV
1
spectroscopy. The H NMR spectra of compounds I
VII contain signals of pimaricin and phenyl protons,
a doublet signal of the proton at phosphorus ( 6.91
7.03 ppm, JPH 555 560 Hz), and a multiplet of the
CH P methine proton ( 4.02 4.19 ppm). The sig-
nals of the protons of the phenyl ring possessing a
para substituent appear as a system of two pairs of
chemically equivalent but magnetically nonequivalent
nuclei (AA BB ). The 13C NMR spectra contain signals
of pimaricin carbon atoms and phenyl fragments; the
carbon atom connected directly to the phosphorus
atom gives a doublet signal in the region of 26.81
28.27 ppm (JCP 132.1 134.3 Hz). The signals of 31P
nuclei of pimaricin derivatives I VII fall to the range
1
The H and 13C NMR spectra were obtained on a
Bruker Avance instrument (Germany) at 500 MHz
(for protons) for 10 15% solutions in MeOH-d4,
internal reference TMS. The 31P NMR spectra were
registered on a Bruker AC-200 instrument (Germany)
with operating frequency 80 MHz (200 MHz for pro-
tons), external reference 85% H3PO4. The IR spectra
were registered on a Bruker Vector 22 spectrophoto-
meter (Germany) from Kßr pellets. The UV spectra
were recorded on an Ultrospec 2100 pro instrument
(Biochrom, UK). Individuality of pimaricin deriva-
tives I VII was verified by TLC on Silica Gel 60
F254 plates (0.25 mm, Merck, Germany) in a me-
thanol acetone acetic acid, 8:1:1, solvent system;
spots were developed by UV illumination. Column
chromatography was performed on Silica Gel 60 (63
200 mm, Merck, Germany).
15.42 15.95 ppm, typical of phosphonous acids
with a tetracoordinate phosphorus atom [69, 70].
P
The IR spectra of compounds I VII contain, along
with adsorption bands characteristic of the parent
1
pimaricin, bands in the regions of 2380 2415 cm
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

SYNTHESIS OF HYDROPHOSPOHORYL DERIVATIVES
307
N-( -Hydrophosphoryl-4-R-benzyl)pimaricins
(I VII) (general procedure). To 0.01 mol of pimari-
cin in 25 ml of DMSO, 0.02 mol of benzaldehyde in
5 ml of DMSO in the presence of a catalytic amount
of triethylamine was added with stirring. The reaction
was carried out at 40 C for 3 h, after which 0.015 mol
of hypophosphorous acid was added, and the reaction
was continued at 30 35 C for 3 4 h. The reaction
progress was monitored by TLC. After reaction com-
pletion, the solution obtained was cooled to 20 C and
filtered. The filtrate was diluted with excess diethyl
ether (300 ml). The oily liquid that dropped was
separated, and methanol (25 ml) was added. The sus-
pension formed was filtered, and the filtrate was
passed through a column of silica gel, eluent chloro-
form methanol, 2:1. The eluates containing the target
substance were collected and concentrated in a
vacuum to reduce the volume 3 4-fold. The concen-
trated solution was diluted with a 5-fold volume of di-
ethyl ether, and the precipitate dropped was filtered
off, washed with ether, and dried in a vacuum at 40 C
for 4 h. Compounds I VII were obtained as fine
white or cream crystals.
(1H, H-3, J3,4 7.5 Hz), 6.43 s (1H, H-18), 6.95 d (1H,
P H, JPH 557 Hz), 6.68 d (2H, phenyl, J 8.2 Hz),
7.16 d (2H, phenyl, J 8.2 Hz), 9.83 s (1H, Ph OH).
13C NMR spectrum, C, ppm: 18.25 (C-6 ), 20.63
(C-26), 27.54 d (C H P, JCP 133.5 Hz), 41.16 (C-6),
42.61 (C-10), 43.10 (C-14), 44.54 (C-24), 47.83 (C-8),
56.48 (C-4), 57.16 (C-3 ), 60.24 (C-5), 61.14 (C-12),
65.93 (C-5 ), 68.22 (C-13), 68.64 (C-11), 69.53 (C-7),
71.92 (C-25), 73.08 (C-2 ), 74.76 (C-4 ), 75.39 (C-5),
81.58 (C-15), 99.73 (C-9), 100.84 (C-1 ), 126.32
(C-2), 115.75 (phenyl), 128.37 (phenyl), 136.16
(phenyl), 156.51 (phenyl), 130.70 (C-16), 133.02
(C-17), 133.43 (C-18), 133.89 (C-19), 134.35 (C-20),
134.59 (C-21), 135.12 (C-22), 137.51 (C-23), 145.56
(C-3), 167.94 (C-1), 178.25 (C-27). 31P NMR spec-
trum, P, ppm: 15.67.
N-[( -Hydrophosphoryl-4-methoxybenzyl)]-
pimaricin (II). Yield 71%, mp 189-194 C (decomp.),
Rf 0.55. 1H NMR spectrum (MeOH-d4), , ppm:
1.17 d (1H, H-6eq, J6eq,7 11.0 Hz), 1.24 d.d (1H,
H-10ax, J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.26 s
(3H, H-6 CH3), 1,28 s (3H, 26-CH3), 1.54 d (1H,
H-8ax, J8ax,8eq 14.2 Hz), 1.59 d.d (1H, H-14ax,
J14ax,14eq 14.0 Hz, J14eq,15 2.0 Hz), 1.64 s (1H, H-8eq),
1.98 d (1H, H-10eq, J10eq,11 4.8 Hz), 1.99 t (1H, H-12,
J12,13 10.5 Hz), 2.08 d.d (1H, H-6ax, J6ax,6eq 14.4 Hz,
J6ax,7 0.9 Hz), 2.23 d.d (1H, H-24ax, J24ax,24eq 13.5 Hz,
J24ax,25 11.0 Hz), 2.30 d (1H, H-14eq, J14eq,15 3.5 Hz),
2.39 d (1H, H-24eq, J24eq,25 5.6 Hz), 2.77 d.d (1H,
H-5, J5,6ax 1.8 Hz, J5,6eq 8.3 Hz), 3.10 d (1H, H-4, J4,5
1.5 Hz), 3.18 d (1H, H-3 , J3 ,4 9.0 Hz), 3.29 d (1H,
H-5 , J5 ,6 Me 6.5 Hz), 3.35 d (1H, H-4 , J4 ,5 9.0 Hz),
3.72 s (OCH3), 3.95 d (1H, H-2 , J2 ,3 3.5 Hz), 4.06 m
(1H, H-1 , CHP,), 4.23 d (1H, H-11, J11,12 10.5 Hz),
4.29 d.d (1H, H-7, J7,8ax 1.3 Hz, J7,8eq 10.2 Hz), 4.32
d.d (1H, H-13, J13,14ax 8.4 Hz, J13,14eq 1.2 Hz), 4.38 d
(1H, H-15, J15,16 8.3 Hz), 4.55 d (1H, H-1 , J1 ,2
1.0 Hz), 4.69 d (1H, H-25, J25,26-Me 6.5 Hz), 5.58 d.d
(1H, H-23, J23,24ax 8.8 Hz, J23,24eq 2.5 Hz), 5.96 d
(1H, H-16, J16,17 15.2 Hz), 6.03 d.d (1H, H-2, J2,3
15.8 Hz, J2,4 0.6 Hz), 6.11 d (1H, H-22, J22,23
15.4 Hz), 6.14 d (1H, H-17, J17,18 10 Hz), 6.17 s (1H,
N-[( -Hydrophosphoryl-4-hydroxybenzyl)]-
pimaricin (I). Yield 67%, mp 173 178 C (decomp.),
Rf 0.51. 1H NMR spectrum (MeOH-d4), , ppm:
1.16 d (1H, H-6eq, J6eq,7 11.0 Hz), 1.23 d.d (1H,
H-10ax, J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.24 s
(3H, H-6 CH3), 1,28 s (3H, 26 CH3), 1.55 d (1H,
H-8ax, J8ax, 8eq 14.2 Hz), 1.57 d.d (1H, H-14ax,
J14ax,14eq 14.0 Hz, J14eq,15 2.0 Hz), 1.66 s (1H, H-8eq),
1.95 d (1H, H-10eq, J10eq,11 4.8 Hz), 1.97 t (1H,
H-12, J12,13 10.5 Hz,), 2.05 d.d (1H, H-6ax, J6ax,6eq
14.4 Hz, J6ax,7 0.9 Hz), 2.20 d.d (1H, H-24ax,
J24ax,24eq 13.5 Hz, J24ax, 25 11.0 Hz), 2.28 d (1H,
H-14eq, J14eq,15 3.5 Hz), 2.36 d (1H, H-24eq, J24eq,25
5.6 Hz), 2.79 d.d (1H, H-5, J5,6ax 1.8 Hz, J5,6eq
8.3 Hz), 3.12 d (1H, H-4, J4,5 1.5 Hz), 3.16 d (1H,
H-3 , J3 ,4 9.0 Hz), 3.28 d (1H, H-5 , J5 ,6 Me 6.5 Hz),
3.35 d (1H, H-4 , J4 ,5 9.0 Hz), 3.98 d (1H, H-2 , J2 ,3
3.5 Hz), 4.08 m (1H, CH P,), 4.25 d (1H, H-11, J11,12
10.5 Hz), 4.28 d.d (1H, H-7, J7,8ax 1.3 Hz, J7,8eq
10.2 Hz), 4.34 d.d (1H, H-13, J13,14ax 8.4 Hz, J13,14eq
1.2 Hz), 4.38 d (1H, H-15, J15,16 8.3 Hz), 4.53 d (1H,
H-1 , J1 ,2 1.0 Hz), 4.68 d (1H, H-25, J25,26-Me 6.5 Hz),
5.56 d.d (1H, H-23, J23,24ax 8.8 Hz, J23,24eq 2.5 Hz,),
5.95 d (1H, H-16, J16,17 15.2 Hz), 6.05 d.d (1H, H-2,
J2,3 15.8 Hz, J2,4 0.6 Hz), 6.09 d (1H, H-22, J22,23
H-20), 6.19 s (1H, H-21), 6.20 s (1H, H-19), 6.36 d
(1H, H-3, J3,4 7.5 Hz), 6.43 s (1H, H-18), 6.96 d (1H,
PH, JPH 557 Hz,), 6.88 d (2H, phenyl, J 8.2 Hz),
7.22 d (2H, phenyl, J 8.2 Hz). 13C NMR spectrum,
,
ppm: 18.29 (C-6 ), 20.68 (C-26), 27.50 d (C H P, JCCP
133.8 Hz), 41.21 (C-6), 42.66 (C-10), 43.15 (C-14),
44.59 (C-24), 47.92 (C-8), 55.82 (OCH3), 56.67 (C-4),
15.4 Hz), 6.11 d (1H, H-17, J17,18 10 Hz), 6.15 s (1H,
H-20), 6.17 s (1H, H-21), 6.20 s (1H, H-19), 6.38 d
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

308
BELAKHOV et al.
57.24 (C-3 ), 60.31 (C-5), 61.19 (C-12), 66.13 (C-5 ),
68.53 (C-13), 68.91 (C-11), 69.70 (C-7), 72.18 (C-25),
73.25 (C-2 ), 74.92 (C-4 ), 75.51 (C-5), 81.69 (C-15),
100.03 (C-9), 101.34 (C-1 ), 126.76 (C-2), 114.17
(phenyl), 127.97 (phenyl), 135.83 (phenyl), 158.65
(phenyl), 131.59 (C-16), 134.33 (C-17), 134.20
(C-18), 134.97 (C-19), 135.16 (C-20), 135.31 (C-21),
136.24 (C-22), 138.65 (C-23), 144.89 (C-3), 166.59
(C-1), 179.02 (C-27). 31P NMR spectrum, P, ppm:
15.49.
135.76 (C-20), 135.98 (C-21), 136.52 (C-22), 137.90
(C-23), 147.01 (C-3), 166.27 (C-1), 179.09 (C-27).
31P NMR spectrum, P, ppm: 15.84.
N-[( -Hydrophosphoryl-4-(dimethylamino)-
benzyl]]pimaricin (IV). Yield 69%, mp 191 196 C
1
(decomp.), Rf 0.61. H NMR spectrum (MeOH-d4),
, ppm: 1.10 d (1H, H-6eq, J6eq,7 11.0 Hz), 1.14 d.d
(1H, H-10ax, J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz),
1.17 s (3H, H-6 CH3), 1,25 s (3H, 26-CH3), 1.46 d
(1H, H-8ax, J8ax,8eq 14.2 Hz), 1.51 d.d (1H, H-14ax,
J14ax,14eq 14.0 Hz, J14eq,15 2.0 Hz), 1.60 s (1H, H-8eq),
1.89 d (1H, H-10eq, J10eq, 11 4.8 Hz), 1.93 t (1H,
H-12, J12,13 10.5 Hz), 2.01 d.d (1H, H-6ax, J6ax,6eq
14.4 Hz, J6ax,7 0.9 Hz), 2.13 d.d (1H, H-24ax,
J24ax,24eq 13.5 Hz, J24ax,25 11.0 Hz), 2.28 d (1H,
H-14eq, J14eq,15 3.5 Hz), 2.28 d (1H, H-24eq, J24eq,25
5.6 Hz), 2.71 d.d (1H, H-5, J5,6ax 1.8 Hz, J5,6eq 8.3 Hz,
H-5), 2.83 s [6H, N(CH3)2], 3.04 d (1H, H-4, J4,5
1.5 Hz), 3.11 d (1H, H-3 , J3 ,4 9.0 Hz), 3.20 d (1H,
H-5 , J5 ,6 Me 6.5 Hz), 3.31 d (1H, H-4 , J4 ,5 9.0 Hz),
3.86 d (1H, H-2 , J2 ,3 3.5 Hz), 4.16 m (1H, CHP,
H-1 ), 4.21 d (1H, H-11, J11,12 10.5 Hz), 4.29 d.d (1H,
H-7, J7,8ax 1.3 Hz, J7,8eq 10.2 Hz), 4.37 d.d (1H, H-13,
J13,14ax 8.4 Hz, J13,14eq 1.2 Hz), 4.43 d (1H, H-15,
J15,16 8.3 Hz), 4.51 d (1H, H-1 , J1 ,2 1.0 Hz), 4.73 d
(1H, H-25, J25,26-Me 6.5 Hz), 5.49 d.d (1H, H-23,
J23,24ax 8.8 Hz, J23, 24eq 2.5 Hz), 5.87 d (1H, H-16,
J16,17 15.2 Hz), 6.00 d.d (1H, H-2, J2,3 15.8 Hz, J2,4
0.6 Hz), 6.05 d (1H, H-22, J22,23 15.4 Hz), 6.13 d (1H,
H-17, J17,18 10 Hz), 6.15 s (1H, H-20), 6.17 s (1H,
H-21), 6.29 s (1H, H-19), 6.33 d (1H, H-3, J3,4
7.5 Hz), 6.47 s (1H, H-18), 6.99 d (1H, PH, JPH
559 Hz), 6.72 d (2H, phenyl, J 8.2 Hz), 6.94 d (2H,
N-[( -Hydrophosphoryl-4-nitrobenzyl)]pimari-
cin (III). Yield 62%, mp 176 181 C (decomp.), Rf
1
0.48. H NMR spectrum (MeOH-d4), , ppm: 1.13 d
(1H, H-6eq, J6eq,7 11.0 Hz), 1.26 d.d (1H, H-10ax,
J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.31 s (3H,
H-6 CH3), 1,35 s (3H, 26-CH3), 1.61 d (1H, H-8ax,
J8ax,8eq 14.2 Hz), 1.65 d.d (1H, H-14ax, J14ax,14eq
14.0 Hz, J14eq,15 2.0 Hz), 1.72 s (1H, H-8eq), 1.91 d
(1H, J10eq, J10eq,11 4.8 Hz), 1.95 t (1H, H-12, J12,13
10.5 Hz), 2.11 d.d (1H, H-6ax, J6ax,6eq 14.4 Hz, J6ax,7
0.9 Hz), 2.28 d.d (1H, H-24ax, J24ax,24eq 13.5 Hz,
J24ax,25 11.0 Hz), 2.32 d (1H, H-14eq, J14eq,15 3.5 Hz),
2.39 d (1H, H-24eq, J24eq,25 5.6 Hz), 2.86 d.d (1H,
H-5, J5,6ax 1.8 Hz, J5,6eq 8.3 Hz), 3.17 d (1H, H-4, J4,5
1.5 Hz), 3.20 d (1H, H-3 , J3 ,4 9.0 Hz), 3.31 d (1H,
H-5 , J5 ,6 Me 6.5 Hz), 3.48 d (1H, H-4 , J4 ,5 9.0 Hz),
4.07 d (1H, H-2 , J2 ,3 3.5 Hz), 4.12 m (1H, CHP,
H-1 ), 4.29 d (1H, H-11, J11,12 10.5 Hz), 4.33 d.d (1H,
H-7, J7,8ax 1.3 Hz, J7,8eq 10.2 Hz), 4.41 d.d (1H, H-13,
J13,14ax 8.4 Hz, J13,14eq 1.2 Hz), 4.48 d (1H, H-15,
J15,16 8.3 Hz), 4.61 d (1H, H-1 , J1 ,2 1.0 Hz), 4.66 d
(1H, H-25, J25,26-Me 6.5 Hz), 5.42 d.d (1H, H-23,
J23,24ax 8.8 Hz, J23,24eq 2.5 Hz), 5.97 d (1H, H-16,
J16,17 15.2 Hz), 6.08 d.d (1H, H-2, J2,3 15.8 Hz, J2,4
0.6 Hz), 6.14 d (1H, H-22, J22,23 15.4 Hz), 6.19 d (1H,
H-17, J17,18 10 Hz), 6.21 s (1H, H-20), 6.27 s (1H,
H-21), 6.32 s (1H, H-19), 6.40 d (1H, H-3, J3,4
7.5 Hz), 6.47 s (1H, H-18), 7.03 d (1H, PH, JPH
555 Hz), 7.53 d (2H, phenyl, J 8.2 Hz), 8.24 d (2H,
phenyl, J 8.2 Hz). 13C NMR spectrum, C, ppm: 17.91
(C-6 ), 21.35 (C-26), 28.14 d (C H P, JCP 132.1 Hz),
40.23 (C-6), 42.98 (C-10), 43.46 (C-14), 44.99 (C-24),
48.12 (C-8), 57.24 (C-4), 57.16 (C-3 ), 61.02 (C-5),
61.81 (C-12), 66.48 (C-5 ), 68.73 (C-13), 69.05
(C-11), 69.53 (C-7), 72.61 (C-25), 73.40 (C-2 ), 75.36
(C-4 ), 75.76 (C-5), 81.03 (C-15), 100.14 (C-9),
101.53 (C-1 ), 126.73 (C-2), 114.12 (phenyl), 127.85
(phenyl), 133.07 (phenyl), 147.62 (phenyl), 131.41
(C-16), 133.76 (C-17), 134.22 (C-18), 134.93 (C-19),
135.64 (C-20), 136.02 (C-21), 136.87 (C-22), 138.90
(C-23), 144.08 (C-3), 168.15 (C-1), 178.89 (C-27).
phenyl, J 8.2 Hz). 13C NMR spectrum, C, ppm: 17.16
(C-6 ), 21.34 (C-26), 26.81 d (C H P, JCP 132.7 Hz),
41.32 (C-6), 42.99 (C-10), 43.22 (C-14), 45.14 (C-24),
47.63 (C-8), 57.06 (C-4), 57.74 (C-3 ), 60.84 (C-5),
61.50 (C-12), 66.04 (C-5 ), 68.85 (C-13), 69.41
(C-11), 70.23 (C-7), 71.46 (C-25), 73.69 (C-2 ), 74.76
(C-4 ), 76.03 (C-5), 81.11 (C-15), 100.30 (C-9),
101.64 (C-1 ), 126.07 (C-2), 123.81 (phenyl), 127.85
(phenyl), 145.92 (phenyl), 149.68 (phenyl), 131.98
(C-16), 133.86 (C-17), 134.71 (C-18), 135.09 (C-19),
31P NMR spectrum, P, ppm: 15.42.
N-[( -Hydrophosphoryl-4-fluorobenzyl)]
pimaricin (V). Yield 75%, mp 172 177 C (decomp.),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

SYNTHESIS OF HYDROPHOSPOHORYL DERIVATIVES
309
Rf 0.57. 1H NMR spectrum (MeOH-d4), , ppm:
1.10 d (1H, H-6eq, J6eq,7 11.0 Hz), 1.20 d.d (1H,
H-10ax, J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.23 s
(3H, H-6 CH3), 1,29 s (3H, 26-CH3), 1.60 d (1H,
H-8ax, J8ax,8eq 14.2 Hz), 1.64 d.d (1H, H-14ax,
J14ax,14eq 14.0 Hz, J14eq,15 2.0 Hz), 1.71 s (1H, H-8eq),
1.91 d (1H, H-10eq, J10eq,11 4.8 Hz), 1.97 t (1H, H-12,
J12,13 10.5 Hz), 2.09 d.d (1H, H-6ax, J6ax,6eq 14.4 Hz,
J6ax,7 0.9 Hz), 2.31 d.d (1H, H-24ax, J24ax,24eq
13.5 Hz, J24ax,25 11.0 Hz), 2.35 d (1H, H-14eq, J14eq,15
3.5 Hz), 2.42 d (1H, H-24eq, J24eq,25 5.6 Hz),
2.95 d.d (1H, H-5, J5,6ax 1.8 Hz, J5,6eq 8.3 Hz), 3.18 d
(1H, H-4, J4,5 1.5 Hz), 3.23 d (1H, H-3 , J3 ,4 9.0 Hz,
H-3 ), 3.30 d (1H, H-5, J5 ,6 Me 6.5 Hz), 3.42 d (1H,
H-4 , J4 ,5 9.0 Hz), 4.11 d (1H, H-2 , J2 ,3 3.5 Hz),
4.19 m (1H, CHP, H-1 ), 4.23 d (1H, H-11, J11,12
10.5 Hz), 4.31 d.d (1H, H-7, J7,8ax 1.3 Hz, J7,8eq
10.2 Hz), 4.37 d.d (1H, H-13, J13,14ax 8.4 Hz, J13,14eq
1.2 Hz), 4.41 d (1H, H-15, J15,16 8.3 Hz), 4.69 d (1H,
H-1 , J1 ,2 1.0 Hz), 4.81 d (1H, H-25, J25,26-Me 6.5 Hz),
5.50 d.d (1H, H-23, J23,24ax 8.8 Hz, J23,24eq 2.5 Hz),
5.99 d (1H, H-16, J16,17 15.2 Hz,), 6.12 d.d (1H, H-2,
J2,3 15.8 Hz, J2,4 0.6 Hz), 6.19 d (1H, H-22, J22,23
15.4 Hz), 6.27 d (1H, H-17, J17,18 10 Hz), 6.33 s (1H,
H-20), 6.38 s (1H, H-21), 6.31 s (1H, H-19), 6.47 d
(1H, H-3, J3,4 7.5 Hz), 6.70 s (1H, H-18), 7.03 d (1H,
PH, JPH 553 Hz), 6.92 d (2H, phenyl, J 8.2 Hz),
J14ax,14eq 14.0 Hz, J14eq,15 2.0 Hz), 1.69 s (1H, H-8eq),
1.98 d (1H, H-10eq, J10eq,11 4.8 Hz,), 2.04 t (1H,
H-12, J12,13 10.5 Hz), 2.09 d.d (1H, H-6ax, J6ax,6eq
14.4 Hz, J6ax,7 0.9 Hz), 2.18 d.d (1H, H-24ax,
J24ax,24eq 13.5 Hz, J24ax,25 11.0 Hz), 2.24 d (1H,
H-14eq, J14eq,15 3.5 Hz), 2.43 d (1H, H-24eq, J24eq,25
5.6 Hz), 2.71 d.d (1H, H-5, J5,6ax 1.8 Hz, J5,6eq
8.3 Hz), 3.25 d (1H, H-4, J4,5 1.5 Hz), 3.36 d (1H,
H-3 , J3 ,4 9.0 Hz), 3.38 d (1H, H-5 , J5 ,6 Me 6.5 Hz),
3.46 d (1H, H-4 , J4 ,5 9.0 Hz), 3.87 d (1H, H-2 , J2 ,3
3.5 Hz), 4.11 m (1H, H-1 , CHP), 4.29 d (1H, H-11,
J11,12 10.5 Hz), 4.32 d.d (1H, H-7, J7,8ax 1.3 Hz, J7,8eq
10.2 Hz), 4.39 d.d (1H, H-13, J13,14ax 8.4 Hz, J13,14eq
1.2 Hz), 4.43 d (1H, H-15, J15,16 8.3 Hz), 4.57 d (1H,
H-1 , J1 ,2 1.0 Hz), 4.71 d (1H, H-25, J25,26-Me 6.5 Hz),
5.43 d.d (1H, H-23, J23,24ax 8.8 Hz, J23,24eq 2.5 Hz),
5.90 d (1H, H-16, J16,17 15.2 Hz), 6.02 d.d (1H, H-2,
J2,3 15.8 Hz, J2,4 0.6 Hz), 6.11 d (1H, H-22, J22,23
15.4 Hz), 6.16 d (1H, H-17, J17,18 10 Hz), 6.19 s (1H,
H-20), 6.22 s (1H, H-21), 6.31 s (1H, H-19), 6.39 d
(1H, H-3, J3,4 7.5 Hz), 6.46 s (1H, H-18), 6.93 d (1H,
PH, JPH 559 Hz), 7.05 d (2H, phenyl, J 8.2 Hz), 7.48
d (2H, phenyl, J 8.2 Hz). 13C NMR spectrum,
,
ppm: 18.09 (C-6 ), 20.74 (C-26), 27.68 d (C H P, JCCP
134.3 Hz), 41.65 (C-6), 42.49 (C-10), 43.22 (C-14),
44.31 (C-24), 47.63 (C-8), 56.08 (C-4), 57.35 (C-3 ),
60.09 (C-5), 61.53 (C-12), 66.14 (C-5 ), 68.58 (C-13),
69.03 (C-11), 69.77 (C-7), 72.12 (C-25), 73.61 (C-2 ),
74.30 (C-4 ), 75.68 (C-5), 81.05 (C-15), 99.39 (C-9),
100.42 (C-1 ), 125.98 (C-2), 120.93 (phenyl), 128.57
(phenyl), 132.36 (phenyl), 141.61 (phenyl), 130.34
(C-16), 133.24 (C-17), 133.49 (C-18), 134.12 (C-19),
134.77 (C-20), 134.94 (C-21), 135.62 (C-22), 137.71
(C-23), 145.36 (C-3), 168.14 (C-1), 178.07 (C-27).
7.10 d (2H, phenyl, J 8.2 Hz). 13C NMR spectrum,
C, ppm: 18.09 (C-6 ), 20.44 (C-26), 27.12 d (C H P,
JCP 134.0 Hz), 41.23 (C-6), 42.54 (C-10), 43.33
(C-14), 44.78 (C-24), 47.50 (C-8), 57.08 (C-4), 57.36
(C-3 ), 60.49 (C-5), 61.71 (C-12), 66.23 (C-5 ), 68.55
(C-13), 68.98 (C-11), 69.32 (C-7), 71.45 (C-25),
73.11 (C-2 ), 74.50 (C-4 ), 75.67 (C-5), 82.03 (C-15),
99.49 (C-9), 100.12 (C-1 ), 125.96 (C-2), 115.38
(phenyl), 128.50 (phenyl), 139.14 (phenyl), 160.92
(phenyl), 131.08 (C-16), 132.90 (C-17), 133.67
(C-18), 133.94 (C-19), 134.57 (C-20), 134.97 (C-21),
135.24 (C-22), 137.83 (C-23), 144.17 (C-3), 166.80
31P NMR spectrum, P, ppm: 15.46.
N-[( -Hydrophosphoryl-4-bromobenzyl)]pi-
maricin (VII). Yield 70%, mp 190 195 C (decomp.),
1
0.44. H NMR spectrum (MeOH-d4), , ppm: 1.18 d
(C-1), 177.61 (C-27). 31P NMR spectrum, P, ppm:
15.43.
(1H, H-6eq, J6eq,7 11.0 Hz), 1.25 d.d (1H, H-10ax,
J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.27 s (3H,
H-6 CH3), 1.32 s (3H, 26-CH3), 1.51 d (1H, H-8ax,
J8ax,8eq 14.2 Hz), 1.55 d.d (1H, H-14ax, J14ax,14eq
14.0 Hz, J14eq,15 2.0 Hz), 1.63 s (1H, H-8eq), 1.91 d
(1H, H-10eq, J10eq,11 4.8 Hz), 1.94 t (1H, H-12, J12,13
10.5 Hz), 2.02 d.d (1H, H-6ax, J6ax,6eq 14.4 Hz, J6ax,7
0.9 Hz), 2.17 d.d (1H, H-24ax, J24ax,24eq 13.5 Hz,
J24ax,25 11.0 Hz), 2.23 d (1H, H-14eq, J14eq,15 3.5 Hz),
N-[( -Hydrophosphoryl-4-chlorobenzyl)]pi-
maricin (VI). Yield 70%, mp 183 188 C (decomp.),
Rf 0.53. 1H NMR spectrum (MeOH-d4), , ppm:
1.13 d (1H, H-6eq, J6eq,7 11.0 Hz), 1.20 d.d (1H,
H-10ax, J10ax,11 11.2 Hz, J10ax,10eq 12.4 Hz), 1.25 s
(3H, H-6 CH3), 1.28 s (3H, 26-CH3), 1.59 d (1H,
H-8ax, J8ax, 8eq 14.2 Hz), 1.62 d.d (1H, H-14ax,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

310
BELAKHOV et al.
2.32 d (1H, H-24eq, J24eq,25 5.6 Hz), 2.58 d.d (1H,
H-5, J5,6ax 1.8 Hz, J5,6eq 8.3 Hz), 3.04 d (1H, H-4, J4,5
1.5 Hz), 3.11 d (1H, H-3 , J3 ,4 9.0 Hz), 3.22 d (1H,
H-5 , J5 ,6 Me 6.5 Hz), 3.30 d (1H, H-4 , J4 ,5 9.0 Hz),
3.91 d (1H, H-2 , J2 ,3 3.5 Hz), 4.02 m (1H, CHP,
H-1 ), 4.20 d (1H, H-11, J11,12 10.5 Hz), 4.24 d.d (1H,
H-7, J7,8ax 1.3 Hz, J7,8eq 10.2 Hz), 4.31 d.d (1H, H-13,
J13,14ax 8.4 Hz, J13,14eq 1.2 Hz), 4.37 d (1H, H-15,
J15,16 8.3 Hz), 4.47 d (1H, H-1 , J1 ,2 1.0 Hz), 4.61 d
(1H, H-25, J25,26-Me 6.5 Hz), 5.49 d.d (1H, H-23,
J23,24ax 8.8 Hz, J23,24eq 2.5 Hz), 5.89 d (1H, H-16,
J16,17 15.2 Hz), 6.00 d.d (1H, H-2, J2,3 15.8 Hz, J2,4
0.6 Hz), 6.06 d (1H, H-22, J22,23 15.4 Hz), 6.13 d (1H,
H-17, J17,18 10 Hz), 6.17 s (1H, H-20), 6.19 s (1H,
H-21), 6.24 s (1H, H-19), 6.32 d (1H, H-3, J3,4
7.5 Hz), 6.40 s (1H, H-18), 6.91 d (1H, PH, JPH
552 Hz), 7.01 d (2H, phenyl, J 8.2 Hz), 7.38 d (2H,
The results of pharmacological testing showed that
the acute toxicity of pimaricin hydrophosphoryl
derivatives I VII is half that of a reference antibiotic
[72, 73], their LD50 value varied from 257 to
1
274 mg kg .
Biological investigations showed that derivatives
III and V VII display a high antifungal activity
toward yeast-like fungi of the genus Candida
(C. albicans, C. utilis, C. tropicalis, C. krusei, C.
1
parapsilosis) (MFC 0.07 0.15 mkg ml ), while
compounds I, I, and IV are much less effective (MFC
1
12.5 25.0 mkg ml ) as compared with pimaricin anti-
1
fungal action (MFC 0.15 0.25 mkg ml ) The pi-
maricin derivatives V VII activity is practically the
1
same (MFC 3.0 12.0 mkg ml ) as that of a reference
1
antibiotic (MFC 3.12 12.5 mkg ml ) toward patho-
gens of mold mycosis (Penicillium granulatum),
aspergillosis (Aspergillus fumigatus, Aspergillus
flavus) and blastomycosis (Blastomyces dermatitidis).
Among the studied compounds, only derivatives VI
and VII revealed antifungal activity on the same level
phenyl, J 8.2 Hz). 13C NMR spectrum, C, ppm: 18.19
(C-6 ), 20.72 (C-26), 28.11 d (C H P, JCP 133.0 Hz),
41.39 (C-6), 42.35 (C-10), 43.30 (C-14), 44.67 (C-24),
47.59 (C-8), 56.07 (C-4), 57.62 (C-3 ), 60.58 (C-5),
61.46 (C-12), 66.27 (C-5 ), 68.48 (C-13), 68.99
(C-11), 69.53 (C-7), 71.85 (C-25), 73.26 (C-2 ), 74.33
(C-4 ), 75.59 (C-5), 81.06 (C-15), 99.38 (C-9), 100.45
(C-1 ), 126.09 (C-2), 121.16 (phenyl), 129.14 (phenyl),
131.42 (phenyl), 142.56 (phenyl), 130.48 (C-16),
133.39 (C-17), 133.92 (C-18), 134.21 (C-19), 134.68
(C-20), 134.92 (C-21), 135.25 (C-22), 137.73 (C-23),
1
as pimaricin (MFC 1.25 3.15 mkg ml ) toward tri-
chophytosis pathogens (Trichophyton violaceum,
Trichophyton tonsurans); the other derivatives dis-
played a lower activity toward these test cultures. The
low sensitivity to pimaricin derivatives I VII (MFC
1
12.5 25.0 mkg ml ) displayed chromomycosis
(Cladosporum carrionii), sporotrichosis (Sporotri-
chum
schenkii),
histoplasmosis
(Histoplasma
capsulatum), and phycomycosis (Rhizopus nigricans,
Mucor mucedo). The most active were pimaricin
derivatives V VII that contain halogen atoms in the
para position of the phenyl ring.
144.97 (C-3), 168.06 (C-1), 177.87 (C-27). 31P NMR
spectrum, P, ppm: 15.42.
Biological investigations. Pimaricin was used as
reference preparation throughout all medical biolo-
gical testing.
Thus, under the Kabachnik Fields reaction condi-
tions we prepared hydrophosphoryl derivatives of the
antifungal tetraene antibiotic pimaricin, which ex-
hibited a lower toxicity and a high antifungal activity.
The studied reactions can be considered as a general
method for chemical modification of polyene macro-
lide antibiotics via phosphorylation, which opens up
the way to derivatives with improved medical
biological properties.
Acute toxicity (LD50) of pimaricin hydrophos-
phoryl derivatives I VII was studied on outbred male
white mice (weight 18 20 g). The studied compounds
were diluted with 0.5% aqueous carboxymethylcellu-
lose and tested as suspensions injected intraperito-
neally. The LD50 values were calculated by the
Kerber method from testing results.
REFERENCES
The antifungal activity of derivatives I VII toward
pathogens of various mycosis infections was deter-
mined by the method of serial dilutions in liquid
culture media. The method is based on consecutive
twice dilution of studied compounds. The minimal
fungistatic concentration (MFC) was determined from
the results of visual estimation of the intensity of a
test culture growing in tested and reference tubes,
obtained in three runs.
1. Omura, S. and Tanaka, H., Macrolide Antibiotics:
Chemistry, Biology and Practice, Omura, S., Ed.,
New York: Academic, 1984, p. 351.
2. Bader, G., Deicke, P., Gedek, B., Gemeihardt, H.,
Muller, J., Sholer, H., Spitzbart, H., and Wiesner, B.,
Endomykosen: Schleimhaut Organ- and Systemmyko-
sen Herausgegeben von Horst Gemeinhardt, Berlin:
Gustvtischer, 1989.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

SYNTHESIS OF HYDROPHOSPOHORYL DERIVATIVES
311
3. Antifungal Drug Therapy (A Complete Guide for the
Practitioner), Jacobs, P.H. and Nall, L., Eds., New
York: Dekker, 1990.
24. Bernardo, J.F., Sabra, R., and Branch, R.A., Clinical
Nephrotoxins, De Broe, M.E., Ed., Dordrecht: Kluwer
Academic, 2003, p. 199.
4. Recent Progress in Antifungal Chemotherapy,
Yamaguchi, H., Kobayashi, G.S., and Takahashi, H.,
Eds., New York: Dekker, 1992.
25. Wingard, J.R. and Leather, H., Biol. Blood Marrow
Transplant., 2004, vol. 10, p. 73.
26. Thomas, A.H., Analyst, 1976, vol. 101, no. 1202,
5. Shneider, M.A., in: Uspekhi v oblasti izucheniya i
proizvodstva antibiotikov (Advances in Studying and
Manufacturing antibiotics), Moscow: 1979, p. 56.
p. 321.
27. Shenin, Yu.D., Belakhov, V.V., Gagarina, A.B., Ka-
saikina, O.T., and Vainshtein, V.A., Polienovye
makrolidnye antibiotiki: inaktivatsiya i sposoby ikh
stabilizatsii (Polyene Macrolide Antibiotics: Inactiva-
tion and Methods of Stabilization), Review Informa-
tion, serried Remedies, Economics, Technology, and
Perspectives of Producing, Moscow: VNIISENTI,
1990, no. 12.
6. Shneider, M.A., Shtil’bans, E.B., Rachkovskaya, L.A.,
and Poltorak, V.A., Antibiotiki, 1983, vol. 28, no. 5,
p. 352.
7. Shneider, M.A., Molek. Genet., Mikrobiol. Virusol.,
1984, no. 5, p. 41.
8. Shneider, M.A and Chizhov, N.P., Vopr. Virusol.,
1986, vol. 31, no. 1, p. 18.
28. Shenin, Yu.D., Belakhov, V.V., Koptelova, T.N., Le-
vina, A.A., and Shchinova, N.E., Antibiot. Khimiot.,
1991, vol. 36, no. 8, p. 20.
9. Ouellette, M., Drummelsmith, J., and Papado-
poulou, B., Drug Resist. Updates, 2004, vol. 7,
nos. 4 5, p. 257.
29. Lamy-Freund, M.T., Ferreira, V.F. and Schreier, S.,
10. Goldsmith, D.R. and Perry, C.M., Drugs, 2004,
J. Antibiot., 1985, vol. 38, no. 6, p. 753.
vol. 64, no. 17, p. 1905.
30. Belakhov, V.V., Shenin, Yu.D., Nifant’ev, E.E., Ku-
khareva, T.S., and Soldatova, I.A., Antibiot. Khimio-
ter., 1997, vol. 42, no. 12, p. 6.
11. Golenser, J. and Domb, A., Mini-Review Med. Chem.,
2006, vol. 6, no. 2, p. 153.
12. Vertut-Croquin A., Brajtburg J., and Medoff, G.,
31. Belousova, I.I., Antibiotiki, 1976, vol. 21, no. 7,
Cancer Res., 1986, vol. 46, no. 12, p. 6054.
p. 661.
13. Coune, A., Eur. J. Cancer Clin. Oncol., 1988, vol. 24,
32. Kaufman, C.H. and Carver, P.L., Drugs, 1997, vol. 53,
no. 2, p. 117.
no. 4, p. 539.
14. Feigin, A.M., Med. Hypotheses., 1999, vol. 52, no. 5,
33. Bossche, H.V., Dromer, F., Improvisi, I., Lozano-
Chiu, M., Rex, J.H., and Sanglard, D., Med. Mycol.,
1998, vol. 36, no. 1, p. 119.
p. 383.
15. Kirkpatrick, C.H., AIDS: Anti-HIV Agents, Therapies
and Vaccines (Annals of New York Academy of
Sciences), Georgiev, V.S. and McGowan, J.J., Eds.,
New York, 1990, vol. 616, p. 461.
34. Stevens, D.A. and Holmberg, K., Curr. Opin. Anti-
Infect. Invest. Drugs, 1999, vol. 1, no. 3, p. 306.
35. Brik, H., in: Analytical Profiles of Drug Substances,
16. Vyadro, M.M., Antibiot. Khimioter., 1991, vol. 36,
New York: Academic, 1981, vol. 10, p. 513.
no. 11, p. 45.
36. Zotchev, S.B., Curr. Med. Chem., 2003, vol. 10,
17. Ablordeppey, S.Y., Fan, P., Ablordeppey, J.H., and
Mardenborough, L., Curr. Med. Chem., 1999, vol. 6,
no. 12, p. 1151.
no. 3, p. 221.
37. Schafner, C.P. and Mechlinski, W., J. Antibiot., 1972,
vol. 25, no. 4, p. 259.
18. Hood, S. and Denning, D.W., J. Antimicrob.
Chemother., 1996, vol. 37, suppl. B, p. 71.
38. Falkowski, L., Stefanska, B., Bylec, E., Golik, J.,
Kolodziejczyk, P., and Borowski, E., J. Antibiot.,
1979, vol. 32, no. 10, p. 1080.
19. Gallis, H.A. and Drew, R.H., Rev. Infect. Dis., 1990,
vol. 12, no. 2, p. 308.
39. Falkowski, L., Stefanska, B., Zielinski, J., Bylec, E.,
Golik, J., and Kolodziejczyk, P., Acta Polon. Pharm.,
1980, vol. 37, no. 6, p. 631.
20. Georgopapadakou, N.H. and Walsh, T.J., Antimicrob.
Agents Chemother., 1996, vol. 40, no. 2, p. 279.
21. Grillot, R. and Lebeau, B., Antimicrobial Agents,
Bryskier, A., Ed., Washington: Publ. Am. Soc.
Microbiol., 2005, p. 1260.
40. Pol. Patent 120035, Chem. Abstr., 1983, vol. 101,
no. 38277.
41. Pol. Patent 120111, Chem. Abstr., 1983, vol. 101,
22. Fanos, V. and Cataldi, L., J. Chemother., 2000,
G6940.
vol. 12, no. 6, p. 463.
42. Nirgudkar, A.G., Sastry, M.K., Swami, M.B., and
Nanda, R.K., Hind. Antibiot. Bull., 1988, vol. 30,
nos. 3 4, p. 66.
23. Deray, G., J. Antimicrob. Chemother., 2002, vol. 49,
suppl. S1, p. 37.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

312
BELAKHOV et al.
43. Falkowski, L., Zielinski, J., Pawlak, J., Golik, J.,
Kolodziejczyk, P., Stefanska, B., Bylec, E., and
Borowski, E., Acta Polon. Pharm., 1980, vol. 37,
no. 5, p. 517.
58. Shenin, Yu.D., Belakhov, V.V., and Araviiskii, R.A.,
Khim.-Farm. Zh., 1998, vol. 32, no. 2, p. 52.
59. Shenin, Yu.D. and Belakhov, V.V., Proc. XVI Mende-
leev Congress on General and Applied Chemistry,
Moscow, 1998, vol. 4, p. 111.
44. Stefanska, B., Borowski, E., and Falkowski, L., Acta
Polon. Pharm., 1988, vol. 45, no. 1, p. 71.
60. Shenin, Yu.D., Belakhov, V.V., Shatik, L.I.,
and Araviiskii, R.A., Antibiot. Khimioter., 1998,
vol. 43, no. 12, p. 8.
45. DE Patent 3013631, Chem. Abstr., 1981, vol. 94,
p. 121884.
46. Swami, M.B., Sastry, M.K., Nirgudkar, A.G., and
Nanda, R.K., Hind. Antibiot. Bull., 1983, vol. 25,
nos. 3 4, p. 101.
61. Shenin, Yu.D. and Belakhov, V.V., Trudy mezhduna-
rodnoi nauchno-prakticheskoi konferentsii, pos-
vyaschennoi 85-letiyu Sankt-Peterburgskoi gosudar-
stvennoi khimiko-farmatsevticheskoi akademii (Proc.
Int. Scientific and Practical Conf. Devoted to 85th
Anniversary of St. Peterburg State Chem.-Pharm.
Academy), St. Petersburg: SPGKhFA, 2004, p. 151.
47. Paquet, V. and Carreira, E.M., Org. Lett., 2006, vol. 8,
no. 9, p. 1807.
48. US Patent 3957754, Chem. Abstr., 1976, vol. 85,
p. 25414.
62. Belakhov, V.V. and Shenin, Yu.D., Khim.-Farm. Zh.,
49. Belg. Patent 877661, Chem. Abstr., 1980, vol. 93,
2007, vol. 41, no. 6, p. 26.
p. 13076.
63. Belakhov, V.V. and Shenin, Yu.D., Khim.-Farm. Zh.,
50. Sulloff, E.C., Marcy, J.E., Hackney, C.R., Sum-
ner, S.S., and Bishop, J.R., J. Food Protect., 2003,
vol. 66, no. 8, p. 1499.
2007, vol. 41, no. 7, p. 20.
64. Kabachnik M.I. and Medved’, T.Ya., Dokl. Akad.
Nauk SSSR, 1952, vol. 83, no. 3, p. 689.
51. Shenin, Yu.D. and Belakhov, V.V., Khimiya polieno-
vykh makrolidnykh antibiotikov (Chemistry of
Polyene Macrolide Antibiotics), Review Information,
series Remedies, Economics, Technology, and
Perspectives of Production, Moscow: VNIISENTI,
65. Fields, E.K., J. Am. Chem. Soc., 1952, vol. 74,
p. 1528.
66. Nifant’ev, E.E., Khimiya gidrofosforil’nykh soedinenii
(Chemistry of Hydrophosphoryl Compounds),
Moscow: Nauka, 1983.
1989,
no.
6.
52. Belakhov, V.V., Levina, A.A., Shenin, Yu.D.,
Ionin, B.I., Shatik, L.I., Zaitseva, M.B., Grin-
berg, G.E., Shtil’bans, E.B., and Rachkovskaya, L.A.,
Antibiot. Khimioter., 1990, vol. 35, no. 8, p. 31.
67. Cherkasov, R.A. and Galkin, V.I., Usp. Khim., 1998,
vol. 67, no. 10, p. 940.
68. Yudelevich, V.I., Sokolov, L.B., and Ionin, B.I., Usp.
Khim., 1980, vol. 49, no. 1, p. 92.
53. Belakhov, V.V., Levina, A.A., Shenin, Yu.D., and
Ionin, B.I., Khim.-Farm. Zh., 1991, vol. 25, no. 3,
p. 86.
69. Ionin, B.I., Ershov, B.A., and Kol’tsov, A.M., YaMR-
spektroskopiya v organicheskoi khimii (NMR Spec-
troscopy in Organic Chemistry), Leningrad: Khimiya,
1983.
54. Belakhov, V.V., Levina, A.A., Shenin, Yu.D.,
Ionin, B.I., Grinberg, G.E., Shatik, L.I., Shtil’-
bans, E.B., and Rachkovskaya, L.A., Khim.-Farm. Zh.,
1991, vol. 25, no. 11, p. 45.
70. Belakhov, V.V., Yudelevich, V.I., Ionin, B.I., Ko-
marov, E.V., and Petrov, A.A., Zh. Obshch. Khim.,
1988, vol. 58, no. 6, p. 1193.
55. Shenin, Yu.D., Belakhov, V.V., and Araviiskii, R.A.,
71. Armarego, W.L.F. and Chai, C., Purification of
Khim.-Farm. Zh., 1993, vol. 27, no. 2, p. 14.
Laboratory
Chemicals,
Oxford:
Butterworth
Heinemann, 2003.
56. Belakhov, V.V., Shenin, Yu.D., Araviiskii, R.A., and
Shtil’bans, E.B., Antibiot. Khimioter., 1996, vol. 41,
no. 7/8, p. 4.
72. Barr, F.S., Antibiot. Chemother., 1959, vol. 9, p. 406.
73. Levinskas, G.J., Ribelin, W.E., and Shaffer, C.B.,
Toxicol. Applied Pharmacol., 1966, vol. 8, no. 1,
p. 97.
57. Shenin, Yu.D. and Belakhov, V.V., Antibiot. Khimio-
ter., 1997, vol. 42, no. 4, p. 34.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008