Synthesis of α-hydroxy(polyprenyl) bisphosphonates

Article abstract of DOI:10.1134/S1070363214040082

Bisphosphonates derived from natural terpenes were synthesized by phosphonylation of corresponding aldehydes. The general strategy of introduction of the phosphonate groups into the polyprenol molecule involves successive treatment of a hydroxyl compound by Swern reagent to oxidize the C-OH group into C=O and a (EtO)₃P/[PyH]⁺ClO _- ⁴ mixture to phosphylate the resulting carbonyl compound.

Full text of DOI:10.1134/S1070363214040082

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 4, pp. 647–653. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © O.O. Kolodyazhnaya, O.I. Kolodyazhnyi, R.A. Cherkasov, A.R. Garifzyanov, N.V. Davletshina, S.A. Koshkin, 2014, published in
Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 4, pp. 567–573.
Synthesis of α-Hydroxy(polyprenyl) Bisphosphonates
a
a
b
O. O. Kolodyazhnaya , O. I. Kolodyazhnyi , R. A. Cherkasov ,
b
b
b
A. R. Garifzyanov , N. V. Davletshina , and S. A. Koshkin
a
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Unkraine
e-mail: olegkol321@rambler.ru
b
Kazan Federal University, Kazan, Tatarstan, Russia
e-mail: rafael.cherkasov@ksu.ru
Received January 9, 2014
Abstract―Bisphosphonates derived from natural terpenes were synthesized by phosphonylation of
corresponding aldehydes. The general strategy of introduction of the phosphonate groups into the polyprenol
molecule involves successive treatment of a hydroxyl compound by Swern reagent to oxidize the С–ОН group
+
–
4
into С=О and a (EtO)
3
P/[PyH] ClO
mixture to phosphylate the resulting carbonyl compound.
Keywords: phosphonylation, pyridinium perchlorate, bisphosphonates, hydrophosphonates, terpene derivatives
DOI: 10.1134/S1070363214040082
Certain lipophilic phosphorus-containing com-
pounds are used polyfunctional liquid extractants and
membrane carriers for rare and trace metals, as well as
mineral, amino, and hydroxycarboxylic acids. It was
found that the extractants having additional coordina-
tion centers, specifically, amino, hydroxy, carboxy, or
other functional groups, exhibit enhanced extractive
power and selectivity [1]. Aimed at developing new
potential membrane and liquid extractants for
substrates of various nature, we synthesized bisphos-
phonate derivatives of terpenes. According to our
previously described procedure [2], we took natural
polyprenols, and oxidized them to aldehydes, and the
latter were first phosphonylated by treatment with di-
ethyl phosphite and then converted into the target hyd-
roxybisphosphonates via α-ketophosphonates (Scheme 1).
The general strategy of the proposed strategy of
introduction of phosphonate groups into the polyprenol
molecule involved treatment of a hydroxyl compound
by Swern reagent to oxidize the С–ОН group into
С=О. The carbonyl-containing intermediate was
+
–
4
further treated with (EtO)
P/[PyH] ClO
to form
3
hydroxybisphosphonate (Scheme 2).
Scheme 1.
R
R
R
HO
P(O)(OR)2
P(O)(OR)2
HO
P(O)(OR)2
HO
H
H
H
R = polyprenyl.
Scheme 2.
R
R
R
R
R
a
a
b
b
HO
H
O
H
HO
O
RP
HO
RP
RP
H
H
RP
+
−
R = polyprenyl; R = (EtO) P(O); a, Me SO, (COCl) , Et N; b, (EtO) P/[PyH] ClO .
P
2
2
2
3
3
4
6
47

6
48
KOLODYAZHNAYA et al.
Scheme 3.
(
COCl) , Me SO
2
2
OH
OH
Et N
O
3
I
O
(
EtO) P/[PyH]ClO4
(COCl) , Me SO
2 2
3
P(O)(OEt)2
Et N
3
P(O)(OEt)2
II
III
OH
(
EtO) P/[PyH]ClO4
3
P(O)(OEt)2
P(O)(OEt)2
IV
1
The oxidation of unsaturated popyprenols and also
hydroxyprenyl)phosphonates with Swern reagent [3,
] proved to be quite a suitable approach in our case,
shows a doublet at 200 ppm ( J 150 Hz) from the
CP
1
3
(
4
carbon atom of the α-keto group. The С NMR
spectrum of bisphosphonate IV contains a triplet at
60 ppm ( J 130 Hz) from the carbon atom linked to
1
because the reaction proceeded exclusively by the
hydroxy group not involving the С=С bond, which was
the case with other oxidants. As a result, we could
obtain high yield of α-ketophosphonates which were
converted into (α-hydroxyisoprenyl)bisphosphonates at
the next stage. Reagent b reacts with carbonyl
compounds to form hydroxyphosphonates in high
yields. This reaction with aldehydes readily occurs in
methylene chloride or without solvents at temperatures
below 0°С and gives rise to corresponding hydroxy-
phosphonates in nearly quantitative yields. This
reagent also readily reacts with α-ketophosphonates.
Thus natural geraniol was oxidized Swern oxidation to
obtain high yield of geranial (I) which was treated with
reagent b to form hydroxyphosphonate II in 80%
yield. Vacuum distillation gave compound II as a
stable colorless oil with a pleasant flower odor. By
Swern oxidation the product was converted into α-
ketophosphonate III (Scheme 3).
CP
two phosphorus atoms.
In a similar way, starting with (+)-(R)-cintronellal
we obtained a chiral bisphosphonate VIII. Citronellal
was reacted with reagent b to obtain hydroxy-
phosphonate VI in quantitative yield. The product was
isolated pure by vacuum distillation and oxidized by
treatment with Swern reagent to a chiral ketophos-
phonate VII in 70% yield. The signal at –1.96 ppm in
the Р NMR spectrum of compound VII is charac-
teristic of α-ketophosphonates. At the final stage,
ketophosphonate VII was treated with triethyl phos-
phite in the presence of pyridinium perchlorate in
methylene chloride for 24 h at room temperature to
obtain a bisphosphonate VIII in high yield. The
product was purified by column chromatography on
3
1
1
silica gel. The Н NMR spectrum of this compound
contains proton signals of ethoxy methyl groups at
.59 and 1.66 ppm, as well as a triplet at 5.1 ppm ( J
Hz) from the of the С=СН proton of the 3,7-
3
1
7
НН
Compound III was purified by vacuum distillation
and isolated as a colorless liquid stable on storage;
however, on contact with atmospheric air it
dimethyloct-6-ene fragment (Scheme 4).
1
31
immediately hydrolyzed to form, according to Н and
The Р NMR spectrum of hydroxyphosphonate VI,
3
1
Р NMR spectra, diethyl phosphite, geranial, and
which contains two chiral centers on the α- and γ-
carbon atoms shows signals at 26.50 and 26.54 ppm
(1 : 1) corresponding to the (S,R)- and (S,S)-dia-
stereomers of this compound. The two phosphono
groups in bisphosphonate VIII containing a chiral
center on the γ-carbon atom have different magnetic
environments, and, therefore, are diasterotopic, and
unknown products. At the final stage, α-keto-
phosphonate was phosphonylated by the same reagent
b to obtain hydroxybisphosphonate IV which was
purified by column chromatography on silica gel. The
structure of products III and IV was established by
NMR spectroscopy. Thus the δ of compound III is
P
3
1
–
2 ppm, which is characteristic of α-ketophosphonates
they are represented in the Р NMR spectrum by two
1
3
of the similar structure, and the С NMR spectrum
signals at 20.55 and 20.65 ppm.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014

SYNTHESIS OF α-HYDROXY(POLYPRENYL) BISPHOSPHONATES
649
Scheme 4.
P(O)(OR)2
(
RO) P/[PyH]ClO4
3
O
OH
*
*
V
(S,R+S,S)-VI
P(O)(OR)2
P(O)(OR)2
O
(
COCl) /Me SO
(RO) P/[PyH]ClO4
2
2
3
*
P(O)(OR)2
OH
*
VII
VIII
R = Et.
Scheme 5.
Me SO + (COCl)2
2
OH
Et N
3
O
IX
OH
(
EtO) P/[PyH]ClO4
Me SO + (COCl)2
2
3
Et N
P(O)(OEt)2
3
X
O
OH
(
EtO) P/[PyH]ClO4
3
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
XI
XII
The synthetic strategy described here was also used
to phosphonylate the natural sesquiterpene farnesol.
The latter was subjected to Swern oxidation to obtain
farnesal IX. By treatment with reagent b the latter
aldehyde was converted into hydroxyphosphonate X
which was purified by vacuum distillation. In view of
the fact that the starting farnesol was isolated from
natural sources as a mixture of the cis and trans
isomers, hydroxyphosphonate X, too, was a mixture of
the cis and trans isomers. Ketophosphonate XI is an
analog of prenylpyrophosphates which are biologically
important compounds [5–7]. Prenylbisphosphonates
III, VI, and XII were synthesized for the first time, but
some phosphorus-containing terpene derivatives
differing in structure from prenylphosphonates and
bisphosphonates described in the present work have
been previously synthesized and studied. Some of such
compounds have been found to exhibit a strongly
pronounced biological activity, among them
enolpyruvylshikimate-3-phosphate (EPSP) synthase,
farnesyl protein transferase (FPT) [7–10], as well as
HIV protease [11] (Scheme 5).
The proposed procedure was also used to prepare
hydroxyphosphonates XIV and XVI, which, too, are
derivatives of natural terpenes. Hydroxyphosphonate
XIV could be distilled in high vacuum and then
isolated as crystals; its monocyclic analog XVI was
also purified by vacuum distillation. By Swern oxida-
tion compound XVI was converted into a ketophos-
3
1
phonate whose formation was detected by Р NMR
spectroscopy (δ –2 ppm). Without special purifica-
P
tion, this phosphonate was reacted with triethyl
phosphite in the presence of pyridine to obtain
bisphosphonate XVII isolated in low yield (~25%) by
column chromatography on silica gel (Scheme 6).
Thus, we have developed a fairly simple method of
synthesis of α-hydroxybisphosphonates derived from
terpenes, which present interest as potential
biologically active compounds, as well as liquid and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014

6
50
KOLODYAZHNAYA et al.
Scheme 6.
CH3
CH3
H
(
EtO) P/[PyH]ClO
3 4
O
P(O)(OEt)2
−EtBr, −Py
H C
H C
CH3
3
CH
XIV
3
3
OH
XIII
(
EtO) P/[PyH]ClO
3
4
O
P(O)(OEt
OH
XV
XVI
Me SO/(COCl)
2
2
(EtO) P/[PyH]ClO
3 4
P(O)(OEt)2
Et N
3
P(O)(OEt)2
P(O)(OEt)2
O
OH
XVII
membrane extractants for substrates of natural and
synthetic origin. Research in this field will be
described in subsequent publications.
OCH ) 4.52 d.d (1H, PCH, J 9, J 9), 5.12 br.s (1H,
2
HH
HP
1
3
CH=C), 5.36 br.s (1H, CH=C). C NMR spectrum
(CDCl ), δ , ppm: 16.4, 17.0, 17.6, 25.60, 26.7, 37.90,
7.9, 61.7, 61.8, 65.1, 66.1, 119.1, 124.0, 131.7, 138.8.
3
С
3
EXPERIMENTAL
3
1
P NMR spectrum (CDCl ): 24.19 ppm [15].
3
The NMR spectra were registered on a Varіan
1
13
Diethyl [(2E)-3,7-dimethyl-1-oxoocta-2,6-dienyl)-
VXR-300 spectrometer at 300 ( H), 60 ( C), and
3
1
1
13
phosphonate (III). A solution of 2 mL of DMSO in
4 mL of methylene chloride and a solution of 2.8 g of
hydroxyphosphonate IIa in 8 mL of methylene
chloride were added in succession to a solution of
mL of oxalyl chloride in 20 mL of dry methylene
chloride at −60°C. After 15 min, 7 mL of triethylаmine
was added −50°C. The reaction mixture was stirred for
min, heated to room temperature, and diluted with
0 mL of ice water. The aqueous layer was separated
and extracted with methylene chloride (2 × 20 mL).
The combined organic layers were dried over MgSO4,
the solvent was evaporated, and the residue was distil-
1
26.16 ( P) MHz relative to Me Sі ( H, C) or 85%-
4
31
ной H PO ( P). Solvents were preliminarily distilled
3
4
in ab inert atmosphere: diethyl ether, hexane heptane,
benzene, and carbon tetrachloride over phosphorus
pentoxide, methanol and triethylamine over sodium,
and ethyl acetate over calcium chloride. Reagents,
silica gel and TLC plates (Polіgram SIL G/UV )
1
2
54
5
5
were purchased from Fluka, Acros, and Sinbias
Donetsk, Ukraine). Geraniol (I), farnesol (IX), and
+)-(R)-citronellal (V) were purchased from Merck.
(
(
Diethyl [(2E)-1-hydroxy-3,7-dimethylocta-2,6-
dienyl]phosphonate (II). Pyridinium perchlorate (1 g,
.01 mol) was added to a cold (0°С) solution of
geranial (0.3 g, 0.02 mol) and triethyl phosphite (3.1 g,
.02 mol), and the reaction mixture was stirred for 2 h
led in a vacuum. Yield 70%, bp 115°С (0.08 mmHg).
1
0
Н NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.87 m
3
(
3H, CH ), 1.24 s (3H, CH C=), 1.29 s (3H, CH C=),
3 3 3
0
1
.31 t (6H, CH CH O, J 7), 1.6 m (2H, CH ), 2.0 m
3 2 HH 2
at room temperature, after which it was filtered, diluted
with diethyl ether, and filtered again to remove
pyridinium perchlorate (~0.009 mol). The solvent was
removed by evaporation, abd the residue was distilled
(
2H, CH ), 2.29 m (2H, CH ), 4.1 m (4H, CH O), 5.33
2 2 2
3
1
m (=CH–C=O). Р NMR spectrum (CDCl ): δ 1.2
ppm. Found P, %: 10.76. C H O P. Calculated P, %:
1
3
P
1
4
25
4
0.74.
1
in a vacuum. Yield 80%, bp 135°С (0.08 mmHg). Н
Tetraethyl [(2E)-1-hydroxy-3,7-dimethylocta-
,6-dienylidene]bisphosphonate (IV). Pyridinium
NMR spectrum (CDCl ), δ, ppm (J, Hz): 1.28 t (3H,
3
2
CH , J 7), 1.29 t (3H, CH , J 7), 1.61 s (3H, CH3),
3
HH
3
HH
perchlorate (0.3 g, 3 mmol) was added to a cold (0°С)
1
.69 s (3H, CH ), 2.1 br.s (4H, CH ), 4.12 m (4H,
3
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014

SYNTHESIS OF α-HYDROXY(POLYPRENYL) BISPHOSPHONATES
651
solution of 0.5 g (3 mmol) of triethyl phosphite and
.7 g (2.5 mmol) of ketophosphonate III in 3 mL of
methylene chloride, and the mixture was left to stand
for 24 h at room temperature. The precipitate that
formed was filtered off, the solvent was evaporated,
and the residue was chromatographed on a column of
stirred for 5 min, heated to room temperature, and
diluted with 35 mL of ice water. The aqueous layer
was separated and extracted with methylene chloride
(2 × 10 mL). The combined organic layers were dried
0
over MgSO , the solvent was evaporated, and the
4
residue was distilled in a vacuum. Yield 70%, mp 115°С
1
silica gel, eluent ethyl acetate–hexane, 1 : 1. Yield
(0.08 mmHg). Н NMR spectrum (CDCl ), δ, ppm (J,
3
1
6
1
5%, oil. Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
Hz): 0.87 m (3H, CH ), 0.91 d (CH CH, J 7), 1.37 t
3
3
3
.27 t (6H, J 7), 1.28 t (6H, J 7), 1.6 s 1.63 s (3H), 1.8
(CH CH , J 7), 1.58 s (3H, CH C=), 1.66 s (3H,
3 2 3
m (3H), 2.0 m (4H, CH ), 4.21 m (8H, OCH ), 4.8 m
CH C=), 1.97 m (2H, CH ), 2.14 m (2H, CH ), 2.6–2.8
3 2 2
2
2
1
3
(
1H, CH=), 5.1 t (1H, CH=, JHH 7). C NMR spectrum
CDCl ), δ , ppm (J, Hz): 16.21, 16.41, 17.59, 17.81,
m (2H, CH C=O), 4.21 m (4H, OCH ), 6.06 t (2H,
2
2
31
(
CH=C, J 6.5). Р NMR spectrum (CDCl ): δ 1.96 ppm.
3 P
3
C
2
1
5.61, 26.87, 36.9, 60.93, 64.53, 67.83, 71.13, 115.5,
24.03, 131.67, 139.77. Р NMR spectrum (CDCl3):
Found Р, %: 10.76. C H O P. Calculated P, %: 10.67.
14 27 4
31
Tetraethyl [(6E)-1-hydroxy-3,7-dimethylocta-6-
enylidene]bisphosphonate (VIII). Pyridinium pe-
rchlorate (0.3 g, 3 mmol) was added to a cold (0°С)
solution of 0.5 g (3 mmol) of triethyl phosphite and
0.7 g (2.5 mmol) of ketophosphonate VII in 3 mL of
methylene chloride, and the mixture was left to stand
overnight at room temperature. The precipitate was
filtered off, the solvent was evaporated, and the residue
δP 23.3 ppm. Found, %: C 50.45; H 8.41; P 14.50.
C H O P . Calculated, %: C 50.70; H 8.51; P 14.53
1
8
36
7 2
Diethyl
[(S /R,R/R )-(6E)-1-hydroxy-3,7-di-
P P
methylocta-2,6-dienyl]phosphonate (VI). Pyridinium
perchlorate (~0.75 g, 0.005 mol) was added to a cold
(
0°С) solution of citronellal (1.5 g, 0.01 mol) and
triethyl phosphite (1.6 g, 0.01 mol). The reaction
mixture was stirred for 2 h at room temperature,
filtered, diluted with diethyl ether, filtered to remove
pyridinium perchlorate, the solvent was evaporated,
and the residue was distilled in a vacuum. Yield 80%,
bp 145–150°С (0.08 mmHg).
was chromatographed on a column of silica gel. Yield
1
65%, oil. Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
3
1.02 d (3H, J 4), 1.34 t (12H, CH CH , J 7), 1.59 s
3
2
(3H, CH C=), 1.66 s (3H, CH C=), 2.0 m (4H, CH ),
3
3
2
3
1
4.23 m (8H, OCH ), 5.1 t (CHC=, J 7). Р NMR
2
1
spectrum (CDCl
3
), δ
P
, ppm: 20.55, 20.65. Found, %: C
Mixture of the (S /R,R /R) diastereomers. Н
P
P
5
5
0.45; H 8.41; P 14.50. C H O P . Calculated, %: C
0.46; H 8.94; P 14.46.
1
8
38
7 2
NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.96 d (3H,
CH , J 7), 1.29 t (3H, CH , J 7), 1.30 t (3H, CH , J 7),
3
3
3
3
1
1
.58 s (3H, CH ), 1.65 s (3H, CH ), 1.83 m (2H, CH ),
Dimethyl [(2E,6E)-1-hydroxy-3,7,11-trimethyl-
3 3 2
.96 m (2H, CH ), 3.82 m (1H, CH), 4.09 m (4H,
dodeca-2,6,10-trienyl]phosphonate (Х). Pyridinium
perchlorate (0.5 g, ~0.005 mol) was added to a cold
(0°С) solution of farnesal (2.2 g, 0.01 mol) and
trimethyl phosphite (1.3 g, 0.01 mol). The reaction
mixture was stirred for 2 h at room temperature and
then filtered, diluted with diethyl ether, and filtered
again to separate ~0.0049 mol of pyridinium per-
chlorate. The solvent was evaporated, and the residue
2
1
3
OCH ), 5.07 t (1H, CH=C, J 7), 5.7 br.s (1H, OH). C
NMR spectrum (CDCl ), δ , ppm (J, Hz): (Sp,R)
1
2
3
C
6.45, 16.49, 17.6, 20.25, 25.19, 25.52, 25.65, 28.30 d
(J 12), 35.75, 38.11, 62.51 d (J 7.5), 62.64 d (J 6),
6
1
3
1
5.59 d (J 158), 124.70, 131.09; (Rp,R) 16.45, 16.49,
8.35, 20.25, 25.19, 25.52, 25.65, 29.0 d (J 12), 37.80,
8.56, 62.51 d (J 7.5), 62.64 d (J 6), 66.06 d (J 157),
31
1
24.72, 131.13. P NMR spectrum (CDCl ): δ , ppm:
was distilled in a vacuum. Yield 90%, oil. Н NMR
3
P
2
6.50, 26.54. Found P, %: 10.69. C H O P. Calcu-
spectrum (CDCl ), δ, ppm (J, Hz): 1.59 s (3H,
1
4
29
4
3
lated P, %: 10.59.
CH
3
C=), 1.66 s (3H, CH
C=), 1.69 d (3H, CH CH, JHH
3 3
1
2
.5), 1.71 (3H, CH CH, J 1.5), 2.09 m (6H, CH2),
3
HH
Diethyl [(6E)-3,7-dimethyl-1-oxooct-6-enyl]phos-
phonate (VII). A solution of 0.9 mL of DMSO in
.25 m (2H, CH ), 3.78 d (3H, CH O, J 10), 3.8 d
2
3
HР
(
3H, CH O, J 10), 4.5 br.s (1H, OH), 4.7 t (1H,
3 HР
2
mL of methylene chloride and a solution of 1.4 g of
PCH, JHР 10), 5.09 br.s (1H, CH=C), 5.35 br.s (2H,
CH=C). Р NMR spectrum (CDCl ): δ 26.05 ppm.
Found P, % 9.39. C H O P. Calculated P, %: 9.37.
hydroxyphosphonate VI in 4 mL of methylene
chloride were added in succession to a solution of
3
1
3
P
17
31
4
0
.5 mL of oxalyl chloride in 10 mL of dry methylene
chloride at −60°C. After 15 min, 3.5 mL of
triethylаmine was added −50°C. The mixture was
Dimethyl [(2E,6E)-3,7,11-trimethyl-1-oxododeca-
2,6,10-trienyl]phosphonate (XI). A solution of
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6
52
KOLODYAZHNAYA et al.
0
.9 mL of DMSO in 2 mL of methylene chloride and a
Pyridinium perchlorate (0.5 g, 0.005 mol) was added
to a cold (0°С) solution of aldehyde XV (0.01 mol)
and triethyl phosphite (1.6 g, 0.01 mol) in 5 mL of
methylene chloride. The reaction mixture was stirred
for a few hours (under TLC control) and then filtered,
diluted with diethyl ether, and filtered again to separate
~0.0049 mol of pyridinium perchlorate. The solvent
was evaporated, and the residue was purified first by
vacuum distillation and then by column chromato-
graphy on silica gel (eluent ethyl acetate–hexane, 1 : 3).
solution of 1.4 g of hydroxyphosphonate X in 4 mL of
methylene chloride were added in succession to a
solution of 0.5 mL of oxalyl chloride in 10 mL of dry
methylene chloride at −60°C. After 15 min, 3.5 mL of
triethylаmine was added −50°C. The reaction mixture
was stirred for 5 min, heated to room temperature, and
diluted with 35 mL of ice water. The aqueous layer
was separated and extracter with methylene chloride
(
2 × 10 mL). The combined organic solutions were
1
dried over MgSO , the solvent was evaporated, and the
Yield 80%. Colorless oil, bp 180°С (0.08 mmHg). Н
4
residue was distilled in a vacuum. Yield 60%, bp 145°С
NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.99 d (3H,
3
1
(
0.1 mmHg). Н NMR spectrum (CDCl ), δ, ppm (J,
CH , J 6), 1.33 t (6H, CH CH , J 7), 1.6 s (3H, CH ),
3
3
3
2
3
Hz): 1.6 s (3H, CH C=), 1.66 s (3H, CH C=), 1.69 d
1.87 s (3H, CH ), 1.91–2.22 m (10H, CH + CH), 3.51
3
3
3
2
(
(
3H, CH C=, J 1.5), 1.71 (3H, CH C=, J 1.5), 2.1 m
br.s (OH), 4.17 m (5H, OCH + PCH, J 7, J 8), 6.28 s
2
(1H, CH=C), 5.32 m (2H, CH=C). C NMR spectrum
3
3
1
3
6H, CH ), 2.25 m (2H, CH ), 3.75 d (3H, CH O, J
2
2
3
HР
1
5
0
0), 3.8 d (3H, CH O, J 10), 5.1 br.s (1H, CH=C),
(CDCl ), δ , ppm (J, Hz): 8.87, 16.28, 17.3, 25.4,
3
HР
3
C
3
1
.5 br.s (2H, CH=C). Р NMR spectrum (CDCl ): δ
25.78, 27.01, 27.08, 29.96, 32.15, 33.69 d (J 150),
3
P
3
1
.98 ppm. Found, %: C 62.38; H 8.89; P 9.45.
42.8, 61.81 d (J 6), 120.6, 123.9, 130.8, 135.59.
P
C H O P. Calculated, %: C 62.18; H 8.90; P 9.43.
NMR spectrum (CDCl ): δ 26.6 ppm. Found, %: C
1
7
29
4
3
6
2.68; H 9.65; P 8.88. C H O P. Calculated, %: C
18 33 4
Tetramethyl [(2E,6E)-1-hydroxy-3,7,11-tri-
methyldodeca-2,6,10-trienylidene]bisphosphonate
XII). Pyridinium perchlorate (3 mmol) was added to a
cold (0°С) solution of 3 mmol of trimethyl phosphite
and 2.5 mmol of ketophosphonate XI in 3 mL of
methylene chloride, and the mixture was left to stand
for 24 h at room temperature. The precipitate that
formed was filtered off, the solvent was evaporated,
and the residue was chromatographed on a column of
62.77; H 9.66; P 8.99.
(
Tetraethyl [(hydroxy)[6-methyl-4-(4-methyl-
pent-3-enyl)cyclohex-3-en-1-yl]methylene]bisphos-
phonate (XVII) was prepared similarly to compound
XII. Yield 25%, oil, purified by column chromato-
graphy. Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
1
3
1.15 d (3H, CH , J 6), 1.3 t (3H, CH , J 7), 1.32 t (3H,
CH , J 7),1.6 m (6H, CH ), 2.0–2.5 m (6H, CH ), 4.4
3
3
3
3
2
silica gel (eluent hexane–ethyl acetate, 3 : 1). Yield
m (4H, OCH ), 5.2 m (1H, CH=), 5.4 m (1H, CH=).
2
1
31
6
1
5%, oil. Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
Р NMR spectrum (CDCl ): δ 23.0 ppm.
3
3
P
.6 s (3H, CH ), 1.69 s (3H, CH ), 1.8 d.d (3H, J 8,
3
3
HP
JHH 7), 2.0 m (4H, CH ), 3,75 d (3H, CH O, J 10)
ACKNOWLEDGMENTS
2
3
HР
3
.8 d (3H, CH O, J 10), 4.8 m (2H, CH=), 5.1 m
3 HР
3
1
(
1H, CH=). NMR spectrum Р (CDCl ), δ 23 ppm.
The work was financially supported by the State
Foundation for Basic Research of Ukraine (project no.
F53.3/016) and Russian Foundation for Basic Research
(project no. 13-03-90448).
3
P
Found P, %: 14.60. C H O P . Calculated P, %: 14.60.
18
34
7 2
Diethyl [(hydroxy)(3,8,8-trimethyl-1,2,3,4,5,6,7,8-
octahydronaphtalen-2-yl)methyl]phosphonate (XIV)
was prepared similarly to compound XI. Yield 80%,
bp 190°C (0.1 mmHg), mp 107–110°C (hexane). Н
NMR spectrum (CDCl ), δ, ppm (J, Hz): 0.957 d (3H,
CH C, J 6), 0.975 s (6H, CH ), 1.34 t (6H, CH CH O,
J 7), 1.43 m (2H, CH ), 1.6 m (4H, CH ), 1.8 m (2H,
CH ), 1.9 m (1H, CH), 2.0 m (1H, CH), 2.19 m (2H,
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1
1
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3
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CH ), 2.91 m ( 1H, OH), 4.2 m (5H, CH O + PCH).
2
2
3
1
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3
P
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