A convenient synthesis of retinal derivatives with modified trimethylcyclohexene ring

Article abstract of DOI:10.1023/A:1021245616117

A method of simultaneous one-stage synthesis of three retinal derivatives (5,6-dioxo-5,6-seco-, 5,6-dihydro-5,6-epoxy-, and 4-oxoretinal) was proposed, with the yield of the first derivative being ～50%. These compounds are useful tools for studying the an

Full text of DOI:10.1023/A:1021245616117

Russian Journal of Bioorganic Chemistry, Vol. 28, No. 6, 2002, pp. 487–493. Translated from Bioorganicheskaya Khimiya, Vol. 28, No. 6, 2002, pp. 535–542.
Original Russian Text Copyright © 2002 by Mironova, Leont’eva, Shevyakov, Alexeeva, Shvets, Demina, Krasnokutskaya, Finkel’shtein, Khodonov.
A Convenient Synthesis of Retinal Derivatives
with Modified Trimethylcyclohexene Ring
E. V. Mironova*, S. V. Leont’eva*, S. V. Shevyakov*, S. G. Alexeeva*, V. I. Shvets*,
1
O. V. Demina**, I. S. Krasnokutskaya*, E. I. Finkel’shtein*, and A. A. Khodonov*
*Lomonosov State Academy of Fine Chemical Technology, pr. Vernadskogo 86, Moscow, 119571 Russia
**Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow
Received August 2, 2001; in final form, November 8, 2001
Abstract—A method of simultaneous one-stage synthesis of three retinal derivatives (5,6-dioxo-5,6-seco-,
5,6-dihydro-5,6-epoxy-, and 4-oxoretinal) was proposed, with the yield of the first derivative being ~50%.
These compounds are useful tools for studying the antitumor activity of retinoids, the reconstituted bacterio-
rhodopsin analogues with changed parameters of photocycle, and the reactivity of retinal derivatives in the pro-
cesses of oxidation by molecular oxygen.
Key words: pyridinium chlorochromate, retinoids, ring oxidation
1
INTRODUCTION
28], whereas those for the derivatives of retinoic acid,
in the books [1–3, 17]. In this study, we would briefly
describe only the variants of oxidative modification of
trimethylcyclohexene ring of retinal (I) (see scheme 1).
The modification of trimethylcyclohexene ring of
retinoids affects their A-vitamin activity, antitumor
action, toxicity of retinoic acid derivatives [1–4], pho-
tochemical properties and transport of proton by the
corresponding bacteriorhodopsin analogues [5, 6], and
the functional activity of analogues of visual rhodopsin
[7]. The modified retinal analogues have been inten-
sively studied to understand the functional role of this
important moiety in retinoid molecules.
In parallel, the reactivity of retinoids and caro-
tenoids toward various oxidative agents have been
investigated in detail, in order to get a deep insight into
the mechanism of antioxidative action of retinoids. The
methods of oxidative degradation of carotenoids iso-
lated from various natural sources were already
described in the first studies for confirmation of their
structures [1, 2]. The processes of oxidation [8, 9, 11–
13], photooxidation [14], and epoxidation [15, 16] of
the retinoid molecule were shown to be of the main
practical importance.
All the known synthetic methods for preparation of
the retinoids with various ring modifications can be
divided into two strategically different groups: total
synthesis that applies a combination of two or more
fragments with the formation of retinoid molecule [17–
23] and the modification of the cyclic part in the ready
ë20-carbon skeleton of a suitable precursor [8–12, 24–
27].
At first, the retinoids with oxidized ring were pro-
posed to obtain by the elongation of polyenic chain of
the corresponding derivative of β-ionone [17–23].
However, all the described syntheses were multistage.
Later, the structure of the commercially available reti-
nal (I) was suggested to modify by introducing func-
tional groups into the trimethylcyclohexene ring by its
oxidation in position 4 [8–11], by allylic bromination
with N-bromosuccinimide [9, 10], by epoxidation of
5,6-double bond [15, 16], or by more complex modifi-
cations with the introduction of several substituents
[27].
2
4-Oxoderivatives now outrank among the retinoid
derivatives with the oxidized ring, because they are the
analogues of metabolites of retinoic acid and retinal [8–
11] and important starting compounds for synthesis of
4-hydroxyderivatives [24], 4,4-difluoroderivatives, and
3-substituted analogues of retinoids [27, 29].
As a rule, the previously studied oxidative agents
exhibited no pronounced regioselectivity and caused
the isomerization of double bonds in the polyenic
chain, which resulted in complex mixtures of products
[11, 13, 14, 30]. Only the preparations of active manga-
nese(IV) oxide obtained by various procedures [8–12]
were of practical importance.
All the known methods of preparation of the retinal
analogues were presented in our previous reviews [5, 6,
Previously, the process of directed allyl oxidation of
methylene group position 4 of the ring in all-E- and
13Z-isomers of retinal by the acidic form of manganese
dioxide with the formation of the corresponding deriv-
atives of 4-oxoretinal was studied in our laboratory. We
1
The author may be contacted by phone, +7 (095) 434-8355 or
e-mail, biotechnology@mtu-net.ru.
Abbreviations: PCC, pyridinium chlorochromate.
2
1068-1620/02/2806-0487$27.00 © 2002 MAIK “Nauka /Interperiodica”

488
MIRONOVA et al.
CHO
CHO
PCC/CH2Cl2
O
(I)
(II)
O
+
CHO
CHO
O
(III)
+
(IV)
O
Scheme 1. Oxidation of retinal by pyridinium chlorochromate.
widely varied the procedure of the reagent preparation ring in a sufficiently high yield. We planned to use these
and the conditions of process (temperature, solvent, and derivatives for the preparation of bacteriorhodopsin
the ratio of oxidative reagent and substrate), but could analogues and for studying the reactivity of retinal and
not achieve the degree of retinal conversion higher than the corresponding retinoic acid derivatives in the oxida-
30–40%. Manganese dioxide caused no remarkable tive processes with molecular oxygen. The oxidation
isomerization, however, the main difficulty was the experiments were necessary to choose the stabilization
preparation of the oxidative agent with a standard oxi- methods for retinoids used as individual substances or
dative capacity. Additional experiments were therefore in complex preparations [31, 32], since fat-soluble
necessary for testing every portion of the oxidative polyenic vitamins, are, as a rule, easily oxidized by
agent [9, 10]. Recent studies [11, 12, 30] significantly molecular oxygen, with the kinetics of these processes
extended the synthetic potential of manganese dioxide being scarcely studied.
as an oxidative agent. The paper [12] is of especial
interest, because a selective cleavage of the polyenic
retinal chain with formation of isomers of ë19 aldehyde
RESULTS AND DISCUSSION
with the retro-arrangement of double bond system was
described in this article. Unfortunately, we failed to
reproduce these results.
We examined the following oxidative agents for the
optimal oxidation of the trimethylcyclohexene ring of
retinal:
In this paper, we propose an approach to the simul-
taneous one-step preparation of three retinal derivatives
(Scheme 1): 5,6-dioxo-5,6-secoretinal (II), 5,6-dihy-
dro-5,6-epoxyretinal (III), and 4-oxoretinal (IV). We
also describe synthesis of the corresponding acids
(VIII)–(X) and their methyl esters (V)–(VII) (Scheme 2).
Retinal (I) was stable under the conditions of oxida-
tion with potassium permanganate in benzene: it was
not modified for two weeks. Its oxidation with cerium
compounds resulted in a number of products with trun-
cated polyenic chains. The most interesting results that
were obtained with the PCC/CH2Cl2 system will be
described below.
Modified retinals (II)–(IV) were obtained by the
treatment of retinal (I) with PCC in dichloromethane;
aldehyde (II) was the main product of this reaction, and
(a) samples of manganese dioxide prepared accord-
ing to various procedures in hexane and dichlo-
romethane;
(b) pyridinium chlorochromate in dichloromethane
(PCC/CH2Cl2);
(c) cerium(IV) ammonium nitrate in dichlo-
romethane;
(d) cerium(IV) sulfate in the methanol–water mix-
ture; and
(e) potassium permanganate in benzene in the pres- its yield was approximately 50%.
ence of 18-crown-6.
Retinal derivatives (II)–(IV) were converted into
The goal of this study was the search for the method the corresponding analogues of retinoic acid methyl
of oxidation that allowed the synthesis of a number of esters (V)–(VII) according to the Corey method [33]
retinal derivatives with modified trimethylcyclohexene (Scheme 2). The corresponding analogues of retinoic
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 6 2002

A CONVENIENT SYNTHESIS OF RETINAL DERIVATIVES
489
OH
CN
Ret
NC
MnO2
CH3OH
NaCN
CH3COOH
Ret CH
C O
Ret CHO
(II)–(IV)
H2O, OH–
Ret CO2R
Ret CO2H
(V)–(VII)
(VIII)–(XI)
(II), (V), (VIII)
Ret =
O
O
(III), (VI), (IX)
(IV), (VII), (X)
O
O
(XI)
O
Scheme 2. Method of synthesis of the analogues of retinoic acid and their methyl esters.
acid (V)–(VII) were obtained by the saponification of thesis of oxidized retinoids in [26]. However, 4-hydroxy-
the methyl esters (VIII)–(X).
retinal was the starting substance and 4-oxoretinal (IV)
was formed in yield of 50%. In this case, trymethylcy-
clohexene ring was not cleaved probably due to the fact
that an oxidized (in position 4) retinal derivative was
the starting compound.
Chromium compounds have already been used for
oxidative modification of retinoids. Schwieter et al.
oxidized retinoic acid and its ethyl ester by the Jones
reagent (solution of H2CrO4 in acetone) [13]. In this
case, the oxidation process in strongly acidic medium
proceeds through the rearrangement of 5,6-epoxide
into 5,8-furanoid derivative with the subsequent cleav-
age of 7,8-bond, which leads to low yields of products
in a complex mixture; for example, the yield of 5,6-
dioxo-5,6-secoretinoic acid (VIII) and its ethyl ester
(V) were obtained in 0.8 and 12.6% yields, respec-
tively.
The target products were also synthesized in rather
low yields by oxidation of retinyldenedimedone by
pyridinium dichromate [25]. In this case, the yield of 2-
(5,6-dioxo-5,6-secoretinyliden)dimedone was 34%,
and the corresponding aldehyde (II) was obtained from
this compound in 12.6% yield (from retinyldenedime-
done).
In our case, we oxidized the unmodified retinal by
the PCC/CH2Cl2 system and obtained predominantly
5,6-dioxo-5,6-secoretinal (II) in yield of 47% after the
selective cleavage of 5,6-double bond in trimethylcy-
clohexene ring. In addition, 4-oxoretinal (IV) (7%) and
5,6-dihidro-5,6-epoxyretinal (III) (19%) were isolated
from the reaction mixture. Note that, at this instant, the
process of cleavage of the trimethylcyclohexene ring
proceeded under comparatively mild conditions
through the intermediate 5,6-epoxide and glycol
(Scheme 3). The presence of 5,6-dihydro-5,6-epoxyret-
inal (III) confirms our conclusions on the reaction path-
way.
The structure of (II) was proved by spectral meth-
ods. Two additional signals from carbonyl groups
(203.6 and 208.2 ppm) were observed in the 13C NMR
It is interesting to note that the PCC/CH2Cl2 system
has already been used as an oxidative agent for the syn- spectrum along with the signal from aldehyde group
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 6 2002

490
MIRONOVA et al.
CHO
CHO
CHO
CHO
PCC/CH2Cl2
O
(III)
(I)
PCC/CH2Cl2
OH
OH
O
(II)
O
Scheme 3. Possible mechanism of the retinal oxidation by pyridinium chlorochromate.
(190.6 ppm), and the signals from protons of all the were characteristic of the spectrum of 5,6-dihydro-5,6-
epoxyretinal (III). It was also noticed that methyl (H16
and H17) groups (δ 1.16 and 1.11 ppm) displayed not
equivalent signals, which was not observed for the most
of retinal analogues. The downfield shifts of the H2 and
H3 multiplets (∆δ 0.37 and 0.89 ppm) were found for
4-oxoretinal (IV).
Thus, the synthesized 5,6-dioxo-5,6-secoretinal (II)
is a promising starting compound for introduction of
various labels and reporter groups into retinoid mole-
cules. Derivatives (III) and (IV) are interesting tools
for studying the retinoid–protein complexes and the
kinetics of the retinoid autooxidation.
The structures of minor oxidation products (III) and
(IV) were established on the basis of spectral data (see
table and the Experimental section) and by the compar-
ison of their physicochemical properties (mps and Rf)
with those of similar compounds previously synthe-
sized in our laboratory by other methods.
fragments of molecular structure (II) were found in the
1H NMR spectrum (see table). Electronic spectra (taken
in methanol) additionally confirmed the structure of
diketone (II). The absorption maximum of analogue
(II) observed at 364 nm and shifted to the short-wave
area by 16 nm relative to unmodified retinal (I) indi-
cated that the conjugated chain length decreased by one
bond. We compared 1H NMR spectra of the main reac-
tion products (II)–(IV) with that of the starting retinal
(I) (see figure) and should point out the following ten-
dencies: the H3 and H11 signals of 5,6-dioxo-5,6-sec-
oretinal (II) were shifted to the upfield area (∆δ –0.24
and –0.18 ppm, respectively), the resonances from H4,
H18, H8, and H12 were shifted to the low field area (∆δ
0.24, 0.25, 1.03, and 0.16 ppm, respectively), and the
downfield shifts for H3 (∆δ 0.14 ppm) and upfield shifts
for H4, H18, and H8 (∆δ –0.13, –0.78, and –0.13 ppm)
It was found during the synthesis of 5,6-dioxo-5,6-
secoretinoic acid (VIII) that the derivatives with such a
modification of the ring [(II), (V), and (VIII)] are
prone to aldol and crotonic condensations at elevated
temperature under acidic or basic conditions. For
example, the recyclization of the cleaved trimethylcy-
clohexene ring with the formation of five-membered
cyclic structure (VI) proceeded when obtaining 5,6-
dioxo-5,6-secoretinoic acid (VIII) from its methyl
ester (V). The data of 1H NMR of (XI) are given in the
table. The reaction should be carried out under more
mild conditions (room temperature and neutralization
with a highly diluted hydrochloric acid) in order to
increase the yield and avoid the recyclization process.
∆δ
Downfield
(II)
(III)
(IV)
1.0
0.5
0
–0.5
Upfield
H16, H2 H3
H17
H18
H8
H7
Protons
H11 H14 H20
H10 H12 H19
H4
EXPERIMENTAL
1
The ç and 13C NMR spectra were recorded on a
Bruker MSL-200 spectrometer (Germany) in chloro-
form-d3 at working frequencies 200 and 50.32 MHz,
respectively. The chemical shifts are given in ppm rela-
tive to hexamethyldisiloxane as internal standard
The dependence of changes in chemical shifts of proton res-
1
onances in H NMR spectra of retinal derivatives (II), (III),
and (IV) on the type of modification of trimethylcyclohex-
ene ring relative to unmodified retinal (I).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 6 2002

Parameters of 1H NMR spectra (δ, ppm, multiplicity of signal, J, Hz) of retinoids (I)–(XI)
H16, H17
OCH3
(3H)
Number
(I)
H2 (2H) H3 (2H) H4 (2H) H18 (3H) H7 (1H) H8 (1H) H10 (1H) H11 (1H) H12 (1H) H14 (1H) H15 (1H) H19 (3H) H20 (3H)
(6H)
1.03, s
1.48, m 1.61, m 2.03, t, 1.72, s
6.5
6.36, d, 6.18, d, 6.20, d, 7.15, dd, 6.37, d, 5.98, d, 10.12, d, 2.03, s
16.5 16.5 12.0 12.0/15.4 15.4 8.0 8.0
2.33, s
2.20, c
–
–
–
–
(II)
1.02, s
1.37, m 1.37, m 2.27, t, 1.97, s
6.0
6.39, d, 7.21, d, 6.42, d, 6.97, dd, 6.53, d, 5.87, d, 9.97, d, 1.91, s
15.0 15.0 11.0 11.0/15.0 15.0 8.0 8.0
(III)
(IV)
(V)
1.16;
1.11, c
1.40, m 1.75, m 1.90, m 0.94, c
6.32, d, 6.05, d, 6.23, d, 7.10, dd, 6.39, d, 5.98, d, 10.11, d, 2.00, d, 2.32, d,
15.5
15.5
11.2
11.2/15.0 15.0
8.0
8.0
1.2
1.5
1.17, c
1.12, s
1.85, t, 2.50, t,
6.5 6.5
–
1.83, c
6.37, d, 6.30, d, 6.25, d, 7.15, dd, 6.40, d, 5.98, d, 10.12, d, 2.05, c
16.0 16.0 11.5 11.5/15.0 15.0 8.0 8.0
2.33, c
1.48, m 1.48, m 2.36, t, 2.07, s
6.5
6.58, d, 7.32, d, 6.49, d, 6.92, dd, 6.58, d, 5.82, s
15.0 15.0 11.5 11.5/15.0 15.0
–
–
–
–
–
–
–
1.97, s
1.95, c
2.03, c
1.96, s
1.93, s
2.01, s
2.01, s
2.31, d, 3.68, c
0.8
(VI)
(VII)
1.13;
1.09, c
1.45, m 1.78, m 1.90, m 0.93, c
6.29, d, 5.97, d, 6.17, d, 6.95, dd, 6.27, d, 5.78, c
15.5 15.5 11.5 11.5/15.0 15.0
2.34, d, 3.70, c
1.5
1.19, c
1.86, t, 2.52, t,
6.5 6.5
–
1.86, c
6.35, m, 6.35, m, 6.25, d, 6.97, dd, 6.35, d, 5.81, c
16.0 16.0 11.5 11.5/15.0 15.0
2.36, c
3.73, c
(VIII) 1.11, s
1.48, m 1.48, m 2.38, t, 2.08, s
6.5
6.42, d, 7.32, d, 6.51, d, 6.94, dd, 6.56, d, 5.83, s
15.0 15.0 15.0 11.0/15.0 15.0
2.30, d,
0.8
–
–
–
–
(IX)
(X)
1.12;
1.08, s
1.42, m 1.75, m 1.85, m 0.91, s
6.29, d, 5.97, d, 6.16, d, 6.95, dd, 6.29, d, 5.79, s
15.5 15.5 11.5 11.5/15.0 15.0
2.31, s
2.33, s
2.34, s
1.16, s
1.26, s
1.82, t, 2.49, t,
7.0 7.0
–
–
1.83, s
2.24, s
6.31, m 6.31, m 6.25, d, 6.99, dd, 6.35, d, 5.81, s
11.5 11.5/15.0 15.0
(XI)
1.73, t, 2.63, t,
7.0 7.0
7.22, d, 6.74, d, 6.29, d, 7.02, dd, 6.35, d, 5.81, s
16.5 16.5 11.5 11.5/15.0 15.0

492
MIRONOVA et al.
(δ 0.055) and the spin–spin coupling constants in Hz. combined filtrate was evaporated. The residue was
The UV-VIS spectra were recorded on a Hitachi 3400 stirred with water (15 ml), the substance was extracted
spectrometer (Japan) in methanolic solution of com- with ether [3 × 15 ml; chloroform was used for methyl
pounds in quartz cells with the length of optical way of ester of 5,6-dioxo-5,6-secoretinoic acid (V)]. The com-
1 cm. The qualitative composition of the reaction mix- bined extract was washed to pH 7, dried by sodium sul-
tures and homogeneity of the compounds were deter- fate, and evaporated. The residue was fractionated on a
mined by TLC on Kieselgel 60 F254 plates (Merck, Ger- silica gel column eluted with a gradient of ether in hex-
ane (from 0 to 50%). The fractions containing methyl
ester of the corresponding acid were combined, evapo-
rated, and the residues were dried for 1 h at 0.1 mmHg.
many) or on Silufol UV-254 plates (Kavalier, Czech
Republic) in 1 : 1 hexane–ether mixture. Spots were
detected by spraying with concentrated sulfuric acid.
The adsorption column chromatography was per-
formed on a Kieselgel 60 (0.063 µm, Merck, Ger-
many). Solvents were removed on a rotary evaporator
in a vacuum at a temperature no higher than 35°ë. Pyri-
dinium chlorochromate (Aldrich, United States), active
manganese dioxide (zur Synthese, Merck, Germany),
salts, and solvents of kh. ch. quality (reagent grade,
Russia) are used in this study.
Modified retinals (II)–(IV).A solution of all-E-ret-
inal (I) (1 g, 3.51 mmol) in dichloromethane (20 ml)
was added to a suspension of PCC (3 g, 13.92 mmol) in
5 ml of dichloromethane, the reaction mixture was
stirred for 1 h, the oxidative agent was removed by fil-
tration through a layer of Celite, and the precipitate was
washed with dichloromethane (10 ml). The filtrate was
evaporated and dissolved in ether (30 ml). The solution
was washed with water (3 × 15 ml), dried with anhy-
drous sodium sulfate, and evaporated. The residue was
fractionated on a silica gel column eluted with a gradi-
ent of ether in hexane (from 0 to 100%). The fractions
containing the corresponding retinal derivatives were
collected, evaporated, and the residue was dried for 1 h
at 0.1 mmHg.
Methyl 5,6-dioxo-5,6-secoretinoate (V) was pre-
pared by a standard procedure from 5,6-dioxo-5,6-sec-
oretinal (II) (82 mg, 0.26 mmol); yield 66 mg (73%);
light-yellow crystals; Rf 0.33; mp 112–115°ë; UV-
spectrum λmax, nm (ε): 263 (8000) and 353 (31700); 1H
NMR see in the table.
Methyl 5,6-dihydro-5,6-epoxyretinoate (VI) was
prepared by a standard procedure from 5,6-dihydro-
5,6-epoxyretinal (III) (100 mg, 0.33 mmol); yield
86 mg (72%); light-yellow crystals; Rf 0.78; mp 88–
89°ë (lit. mp 86–87°ë [21]); UV-spectrum λmax, nm
(ε): 236 and 326 (28600); 1H NMR see in the table.
Methyl 4-oxoretinoate (VII) was prepared by a
standard procedure from 4-oxoretinal (IV) (100 mg,
0.34 mmol); yield 80 mg (70%), yellow crystals; Rf
0.56; mp 90–91°ë (lit. mp 90–94°ë [12, 21]); UV-
spectrum λmax, nm (ε): 362 (53000); 1H NMR see in the
table.
Retinoic acids (IX), (X). Water (1 ml) and 5 N KOH
(2 ml) were added to a solution of the corresponding
ester (0.15 mmol) in methanol (10 ml). The reaction
mixture was heated in argon atmosphere for 1.5 h,
cooled to 0°ë, and neutralized with 1 N HCl. The sub-
stance was extracted with ether (3 × 15 ml) and the
combined extract was dried by sodium sulfate and
evaporated. The residue was fractionated on a silica gel
column eluted with a gradient of ether in hexane (from
0 to 50%). The fractions containing the corresponding
acid were combined and evaporated. The residue was
dried 1 h at 0.1 mmHg.
5,6-Dioxo-5,6-secoretinal (II); yield 525 mg
(47%); Rf 0.09; mp 76–78°ë (lit. mp 77–79°ë [24]);
1
UV-spectrum, λmax, nm (ε): 364 (58000); H NMR
spectrum: see the table; 13C NMR: 13.0 (C19, C20),
19.0 (C3), 24.2 (C16, C17), 29.8 (C18), 39.1 (C2), 43.7
(C4), 46.4 (C1), 121.5 (C14), 130.4 (C7), 131.0 (C11),
137.7 (C12), 138.7 (C10), 138.4 (C9), 146.1 (C8),
153.4 (C13), 190.6 (C15), 203.6, and 208.2 (C6, C5).
5,6-Dihydro-5,6-epoxyretinoic acid (IX) was
obtained by a standard procedure from (VI) (144 mg,
0.44 mmol); yield 100 mg (72%); light-yellow crystals;
Rf 0.37; mp 160–165°ë (lit. mp 163–164°ë [21]); UV-
5,6-Dihydro-5,6-epoxyretinal (III); yield 204 mg
(19%); Rf 0.48; mp 104–106°ë; UV-spectrum, λmax, nm
(ε): 362 (53500); 1H NMR: see the table.
4-Oxoretinal (IV); yield 73 mg (7%); Rf 0.39; mp
113–115°ë (lit. mp 113–114.5 [16, 18, 19]; UV-spec-
spectrum λmax, nm (ε): 237 (1200) and 326 (28600); 1H
NMR see in the table.
1
trum, λmax, nm (ε): 374 (50 500); H NMR spectrum:
4-Oxoretinoic acid (X) was obtained by a standard
procedure from (VII) (100 mg, 0.3 mmol); yield 82 mg
(87%); yellow crystals; Rf 0.17; mp 175–179°ë (lit.
186–189°ë [12]); UV-spectrum λmax, nm (ε): 354
see the table.
Methyl esters of retinoic acid derivatives (V)–
(VII). The corresponding retinal derivative
(0.35 mmol), active manganese dioxide (1.0 g), and
glacial acetic acid (0.06 ml) were successively added to
a suspension of sodium cyanide (200 mg) in methanol
(42000); 1H NMR see in the table.
5,6-Dioxo-5,6-secoretinoic acid (VIII). A 5 N
(25 ml) under stirring at 4°ë in argon atmosphere. The KOH solution in methanol (4 ml) and water (1 ml) were
reaction mixture was stirred for 1 h at 4°ë and 24–26 h added to a solution of (V) (50 mg, 0.14 mmol) in meth-
at 20°ë and filtered through a layer of Celite. The pre- anol (10 ml). The reaction mixture was kept at room
cipitate was washed with methanol (10 ml), and the temperature for 14 h, cooled to 0°ë, neutralized with
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A CONVENIENT SYNTHESIS OF RETINAL DERIVATIVES
493
14. Oyler, A.R., Motto, M.G., Naldi, R.E., Facchine, K.L.,
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nm (ε): 256 (3000) and 356 (25200); H NMR see in
,
1
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ACKNOWLEDGMENTS
This study was partially supported by the Russian
Foundation for Basic Research, project no. 01-03-32078.
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RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 28 No. 6 2002