Retinoids and related compounds. Part 26.1 Synthesis of (11Z)-8,18-propano- and methano-retinals and conformational study of the rhodopsin chromophore

Article abstract of DOI:10.1039/b104394n

In order to clarify the conformation of the chromophore in rhodopsin, especially the effect of the torsional angle around the C6-C7 single bond on the CD spectrum, 8,18-propano- and methano-retinal 4 and 5 were prepared via the palladium-catalyzed couplin

Full text of DOI:10.1039/b104394n

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Retinoids and related compounds. Part 26.1 Synthesis of
(11Z )-8,18-propano- and methano-retinals and conformational
study of the rhodopsin chromophore†
1
Akimori Wada,*a Masako Tsutsumi,a Yuka Inatomi,a Hiroo Imai,b Yoshinori Shichidab and
Masayoshi Ito*a
a Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku,
Kobe 658-8558, Japan
b Department of Biophysics, Graduate School of Science, Kyoto University,
Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan
Received (in Cambridge, UK) 18th May 2001, Accepted 7th August 2001
First published as an Advance Article on the web 13th September 2001
In order to clarify the conformation of the chromophore in rhodopsin, especially the effect of the torsional angle
around the C6–C7 single bond on the CD spectrum, 8,18-propano- and methano-retinal 4 and 5 were prepared
via the palladium-catalyzed coupling reaction of vinyl triflates derived from bicyclic ketones 10 and 27 with methyl
(E)-3-(trimethylstannyl)but-2-enoate. In a binding experiment with bovine opsin, retinal analogs 4 and 5 afforded
the new rhodopsin analogs. Although the opsin shifts of these pigments were similar to that of the native rhodopsin,
CD spectra exhibited the characteristic feature owing to the locked structures of retinal analogs. This fact strongly
indicates that the CD spectra were significantly influenced by the torsional angles around the 6–7 and 8–9 single
bonds of the chromophore in the protein.
In the visual pigment rhodopsin (Rho) 1 (Fig. 1), the chromo-
phore (11Z)-retinal 2 is bound to the ε-amino group of the
apoprotein lysine residue through a protonated Schiff base
(PSB),2 and exhibits a characteristic circular dichroism (CD)
signal at α and β bands in the visible (VIS) and near-ultraviolet
(UV) region [α-band: 487 nm (ϩ7.5), β-band: 335 nm (ϩ15.4)],
in spite of CD-silence in both the (11Z)-retinal and apoprotein
opsin.3 It is of particular interest for the conformational anal-
ysis of the Rho chromophore to elucidate the origin of the CD
bands of Rho, since the CD spectrum gives precise information
about the interaction between the chromophore and the protein
in the photo-bleaching intermediate of Rho.3,4 We have found
that the α-CD band originates from the torsion around the 12–
13 single bond of the chromophore and that the twisted 6s-
single bond strongly affects the β-band of Rho using the retinal
analog, in which the 12–13 or 5–6 single bond of retinal was
fixed by the five-membered ring.5 Very recently, we have also
shown that the torsional angle around the 6–7 single bond of
retinal chromophore in Rho is very close to that of 8,18-
ethanoretinal 3, in which the C8 and C18 positions of 2 are
connected by an ethylene group, from the comparison of opsin
shift and CD spectrum of the artificial pigment with those of
native rhodopsin.6 In this paper, we describe the synthesis of
(11Z)-8,18-propano- and methano-retinal 4 and 5, which have
one more or fewer methylene group than does 3, and their
interaction with bovine opsin in order to clarify the effect on the
CD spectrum of a change of the torsional angle around the 6–7
single bond in the chromophore, including a full account of our
preliminary communication.7
Fig. 1
in the same manner as described for the preparation of 38 in
seven steps (11% yield, Scheme 1). The reaction of 10 with tri-
methylsilylethynylcerium() reagent9 smoothly proceeded to
afford the alcohol 11 in 87% yield. The attempted conversion of
11 to the corresponding β-ionone analog 12Ј using formic
acid10 was unsuccessful, because the conjugated geometrical
double-bond isomer 12 was obtained as a sole product in poor
yield. From this fact, we speculated that the thermodynamic
energy difference between the olefinic compounds 12 and 12Ј
was not enough to produce the more conjugated olefin 12 in the
dehydration process due to a torsion of the 6–7 (ref. 11) single
bond of the bicyclic ring skeleton. To circumvent this problem,
we tried to perform dehydration after elongation of the side
chain.
Hydration of 11 was achieved by the usual manner using
mercury() oxide and sulfuric acid to give the ketone 13 in
68% yield. After acetylation of the hydroxy group in 13, the
Horner–Emmons reaction of 14 with a C-2 phosphonate gave
the nitrile 15 as a mixture of newly produced double-bond iso-
mers. In the diisobutylaluminium hydride (DIBAL-H) reduc-
tion of 15, isomerization of the double bond and deacetylation
of the acetoxy group occurred at the same time to afford the
aldehyde 16 as a single product. Dehydration of 16 by thionyl
dichloride gave the more conjugated aldehyde 17 as the sole
product in moderate yield (Scheme 2). The structure of 17 was
Results and discussion
(11Z )-8,18-Propanoretinal 4. The bicyclic ketone 10 was pre-
pared from the β-keto ester 6 via the Dieckmann condensation
† Electronic supplementary information (ESI) available: UV-VIS and 1H
NMR data are available for retinal, 8,18-propanoretinal and 8,18-meth-
anoretinal isomers. See http://www.rsc.org/suppdata/p1/b1/b104394n/
2430
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104394n

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another approach for the synthesis of trienyl compound 19. It is
well known that the palladium-catalyzed cross-coupling reac-
tion of a vinyl group and an aryl triflate with organometallics is
a powerful tool for the preparation of alkenes and alkynes.12
So, we adopted this methodology for the preparation of β-
ionylideneaceto ester analog 19. Treatment of vinyl triflate 18,
derived from 10 in 57% yield by the reaction of N,N-bis-
(trifluoromethylsulfonyl)aniline (Tf2NPh) and lithium diiso-
propylamide (LDA) in 1,2-dimethoxyethane (DME), with
methyl (E)-3-trimethylstannylbut-2-enoate13 in the presence of
palladium diacetate and triethylamine afforded the coupling
product 19 in 39% yield, accompanied by the recovery of tri-
flate 18 (28%).
The transformation of 19 into the Wittig salt 20 was accom-
plished by the sequence of lithium aluminium hydride (LiAlH4)
reduction and treatment with triphenylphosphine hydrobro-
mide. The Wittig reaction of 20 with methyl (E)-3-formyl-
crotonate14 was achieved using NaOMe as a base to give the
ester 21 in 84% yield as a mixture of geometrical isomers.
Without isolation of this mixture, the final conversion of 21 to
the corresponding aldehyde was established according to the
usual method of LiAlH4 reduction and manganese() dioxide
(MnO2) oxidation, and the 11Z-isomer 4 was isolated in pure
form by repeated preparative high-performance liquid chrom-
atography (HPLC) in the dark (Scheme 3). The structures of 4
Scheme 1 Reagents and conditions (and yields): i, NaH, Br(CH2)4-
CO2Et, reflux, ii, c. HCl, reflux; iii, c. H2SO4, EtOH, reflux (49% from
6); iv, LDA, AcOEt, THF, Ϫ70 ЊC (91%); v, SOCl2, pyridine, 0 ЊC
(95%); vi, t-BuOK, o-xylene, reflux, viii, MgCl2ؒ6H2O, DMSO, 160 ЊC
(27% from 9).
1
and its all-E-isomer were determined on the basis of their H
NMR spectra. The assignments of all signals were carried out
by a comparison of chemical-shift values with those of retinal
isomers in CD3OD (see Supplementary information).
Scheme 3 Reagents and conditions (and yields): i, LDA, Tf2NPh,
᎐
Scheme 2 Reagents and conditions (and yields): i, TMS C᎐CCeCl2,
᎐
DME, rt, (57%); ii, Me3Sn(Me)C᎐CHCO2Me, Pd(OAc)2, DMF, rt,
᎐
THF, Ϫ70 ЊC (87%); ii, 85% HCOOH, 90 ЊC, (3%); iii, HgO, H2SO4,
120 ЊC, (68%); iv, Ac2O, Et3N, DMAP, 100 ЊC (72%); v, n-BuLi,
(i-PrO)2P(O)CH2CN, THF, 0 ЊC (75%); vi, DlBAL-H, CH2Cl2, 0 ЊC
(57%); vii, SOCl2, pyridine, 0 ЊC (95%).
(39%); iii, LiAIH4, Et2O; iv, Ph3PؒHBr; v, NaOMe, OHC(Me)C᎐
᎐
CHCO2Me, CH2Cl2, (84% from 19); vi, MnO2, CH2Cl2, (27% from 20);
vii, prep HPLC.
(11Z )-8,18-Methanoretinal 5. A preparation of (all-E)-8,18-
methanoretinal 5Ј had been reported by Lugtenburg and
co-workers,15 via the β-ionone analog 22 (Fig. 2). The trans-
formation of the β-ionone analog into the corresponding
(11Z)-retinal via the Wittig reaction between the analog of β-
ionylideneethyltriphenylphosphonium salt and the appropriate
C5 aldehyde is well established.6,16 To adopt this methodology
for the synthesis (11Z)-8,18-methanoretinal 5, our first attempt
confirmed from the nuclear Overhauser effect (NOE) experi-
ment in its H NMR spectrum, in which both the cross-peaks
between the olefinic proton in the side chain (10 position) with
the methylene protons and the methyl protons at the 9 position
with the olefinic proton at 7 position were detected.
1
Although we could obtain the trienyl aldehyde 17, it required
many steps and the total yield is not satisfactory, so we tried
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
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Fig. 2
Fig. 3
at the preparation of 22 according to the previously reported
method being unsuccessful, we decided to develop our original
method.
The Dieckmann condensation of the diester 25, prepared
from the β-keto ester 6 in the same manner as that described for
the preparation of 9 in five steps (49% yield), and subsequent
deethoxycarbonylation, gave the aromatized phenol 26 and the
bicyclic ketone 27 in 7% and 14% yield, respectively (Scheme 4).
It seemed that the conditions used in these reactions were too
drastic to produce the ketone 27 because the yield was low and
the phenol 26 was obtained as a by-product.
Scheme 5 Reagents and conditions (and yields): i, c. HCl; ii, DCC,
DMAP, CH2᎐᎐CHCH2OH, CH2Cl2, rt, 86% from 23; iii, LDA,
AcOallyl, THF, Ϫ70 ЊC, 82%; iv, SOCl2, pyridine, 0 ЊC (85%); v, LDA,
THF, 0 ЊC, (49%) or LiTMP, THF, 0 ЊC (62%); vi, Pd(OAc)2, PPh3,
HCO2H, Et3N, rt, 68% from 31 and 32.
Subsequently, we focused our attention on the transform-
ation of the ketone 27 into the (11Z)-retinal analog. The
trienyl ester 35 was prepared by the palladium-catalyzed cross-
coupling reaction of the triflate 34, derived from 27 (58%),
with methyl (E)-3-(trimethylstannyl)but-2-enoate in 62% yield.
According to the same procedure described for the prepar-
ation of (11Z)-8,18-propanoretinal 4, the ester 35 was con-
verted to the Wittig salt 36 followed by condensation with
methyl (E)-3-formylcrotonate to give the two products 37 and
38 as a mixture of double-bond isomers. Without isolation of
this mixture, upon the transformation of the esters 37 and 38
into the corresponding aldehydes by LiAlH4 reduction and
subsequent MnO2 oxidation, the desired (11Z)-8,18-
methanoretinal 5 was not detected at all, and the aromatized
aldehyde 39 was obtained as an isomeric mixture. It seemed
that aromatization of 37 had occurred during the oxidation
step (Scheme 6).
To avoid aromatization of the dihydrobenzene ring, (E)-3-
formylbut-2-enenitrile18 was used in a condensation of the
Wittig salt 36, because it is well known that a nitrile group
can easily be converted to an aldehyde group by DIBAL-H
reduction. The Wittig reaction of 36 with (E)-3-formylbut-2-
enenitrile proceeded to afford the pentaenyl nitrile 40 in 24%
yield as a mixture of geometrical isomers. Without isolation of
these isomers, the transformation of 40 into the corresponding
aldehyde mixture was achieved by DIBAL-H reduction in 44%
yield. The 11Z-isomer 5 was isolated in pure form by repeated
preparative HPLC in the dark (Scheme 7). The structures of 5
and its isomers were determined on the basis of their 1H NMR
spectra, and the assignments of all signals were carried out by
a comparison of chemical-shift values with those of retinal
isomers (see Supplementary information).
Scheme 4 Reagents and conditions (and yields): i, NaOEt, CH2᎐᎐
CHCO2Et, rt, ii, c. HCl, reflux; iii, c. H2SO4, EtOH, reflux (82% from
6); iv, LDA, AcOEt, THF, Ϫ70 ЊC (73%); v, SOCl2, pyridine, 0 ЊC
(82%); vi, t-BuOK, o-xylene, reflux; vii, MgCl2ؒ6H2O, DMSO, 160 ЊC
(21% from 25).
Tsuji et al.17 reported a dealkoxycarbonylation of an allyl
ester using a palladium catalyst under mild conditions. Thus, to
apply this methodology to the preparation of bicyclic ketone
27, diallyl ester 30 was prepared from the ester 23 in four steps
(60% yield). Initially, the Dieckmann condensation of the
diester 30 under mild conditions was tried. When LDA in THF
at 0 ЊC was used as a base, three cyclized products 31, 32 and
33 were obtained in 10%, 21% and 18% yield, respectively.
These structures were determined on the basis of their 1H
NMR spectra. On the other hand, in the case of using lithium
tetramethylpiperidide (LiTMP), the two cyclized products 32
and 33 were generated in 33% and 29% yield, respectively. This
fact was easily understandable upon consideration of the
anionic reaction intermediate. Thus, in the case of a small base
such as LDA, two different anionic intermediates 30ЈA and
30ЈB (Fig. 3) were generated to give three products. On the other
hand, in the case of a bulky base, only a single intemediate 30ЈB
was produced, to afford the two cyclized products. Deallyloxy-
carbonylation of a mixture of 31 and 32 proceeded smoothly by
treatment with formic acid and triethylamine in the presence
of palladium() acetate and triphenylphosphine to afford the
desired ketone 27 in 68% yield (Scheme 5).
Binding with bovine opsin. Binding experiments of 4 and 5
with bovine opsin purified according to the previously reported
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Fig. 4
Scheme 7 Reagents and conditions (and yields): i, LiAlH4, Et2O; ii,
Ph3PؒHBr; iii, NaOMe, OHC(Me)C᎐CHCN, CH2Cl2 (24% from 35); iv,
᎐
DlBALH, hexane (44%); v, prep. HPLC.
ition, this speculation was supported by the fact that the opsin
shift of 5, in which the torsional angle of the C6–7 single bond
is about 30Њ, is very close to those of 3 and 4 (only 150 cmϪ1 in
difference). In contrast, from a comparison of CD spectra, we
found important features in the both α- and β-bands. Thus, the
intensity of the α-band increased according to increasing tor-
sional angle around the C6–7 single bond (5
3
4), whereas
the intensity of the β-band decreased. In addition, in respect of
the change of the intensity-degree in both α- and β-bands, the
difference of the β-band is greater than that of the α-band. In
connection with the fact that the bicyclic retinal 41 had no
twisted conformation around the C6–7 single bond, which was
fixed by the five-membered ring, and also exhibits the β-band,6
it is strongly suggested that the origin of the β-band would be
the total combination of both the twisted conformations of the
C6–7 and C8–9 single bonds of the chromophore.
In summary, an important conclusion was obtained from the
above experiments that the β-band was affected by the torsional
angle of the C6–7 single bond and that the origin of the β-
band was expected to be the total combination of the twisted
conformation of both the C6–7 and C8–9 single bonds in the
retinal chromophore.
Scheme 6 Reagents and conditions (and yields): i, LDA, Tf2NPh,
DME, rt, (58%); ii, Me3Sn(Me)C᎐CHCO2Me, Pd(OAc)2, DMF, rt,
᎐
(62%); iii, LiAlH4, Et2O; iv, Ph3PؒHBr; v, NaOMe, OHC(Me)C᎐
᎐
CHCO2Me, CH2Cl2 (28% from 35); vi, MnO2, CH2Cl2.
method19 were carried out in a 3-[(3-cholamidopropyl)dimethyl-
ammonio]propane-1-sulfonate–phosphatidyl choline (CHAPS–
PC) mixture to afford the novel rhodopsin analogs. The PSBs of
4 and 5 with n-butylamine were formed by the usual method.
The absorption maxima, opsin shifts and CD data of artificial
pigments derived from 3–5 and retinal analog (41, Fig. 4; n = 0 in
Fig. 1), whose 8 and 18 positions were directly connected, are
shown in Table 1 and Fig. 5 with those of native rhodopsin.
We had not expected that the opsin shift of 4 would exhibit
almost the same value as that of 3, although the torsion angles
around the cyclohexene ring and the polyene side chain in 3 and
4 are very different, e.g. 50–55 and 80–85Њ, respectively, from an
examination of their Dreiding models. This fact indicates that
such a difference in torsional angle between compounds 3 and 4
does not cause a significant effect on the opsin shift. In add-
Experimental
Ether refers to diethyl ether, and hexane to n-hexane. n-BuLi
was used as a solution in hexane. UV-VIS spectra were
recorded on a JASCO Ubest-55 instrument, and IR or FT-IR
spectra on a Shimadzu IR-27G or Shimadzu FT-IR-4200
1
spectrometer. H NMR spectra at 200 MHz or 500 MHz were
measured on a Varian XL-200 or a Varian VXR-500 super-
conducting FT-NMR spectrometer with tetramethylsilane as
internal standard. 13C NMR spectra were recorded on a Varian
VXR-500 instrument operating at 125 MHz. Mass spectra were
determined on a Hitachi M-4100 spectrometer. Analytical
HPLC was carried out on a Shimadzu LC-5A instrument with
a Shimadzu photodiode array UV-VIS detector SPD-M6A
Table 1 Absorption maxima, CD data and opsin shift of rhodopsin and its analogs
Rhodopsinc CD/nm
(mdeg/absorption)
Aldehydesa
λmax/nm
PSBb
λmax/nm
Opsin shifts
Chromophores (compound no.)
λmax/nm
α-band
β-band
∆ν/cmϪ1
6,7-Bicyclic retinal 3
6,8-Bicyclic retinal 4
6,6-Bicyclic retinal 5
6,5-Bicyclic retinal 41
(11Z)-Retinal 2
386
374
416
422
377
457
440
496
506
440
503d
483
491d (ϩ8.2)
475 (ϩ11.0)
545 (ϩ5.5)
526e (ϩ12.3)
489e (ϩ8.7)
335d (ϩ17.0)
340 (ϩ12.0)
340 (ϩ32.0)
332e (ϩ31.0)
332e (ϩ17.5)
2000
2000
1850
1200
2650
546
539e
498e
a In ethanol. b In methanol. c In CHAPS–PC mixture. d Ref. 6. e Ref. 5b.
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
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Fig. 5
using a column, LiChrosorb Si-60 (5 µm), 0.4 × 30 cm. Prepar-
ative HPLC was conducted on a Shimadzu LC-6A instrument
with a Shimadzu UV-VIS detector, SPD-6AV. Column chrom-
atography (CC) under reduced pressure was performed by using
Merck silica gel 60. All reactions were carried out in a nitrogen
atmosphere. THF and ether were purified by distillation from
benzophenone ketyl–sodium under nitrogen. Other solvents
used for reaction were dried prior to use. NaH was a 60% dis-
persion in mineral oil and used after washing with dry hexane.
Other chemicals were of reagent grade and used without purifi-
cation. Standard work-up means that the organic layers were
finally washed with brine, dried over anhydrous sodium sulfate
(Na2SO4), filtered, and concentrated in vacuo below 30 ЊC using
a rotary evaporator.
(14.5 g, 70%) as a colorless oil, δH (CDCl3) 1.03 (3H, s, Me),
1.07 (3H, s, Me), 1.25 (3H, t, J = 7 Hz, CO2CH2CH3), 1.3–1.8
(9H, m, CH2 × 4 and CH2 × 1/2), 1.8–2.1 (2H, m, CH2), 2.2–2.4
(2H, m, CH2), 2.5–2.6 (1H, m, CH2 × 1/2), 3.66 (3H, s,
CO2CH3), 4.14 (2H, q, J = 7 Hz, CO2CH2CH3).
A mixture of this keto diester (17 g, 54.5 mmol) and c. HCl
(70 cm3) was refluxed for 18 h. After cooling, water (150 cm3)
was added, and the organics were extracted with ether (3 × 80
cm3), followed by standard work-up to give the crude acid. To
the residue were added anhydrous ethanol (160 cm3) and c.
H2SO4 (1 cm3) and the resulting mixture was refluxed for 20 h.
After cooling, the mixture was poured into water (100 cm3) and
the organics were extracted with ether (2 × 100 cm3), followed
by standard work-up. The residue was purified by CC (ether–
hexane, 1 : 6) to afford the keto ester 7 (9.7 g, 70%) as a pale
yellow oil, νmax (CHCl3)/cmϪ1 1725, 1700; δH (CDCl3) 1.04 (3H,
s, Me), 1.19 (3H, s, Me), 1.27 (3H, t, J = 7 Hz, CO2CH2CH3),
1.4–1.9 (11H, m, CH2 × 5 and CH2 × 1/2), 2.12 (1H, ddt like,
J = 13, 6, 3 Hz, CH2 × 1/2), 2.32 (2H, t, J × 7 Hz, CH2), 2.54
(1H, m, CH), 4.17 (2H, q, J × 7 Hz, CO2CH2CH3) [Found
(HRMS): Mϩ, 254.1898. Calc. for C15H26O3: M, 254.1880].
Synthesis of (11Z )-8,18-propanoretinal 4
Ethyl 5-(3,3-dimethyl-2-oxocyclohexyl)pentanoate 7. To a
suspension of NaH (60% dispersion in oil; 3.4 g, 0.085 mol) in
THF (65 cm3) and DMF (7 cm3) was added a solution of β-keto
ester 68 (12.2 g, 0.066 mol) in THF (70 cm3) at 0 ЊC. After
stirring of the mixture for 15 min at room temperature, a sol-
ution of ethyl 5-bromopentanoate (28 g, 0.13 mmol) in THF
(70 cm3) was added dropwise and the resulting mixture was
heated under reflux for 18 h. After cooling, the mixture was
poured into 10% HCl (100 cm3) and the organics were extracted
with ether (2 × 100 cm3), followed by standard work-up. The
residue was purified by CC (ether–hexane, 1 : 4) to give ethyl 5-
(1-methoxycarbonyl-3,3-dimethyl-2-oxocyclohexyl)pentanoate
Ethyl
5-(2-ethoxycarbonylmethyl-2-hydroxy-3,3-dimethyl-
cyclohexyl)pentanoate 8. To a stirred solution of LDA, pre-
pared from n-BuLi (1.7 M hexane solution; 24.8 cm3, 42.3
mmol) and diisopropylamine (4.27 g, 42.3 mmol) in THF (30
cm3), was added a solution of ethyl acetate (4.1 cm3, 42.3 mmol)
in THF (7 cm3) at Ϫ70 ЊC, and the resulting mixture was stirred
for an additional 30 min. A solution of the keto ester 7 (3.58 g,
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14 mmol) in THF (10 cm3) was added at Ϫ70 ЊC and the mix-
ture was further stirred for 2 h. After addition of saturated aq.
NH4Cl (80 cm3) and evaporation of the solvent, the organics
were extracted with ether (3 × 70 cm3), followed by standard
work-up. The residue was purified by CC (ether–hexane, 1 : 5)
to give a mixture of stereoisomers 8 (4.41 g, 91%) as a pale
yellow oil. NMR analysis indicated that the ratio of stereo-
isomers was 2 : 1; νmax (CHCl3)/cmϪ1 3470, 1720, 1710; δH
(CDCl3) 0.88 (1/3 × 3 H, s, Me), 0.92 (2/3 × 6H, s, Me × 2), 1.02
(1/3 × 3H, s, Me), 1.25 (3H, t, J = 7 Hz, CO2CH2CH3), 1.29 (3H,
t, J = 7 Hz, CO2CH2CH3), 1.1–1.9 (13H, m, CH2 × 6 and CH),
2.31 (2H, t, J = 7 Hz, CH2), 2.38 (2/3 × 1H, d, J = 16 Hz,
CH2COO), 2.42 (1/3 × 1H, d, J = 16 Hz, CH2COO), 2.56 (2/3H,
d, J = 16 Hz, CH2COO), 2.60 (1/3H, d, J = 16 Hz, CH2COO),
4.16 (2H, q, J = 7 Hz, CO2CH2CH3), 4.20 (2H, q, J = 7 Hz,
CO2CH2CH3), 4.33 (2/3 × 1H, s, OH, disappeared with D2O),
4.92 (1/3 × 1H, s, OH, disappeared with D2O) [Found (HRMS):
Mϩ, 342.2421. Calc. for C19H34O5: M, 342.2404].
suspension of anhydrous cerium() chloride (0.8 g, 3.3 mmol)
in THF (13 cm3) was added dropwise at Ϫ70 ЊC a solution of
lithium trimethylsilylacetylene, prepared from trimethylsilyl-
acetylene (0.45 cm3, 3.3 mmol) and n-BuLi (1.7 M hexane solu-
tion; 1.9 cm3, 3.3 mmol) in THF (6 cm3). After stirring had been
continued for 1 h, a solution of 10 (260 mg, 1.3 mmol) in THF
(6 cm3) was added and the resulting mixture was stirred for an
additional 3 h at Ϫ70 ЊC. The reaction mixture was quenched
with saturated aq. NH4Cl (20 cm3) and filtered through Celite.
The filtrate was extracted with ether (3 × 20 cm3), followed by
standard work-up. The residue was purified by CC (ether–
hexane, 1 : 7) to afford the acetylenic alcohol 11 (333 mg, 87%)
as a colorless oil, νmax (CHCl3)/cmϪ1 3600, 2250; δH (CDCl3)
0.16 (9H, s, SiMe3, 1.10 (3H, s, Me), 1.13 (3H, s, Me), 1.4–1.8
(10 H, m, CH2 × 5), 1.88 (1H, br s, OH, disappeared with D2O),
1.9–2.1 (4H, m, CH2 × 2), 2.57 (1H, d, J = 14 Hz, CH2 × 1/2),
2.66 (1H, d, J = 14 Hz, CH2 × 1/2) [Found (HRMS): Mϩ,
304.2237. Calc. for C19H32OSi: M, 304.2221].
Dehydration of 8. To a solution of the hydroxy diester 8
(9.65 g, 28.2 mmol) in pyridine (120 cm3) was added thionyl
dichloride (2.4 cm3, 34 mmol) at 0 ЊC, and the resulting mixture
was stirred for 10 min. The reaction was quenched with 5% HCl
(200 cm3) in an ice-bath, and the organics were extracted with
ether (3 × 80 cm3), followed by standard work-up. The residue
was purified by CC (ether–hexane, 1 : 6) to give a mixture
of diesters 9 (8.70 g, 95%) as a colorless oil. NMR analysis
indicated that the endo and exo double-bond isomers were
present in the ratio of 5 : 1. Analytical samples were obtained
respectively by further CC using the same eluent.
9-Acetyl-1,1-dimethyl-1,2,3,4,5,6,7,10-octahydrobenzocyclo-
octene 12. A mixture of the acetylenic alcohol 11 (105 mg, 0.35
mmol) and 85% HCOOH (0.6 cm3) was heated at 90 ЊC for
4.5 h. After cooling, the reaction mixture was neutralized with
cold 5% NaOH in an ice-bath. The organics were extracted with
ether (3 × 20 cm3), followed by standard work-up. The residue
was purified by CC (ether–hexane, 1 : 5) to afford the ketone 12
(2.8 mg, 3%) as a pale yellow oil; δH (CDCl3) 1.00 (6H, s, Me ×
2), 1.4–1.8 (8H, m, CH2 × 3 and [CH2 × 1/2] × 2), 1.8–2.0 (2H,
m, [CH2 × 1/2] × 2), 2.0–2.2 (2H, m, CH2), 2.34 (3H, s,
COCH ), 3.00 (2H, br s, CH ), 6.88 (1H, tt, J = 8, 2 Hz, ᎐CH).
᎐
3
2
Endo-isomer. νmax (CHCl3)/cmϪ1 1730; δH (CDCl3) 0.98 (6H, s,
Me × 2), 1.28 (6H, t, J = 7 Hz, CO2CH2CH3 × 2), 1.4–1.7 (9H,
m, CH2 × 4 and CH2 × 1/2), 1.9–2.1 (3H, m, CH2 and CH2 ×
1/2), 2.2–2.4 (2H, m, CH2), 3.04 (2H, s, CH2COO), 4.14 (2H, q,
J = 7 Hz, CO2CH2CH3), 4.15 (2H, q, J = 7 Hz, CO2CH2-
CH3) [Found (HRMS): Mϩ, 324.2312. Calc. for C19H32O4: M,
324.2299].
9-Acetyl-9-hydroxy-1,1-dimethyl-1,2,3,4,5,6,7,8,9,10-deca-
hydrobenzocyclooctene 13. A mixture of acetylenic alcohol 11
(19.7 mg, 0.065 mmol), HgO (yellow, 42 mg, 0.19 mmol) and
1.5 M H2SO4 (1 cm3) in THF (4 cm3) was heated at 120 ЊC for 40
min. After cooling, NH4Cl was added and the organics were
extracted with CH2Cl2 (3 × 20 cm3), followed by standard work-
up. The residue was purified by CC (ether–hexane, 1 : 5) to
afford the hydroxy ketone 13 (11 mg, 68%) as a pale yellow oil,
νmax (CHCl3)/cmϪ1 3500, 1705; δH (CDCl3) 0.91 (3H, s, Me),
1.10 (3H, s, Me), 1.3–1.9 (14H, m, CH2 × 7), 2.05 (1H, d, J = 16
Hz, CH2 × 1/2), 2.28 (3H, s, COCH3), 2.61 (1H, d, J = 16 Hz,
CH2 × 1/2), 3.33 (1H, s, OH, disappeared with D2O) [Found
(HRMS): Mϩ, 250.1917. Calc. for C16H26O2: M, 250.1931].
Exo-isomer. νmax (CHCl3)/cmϪ1 1725, 1710, 1620; δH (CDCl3)
1.14 (3H, s, Me), 1.16 (3H, s, Me), 1.28 (3H, t, J = 7 Hz,
CO2CH2CH3), 1.31 (3H, t, J = 7 Hz, CO2CH2CH3), 1.4–1.9
(12H, m, CH2 × 6), 2.34 (2H, t, J = 7 Hz, CH2), 3.8–3.9 (1H, m,
CH), 4.18 (2H, q, J = 7 Hz, CO2CH2CH3), 4.19 (2H, q, J = 7 Hz,
CO CH CH ), 5.82 (1H, s, ᎐CH) [Found (HRMS): Mϩ,
᎐
2
2
3
324.2290. Calc. for: C19H32O4 : M, 324.2299].
4,4-Dimethyl-1,2,3,4,7,8,9,10-octahydrobenzocycloocten-
6(5H)-one 10. A solution of the diester 9 (80 mg, 0.24 mmol) in
o-xylene (2 cm3) was added dropwise to a stirred suspension of
t-BuOK (0.14 g, 1.2 mmol) in o-xylene (12 cm3) at 160 ЊC.
The mixture was further stirred for 5 min at this temperature,
and then cooled to room temperature. Saturated aq. NH4Cl
(100 cm3) was added, and the organic layer was separated. The
aqueous layer was extracted with ether (2 × 10 cm3), and the
combined organic extracts were treated as standard work-up.
The residue was purified by CC (ether–hexane, 1 : 7) to give
an isomeric mixture of the β-keto esters (35.3 mg, 52%) as a
colorless oil.
The mixture of β-keto esters (35.3 mg) and MgCl2ؒ6H2O
(0.1 g, 5 eq.) in DMSO (4 cm3) was heated at 160 ЊC for 3 h.
After cooling, water (25 cm3) was added and the organics were
extracted with ether (3 × 10 cm3), followed by standard work-
up. The residue was purified by CC (ether–hexane, 1 : 6) to
afford the bicyclic ketone 10 (13.6 mg, 27%) as a colorless oil.
νmax (CHCl3)/cmϪ1 1690; δH (CDCl3) 0.98 (6H, s, Me × 2), 1.4–
1.5 (2H, m, CH2), 1.5–1.8 (6H, m, CH2 × 3), 2.0–2.1 (4H, m,
CH2 × 2), 2.4–2.5 (2H, m, CH2), 3.15 (2H, s, CH2) [Found
(HRMS): Mϩ, 206.1690. Calc. for C14H22O: M, 206.1669].
9-Acetoxy-9-acetyl-1,1-dimethyl-1,2,3,4,5,6,7,8,9,10-deca-
hydrobenzocyclooctene 14. A solution of the hydroxy ketone 13
(52 mg, 0.20 mmol) in triethylamine (3 cm3) were added acetic
anhydride (0.4 cm3, 4.2 mmol) and DMAP (50 mg, 0.40 mmol)
at 0 ЊC, and the resulting mixture was heated at 100 ЊC for 2 h.
After cooling, 10% HCl was added and the organics were
extracted with ether (3 × 20 cm3), followed by standard work-
up. The residue was purified by CC (ether–hexane, 1 : 7) to
afford the acetoxy ketone 14 (44 mg, 72%) as a pale yellow oil,
νmax (CHCl3)/cmϪ1 1730, 1720; δH (CDCl3) 0.93 (3H, s, Me),
1.09 (3H, s, Me), 1.3–1.7 (8H, m, CH2 × 4), 1.7–2.0 (4H, m,
CH2 × 2), 2.09 (3H, s, COMe), 2.12 (3H, s, OAc), 2.1–2.4 (2H,
m, CH2), 2.54 (1H, d, J = 16 Hz, CH2 × 1/2), 2.72 (1H, d, J = 16
Hz, CH2 × 1/2) [Found (HRMS): Mϩ, 292.2030. Calc. for
C18H28O3: M, 292.2037].
(2E/Z )-3-(6-Acetoxy-4,4-dimethyl-1,2,3,4,5,6,7,8,9,10-
decahydrobenzocycloocten-6-yl)but-2-enenitrile 15. To a stirred
solution of diisopropyl cyanomethylphosphonate (64 mg, 0.36
mmol) in THF (3 cm3) was added a hexane solution of n-BuLi
(1.6 M; 0.22 cm3, 0.36 mmol) at 0 ЊC. After stirring of the
mixture for 30 min, a solution of the acetoxy ketone 14 (21 mg,
0.072 mmol) in THF (2 cm3) was added slowly at 0 ЊC, and the
resulting mixture was stirred for 48 h at room temperature. The
reaction was quenched with saturated aq. NH4Cl (10 cm3), and
9-Hydroxy-1,1-dimethyl-9-(2-trimethylsilylethynyl)-
1,2,3,4,5,6,7,8,9,10-decahydrobenzocyclooctene 11. To a stirred
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
2435

View Article Online
the organics were extracted with ether (3 × 20 cm3), followed by
standard work-up. The residue was purified by CC (ether–
hexane, 1 : 6) to provide the nitrile 15 (17 mg, 75%) as a mixture
of stereoisomers. NMR analysis indicated that the double-bond
stereoisomers were present in the ratio 4 : 3; νmax (CHCl3)/cmϪ1
2250, 1725, 1620; δH (CDCl3) 0.93 (3/7 × 3H, s, Me), 0.95 (4/7 ×
3H, s, Me), 1.10 (3/7 × 3H, s, Me), 1.13 (4/7 × 3H, s, Me), 1.3–
2.0 (12 H, m, CH2 × 6), 2.04 (4/7 × 3H, s, OAc), 2.05 (3/7 × 3H,
s, OAc), 2.10 (3/7 × 3H, s, CH3), 2.14 (4/7 × 3H, s, CH3), 2.2–2.4
(2H, m, CH2), 2.54 (1H, d, J = 16 Hz, CH2 × 1/2), 2.63 (1H, d,
nitrogen. The resulting mixture was stirred for an additional
24 h at room temperature. After addition of saturated aq. NH4Cl
(20 cm3), the organics were extracted with ether (3 × 20 cm3),
followed by standard work-up. The residue was purified by
HPLC [LiChrosorb Si-60 (5 µm), 1 × 25 cm, hexane–ether
(98 : 2), detection in wavelength 240 nm, flow rate 2.2 cm3
minϪ1] to afford the trienyl ester 19 (20 mg, 39%) as a pale
yellow oil, accompanied by the recovery of triflate 18 (19 mg,
28%); λmax (EtOH)/nm 270, 295; νmax (CHCl3)/cmϪ1 1715, 1615;
δH (CDCl3) 0.84 (3H, s, Me), 1.05–1.14 (2H, m, [CH2 × 1/2] ×
2), 1.12 (3H, s, Me), 1.46–1.52 (2H, m, CH2), 1.58–1.64 (1H, m,
CH2 × 1/2), 1.64–1.72 (2H, m, CH2), 1.76 (1H, t, J = 8.5 Hz,
CH2 × 1/2), 1.82–1.87 (2H, m, CH2), 1.95 (2H, br t, J = 10.5 Hz,
[CH2 × 1/2] × 2), 2.22 (1H, dt, J = 18.5, 4 Hz, CH2 × 1/2), 2.39
(3H, s, Me), 2.46 (1H, dd, J = 14, 8.5 Hz, CH2 × 1/2), 3.73 (3H,
J = 16 Hz, CH × 1/2), 5.27 (4/7H, s, ᎐CH), 5.70 (3/7H, s, ᎐CH)
᎐
᎐
2
[Found (HRMS): Mϩ, 315.2207. Calc. for C20H29NO2: M,
315.2197].
(2E )-3-(6-Hydroxy-4,4-dimethyl-1,2,3,4,5,6,7,8,9,10-deca-
hydrobenzocycloocten-6-yl)but-2-enal 16. To a solution of the
nitrile 15 (27 mg, 0.09 mmol) in CH2Cl2 (2 cm3) was added
dropwise DIBAL-H (0.03 cm3, 0.17 mmol) in dry CH2Cl2
(1 cm3) at 0 ЊC. After stirring of the mixture for an additional 10
min at 0 ЊC, the excess of DIBAL-H was destroyed by addition
of moist silica gel. The silica gel was filtered off, and the filtrate
was extracted with CH2Cl2 (3 × 10 cm3), followed by standard
work-up. The residue was purified by CC (ether–hexane, 1 : 4)
to provide the aldehyde 16 (13 mg, 57%) as a single stereo-
isomer, λmax (EtOH)/nm 240; νmax (CHCl3)/cmϪ1 3600–3200,
1665; δH (CDCl3) 0.93 (3H, s, Me), 1.12 (3H, s, Me), 1.40–1.48
(2H, m, CH2), 1.50–1.60 (3H, m, CH2 and CH2 × 1/2), 1.60–
1.70 (4H, m, CH2 × 2), 1.76–1.88 (2H, m, [CH2 × 1/2] × 2), 1.83
(1H, s, OH, disappeared with D2O), 2.14–2.22 (2H, m, [CH2 ×
1/2] × 2), 2.19 (1H, d, J = 15 Hz, CH2 × 1/2), 2.26 (3H, d, J = 1
Hz, CH3), 2.42 (1H, td, J = 14, 4 Hz, CH2 × 1/2), 2.63 (1H, d,
s, CO CH ), 5.97 (1H, br s, ᎐CH), 6.54 (1H, t, J = 1.5 Hz, ᎐CH);
᎐
᎐
2
3
δC (CDCl3) 15.75 (Me), 19.63 (CH2), 23.98 (CH2), 24.31 (CH2),
27.61 (CH2), 28.12 (Me), 28.60 (Me), 30.90 (CH2), 33.82 (CH2),
34.11 (C), 38.92 (CH2), 50.99 (OMe), 114.75 (CH), 129.94
(CH), 134.98 (C), 136.33 (C), 142.42 (C), 155.35 (C), 168.06
(CO) [Found (HRMS): Mϩ, 288.2065. Calc. for C19H28O2: M,
288.2087].
(11Z )-8,18-Propanoretinal 4. A solution of the trienyl ester
19 (55 mg, 0.18 mmol) in dry Et2O (2 cm3) was added to a
stirred suspension of LiAlH4 (14 mg, 0.36 mmol) in dry Et2O
(5 cm3) at 0 ЊC under nitrogen, and the resulting mixture was
stirred for an additional 15 min. The excess of LiAlH4 was
destroyed by the successive addition of moist Et2O and water,
and the mixture was extracted with Et2O. The extract was
washed with brine, dried (Na2SO4) and concentrated to afford
the crude alcohol, which was used the next reaction without
further purification.
Triphenyphosphine hydrobromide (84 mg, 0.24 mmol) was
added dropwise to a stirred solution of the crude alcohol in
methanol (2 cm3), and the resulting mixture was stirred for 20 h
at room temperature. Evaporation of the solvent gave a residue,
which was washed with ether to provide the Wittig salt 20.
A solution of the Wittig salt in CH2Cl2 (2 cm3) was added to
a stirred solution of methyl (E)-3-formylcrotonate14 (30 mg,
0.24 mmol) in MeOH (2 cm3, containing NaOMe, 0.24 mmol)
at 0 ЊC. The resulting mixture was stirred for 1 h, and water
(5 cm3) was added. After removal of the solvent, the residue was
extracted with ether. The extract was washed with brine and
then dried over Na2SO4. The solvent was removed in vacuo to
give a crude product, which was purified by CC (ether–hexane,
1 : 9) to afford the pentaenyl ester 21 (56 mg, 84% from 19) as a
mixture of stereoisomers.
J = 15 Hz, CH × 1/2), 6.29 (1H, dq, J = 8, 1 Hz, ᎐CH), 10.08
᎐
2
(1H, d, J = 8 Hz, CHO) [Found (HRMS): Mϩ, 276.2099. Calc.
for C18H28O2: M, 276.2088].
(2E )-3-(4,4-Dimethyl-1,2,3,4,7,8,9,10-octahydrobenzocyclo-
octen-6-yl)but-2-enal 17. As the same manner described for the
preparation of 9, dehydration of the hydroxy aldehyde 16
(13 mg, 0.047 mmol) was achieved. The crude product was
purified by CC (ether–hexane, 1 : 6) to give the trienal 17
(13 mg, 95%) as a pale yellow oil, λmax (EtOH)/nm 314, 281;
νmax (CHCl3)/cmϪ1 1660, 1600; δH (CDCl3) 0.88 (3H, s, Me),
0.99 (3H, s, Me), 1.3–2.5 (14H, m, CH2 × 7), 2.30 (3H, s,
Me), 6.14 (1H, d, J = 8 Hz, ᎐CH), 6.67 (1H, t-like, J = 2 Hz,
᎐
᎐CH), 10.14 (1H, d, J = 8 Hz, CHO) [Found (HRMS): Mϩ,
᎐
258.1990. Calc. for C18H26O: M, 258.1983].
4,4-Dimethyl-1,2,3,4,7,8,9,10-octahydrobenzocycloocten-6-yl
trifluoromethanesulfonate 18. To a stirred solution of LDA,
prepared from n-BuLi (1.7 M hexane solution; 1.17 cm3, 1.9
mmol) and diisopropylamine (0.27 cm3, 1.9 mmol) in DME
(6 cm3) was added a solution of the ketone 10 (157 mg, 0.76
mmol) in DME (2 cm3) at 0 ЊC, and the resulting mixture was
stirred for an additional 1 h. A solution of Tf2NPh (0.33 mg,
0.8 mmol) in DME (2 cm3) was added at 0 ЊC and the mixture
was further stirred for 3 h at rt. After addition of saturated aq.
NH4Cl (30 cm3), the organics were extracted with ether (3 × 70
cm3), followed by standard work-up. The residue was purified
by CC (ether–hexane, 1 : 9) to give the triflate 18 (147 mg, 57%)
as a pale yellow oil, λmax (EtOH)/nm 237; νmax (CHCl3)/cmϪ1
1410, 1135; δH (CDCl3) 1.00 (6H, s, Me × 2), 1.4–1.7 (8H, m,
CH2 × 4), 1.9–2.2 (4H, m, CH2 and [CH2 × 1/2] × 2), 2.3–2.4
A solution of the ester 21 (56 mg) in dry Et2O (5 cm3) was
added to a stirred suspension of LiAlH4 (12 mg, 0.32 mmol) in
dry Et2O at 0 ЊC. After the mixture had been stirred at 0 ЊC for
15 min, the excess of LiAlH4 was destroyed by the successive
addition of moist Et2O and water, and the whole was twice
extracted by Et2O. The combined extracts were washed with
brine, dried (Na2SO4) and concentrated in vacuo to give the
hydroxy compound as a pale yellow amorphous product.
A mixture of the resulting hydroxy compound and active
MnO2 (700 mg, 8 mmol) in dry CH2Cl2 (6 cm3) was shaken at
room temperature for 2 h and then filtered through Celite.
Evaporation of the filtrate gave an oil, which was purified by
CC (ether–hexane, 1 : 9) to yield an isomeric mixture of the
aldehydes (14 mg, 27%) as an orange oil. Separation of the
isomers was achieved by preparative HPLC [LiChrosorb Si-60
(7 µm) 1 × 25 cm; hexane–ether (98 : 2), 5 cm3 minϪ1, 350 nm] to
give 11Z-isomer 4 and all-E-isomer in the ratio 7 : 12.
(2H, m, [CH × 1/2] × 2), 6.10 (1H, t, J = 2 Hz, ᎐CH) [Found
᎐
2
(HRMS): Mϩ, 338.1168. Calc. for C15H21F3O3S: M, 338.1163].
Methyl (2E )-3-(4,4-dimethyl-1,2,3,4,7,8,9,10-octahydrobenzo-
cycloocten-6-yl)but-2-enoate 19. To a stirred solution of the
triflate 18 (69 mg, 0.2 mmol) and methyl (E)-trimethyl-
stannylbut-2-enoate13 (75 mg, 0.24 mmol) in DMF (1 cm3) was
added Pd(OAc)2 (1.6 mg, 3 mol%) at room temperature under
11Z-Isomer 4. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 258.5 (13
100), 374 (17 600); νmax (KBr)/cmϪ1 1660, 1575; δH (CD3OD)
0.86 (3H, s, Me), 1.14 (3H, s, Me), 1.06–1.20 (2H, m, [CH2 ×
1/2] × 2), 1.48–1.54 (2H, m, CH2), 1.57–1.63 (1H, m, CH2 ×
1/2), 1.63–1.72 (2H, m, CH2), 1.72–1.80 (1H, m, CH2 × 1/2),
2436
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439

View Article Online
1.86–1.90 (2H, m, CH2), 1.96–2.01 (1H, m, CH2 × 1/2), 2.01–
2.06 (1H, m, CH2 × 1/2), 2.05 (3H, s, Me), 2.24–2.30 (1H, m,
CH2 × 1/2), 2.39 (3H, d, J = 1 Hz, Me), 2.51 (1H, dd, J = 12.5,
1.4–2.7 (11H, m, CH2 × 5 and CH), 4.56 (2H, dt, J = 5.5, 1.5
Hz, CO CH CH᎐CH ), 5.24 (1H, dq, J = 10, 1.5 Hz,
᎐
2
2
2
CO CH CH᎐CH ), 5.28 (1H, dq, J = 17, 1.5 Hz, CO CH CH᎐
᎐
᎐
2
2
2
2
2
8.5 Hz, CH × 1/2), 6.02 (1H, br d, J = 8.5 Hz, ᎐CH), 6.06 (1H,
CH ), 5.8–6.0 (1H, m, CO CH CH᎐CH ) [Found (HRMS):
᎐
2 2 2 2
᎐
2
br d, J = 10 Hz, ᎐CH), 6.44 (1H, br s, ᎐CH), 6.83 (1H, d, J =
Mϩ, 238.1560. Calc. for C14H22O3: M, 238.1568].
᎐
᎐
11.5 Hz, ᎐CH), 6.86 (1H, dd, J = 11.5, 10 Hz, ᎐CH), 10.05 (1H,
᎐
᎐
d, J = 8.5 Hz, CHO); δC (CD3OD) 14.37 (Me), 18.30 (Me), 20.76
(CH2), 25.28 (CH2), 26.17 (CH2), 28.64 (Me), 29.20 (Me), 30.76
(CH2), 31.92 (CH2), 33.07 (C), 35.05 (CH2), 40.23 (CH2), 123.63
(CH), 128.24 (CH), 130.86 (CH), 131.74 (CH), 133.08 (C),
133.47 (CH), 135.70 (C), 137.96 (C), 142.98 (C), 144.20 (C),
193.36 (CHO) [Found (HRMS): Mϩ, 324.2422. Calc. for
C23H332O: M, 324.2451].
Ethyl
3-(2-ethoxycarbonylmethyl-2-hydroxy-3,3-dimethyl-
cyclohexyl)propanoate 24. This compound was prepared from
the keto ester 23 (6.8 g, 30 mmol) and ethyl acetate (5.3 g, 60
mmol) in 73% yield (6.8 g) as a pale yellow oil according to the
same procedure as described for the preparation of 8. NMR
analysis indicated that the ratio of stereoisomers was 1 : 3; νmax
(CHCl3)/cmϪ1 3450, 1720, 1710; δH (CDCl3) 0.92 (6H, s, Me ×
2), 1.25 (3H, t, J = 7 Hz, CO2CH2CH3), 1.29 (3H, t, J = 7 Hz,
CO2CH2CH3), 1.4–2.4 (11H, m, CH2 × 5 and CH), 2.46 (1/4 ×
1H, d, J = 16 Hz, CH2COO), 2.48 (3/4 × 1H, d, J = 16 Hz,
CH2COO), 2.52 (3/4 × 1H, d, J = 16 Hz, CH2COO), 2.53 (1/4 ×
1H, d, J = 16 Hz, CH2COO), 4.12 (2H, q, J = 7 Hz,
CO2CH2CH3), 4.16 (2H, q, J = 7 Hz, CO2CH2CH3), 4.40 (3/4 ×
1H, s, OH, disappeared with D2O), 4.93 (1/4 × 1H, s, OH,
disappeared with D2O) [Found (HRMS): Mϩ, 314.2104. Calc.
for C17H30O5: M, 314.2091].
All-E-isomer. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 378.5 (36
800); νmax (KBr)/cmϪ1 1660, 1575; δH (CD3OD) 0.87 (3H, s, Me),
1.14 (3H, s, Me), 1.04–1.22 (2H, m, [CH2 × 1/2] × 2), 1.48–1.54
(2H, m, CH2), 1.60–1.74 (3H, m, CH2 and CH2 × 1/2), 1.78–
1.86 (1H, m, CH2 × 1/2), 1.86–1.89 (2H, m, CH2), 1.94–2.02
(2H, m, [CH2 × 1/2] × 2), 2.11 (3H, d, J = 0.5 Hz, Me), 2.24–
2.32 (1H, m, CH2 × 1/2), 2.38 (3H, d, J = 1 Hz, Me), 2.60 (1H,
dd, J = 13.5, 8.5 Hz, CH × 1/2), 5.98 (1H, br d, J = 8 Hz, ᎐CH),
᎐
2
6.46 (1H, br s, ᎐CH), 6.51 (1H, br d, J = 11 Hz, ᎐CH), 6.52 (1H,
᎐
᎐
d, J = 15 Hz, ᎐CH), 7.36 (1H, dd, J = 15, 11 Hz, ᎐CH), 10.07
᎐
᎐
(1H, d, J = 8 Hz, CHO); δC (CD3OD) 13.23 (Me), 15.14 (Me),
20.81 (CH2), 25.33 (CH2), 26.08 (CH2), 28.39 (CH2), 28.67
(Me), 29.22 (Me), 31.96 (CH2), 35.05 (CH2), 35.21 (C), 40.28
(CH2), 127.76 (CH), 128.46 (CH), 129.72 (CH), 135.22 (CH),
135.76 (C), 136.11 (CH), 138.04 (C), 143.33 (C), 144.21 (C),
158.22 (C), 193.52 (CHO) [Found (HRMS): Mϩ, 324.2448. 22.
Calc. for C23H32O: M, 324.2451].
Allyl
3-(2-allyloxycarbonylmethyl-2-hydroxy-3,3-dimethyl-
cyclohexyl)propanoate 29. This compound was prepared from
the keto ester 28 (4.90 g, 21 mmol) and allyl acetate (6.10 g, 61
mmol) in 82% yield (5.74 g) as a mixture of diastereoisomers
according to the same procedure described for the preparation
of 8. NMR analysis indicated that the ratio of stereoisomers
was 1 : 2; νmax (CHCl3)/cmϪ1 3450, 1725; δH (CDCl3) 0.86 (1/3 ×
3H, s, Me), 0.92 (2/3 × 6H, s, Me × 2), 1.01 (1/3 × 3H, s, Me),
1.3–2.4 (11H, m, CH2 × 5 and CH), 2.50 (1/3 × 1H, d, J = 18
Hz, CH2COO), 2.54 (2/3 × 1H, d, J = 18 Hz, CH2COO), 2.63
(2/3 × 1H, d, J = 18 Hz, CH2COO), 2.66 (1/3 × 1H, d, J = 18 Hz,
CH2COO), 4.24 (2/3 × 1H, s, OH, disappeared with D2O), 4.58
Synthesis of (11Z )-8,18-methanoretinal 5
Ethyl 3-(3,3-dimethyl-2-oxocyclohexyl)propanoate 23. To a
stirred solution of the keto ester 6 (5.00 g, 27 mmol) in benzene
(100 cm3) and NaOEt (0.55 g, 8.2 mmol) was added a solution
of ethyl acrylate (5.4 g, 54 mmol) in benzene (25 cm3) at 0 ЊC
under nitrogen, and the resulting mixture was stirred for an
additional 6 h. After addition of saturated aq. NH4Cl (60 cm3),
the organics were extracted with benzene (3 × 80 cm3), followed
by standard work-up. The residue was purified by CC (hexane–
ether, 4 : 1) to afford ethyl 3-(1-methoxycarbonyl-3,3-dimethyl-
2-oxocyclohexyl)propanoate as a pale yellow oil, νmax (KBr)/
cmϪ1 1740, 1730; δH (CDCl3) 1.08 (3H, s, Me), 1.12 (3H, s, Me),
1.15 (3H, t, J = 7 Hz, CO2CH2CH3), 1.5–2.6 (10H, m, CH2 × 5),
3.68 (3H, s, CO2CH3), 4.11 (2H, q, J = 7 Hz, CO2CH2CH3).
This keto diester was converted to the ester 23 according to
the same manner as described for the preparation of 7, in 82%
yield (5.1 g) as a pale yellow oil, νmax (CHCl3)/cmϪ1 1730, 1705;
δH (CDCl3) 1.04 (3H, s, Me), 1.17 (3H, s, Me), 1.25 (3H, t, J = 7
Hz, CO2CH2CH3), 1.4–2.6 (11H, m, CH2 × 5 and CH), 4.17
(2H, q, J = 7 Hz, CO2CH2CH3) [Found (HRMS): Mϩ,
226.1553. Calc. for C13H22O3: M, 226.1567].
(4H, dt, J = 6, 1.5 Hz, CO CH CH᎐CH × 2), 4.81 (1/3 × 1H, s,
OH, disappeared with D O), 5.2–5.4 (4H, m, CO CH CH᎐
᎐
2
2
2
᎐
2
2
2
CH2 × 2), 5.8–6.0 (2H, m, CO CH CH᎐CH × 2) [Found
᎐
2
2
2
(HRMS): Mϩ, 338.2086. Calc. for C19H30O5: M, 338.2091].
Dehydration of 24. The diester 25 was prepared from the
hydroxy diester 24 (1.65 g, 5 mmol) and thionyl dichloride (0.75
cm3, 10 mmol) in 82% yield (1.39 g) as a mixture of double-
bond isomers according to the same procedure as described
for the preparation of 9. NMR analysis indicated that the endo
and exo double-bond isomers were present in the ratio 3 : 1.
Analytical samples were obtained by further CC (ether–hexane,
1 : 6), respectively.
Endo-Isomer. νmax (CHCl3)/cmϪ1 1720; δH (CDCl3) 0.96
(6H, s, Me × 2), 1.25 (6H, t, J = 7 Hz, CO2CH2CH3 × 2), 1.4–1.7
(4H, m, CH2 × 2), 1.98 (2H, t, J = 5 Hz, CH2), 2.2–2.5 (4H, m,
CH2 × 2), 3.08 (2H, s, CH2), 4.14 (4H, q, J = 7 Hz, CO2CH2-
CH3 × 2) [Found (HRMS): Mϩ, 296.1959. Calc. for C17H28O4:
M, 296.1986].
Allyl 3-(3,3-dimethyl-2-oxocyclohexyl)propanoate 28. A mix-
ture of ethyl 3-(1-methoxycarbonyl-3,3-dimethyl-2-oxocyclo-
hexyl)propanoate (6.64 g, 23 mmol), prepared as described for
the preparation of 23, and c. HCl (70 cm3) was refluxed for 18 h.
After cooling of the mixture, water (150 cm3) was added and
the organics were extracted with ether (3 × 80 cm3), followed by
standard work-up to give the crude acid.
Exo-Isomer. νmax (CHCl3)/cmϪ1 1725, 1710, 1620; δH (CDCl3)
1.12 (3H, s, Me), 1.15 (3H, s, Me), 1.25 (3H, t, J = 7 Hz,
CO2CH2CH3), 1.28 (3H, t, J = 7 Hz, CO2CH2CH3), 1.2–2.0
(8H, m, CH2 × 4), 2.3–2.5 (2H, m, CH2), 3.7–3.9 (1H, m, CH),
4.13 (2H, q, J = 7 Hz, CO2CH2CH3), 4.15 (2H, q, J = 7 Hz,
CO CH CH ), 5.86 (1H, s, ᎐CH) [Found (HRMS): Mϩ,
᎐
2
2
3
296.7971. Calc. for C17H28O4: M, 296.1986].
To a stirred solution of this crude acid, DMAP (40 mg, 0.33
mmol) and allyl alcohol (5.30 g, 92 mmol) in CH2Cl2 (90 cm3)
was added a solution of DCC (5.39 g, 25 mmol) in CH2Cl2 (40
cm3) at 0 ЊC, and the resulting mixture was further stirred for an
additional 2 h at room temperature. After filtration of the pre-
cipitate, the filtrate was concentrated under reduced pressure.
The residue was purified by CC (ether–hexane, 1 : 6) to afford
the keto ester 28 (4.79 g, 86%) as a pale yellow oil, νmax (CHCl3)/
cmϪ1 1720, 1700; δH (CDCl3) 1.03 (3H, s, Me), 1.17 (3H, s, Me),
Dehydration of 29. The diester 30 was prepared from the
hydroxy diester 29 (944 mg, 2.79 mmol) and thionyl dichloride
(664 mg, 5.58 mmol) in 85% yield (757 mg) as a mixture of
double-bond isomers according to the procedure described
for the preparation of 9. NMR analysis indicated that the endo
and exo double-bond isomers were present in the ratio 1 : 1.
Analytical samples were obtained by further CC (ether–hexane,
1 : 6).
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
2437

View Article Online
Endo-Isomer. νmax (CHCl3)/cmϪ1 1725; δH (CDCl3) 0.96 (6H,
s, Me × 2), 1.4–1.5 (2H, m, CH2), 1.5–1.7 (2H, m, CH2), 1.9–2.1
(2H, m, CH2), 2.2–2.5 (4H, m, CH2 × 2), 3.12 (2H, s, CH2), 4.56
(22 mg, 0.084 mmol) in THF (25 cm3) was added a solution of
formic acid (0.13 cm3, 3.3 mmol) and Et3N (0.58 cm3, 4.2 mmol)
in THF (25 ml) at room temperature under nitrogen. To the
resulting mixture was added a solution of cyclized ester 32 (437
mg, 1.67 mmol) in THF (15 ml), and the mixture was stirred for
an additional 20 h. After addition of Et2O and filtration with
Celite, the filtrate was concentrated under reduced pressure.
The residue was purified by CC (hexane–ether, 6 : 1) to afford
the bicyclic ketone 27 (202 mg, 68%) as a pale yellow oil,
accompanied by starting ester 32 (90 mg, 21% recovery). Com-
pound 27 was identical with an authentic specimen obtained
from the diester 25.
(4H, dt, J = 6, 1.5 Hz, CO CH CH᎐CH × 2), 5.2–5.4 (4H, m,
᎐
2
2
2
CO CH CH᎐CH × 2), 5.8–6.0 (2H, m, CO CH CH᎐CH ×
᎐
᎐
2
2
2
2
2
2
2) [Found (HRMS): Mϩ, 320.2003. Calc. for C19H28O4: M,
320.1986].
Exo-Isomer. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 232; νmax
(CHCl3)/cmϪ1 1730, 1715; δH (CDCl3) 1.12 (3H, s, Me), 1.15
(3H, s, Me), 1.4–2.0 (8H, m, CH2 × 4), 2.4–2.5 (2H, m, CH2),
3.8–4.0 (1H, m, CH), 4.57 (4H, dq, J = 6, 1.5 Hz, CO CH CH᎐
᎐
2
2
CH × 2), 5.2–5.4 (4H, m, CO CH CH᎐CH × 2), 5.8–6.0 (2H,
᎐
2
2
2
2
m, CO CH CH᎐CH × 2), 5.84 (1H, s, ᎐CH) [Found (HRMS):
᎐
᎐
2
2
2
Mϩ, 320.2000. Calc. for C19H28O4: M, 320.1986].
8,8-Dimethyl-3,4,5,6,7,8-hexahydronaphthalen-2-yl trifluoro-
methanesulfonate 34. This was prepared from the ketone 27 (217
mg, 2.0 mmol) and Tf2NPh (1.34 g, 3.7 mmol) by the same
method as described for the preparation of 18, in 58% yield
(220 mg); λmax (EtOH)/nm 268; νmax (CHCl3)/cmϪ1 1415, 1140;
δH (CDCl3) 0.98 (6H, s, Me × 2), 1.4–1.5 (2H, m, CH2 × 2), 1.5–
1.7 (2H, m, CH2), 1.9–2.0 (2H, m, [CH2 × 1/2] × 2), 2.2–2.4 (2H,
m, [CH2 × 1/2] × 2), 2.4–2.6 (2H, m, CH2), 5.97 (1H, br s, 1-H)
[Found (HRMS): Mϩ, 310.0840. Calc. for C13H17F3O3S: M,
310.0851].
Cyclization and deethoxycarbonylation of 25. In the same
manner as described for the preparation of 10, compounds 26
and 27 were obtained from the diester 25 (150 mg, 0.51 mmol)
in 7% (5 mg) and 14% (10 mg) yield, respectively.
Tetrahydro-2-naphthol derivative 26. δH (CDCl3) 1.24 (6H, s,
Me × 2), 1.5–1.9 (4H, m, CH2 × 2), 2.71 (2H, t, J = 6 Hz, CH2),
4.53 (1H, s, OH), 6.62 (1H, dd, J = 8, 2.5 Hz, ArH), 6.83 (1H, d,
J = 2.5 Hz, ArH), 6.96 (1H, d, J = 8 Hz, ArH).
Bicyclic ketone 27. νmax (CHCl3)/cmϪ1 1705; δH (CDCl3) 0.98
(6H, s, Me × 2), 1.4–1.5 (2H, m, CH2), 1.5–1.7 (2H, m, CH2),
1.9–2.0 (2H, m, [CH2 × 1/2] × 2), 2.2–2.5 (4H, m, CH2 and
[CH2 × 1/2] × 2), 2.84 (2H, br s, CH2) [Found (HRMS): Mϩ,
178.1362. Calc. for C12H18O: M, 178.1357].
Methyl (2E )-3-(4,4-dimethyl-1,2,3,4,7,8-hexahydronaphthal-
en-6-yl)but-2-enoate 35. This was prepared from the triflate 34
(219 mg, 0.7 mmol) and methyl (E)-(trimethylstannyl)but-
2-enoate13 (223 mg, 0.85 mmol) by the same procedure as
described for the preparation of 19, in 62% yield (116 mg) as a
pale yellow oil, λmax (EtOH)/nm 339, 227; νmax (CHCl3)/1700,
1600; δH(CDCl3) 1.04 (6H, s, Me × 2), 1.44–1.54 (2H, m, CH2),
1.54–1.70 (2H, m, CH2), 2.00–2.20 (4H, m, CH2 × 2), 2.24–2.38
(2H, m, CH2), 2.39 (3H, d, J = 1 Hz, Me), 3.71 (3H, s, CO2Me),
5.88 (1H, br s, ᎐CH), 6.50 (1H, br s, ᎐CH); δ (CDCl3) 17.36
Cyclization of 30. (i) To a stirred solution of LDA in THF (15
cm3, 8.0 mmol) was added a solution of diallyl ester 30 (1.28 g,
4 mmol) in THF (10 cm3) at 0 ЊC under nitrogen, and the result-
ing mixture was stirred for an additional 30 min. After addition
of saturated aq. NH4Cl (40 cm3), the organics were extracted
with benzene (3 × 40 cm3), followed by standard work-up. The
residue was purified by CC (hexane–ether, 6 : 1) to afford the
cyclized products 31 (110 mg, 10%), 32 (220 mg, 21%), and 33
(190 mg, 18%), as pale yellow oils.
᎐
᎐
C
(Me), 21.71 (CH2), 26.55 (CH2), 31.01 (Me × 2), 31.96 (CH2),
33.59 (CH2), 35.06 (C), 41.54 (CH2), 53.39 (OMe), 114.83 (CH),
129.58 (CH), 136.45 (C), 137.13 (C), 137.55 (C), 157.22
(C), 170.72 (CO) [Found (HRMS): Mϩ, 260.1783. Calc. for
C17H24O2: M, 260.1777].
(ii) Two cyclized products 32 (180 mg, 33%) and 33 (157 mg,
29%) were prepared from the diallyl ester 30 (660 mg, 2.1 mmol)
and LiTMP (4.1 mmol) by the same procedure as described in
method (i). These compounds were identical with authentic
specimens obtained by the previous method.
Wittig reaction of 36. As the same manner as described for
the preparation of 21, the trienyl ester 35 (160 mg, 0.62 mmol)
was converted to the Wittig salt 36, followed by condensation
with methyl (E)-3-formylcrotonate14 (106 mg, 0.83 mmol). The
crude product was purified by CC (ether–hexane, 1 : 9) to afford
the condensed products (56 mg, ca. 28% from 35). Separation
of these products was achieved by preparative HPLC
[LiChrosorb Si-60 (7 µm) 1 × 25 cm; hexane–ether (97 : 3), 3
cm3 minϪ1; 360 nm] to give 37 (all-E-:11Z-) and 38 (all-E-:11Z-),
all in pure state, in the proportion of 7 : 3 : 5 : 4.
2,1-Keto-ester 31. νmax (CHCl3)/cmϪ1 1725, 1710; δH (CDCl3)
0.95 (3H, s, Me), 0.99 (3H, s, Me), 1.4–1.7 (4H, m, CH2 × 2),
1.9–2.4 (4H, m, CH2 × 2), 2.6–2.8 (2H, m, CH2), 3.96 (1H, s,
CH), 4.59 (2H, dt, J = 5.5, 1.5 Hz, CO CH CH᎐CH ), 5.24 (1H,
᎐
2
2
2
dq, J = 10, 1.5 Hz, CO CH CH᎐CH ), 5.32 (1H, dq, J = 17,
᎐
2
2
2
1.5 Hz, CO CH CH᎐CH ), 5.8–6.0 (1H, m, CO CH CH᎐
᎐
᎐
2
2
2
2
2
CH2) [Found (HRMS): Mϩ, 262.1572. Calc. for C16H22O3: M,
262.1567].
All-E-isomer of 37. λmax (EtOH)/nm 385; νmax (KBr)/cmϪ1
1705, 1590; δH 1.10 (6H, s, Me × 2), 1.50–1.60 (2H, m, CH2),
1.70–1.80 (2H, m, CH2), 2.10–2.20 (4H, m, CH2 × 2), 2.11 (3H,
s, Me), 2.35–2.45 (2H, m, CH2), 2.39 (3H, d, J = 1 Hz, Me), 3.73
Hydroxy-ester 32. νmax (CHCl3)/cmϪ1 3600–3000, 1660, 1615;
δH (CDCl3) 1.01 (6H, s, Me × 2), 1.4–1.8 (4H, m, CH2 × 2), 1.93
(2H, br t, J = 6.5 Hz, CH2), 2.8–3.0 (4H, m, CH2 × 2), 4.68 (2H,
dt, J = 5.5, 1.5 Hz, CO CH CH᎐CH ), 5.24 (1H, dq, J = 10.5,
(3H, s, CO Me), 5.84 (1H, br s, ᎐CH), 6.38 (1H, br s, ᎐CH), 6.41
᎐ ᎐
2
᎐
2
2
2
1.5 Hz, CO CH CH᎐CH ), 5.33 (1H, dq, J = 16.5, 1.5 Hz,
(1H, d, J = 15 Hz, ᎐CH), 6.45 (1H, d, J = 11 Hz, ᎐CH), 7.19
᎐
᎐ ᎐
2
2
2
CO CH CH᎐CH ), 5.8–6.1 (1H, m, CO CH CH᎐CH ), 12.01
(1H, dd, J = 15, 11 Hz, ᎐CH) [Found (HRMS): Mϩ, 326.2250.
᎐
᎐
᎐
2
2
2
2
2
2
(1H, s, OH) [Found (HRMS): Mϩ, 262.1557. Calc. for
C16H22O3: M, 262.1567].
Calc. for C22H30O2: M, 326.2244].
11Z-Isomer of 37. λmax (EtOH)/nm 376, 293, 225; νmax (KBr)/
cmϪ1 1705, 1590; δH 1.05 (6H, s, Me × 2), 1.48–1.54 (2H, m,
CH2), 1.60–1.70 (2H, m, CH2), 2.01 (3H, s, Me) 2.02–2.13 (4H,
m, CH2 × 2), 2.26–2.36 (2H, m, CH2), 2.33 (3H, d, J = 1.5 Hz,
3,2-Keto-ester 33. λmax (EtOH)/nm 240; νmax (CHCl3)/cmϪ1
1730, 1665, 1605; δH (CDCl3) 1.12 (3H, s, Me), 1.14 (3H, s, Me),
1.4–2.1 (6H, m, CH2 × 2 and [CH2 × 1/2] × 2), 2.22 (1H, dt, J =
13, 5 Hz, CH), 2.4–2.8 (2H, m, [CH2 × 1/2] × 2), 3.35 (1H, dd,
13-Me), 3.69 (3H, s, CO Me), 5.84 (1H, br s, ᎐CH), 5.94 (1H, br
᎐
2
J = 15, 5 Hz, CH), 4.5–4.7 (2H, m, CO CH CH᎐CH ), 5.2–5.4
d, J = 11.5 Hz, ᎐CH), 6.33 (1H, br s, ᎐CH), 6.66 (1H, t, J = 11.5
᎐
᎐ ᎐
2
2
2
(2H, m, CO CH CH᎐CH ), 5.8–6.0 (1H, m, CO CH CH᎐
Hz, ᎐CH), 6.76 (1H, br d, J = 11.5 Hz, ᎐CH) [Found (HRMS):
᎐ ᎐
᎐
᎐
2
2
2
2
2
CH ), 6.00 (1H, m, ᎐CH) [Found (HRMS): Mϩ, 262.1562. Calc.
Mϩ, 326.2261. Calc. for C22H30O2: M, 326.2244].
᎐
2
for C16H22O3: M, 262.1567].
All-E-isomer of 38. λmax (EtOH)/nm 347, 254; νmax (KBr)/
cmϪ1 1705, 1595; δH 1.35 (6H, s, Me × 2), 1.70–1.78 (2H, m,
CH2), 1.80–1.92 (2H, m, CH2), 2.28 (3H, d, J = 1 Hz, Me), 2.41
(3H, d, J = 1 Hz, Me), 2.80 (2H, t, J = 6 Hz, CH2), 3.74 (3H, s,
8,8-Dimethyl-3,4,5,6,7,8-hexahydronaphthalen-2(1H)-one 27.
To a stirred mixture of Pd(OAc)2 (9 mg, 0.040 mmol) and PPh3
2438
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439

View Article Online
CO Me), 5.88 (1H, br s, ᎐CH), 6.50 (1H, d, J = 15 Hz, ᎐CH),
135.42 (CH), 136.64 (C), 136.70 (C), 143.18 (C), 158.34 (C),
᎐
᎐
2
6.62 (1H, br d, J = 11 Hz, ᎐CH), 7.04 (1H, d, J = 8 Hz, ArH),
193.41 (CHO) [Found (HRMS): Mϩ, 296.2140. Calc. for
᎐
7.18 (1H, dd, J = 15, 11 Hz, ᎐CH), 7.24 (1H, dd, J = 8, 2 Hz,
C21H28O: M, 296.2139].
᎐
ArH), 7.49 (1H, d, J = 2 Hz, ArH) [Found (HRMS): Mϩ,
324.2094. Calc. for C22H28O2: M, 324.2088].
Binding of retinal analogs with bovine opsin
11Z-Isomer of 38. λmax (EtOH)/nm 340, 250; νmax (KBr)/cmϪ1
1705, 1590; δH 1.29 (6H, s, Me × 2), 1.65–1.70 (2H, m, CH2),
1.75–1.85 (2H, m, CH2), 2.20 (3H, s, Me), 2.33 (3H, s, Me), 2.75
(2H, t, J = 6 Hz, CH2), 3.69 (3H, s, CO2Me), 5.90 (1H, br s,
(11Z)-8,18-Alkanoretinal (4 or 5) dissolved in a small amount
of ethanol was added to the opsin preparation and incubated at
23 ЊC in the dark for 40 h. The amount of retinal analog added
to the opsin preparation was 3–4-fold molar excess over opsin.
The formation of artificial pigment was monitored by UV-VIS
spectroscopy. The reaction mixture was then applied to a
DEAE-Sepharose column (Pharmacia) which had been equi-
librated with buffer C [50 mM NЈ-(2-hydroxyethyl)piperazine-
NЈ-ethane-2-sulfonic acid (HEPES), 0.6% CHAPS, 0.8 mg
cmϪ3 PC, 20% (w/v) glycerol, pH 6.6]. The column was washed
with buffer C supplemented with 10 mM hydroxylamine to
remove the excess of retinal analog, and then hydroxylamine
was removed by washing the column with buffer C. The rhod-
opsin analog was eluted with buffer C supplemented with 140
mM aq. NaCl.
᎐CH), 6.00 (1H, d, J = 12 Hz, ᎐CH), 6.66 (1H, t, J = 12 Hz,
᎐
᎐
᎐CH), 6.90 (1H, br d, J = 12 Hz, ᎐CH), 6.99 (1H, d, J = 8 Hz,
᎐
᎐
ArH), 7.13 (1H, dd, J = 8, 2 Hz, ArH), 7.41 (1H, d, J = 2 Hz,
ArH) [Found (HRMS): Mϩ, 324.2092. Calc. for C22H28O2: M,
324.2088].
(11Z )-8,18-Methanoretinal 5. In the same manner as
described for the preparation of 4, the trienyl ester 35 (204 mg,
0.78 mmol) was converted to the Wittig salt 36, followed
by condensation with methyl (E)-3-formylbut-2-enenitrile18
(170 mg, 1.79 mmol). The crude product was purified by CC
(ether–hexane, 1 : 9) to afford the pentaenyl nitrile 40 (56 mg,
24% from 35).
To a stirred solution of this nitrile (56 mg) in dry hexane
(5 cm3) was added a hexane solution of DIBAL-H (63 mg,
0.44 mmol) at Ϫ70 ЊC under nitrogen. After the mixture had
been stirred at 0 ЊC for 15 min, the excess of DIBAL-H was
destroyed by the successive addition of moist Et2O and water.
The resulting mixture was extracted with hexane, followed by
standard work-up. The residue was purified by CC (ether–
hexane, 1 : 9) to yield an isomeric mixture of the aldehydes
(25 mg, 44%) as an orange oil. Separation of the isomers was
achieved by preparative HPLC [LiChrosorb Si-60 (7 µm) 1 ×
25 cm; hexane–ether (9 : 1), 5 cm3 minϪ1; 360 nm] to give
11Z-isomer 5, 9Z-isomer, and all-E-isomer 5Ј all pure, in the
proportions 4.4 : 1 : 2.2.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science
and Culture, and the Science Research Promotion Fund from
the Japan Private School Promotion Foundation.
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S. Horiuchi, F. Tokunaga and T. Yoshizawa, Biochim. Biophys. Acta,
1980, 591, 445; (c) M. Ito, Y. Mantani, K. Tsukida, Y. Shichida,
S. Ioshida, Y. Fukada and T. Yoshizawa, J. Nutr. Sci. Vitaminol.,
1988, 34, 641.
5 (a) Y. Fukada, Y. Shichida, T. Yoshizawa, M. Ito, A. Kodama and
K. Tsukida, Biochemistry, 1984, 23, 5826; (b) M. Ito, Y. Katsuta,
Y. Imamoto, Y. Shichida and T. Yoshizawa, Photochem. Photobiol.,
1992, 56, 915.
6 (a) A. Wada, M. Sakai, Y. Imamoto, Y. Shichida and M. Ito, Chem.
Pharm. Bull., 1993, 41, 793; (b) A. Wada, M. Sakai, Y. Imamoto,
Y. Shichida, M. Yamauchi and M. Ito, J. Chem. Soc., Perkin Trans.
1, 1997, 1773.
7 A. Wada, M. Tsutsumi, Y. Inatomi, H. Imai, Y. Shichida and M. Ito,
Chem. Pharm. Bull., 1995, 43, 1419.
8 A. Wada, M. Sakai, T. Kinumi, K. Tsujimoto, M. Yamauchi and
M. Ito, J. Org. Chem., 1994, 59, 6922.
9 T. Imamoto, T. Kusumoto, Y. Tawarayamo, Y. Sugiura, T. Mita,
Y. Hamanaka and M. Yokoyama, J. Org. Chem., 1984, 49, 3904.
10 S. Swaminathan and K. V. Narayanan, Chem. Rev., 1971, 71, 429.
11 Standard retinoid numbering is used.
11Z-Isomer 5. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 408
(14 700), 308 (10 200), 233 (8700); νmax (KBr)/cmϪ1 1660, 1580,
1550; δH (CD3OD) 1.05 (6H, s, Me × 2), 1.50–1.54 (2H, m,
CH2), 1.63–1.68 (2H, m, CH2), 2.05 (3H, s, Me), 2.06–2.12 (4H,
m, CH2 × 2), 2.33 (2H, t, J = 5.5 Hz, CH2), 2.40 (3H, d, J = 1
Hz, Me), 6.01 (1H, dq, J = 8.5, 1 Hz, ᎐CH), 6.02 (1H, br d, J =
᎐
10.5 Hz, ᎐CH), 6.39 (1H, br s, ᎐CH), 6.81 (1H, br d, J = 11 Hz,
᎐
᎐
᎐CH), 6.83 (1H, br t, J = 11 Hz, ᎐CH), 10.03 (1H, d, J = 8.5 Hz,
᎐
᎐
CHO); δC (CD3OD) 13.71 (Me), 18.30 (Me), 20.42 (CH2), 25.06
(CH2), 29.00 (Me × 2), 30.60 (CH2), 32.01 (CH2), 33.61 (C),
40.41 (CH2), 121.76 (CH), 125.30 (CH), 130.57 (CH), 131.06
(CH), 133.41 (C), 133.76 (CH), 136.64 (C), 136.72 (C), 143.34
(C), 159.18 (C), 193.50 (CHO) [Found (HRMS): Mϩ, 296.2138.
Calc. for C21H28O: M, 296.2139].
9Z-Isomer. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 366 (9600);
νmax (KBr)/cmϪ1 1660, 1635, 1585; δH (CD3OD) 1.08 (6H, s,
Me × 2), 1.52–1.56 (2H, m, CH2), 1.66–1.72 (2H, m, CH2), 1.93
(2H, br t, J = 6 Hz, CH2), 2.07 (3H, s, Me), 2.37 (3H, s, Me),
2.70–2.76 (2H, m, CH2), 2.83–2.88 (2H, m, CH2), 5.98 (1H, br
d, J = 8 Hz, ᎐CH), 6.13 (1H, br t, J = 4 Hz, ᎐CH), 6.38 (1H, br
᎐
᎐
12 W. J. Scott, G. T. Grip and J. K. Still, J. Am. Chem. Soc., 1984, 106,
d, J = 11 Hz, ᎐CH), 6.54 (1H, br d, J = 15 Hz, ᎐CH), 7.33 (1H,
᎐
᎐
865.
dd, J = 15, 11 Hz, ᎐CH), 10.06 (1H, d, J = 8 Hz, CHO) [Found
13 E. Piers, J. M. Chong and H. E. Morton, Tetrahedron Lett., 1981, 22,
4905.
᎐
(HRMS): Mϩ, 296.2144. Calc. for C21H28O: M, 296.2139].
All-E-Isomer 5Ј. λmax (MeOH, ε/dm3 molϪ1 cmϪ1)/nm 416.5
(26 100); νmax (KBr)/cmϪ1 1660, 1585, 1545; δH (CD3OD) 1.06
(6H, s, Me × 2), 1.50–1.54 (2H, m, CH2), 1.64–1.70 (2H, m,
CH2), 2.06–2.13 (4H, m, CH2 × 2), 2.10 (3H, s, Me), 2.34–2.40
(2H, m, CH2), 2.37 (3H, d, J = 1 Hz, Me), 5.95 (1H, br d, J = 8.5
14 G. Solladie and A. Girardin, J. Org. Chem., 1989, 54, 2620.
15 (a) R. van der Steen, P. L. Biesheuvel, R. A. Mathies and
J. Lugtenburg, J. Am. Chem. Soc., 1986, 108, 6410; (b) R.
van der Steen, P. L. Biesheuvel, C. Erkelens, R. A. Mathies and
J. Lugtenburg, Recl. Trav. Chim. Pays-Bas, 1989, 108, 83.
16 (a) M. Ito, K. Hirata, A. Kodama, K. Tsukida, H. Mastumoto,
K. Horiuchi and T. Yoshizawa, Chem. Pharm. Bull., 1978, 26, 925;
(b) M. Ito, N. Matsuoka, K. Tsukida and T. Seki, Chem. Pharm.
Bull., 1988, 36, 78.
17 J. Tsuji, M. Nisar and I. Shimizu, J. Org. Chem., 1985, 50, 3416.
18 S. Chen, Experientia, 1981, 37, 543.
19 T. Okano, Y. Fukada, I. D. Artamonov and T. Yashizawa,
Biochemistry, 1989, 28, 8848.
Hz, ᎐CH), 6.40 (1H, br s, ᎐CH), 6.46 (1H, br d, J = 11.5 Hz,
᎐
᎐
᎐CH), 6.48 (1H, br d, J = 15 Hz, ᎐CH), 7.35 (1H, dd, J = 15,
᎐
᎐
11.5 Hz, ᎐CH), 10.05 (1H, d, J = 8.5 Hz, CHO); δ (CD3OD)
᎐
C
13.17 (Me), 14.25 (Me), 20.38 (CH2), 24.81 (CH2), 28.97 (Me ×
2), 30.60 (CH2), 32.00 (CH2), 33.58 (C), 40 38 (CH2), 125.34
(CH), 125.34 (CH), 126.30 (C), 129.41 (CH), 135.26 (CH),
J. Chem. Soc., Perkin Trans. 1, 2001, 2430–2439
2439