Synthesis of 11Z-9-demethyl-9-((3-indolyl)methyl)retinal [1]

Article abstract of DOI:10.1002/jhet.5570380138

A convenient synthesis of 11Z-9-demethyl-9-((3-indolyl)methyl)retinal, which has an amino acid residue of tryptophan at the 9 position in retinal, is described using a tricarbonyliron complex.

Full text of DOI:10.1002/jhet.5570380138

Jan-Feb 2001
Synthesis of 11Z-9-Demethyl-9-((3-indolyl)methyl)retinal [1]
259
Akimori Wada*, Naoko Fujioka and Masayoshi Ito
Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
Received May 24, 2000
A convenient synthesis of 11Z-9-demethyl-9-((3-indolyl)methyl)retinal, which has an amino acid residue
of tryptophan at the 9 position in retinal, is described using a tricarbonyliron complex.
J. Heterocyclic Chem., 38, 259 (2001).
11Z-Retinal analogs are very important compounds for
methanol [8] to give the acetal 4 in 88 % yield. After
S,S-acetal of 4 by the usual method
investigating the interaction between the signal molecule
and apo-protein opsin in the visual transduction process of
photosensitive pigments such as rhodopsin and iodopsin
[2]. Recently, we reported a novel method for a
stereoselective synthesis of 11Z-retinal from the β-ionone-
tricarbonyliron complex via the Peterson reaction, in
which the Z-olefin was predominantly produced [3].
Continuing our investigation for the conformational
deprotection of the
using mercury(II) chloride and mercury(II) oxide in
methanol, the β-ionone analog 5 was converted to the
corresponding tricarbonyliron complex 6 by treatment
with dodecacarbonyl-triiron(0) [9] in benzene in good
1
yield (62%). The H-nmr, ir and high resolution mass
spectral data were consistent with the indicated
structure of 6 (Scheme 1).
Treatment of 6 with the lithium salt of acetonitrile in
THF at -70 °C gave the nitrile-tricarbonyliron complexes
7a and 7b (ratio ca. 1:1) via addition, dehydration and
subsequent migration of the tricarbonyliron complex. A
similar migration of tricarbonyliron has already been
reported by Salzer et al. in the reaction of sorbaldehyde-
tricarbonyliron with carbanions[10]. These products were
used in the next reaction without isolation because it is
difficult to the separate them at this stage. Reduction of
7a,b by diisobutylaluminum hydride (DIBAL-H) in
dichloromethane at 0 °C afforded the aldehydes 8a and 8b
in 49% and 31% yields, respectively. The stereochemistry
at position 9 of these compounds [11] was determined by
analysis of the retinal chromophore in rhodopsin [4], we
attempted to prepare the 11Z-9-demethyl-9-((3-
indolyl)methyl)retinal, which has the amino acid residue
of tryptophan at the 9 position in 11Z-retinal, by applica-
tion of our developed methodology for the synthesis of
11Z-retinal.
β-Ionone analog-tricarbonyliron complex 6, in which
the indole substituent was introduced on the methyl
group at the 9 position, was prepared from S,S-acetal 1
[5] by a small modification of the previously reported
method [6]. Alkylation of the lithium salt of 1, produced
by deprotonation using n-butyl lithium as a base, with
1-benzenesulfonyl-3-bromomethylindole 2 [7]
proceeded smoothly to afford the sulfone 3 in quan-
titative yield. Cleavage of the N-benzenesulfonyl group
of 3 was accomplished by magnesium metal in
1
H-NMR spectral analysis based on the fact that the
chemical shift of 7-H cis to an aldehyde group appears
further downfield due to the anisotropic effect of a

260
A. Wada, N. Fujioka and M. Ito
Vol. 38
was transformed to the amide 10 by the reaction with N-
hydrochloride in the presence of
carbonyl group (δ 3.17 for 8b, δ 2.49 for 8a). In contrast to
our previous report for the reaction of β-ionone-tri-
carbonyliron complex with the lithium salt of acetonitrile
[12], the stereoselective formation of E-isomer was lost,
and almost the same amount of E- and Z-isomers were
produced. We speculated that this is due to the steric bulk-
iness of the indole substituent, which reduces the relative
thermodynamic energy difference between the isomeric
products 7a and 7b. The Peterson reaction of 8a using
ethyl trimethylsilylacetate afforded predominantly the
Z-ester 9a (64%) accompanied by the E-ester 9b (17%).
The stereochemistry of the newly produced double bond in
9a,b was determined based on the coupling constants of
the 11-H signal in their NMR spectrum (δ 6.58, t, 11.5 Hz
for 9a, δ 7.31, dd, 15, 11 Hz for 9b), respectively. Our first
attempt at transformation of the Z-ester 9a to the ketone-
tricarbonyliron complex 11 directly using triphenyl-
stannylmethyl lithium [13] was unsuccessful. So, we
investigated another route for the conversion of ester 9a
methoxy-N-methylamine
isopropylmagnesium bromide [16], quantitatively. The
reaction of 10 with methyllithium proceeded smoothly to
give ketone 11 in excellent yield. Among these conver-
sions, the geometry of the 11-12 double bond was
unchanged, and it was found that this method would
provide a convenient alternative for the conversion of the
ester to the ketone in the retinal synthesis. The Emmons-
Horner reaction of ketone 11 with diisopropyl-
cyanomethylphosphonate using sodium hydride as a base
in THF gave the nitrile-tricarbonyliron complex 12 as the
sole product (98% yield). The newly produced double
1
bond was determined as E by comparison of H- and
13
C-NMR spectral data with those of the 9-methyl analog
of the tricarbonyliron complex [1]. The final transforma-
tion of nitrile 12 to the 11Z-retinal analog 14 was accom-
plished by the sequence of decomplexation with copper(II)
chloride and DIBAL-H reduction (Scheme 2).
known that N-methoxy-N-methyl-
into ketone 11. It is well
In summary, we have shown the preparation of the 11Z-
9-demethyl-9-((3-indolyl)methyl)retinal by a slight modi-
fication of our previously developed method using tricar-
bonyliron complex. The interaction of this compound with
the apoprotein of rhodopsin is under investigation.
amide (Weinreb amide) is a powerful tool for the
conversion of acid or ester functional groups to ketones
[14] and has been used for the synthesis of some natural
products [15]. In order to apply this method, the ester 9a

Jan-Feb 2001
Measurements.
Synthesis of 11Z-9-Demethyl-9-((3-indolyl)methyl)retinal
261
EXPERIMENTAL
residue was chromatographed on silica gel (ether:hexane, 1:9)
to give 4 in 88% yield (0.65 g) as a colorless oil; ir
(chloroform): 3480, 2932, 2361 cm ; uv (ethanol): 390, 383,
222 nm; H nmr (deuteriochloroform): δ 0.93 (s, 6H),
–1
1
1.41–1.58 (m, 4H), 1.59 (s, 3H), 1.84–1.89 (m, 1H), 1.96 (brt,
2H, J = 6 Hz), 2.02–2.08 (m, 1H), 2.67–2.72 (m, 2H),
2.93–2.99 (m, 2H), 3.35 (s, 2H), 5.53 (d, 1H, J = 16 Hz), 6.32
(d, 1H, J = 16 Hz), 7.10 (t, 1H, J = 8 Hz, ArH), 7.15 (t, 1H,
J = 8 Hz, ArH), 7.19 (s, 1H, ArH), 7.30 (d, 1H, J = 8 Hz,
ArH), 7.70 (d, 1H, J = 8 Hz, ArH), 8.04 (brs, 1H, NH) ppm;
C nmr (deuteriochloroform): δ 19.2, 21.7, 25.2, 27.5 (2C),
28.9 (2C), 32.9, 34.1, 38.4, 39.5, 57.0, 109.8, 110.9, 119.3,
119.5, 121.8, 124.2, 128.6, 129.0, 131.2, 135.6, 136.0, 136.6
All melting points were determined using a Yanagimoto micro
melting point apparatus and uncorrected. Infrared spectra were
recorded on a Perkin Elmer Paragon 1000 spectrometer. Proton
and carbon magnetic resonance spectra were determined using
Varian 200, 300 and 500 MHz instruments with tetramethylsilane
as the internal standard. Mass spectra were obtained on a Hitachi
M-80 instrument. High-performance liquid chromatography
(HPLC) was performed on a Shimadzu LC-10A instrument using
Chemcosorb 7-ODS-H (10 x 300 mm) column. All new
compounds are unstable oils, therefore high resolution mass
measurements were used to obtain molecular formula
information. Due to instability their purity could not be measured
by elemental analysis.
13
ppm. Exact mass Calcd. for C
397.1901.
H NS : 397.1899. Found:
24 31 2
(3E)-1-(3-Indolyl)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-
buten-2-one (5)
1-(Phenylsulfonyl)-3-[[2-[(E)-(2,6,6-trimethyl-1-cyclohexenyl)-
1-ethenyl]-1,3-dithian-2-yl]-methyl]-1H-indole (3).
To a solution of 4 (105 mg, 0.26 mmole) in methanol (80 ml),
was added mercury (II) chloride (180 mg, 0.66 mmole) and
mercury(II) oxide (86 mg, 0.40 mmole) and the resulting mixture
was stirred for 15 minutes at room temperature. After removal of
methanol, the crude product was isolated by filtration through
Celite with ether and the filtration was washed with saturated
aqueous sodium chloride, and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure, and
the residue was chromatographed on silica gel (ether:hexane, 1:4)
to give 5 in 68% yield (55.5 mg) as a red oil; ir (chloroform):
A solution of n-butyllithium (1.65 mole hexane solution,
3.1 ml, 4.93 mmoles) was added dropwise to a stirred solution
of the S,S-acetal (1, 1.2 g, 4.48 mmoles) [4] in tetrahydrofuran
(20 ml) at 0 °C. The resulting mixture was stirred for an
additional 30 minutes at room temperature, and cooled to
-78 °C. To the above solution, was added a solution of
N-benzensulfonyl-3-(bromomethyl)indole ( 2, 1.25 g, 3.60
mmoles) [5] in tetrahydrofuran (4 ml) at -78 °C. After stirring
for an additional 30 minutes under the same conditions, the
reaction was quenched with saturated aqueous ammonium
chloride (50 ml) and then extracted with ether (3 x 50 ml). The
combined extracts were washed with saturated aqueous
sodium chloride (80 ml) and then dried with sodium sulfate.
The solvent was removed under reduced pressure, and the
residue was chromatographed on silica gel (ether:hexane, 1:4)
to give 3 in quantitative yield (1.96 g); ir (chloroform): 2933
–1
3479, 3019, 2935, 1677, 1600 cm ; uv (ethanol): 290, 220 nm;
1
H nmr (deuteriochloroform): δ 0.97 (s, 6H), 1.40–1.60 (m, 4H),
1.63 (s, 3H), 2.01 (t, 2H, J = 6.5 Hz), 3.98 (s, 2H), 6.23 (d, 1H,
J = 16 Hz), 7.11 (s, 1H, ArH), 7.12 (td, 1H, J = 8, 1Hz, ArH),
7.19 (td, 1H, J = 8, 1Hz, ArH), 7.34 (d, 1H, J = 8 Hz, ArH), 7.41
(d, 1H, J = 16 Hz), 7.59 (d, 1H, J = 8 Hz, ArH), 8.09
13
(brs, 1H, NH) ppm; C nmr (deuteriochloroform): δ 18.2, 21.6,
28.7 (2C), 33.6, 34.0, 38.2, 39.8, 109.2, 111.1, 118.8, 119.6,
122.1, 123.0, 127.4, 129.2, 136.1, 136.2, 136.4, 142.6, 198.3
–1
1
cm ; uv (ethanol): 253 nm; and H nmr (deuterio-
chloroform): δ 0.86 (s, 6H), 1.38–1.41 (m, 4H), 1.42 (s, 3H),
1.84–1.88 (m, 1H), 1.90–1.92 (m, 2H), 2.02–2.08 (m, 1H),
2.70–2.76 (m, 2H), 2.92–2.98 (m, 2H), 3.26 (s, 2H), 5.41
(d, 1H, J = 16 Hz), 6.28 (d, 1H, J = 16 Hz), 7.18-7.28 (m, 2H,
ArH), 7.34-7.52 (m, 3H, ArH), 7. 56 (d, 1H, J = 8 Hz, ArH),
7.63 (s, 1H, ArH), 7.85 (d, 2H, J = 8 Hz, ArH), 7.93 (d, 1H,
ppm. Exact mass Calcd. for C
307.1917.
H NO: 307.1937. Found:
21 25
4
Tricarbonyl[(η -3,4,1,2)-(3E)-1-(3-indolyl)-4-(2,6,6-trimethyl-
1-cyclohexen-1-yl)-3-buten-2-one]iron(0) (6).
A mixture of 5 (232 mg, 0.76 mmole) and dodecacarbonyl-
triiron (570 mg, 1.13 mmoles) in benzene (50 ml) was heated
under reflux for 4 hours. After cooling, the resulting mixture
was passed through a short alumina column to remove the
excess reagent. The solvent was removed under reduced
pressure, and the residue was chromatographed on silica gel
13
J = 8 Hz, ArH) ppm; C nmr (deuteriochloroform): δ 19.2,
21.4, 25.1, 27.5 (2C), 28.8 (2C), 32.8, 33.9, 37.6, 39.4, 55.8,
113.4, 116.7, 120.0, 123.1, 124.5, 125.9, 126.8 (2C), 129.1
(2C), 129.3, 131.7, 132.0, 133.5, 134.6,135.0, 136.3, 138.3
ppm. Exact mass Calcd. for C
537.1829.
H NO S : 537.1832. Found:
30 35 2 3
(ether:hexane, 1:4) to give 6 in 62% yield (202mg) as a yellow
–1
oil; ir (chloroform): 3480, 2933, 2047, 1987, 1970, 1668 cm
;
3-[[2-[(E)-(2,6,6-Trimethyl-1-cyclohexenyl)-1-ethenyl]-1,3-
dithian-2-yl]methyl]-1H-indole (4).
1
uv (ethanol): 260, 217 nm; H nmr (deuteriochloroform): δ
0.90 (s, 3H), 1.24–1.30 (m, 2H), 1.37 (s, 3H), 1.38 (s, 3H),
1.42–1.58 (m, 2H), 1.78–1.82 (m, 2H), 2.48 (d, 1H, J = 9 Hz),
3.78 (d, 1H, J = 16 Hz), 3.83 (d, 1H, J = 16 Hz), 5.63 (d, 1H,
J = 9 Hz), 7.13 (t, 1H, J = 8 Hz, ArH), 7.18 (s, 1H, ArH), 7.20
(t, 1H, J = 8 Hz, ArH), 7.37 (d, 1H, J = 8 Hz, ArH), 7.59 (d,
To a solution of 3 (1 g, 1.86 mmoles) in methanol (20 ml),
magnesium metal (1.5 g, 62.5 mmoles) was added all at once
at 0 °C. The resulting mixture was stirred for 20 hours at room
temperature, and the reaction was quenched with saturated
aqueous ammonium chloride (50 ml). After removal of
methanol, the residue was extracted with ether (3 x 100 ml).
The combined extracts were washed with saturated aqueous
sodium chloride (100 ml), and then dried with sodium sulfate.
The solvent was removed under reduced pressure, and the
13
1H, J = 8 Hz, ArH), 8.11 (brs, 1H, NH) ppm; C nmr (deuteri-
ochloroform): 19.5, 23.7, 29.6, 34.0, 35.2, 38.7, 40.0, 42.3,
49.4, 69.8, 82.1, 109.8, 111.2, 116.9, 118.8, 119.8, 122.2,
123.1, 127.4, 136.3, 187.2, 205.9 (3C) ppm. Exact mass Calcd.
for C
H FeNO : 447.1134. Found: 447.1149.
24 25 4

262
A. Wada, N. Fujioka and M. Ito
Vol. 38
4
added a solution of ethyl (trimethylsilyl)acetate (0.16 ml,
0.87 mmoles) at -78 °C, and the resulting mixture was stirred for
an additional 20 minutes. A solution of 8a (82.6 mg,
0.17 mmoles) in tetrahydrofuran (10 ml) was added at -78 °C,
and the resulting mixture was further stirred for 20 minutes. The
reaction was quenched with saturated aqueous ammonium
chloride (20 ml) and then extracted with ether (2 x 30 ml). The
combined extracts were washed with saturated aqueous sodium
chloride (50 ml), and then dried with sodium sulfate. The solvent
was removed under reduced pressure, and the residue was
chromatographed on silica gel (ether:hexane, 1:4) to give the
esters 9a (57.2 mg, 66%) and 9b (14.4 mg, 13%) as a orange oil,
respectively.
Tricarbonyl[(η -2,3,4,5)-(2E,4E)-3-(3-indolyl)methyl-5-(2,6,6-
trimethyl-1-cyclohexen-1-yl)-2,4-pentadienal]iron(0) (8a) and
4
Tricarbonyl[(η -2,3,4,5)-(2Z,4E)-3-(3-indolyl)methyl-5-(2,6,6-
trimethyl-1-cyclohexen-1-yl)-2,4-pentadienal]iron(0) (8b).
To a solution of LDA, prepared from n-butyllithium (1.65 mole
hexane solution, 1.92 ml, 3.2 mmoles) and diisopropylamine
(0.43 ml, 3.2 mmoles) in tetrahydrofuran (10 ml) was added a solu-
tion of acetonitrile (0.18 ml, 3.2 mmoles) at -78 °C, and the resulting
mixture was stirred for an additional 20 minutes. A solution of 6
(277 mg, 0.64 mmole) in tetrahydrofuran (5 ml) was added at -78 °C,
and the resulting mixture was stirred for an additional 20 minutes.
The reaction was quenched with saturated aqueous ammonium
chloride (20 ml), and then extracted with ether (2 x 30 ml). The
combined extracts were washed with saturated aqueous sodium
chloride, and then dried with sodium sulfate. The solvent was
removed under reduced pressure to give the nitriles 7a and 7b
(232 mg, 77%). To the isomeric mixture of 7 (445 mg, 1 mmole) in
anhydrous dichloromethane (10 ml ) was added a solution of
DIBAL-H (1.0 mole hexane solution, 1.4 ml, 1.4 mmoles) in
anhydrous dichloromethane (5 ml ) at 0 °C, and the resulting mixture
was stirred for an additional 15 minutes. After the reaction was
quenched with water (20 ml), and after adding dichloromethane
(80 ml), the resulting mixture was filtrated through Celite. The
organic layer was separated and then dried with sodium sulfate. The
solvent was removed under reduced pressure, and the residue was
chromatographed on silica gel (ether:hexane, 1:4) to give the
aldehydes 8a (222 mg, 49%) and 8b (137 mg, 31%) as an orange
solid, respectively.
Z-Isomer 9a had ir (chloroform): 3479, 2960, 2038, 1979,
–1
1
1698, 1610 cm ; uv (ethanol): 281, 208 nm; H nmr (deuterio-
chloroform): δ 1.00 (s, 3H), 1.13 (s, 3H), 1.28 (t, 3H, J = 7 Hz),
1.34–1.60 (m, 4H), 1.77(s, 3H), 1.96 (brt, 2H, J = 5 Hz), 2.47
(d, 1H, J = 11 Hz), 3.20 (d, 1H, J = 11.5 Hz), 3.99 (d, 1H, J =
16 Hz), 4.12–4.20 (m, 2H), 4.20 (d, 1H, J = 16 Hz), 5.65 (d, 1H,
J = 11.5 Hz), 5.71 (d, 1H, J = 11 Hz), 6.58 (t, 1H, J = 11.5 Hz),
7.09 (brs, 1H, ArH), 7.17 (brt, 1H, J = 6.5 Hz, ArH), 7.23
(brt, 1H, J = 6.5 Hz, ArH), 7.40 (d, 1H, J = 8 Hz, ArH), 7.73
13
(d, 1H, J = 8 Hz, ArH), 8.07 (brs, 1H, NH) ppm; C nmr
(deuteriochloroform): δ 14.4, 18.9, 23.0, 28.7, 29.0, 29.7, 34.8,
35.1, 42.3, 53.5, 59.9, 63.8, 86.5, 100.9, 111.3, 114.5, 116.1,
118.8, 119.8, 122.4 (2C), 122.4, 127.2, 135.2, 135.5, 136.2,
145.7, 212.0 (3C) ppm. Exact mass Calcd. for C H FeNO :
30 33
5
543.1710. Found: 543.1692.
E-Isomer 9b had ir (chloroform): 3479, 2932, 2039, 1978,
E-isomer 8a had ir (chloroform): 3477, 2927, 2049, 1981, 1659
–1
1
1699, 1623 cm ; uv (ethanol): 282, 211 nm; H nmr (deuterio-
chloroform): 0.98 (s, 3H), 1.12 (s, 3H), 1.30 (t, 3H, J = 7Hz),
1.34–1.59 (m, 4H), 1.58 (d, 1H, J = 11Hz), 1.72 (s, 3H), 1.96
(brt, 2H, J = 4.5Hz), 2.21 (d, 1H, J = 11Hz), 4.01 (d, 1H, J =
15Hz), 4.20 (d, 1H, J = 15Hz), 4.20 (q, 2H, J = 7Hz), 5.73 (d, 1H,
J = 11Hz), 5.98 (d, 1H, J = 15Hz), 7.11 (brs, 1H, ArH), 7.16
(t, 1H, J = 8Hz, ArH), 7.23 (t, 1H, J = 8Hz, ArH), 7.31 (dd, 1H,
J = 15, 11Hz), 7.39 (d, 1H, J = 8Hz, ArH), 7.76 (d, 1H, J = 8Hz,
-1
1
cm ; uv (ethanol): 269, 219 nm; H nmr (deuteriochloroform): δ
0.98 (s, 3H), 1.13 (s, 3H), 1.18 (d, 1H, J = 6.5 Hz), 1.26-1.52
(m, 4H), 1.72 (s, 3H), 1.97-1.99 (m, 2H), 2.49 (d, 1H, J = 11.5 Hz),
4.17 (d, 1H, J = 15.5 Hz), 4.48 (d, 1H, J = 15.5 Hz), 5.81 (d, 1H, J =
11.5 Hz), 7.13 (brs, 1H, ArH), 7.17 (t, 1H, J = 8 Hz, ArH), 7.24
(t, 1H, J = 8 Hz, ArH), 7.27 (d, 1H, J = 8 Hz, ArH), 7.73 (d, 1H, J =
8 Hz, ArH), 8.12 (brs, 1H, NH), 9.62 (d, 1H, J = 6.5 Hz) ppm;
nmr (deuteriochloroform): δ 18.7, 23.0, 29.4, 29.5, 31.6, 34.8, 35.2,
42.2, 55.5, 66.4, 88.6, 101.9, 111.4, 114.2, 118.7. 119.9, 122.5,
122.6, 127.1, 134.7, 136.2, 137.3, 195.3, 210.3 (3C) ppm. Exact
13
C
13
ArH), 8.10 (brs, 1H, NH) ppm ; C nmr (deuteriochloroform): δ
14.3, 18.8, 22.9, 28.6, 29.6, 29.7, 34.8, 35.1, 42.3, 56.3, 60.2,
63.4, 86.0, 100.9, 111.3, 114.2, 118.9, 119.2, 119.8, 122.4, 122.5,
127.2, 135.1, 135.7, 136.2, 145.9, 166.7, 211.9 (3C) ppm. Exact
mass Calcd. for C H FeNO : 543.1710. Found: 543.1693.
mass Calcd. for C H NFeO : 473.1291. Found: 473.1261.
Z-Isomer 8b had ir (chloroform): 3478, 2935, 2049, 1992, 1668
26 27
4
-1
1
30 33
5
cm ; uv (ethanol): 266, 219 nm; H nmr (deuteriochloroform): δ
0.92 (s, 3H), 1.11 (s, 3H), 1.26-1.50 (m, 4H), 1.62 (s, 3H), 1.93-1.96
(m, 2H), 3.12 (d, 1H, J = 3Hz), 3.17 (d, 1H, J = 11.5 Hz), 3.89 (d,
1H, J = 16 Hz), 3.98 (d, 1H, J = 16 Hz), 5.99 (d, 1H, J = 11.5 Hz),
7.13 (s, 1H, ArH), 7.18 (t, 1H, J = 8 Hz, ArH), 7.24 (t, 1H, J = 8 Hz,
ArH), 7.40 (d, 1H, J = 8 Hz, ArH), 7.72 (d, 1H, J = 8 Hz, ArH), 8.13
4
Tricarbonyl[(η -4,5,6,7)-(2Z,4E,6E)-N-methoxy-N-methyl-5-(3-
indolyl)methyl-7-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6-hep-
tatrienamido]iron(0) (10).
To a solution of the ester 9a (22.4 mg, 0.04 mmoles) and
N,O–dimethylhydroxylamine hydrochloride (48 mg , 0.5 mmole)
in tetrahydrofuran (5 ml) was added dropwise isopropylmagne-
sium bromide (0.63 M solution, 11.4 ml, 1 m) at -78 °C. After
stirring for an additional 30 minutes, the reaction was quenched
with saturated aqueous ammonium chloride (10 ml) and then
extracted with ether (2 x 20 ml). The combined extracts were
washed with saturated aqueous sodium chloride (30 ml), and then
dried with sodium sulfate. The solvent was removed under
reduced pressure, and the residue was chromatographed on silica
gel (ether:hexane, 1:4) to give the amide 10 (17.7 mg, quant.); ir
13
(brs, 1H, NH), 9.32 (d, 1H, J = 3 Hz) ppm ; C nmr (deuterio-
chloroform): δ 18.8, 23.0, 28.6, 29.6, 34.3, 34.8, 35.4, 42.1, 57.8,
68.9, 94.6, 103.4, 111.3, 114.1, 118.7, 120.0, 122.5, 122.7, 127.2,
135.4, 136.1, 137.1, 194.2, 210.1 (3C) ppm. Exact mass Calcd. for
C H NFeO : 473.1291. Found: 473.1269.
26 27
4
4
Tricarbonyl[ethyl (η -4,5,6,7)-(2Z,4E,6E)-5-(3-indolyl)methyl-
7 - ( 2 , 6 , 6 - t r i m e t h y l - 1 - c y c l o h e x e n - 1 - y l ) - 2 , 4 , 6 -
heptatrienoate]iron(0) (9a) and Tricarbonyl[ethyl (η -4,5,6,7)-
(2E,4E,6E)-5-(3-indolyl)methyl-7-(2,6,6-trimethyl-1-cyclo-
hexen-1-yl)-2,4,6-heptatrienoate]iron(0) (9b).
4
-1
(potassium bromide): 3479, 2935, 2036, 1976, 1639, 1600 cm ;
1
uv (ethanol): 282, 206 nm; H nmr (deuteriochloroform): δ 0.98
To a solution of LDA, prepared from n-butyllithium (1.53
mole hexane solution, 0.57 ml, 0.87 mmole) and diisopropyl-
amine (0.12 ml, 0.87 mmole) in tetrahydrofuran (10 ml) was
(s, 3H), 1.10 (s, 3H), 1.22–1.52 (m, 4H), 1.77 (s, 3H), 1.94-1.98
(m, 2H), 2.48 (d, 1H, J = 11 Hz), 3.20 (s, 3H), 3.47 (d, 1H,

Jan-Feb 2001
Synthesis of 11Z-9-Demethyl-9-((3-indolyl)methyl)retinal
263
J = 11.5 Hz), 3.67 (s, 3H), 3.98 (d, 1H, J = 16 Hz), 4.15 (d, 1H,
J = 16 Hz), 5.67 (d, 1H, J = 11 Hz), 6.18 (d, 1H, J = 11.5 Hz),
6.49 (t, 1H, J = 11.5 Hz), 7.10 (brs, 1H, ArH), 7.17 (t, 1H, J = 8
Hz, ArH), 7.23 (t, 1H, J = 8 Hz, ArH), 7.39 (d, 1H, J = 8 Hz,
ArH), 7.73 (d, 1H, J = 8 Hz, ArH), 8.07 (brs, 1H, NH) ppm;
(d, 1H, J = 11 Hz), 5.87 (t, 1H, J = 12 Hz), 6.61 (brs, 1H, NH),
6.69 (brs, 1H, ArH), 7.04–7.06 (m, 1H, ArH), 7.21–7.24 (m, 2H,
13
ArH), 7.72–7.74 (m, 1H, ArH) ppm; C nmr (deuteriobenzene):
δ 19.1, 20.7, 22.9, 28.8, 29.0, 29.6, 34.9, 35.1, 42.6, 55.8, 64.3,
85.7, 99.6, 100.5, 111.7, 113.9, 117.3, 119.1, 120.1, 122.4, 122.7,
134.8, 135.3, 136.4, 136.6, 156.7, 212.9 (3C) ppm, and two car-
bons were hidden by benzene peak. Exact mass Calcd. for
13
C nmr (deuteriochloroform): δ 18.9, 23.1, 28.6, 29.0, 29.7,
32.0, 34.7, 35.0, 42.4, 54.5, 61.6, 63.8, 86.2, 100.9, 111.2, 114.4,
114.7, 118.8, 119.7, 122.3, 122.5, 127.2, 135.2, 135.3, 136.2,
144.0, 166.8, 212.4 (3C) ppm. Exact mass Calcd. for
C H FeN O : 536.1764. Found: 536.1746.
31 32
2 3
(2E,4Z,6E,8E)-7-(3-Indolyl)methyl-3-methyl-9-(2,6,6-trimethyl-
1-cyclohexen-1-yl)-2,4,6,8-nonatetraenenitrile (13).
C H FeN O (M-H): 557.1740. Found: 557.1752.
30 33
2 5
4
Tricarbonyl[(η -5,6,7,8)-(3Z,5E,7E)-6-(3-indolyl)methyl-8-
(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,5,7-octatrien-2-
one]iron(0) (11).
To a solution of the tricarbonyliron complex 13 (120 mg,
0.22 m) in ethanol (2 ml) was added a solution of anhydrous
copper(II) chloride (151 mg, 1.1 mmoles) in ethanol (3 ml) at
0 °C. After stirring for an additional 20 minutes, the reaction was
quenched with saturated aqueous ammonium chloride (10 ml)
and then extracted with ether (2 x 30 ml). The combined extracts
were washed with saturated aqueous sodium chloride (30 ml),
and then dried with sodium sulfate. The solvent was removed
under reduced pressure, and then the residue was
chromatographed on silica gel (ether:hexane, 1:4) to give the
nitrile 13 (93 mg, quant.) as a yellow oil; ir (potassium bromide):
To a solution of the amide 10 (141 mg, 0.25 mmoles) in
tetrahydrofuran (10 ml) was added dropwise methyl lithium
(1.09 M solution, 0.93 ml, 1 mmole) at -40 °C. After stirring for
an additional 10 minutes, the reaction was quenched with
saturated aqueous ammonium chloride (20 ml) and then extracted
with ether (2 x 30 ml). The extract was washed with saturated
aqueous sodium chloride (30 ml), and then dried with sodium
sulfate. The solvent was removed under reduced pressure, and
the residue was chromatographed on silica gel (ether:hexane, 1:4)
to give ketone 11 (127 mg, 98%) as a orange oil; ir (potassium
–1
3413, 2927, 2864, 2208, 1572 cm ; uv (ethanol): 351, 290, 222
1
nm; H nmr (deuteriobenzene): δ 0.89 (s, 6H), 1.20–1.60
–1
bromide): 3479, 2934, 2038, 1980, 1673 cm ; uv (ethanol): 282,
(m, 4H), 1.68 (s, 3H), 1.88 (s, 3H), 1.90 (brt, 2H, J = 5.5 Hz),
3.83 (s, 2H), 4.77 (s, 1H), 5.33 (d, 1H, J = 12 Hz), 6.24 (d, 1H,
J = 16 Hz), 6.43 (t, 1H, J = 12 Hz), 6.49 (d, 1H, J = 16 Hz), 6.53
(brs, 1H, ArH), 6.60 (d, 1H, J = 12 Hz), 6.61 (brs, 1H, NH),
7.03–7.04 (m, 1H, ArH), 7.22–7.24 (m, 2H, ArH), 7.69–7.71
1
222 nm; H nmr (deuteriobenzene): δ 1.06 (s, 3H), 1.21 (s, 3H),
1.25–1.40 (m, 4H), 1.70–1.74 (m, 2H), 1.78 (s, 3H), 1.82 (s, 3H),
2.78 (d, 1H, J = 11 Hz), 3.80 (d, 1H, J = 16 Hz), 3.95 (d, 1H, J =
11 Hz), 4.06 (d, 1H, J = 16 Hz), 5.61 (d, 1H, J = 11 Hz), 5.69
(d, 1H, J = 11 Hz), 6.31 (t, 1H, J = 11 Hz), 6.63–6.64 (m, 1H,
ArH), 6.75 (brs, 1H, NH), 7.03–7.05 (m, 1H, ArH), 7.21–7.24
13
(m, 1H, ArH) ppm ; C nmr (deuteriobenzene): δ 19.6, 21.0,
21.9, 23.1, 28.9 (2C), 33.2, 34.5, 39.8, 99.8, 111.5, 114.2, 117.5,
118.8, 119.8, 121.9, 122.5, 125.8, 129.9, 130.7, 131.0, 136.5,
136.7, 138.1, 144.4, 156.8 ppm, and two carbons were hidden by
13
(m, 2H, ArH), 7.70–7.72 (m, 1H, ArH) ppm; C nmr (deuterio-
benzene): δ 19.2, 23.1, 28.6, 28.8, 29.8, 31.4, 35.0, 35.2, 42.5,
55.3, 65.1, 86.6, 102.3, 111.5, 114.2, 119.1, 120.0, 122.5 (2C),
122.6, 122.9, 135.4, 136.1, 136.6, 144.2, 197.6, 212.8 (3C) ppm.
benzene peak. Exact mass Calcd. for C
Found: 396.2579.
H N : 396.2567.
28 32 2
Exact mass Calcd. for C
513.1586.
H FeNO : 513.1604. Found:
29 31 4
(2E,4Z,6E,8E)-7-(3-Indolyl)methyl-3-methyl-9-(2,6,6-trimethyl-
1-cyclohexen-1-yl)- 2,4,6,8-nonatetraenal (14).
4
Tricarbonyl[(η -6,7,8,9)-(2E,4Z,6E,8E)-7-(3-indolyl)methyl-3-
methyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonate-
traenenitrile]iron(0) (12).
To a solution of the nitrile 13 (93 mg 0.23 mmole) in toluene
(5 ml) was added dropwise a solution of DIBAL-H (1 mole
hexane solution, 0.35 ml, 0.35 m) at 0 °C. After stirring for an
additional 10 minutes, the reaction was quenched with water and
then extracted with ether (2 x 20 ml). The combined extracts
were washed with saturated aqueous sodium chloride and then
dried with sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by reverse phase
preparative HPLC (water:methanol, 1: 9) to give the aldehyde 14
(9.2 mg, 10%) as a red oil; ir (potassium bromide): 3385, 2926,
To a solution of sodium hydride (60% oil dispersion, 45 mg,
1.15 mmoles) in tetrahydrofuran (5 ml) was added drowise
diisopropylcyanomethylphosphonate (0.22 ml, 1.15 mmoles) at
0 °C. After stirring for an additional 30 minutes at room
temperature, and to this mixture was added a solution of the
ketone 11 (116 mg, 0.23 m) in tetrahydrofuran (5 ml) at 0 °C. The
resulting mixture was allowed to come to the room temperature
and stirred for 24 hours. The reaction was quenched with
saturated aqueous ammonium chloride (10 ml) and then extracted
with ether (2 x 20 ml). The combined extracts were washed with
saturated aqueous sodium chloride (20 ml), and then dried with
sodium sulfate. The solvent was removed under reduced
pressure, and the residue was chromatographed on silica gel
(ether:hexane, 1:9) to give the tricarbonyliron complex 12 (120
mg, 99%) as a orange oil; ir (potassium bromide): 3479, 2933,
–1
1
2854, 1654, 1570 cm ; uv (ethanol): 375, 286, 256, 226 nm; H
nmr (deuteriobenzene): δ 0.88 (s, 6H), 1.50–1.54 (m, 4H), 1.66
(s, 3H), 1.79 (s, 3H), 1.88 (brt, 2H, J = 5.5 Hz), 3.86 (s, 2H), 5.55
(d, 1H, J = 12 Hz), 6.16 (d, 1H, J = 8 Hz), 6.28 (d, 1H, J = 16 Hz),
6.50 (d, 1H, J = 16 Hz), 6.55–6.56 (m, 1H, ArH), 6.54 (t, 1H, J =
12 Hz), 6.63 (brs, 1H, NH), 6.81 (d, 1H, J = 12 Hz), 7.03–7.06
(m, 1H, ArH), 7.22–7.23 (m, 2H, ArH), 7.69–7.71 (m, 1H, ArH),
13
–1
1
9.92 (d, 1H, J = 8 Hz) ppm; C nmr (deuteriobenzene): δ 17.5,
2211, 2036, 1974 cm ; uv (ethanol): 320, 289, 222 nm; H nmr
(deuteriobenzene): δ 1.01 (s, 3H), 1.17 (s, 3H), 1.21–1.38 (m,
4H), 1.63 (s, 3H), 1.68–1.74 (m, 2H), 1.93 (s, 3H), 1.98 (d, 1H, J
= 12 Hz), 2.20 (d, 1H, J = 11 Hz), 3.73 (d, 1H, J = 16 Hz), 3.97
(d, 1H, J = 16 Hz), 4.83 (s, 1H), 5.33 (d, 1H, J = 12 Hz), 5.66
19.6, 21.9, 23.1, 28.9 (2C), 33.2, 34.5, 39.8, 111.5, 114.2, 118.9,
119.8, 121.9 (2C), 122.4, 126.5, 129.9, 130.6, 130.8, 130.9,
131.6, 136.6, 136.7, 138.1, 144.1, 154.1, 190.0 ppm. Exact mass
Calcd. for C H NO 399.2564. Found: 399.2572.
28 33

264
A. Wada, N. Fujioka and M. Ito
Vol. 38
[6] A. Wada, N. Fujioka and M. Ito, Chem. Pharm. Bull., 47,
171 (1999).
[7] R. Liu, P. Zhang, T. Gan and J. M. Cook, J. Org. Chem., 62,
7447 (1997).
[8] H. Muratake and M. Natume, Heterocycles, 29, 783 (1989).
[9] W. MacFarlane and G. Wilkinson, Inorg. Synth., 8,
181 (1966).
Acknowledgment.
This research was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science and
Culture (Japan) and the Science Research Promotion Fund from
Japan Private School Promotion Foundation.
[10] A. Hafner, W. von Philpsborn and A. Saltzer, Angew. Chem.,
Int. Ed. Engl. 24, 126 (1985).
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