Efficient preparation of 9-Z-11-methylretinal and 11-Z-11-methylretinal

Article abstract of DOI:10.1016/j.tetlet.2010.11.144

[2-(β-Ionylidene)propyl]triphenylphosphonium bromide is reacted with 3-methyl-4-oxobut-2-enenitrile in refluxing 1,2-epoxybutane to give a mixture of 11-Z- and all-E-11-methylretinal via DIBAL-H reduction. In an analogous fashion, β-ionyl triphenylphospho

Full text of DOI:10.1016/j.tetlet.2010.11.144

Tetrahedron Letters 52 (2011) 602–604
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Tetrahedron Letters
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Efficient preparation of 9-Z-11-methylretinal and 11-Z-11-methylretinal
⇑
Prativa B. S. Dawadi , Michiel A. Verhoeven, Johan Lugtenburg
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
[2-(b-Ionylidene)propyl]triphenylphosphonium bromide is reacted with 3-methyl-4-oxobut-2-enenitrile
in refluxing 1,2-epoxybutane to give a mixture of 11-Z- and all-E-11-methylretinal via DIBAL-H
reduction. In an analogous fashion, b-ionyl triphenylphosphonium bromide is reacted with
3,5-dimethyl-6-oxohexa-2,4-dienenitrile in 1,2-epoxybutane followed by subsequent DIBAL-H reduction
to afford a mixture of new products consisting of 9-Z-11-methylretinal, its all-E isomer and 1-(20,60,60-
trimethylcyclohex-20-en-10-yl)-6-(buten-200-al-300-yl)-3,5-dimethylcyclohexa-1,3-diene. These molecules
were obtained in pure form by HPLC.
Received 15 October 2010
Revised 16 November 2010
Accepted 26 November 2010
Available online 3 December 2010
Keywords:
1-(2060,60-Trimethylcyclohex-20-en-10-yl)-6-
(buten-200-al-300-yl)-3,5-dimethylcyclohexa-
1,3-diene
Ó 2010 Elsevier Ltd. All rights reserved.
1,4-conjugated Wittig reaction
Cyclohexadiene formation
For our investigations on rhodopsin chemistry we needed an
easy access to 11-Z-11-methylretinal and its 9-Z-isomer. The prep-
aration of 11-Z-11-methylretinal and its all-E isomer has been
reported via complicated reactions that did not fulfill our require-
ments.1 We were aware that retinoids and carotenoids are
produced on an industrial scale via Wittig reaction of triphenyl-
phosphonium ylides.2–4 In these reactions an appreciable amount
of the 11-Z isomer is formed. A similar situation holds for the prep-
aration of retinoic acids and their metabolites.5 Thus, we reasoned
that a scheme based on Wittig chemistry between [2-(b-ionylid-
ene)propyl]triphenylphosphonium bromide (3) and 3-methyl-4-
oxobut-2-enenitrile (4) should give 11-methylretinonitrile with
the bromide anion to afford a transient alcoholate anion that fur-
ther reacts with product 3.
Base-sensitive materials such as 11-Z-11-methylretinonitrile
did not undergo base-catalyzed conversions under these condi-
tions. After work-up and subsequent DIBAL-H reduction, a ca. 1:1
mixture of 11-Z-11-methylretinal and its all-E isomer was ob-
tained. Silica gel column chromatography afforded 11-Z-11-meth-
ylretinal (1) (0.20 g) and the all-E form (0.25 g) in pure state. The
1H NMR spectra of these materials were in agreement with pub-
lished data within experimental error.1 UV spectroscopy of 11-Z-
11-methylretinal (1) showed kmax values at 363 nm and 250 nm.
Upon treatment with light in the presence of a small amount of io-
dine, it was fully converted into all-E-11-methylretinal (1).
In order to prepare the novel 9-Z-11-methylretinal (1) we
developed a scheme in which the C9–C10 carbon–carbon bond
was formed via Wittig coupling. The required b-ionyltriphenyl-
phosphonium bromide (5) was prepared according to the litera-
ture,8 and the aldehyde precursor, 3,5-dimethyl-6-oxohexa-2,4-
dienenitrile (6) was prepared by treating 1,1-dimethoxyacetone
with the anion of 4-diethylphosphono-3-methylbut-2-enenitrile,
analogous to the preparation of product 4.
Reagents 5 (5.20 g, 10 mmol) and 6 (1.00 g, 8.1 mmol) were
heated at reflux in 1,2-epoxybutane (50 mL) for 8 h. After work-
up, a mixture of conjugated nitriles was isolated, which underwent
subsequent DIBAL-H reduction and chromatography on silica gel.
All-E-11-methylretinal (1) was isolated along with two new com-
pounds: 9-Z-11-methylretinal (1) and aldehyde 7, by HPLC tech-
niques. Based on 1H NMR and 13C NMR spectroscopy the product
7 was identified as 1-(20,60,60-trimethylcyclohex-20-en-10-yl)-6-
(buten-200-al-300-yl)-3,5-dimethylcyclohexa-1,3-diene. Compound
7 results from 1,4-conjugated Wittig addition of 5 to aldehyde 6
a
high contribution of 11-Z-11-methylretinal in the product
mixture.
All-E b-ionylideneacetaldehyde (2) (prepared from b-ionone4)
was reacted with methyllithium in THF to give the corresponding
alcohol, and then treated with triphenylphosphonium hydrobro-
mide in ethanol to give [2-(b-ionylidene)propyl]triphenylphos-
phonium bromide (3). 3-Methyl-4-oxobut-2-enenitrile (4) was
prepared via a known procedure6 involving reaction of 1,1-dim-
ethoxyacetone and diethylphosphonoacetonitrile followed by
subsequent deprotection of the aldehyde function.
The reagents 3 (2.20 g, 4.0 mmol) and 4 (0.29 g, 3.0 mmol) were
dissolved in 1,2-epoxybutane (50 mL) and heated at reflux (65 °C).
1,2-Epoxybutane was used as the solvent in the commercial syn-
thesis of astaxanthin.7 During the reaction, the concentration of
base was very small; 1,2-epoxybutane (a cryptobase) reacts with
⇑
Corresponding author.
E-mail addresses: p.b.s.dawadi@gmail.com (P.B.S. Dawadi), lugtenbu@chem.
leidenuniv.nl (J. Lugtenburg).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.144

P. B. S. Dawadi et al. / Tetrahedron Letters 52 (2011) 602–604
603
in which the charged carbon (C7) of ylide 5 reacts with C3 of the
nitrile 6. After internal proton exchange, intramolecular 1,4-conju-
gated Wittig reaction afforded a nitrile corresponding to the prod-
uct 7. The 1,4-conjugated Wittig reaction has been reported
previously for simple conjugated aldehydes.9 In those cases the
normal Wittig component was totally absent or present only in
very small amounts. In the present case, the ratio between all-E-
1, 9-Z-1, and 7 is 1:1:2, making our procedure useful for obtaining
sufficient quantities of 9-Z-11-methylretinal (1). Furthermore, 9-Z-
11-methylretinal (1) was converted into all-E-11-methylretinal (1)
upon treatment with light in the presence of a small amount of
iodine.
It was clear that the reaction between 3 and 4 afforded clean
products without formation of the 1,4-addition product 7. Our
present method can be adjusted easily to afford many more 11-
modified all-E and 11-Z retinals via a simple isolation procedure
in the absence of light. The corresponding 9-Z 11-modified system
would be accessible via more difficult isolation procedures. Earlier,
we reported a simple preparation of pure all-E and 9-Z modified
retinals (modified in many positions except position 11). The
corresponding 11-Z systems were available together with the
all-E form as mixtures, which were isolated as described
previously10–12 (see Scheme 1).
Chemical modification of 11-Z and all-E retinals is straightfor-
ward via the chemistry described in this Letter. This provides an
access to systems with modification of the substituent on the
C11–C12 double bond. The influence of modification on this double
bond in photochemical isomerization can now be studied system-
atically and we feel that this will contribute to the understanding
of rhodopsin photochemistry.
[2-(b-Ionylidene)propyl]triphenylphosphonium bromide (3): To a
cold solution (ꢀ70 °C) of b-ionylidene acetaldehyde (2)13 (4.90 g,
22 mmol) in THF (100 mL) was added 1 M CH3Li (18 mL) via a syr-
inge. The extent of reaction was monitored by TLC. After stirring for
2 h, a saturated solution of NH4Cl (100 mL) was added and the
aqueous layer was extracted with Et2O (100 mL ꢁ 3). The ethereal
phases were combined, washed with brine (100 mL), dried over
MgSO4, and filtered. The solvent was evaporated under vacuum.
The crude product, 1,3-dimethyl-5-(2,6,6-trimethylcyclohexa-1-
enyl)-penta-2,4-dienol, was purified by silica gel column chroma-
tography (Et2O/petroleum ether, 1:1) to afford the pure product
(22 mmol, 99%). The product was dissolved in dry EtOH (20 mL)
and Ph3PHBr (7.80 g, 23 mmol) added. The mixture was stirred
for 72 h at rt in the absence of light to prevent isomerization.
The solvent was removed under reduced pressure to afford a yel-
low oil which was crystallized from a mixture of EtOAc and Et2O
CH
CH
3
3
CH
H C
3
3
CH
3
CH
H C
3
3
+
CH3Li
PPh Br
3
O
P(Ph)3HBr
CH
3
CH
3
3
2
CH
CH
CH
H C
3
3
3
3
H3C
1,2-epoxybutane, 65 ºC
then DIBAL-H
O
CN
(all- )-1
E
3
+
+
H C
3
CH
3
4
O
(11 )-1
Z
CH
H C
3
CH
3
CH
3
3
CH
3
H C
3
CN
+
1,2-epoxybutane,
reflux
CH3
PPh Br
3
(all- )-1
E
+
+
O
+
CH3
then
DIBAL-H
CH
3
H C
3
CH
3
5
(9 )-1
Z
CH
6
3
O
H C
3
CH
H
3
H
O
H C
3
CH
3
CH
3
CH
3
7
Scheme 1. The preparation of 11-Z-11-methylretinal (11Z-1), 9-Z-11-methylretinal (9Z-1), all-E-11-methylretinal (all-E-1) and 1-(20,60,60-trimethylcyclohex-20-en-10-yl)-6-
(buten-200-al-300-yl)-3,5-dimethylcyclohexa-1,3-diene (7) via Wittig reactions.

604
P. B. S. Dawadi et al. / Tetrahedron Letters 52 (2011) 602–604
to afford the product 3 (7.30 g, 13 mmol). 1H NMR (400 MHz,
CDCl3/TMS) d = 0.97 (s, 3H, CH3), 0.98 (s, 3H, CH3), 1.44 (m, 2H,
nylphosphonium bromide (5)8 (5.20 g, 10 mmol) and 3,5-di-
methyl-6-oxohexa-2,4-dienenitrile (6) (1.20 g, 10 mmol) in 1,2-
epoxybutane (50 mL) was heated under reflux for 60 h. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography (Et2O/petroleum ether, 1:4) to afford a
mixture of the conjugated nitriles 9-Z-1, all-E-1 and 7 (2.35 g,
7.7 mmol, 82%).
3
CH2), 1.59 (m, 2H, CH2), 1.63 (s, 3H, CH3), 1.66 (d, JH–P = 7 Hz,
5
3H, CH3), 1.91 (d, JH–P = 3 Hz, 3H, CH3), 1.98 (d, 2H, CH2), 5.00
3
3
(dd, JH–H = 8.50 Hz JH–H = 9.50 Hz, 1H, CH), 5.50 (m, 1H, CH),
3
3
5.89 (d, JH–H = 16 Hz, 1H, CH), 6.15 (d, JH–H = 16 Hz, 1H, CH),
7.87–7.32 (m, 15H, Ph). 13C NMR (100 MHz, CDCl3/TMS): d = 14.2
(CH3), 16.9 (CH3), 18.9 (CH2), 21.4 (CH3), 28.6 (2 ꢁ CH3), 30.8 (d,
To a cold solution (ꢀ60 °C) of the mixture of conjugated nitriles
(2.30 g, 8 mmol) in petroleum ether (50 mL) was added DIBAL-H
(1 M, 11 mL, 11 mmol) via a syringe. The solution was stirred for
30 min at ꢀ60 °C, and then for 2 h at rt. The extent of reaction
was monitored by TLC. To this solution at 0 °C was added a mixture
of silica gel–H2O (20.00 g/0.4 mL) and stirring was continued for
1 h. The mixture was dried over MgSO4 and filtered. The residue
was rinsed with Et2O (50 mL ꢁ 3) and the solvent was evaporated
under vacuum. The residue was purified by silica gel column chro-
matography (Et2O/petroleum ether, 5:95) to afford a mixture of
aldehydes 9-Z-1 and all-E-1 (0.83 g, 2.8 mmol, 41%) and aldehyde
7 (0.78 g, 2.60 mmol, 39%). The three aldehyde products were iso-
lated in pure form after separation by HPLC.
1JC–P = 47 Hz, CH), 32.6 (CH2), 33.9 (CH2), 39.2 (CH2), 117.4 (d, JC–
1
2
5
P = 82 Hz, Ph), 120.0 (d, JC–P = 7 Hz, CH), 129.3 (d, JC–P = 4 Hz,
4
CH), 129.6 (CH2), 130.2–134.8 (Ph), 135.3 (d, JC–P = 4 Hz, CH),
137.0 (C), 142.6 (d, JC–P = 14 Hz, CH). 31P (162 MHz, CDCl3/TMS)
3
d = 27.2.
11-Z-11-Methylretinal (1) and all-E-11-methylretinal (1): A solu-
tion of 3 (2.25 g, 5 mmol) and 3-methyl-4-oxobut-2-enenitrile (4)6
(0.48 g, 5 mmol) in 1,2-epoxybutane (50 mL) was heated under re-
flux at 65 °C for 60 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(Et2O/petroleum ether, 1:4) to afford a mixture of conjugated ni-
triles 11-Z-1 and all-E-1 (0.78 g, 87%).
To a cold solution (ꢀ60 °C) of the mixture of the conjugated ni-
triles (0.78 g, 2.60 mmol) in petroleum ether (20 mL) was added
DIBAL-H (1 M, 4 mL, 4 mmol) via a syringe. The solution was stir-
red for 30 min at ꢀ60 °C, then for 1 h at rt. On completion of the
reaction a mixture of silica gel–H2O (5.00 g) (prepared by mixing
20.00 g of silica gel and 0.4 mL of H2O) was added at 0 °C and stir-
ring continued for 1 h. The mixture was dried over MgSO4 and fil-
tered; the residue was washed with Et2O (10 mL ꢁ 3) and the
solvent was evaporated under vacuum. The residue was purified
by silica gel column chromatography (Et2O/petroleum ether,
5:95) to afford a mixture of 11-Z-11-methylretinal (1) (0.20 g)
and all-E-11-methylretinal (1) (0.25 g). The spectroscopic data
were identical to those in Ref. 1.
3,5-Dimethyl-6-oxohexa-2,4-dienenitrile (6): To a cold solution
(0 °C) of (diethylphosphono)-3-methyl-2-butenenitrile14 (5.43 g,
25 mmol) in THF (125 mL) was added nBuLi (1.6 M in hexanes,
15.60 mL, 25 mmol) via a syringe. After stirring for 15 min at
0 °C, 1,1-dimethoxyacetone (2.36 g, 20 mmol) was added. The ex-
tent of reaction was monitored by TLC (EtOAc/petroleum ether,
1:3) with 2,4-dinitrophenylhydrazine as the staining reagent. After
stirring for 2 h, a saturated solution of NH4Cl (100 mL) was added.
The aqueous layer was extracted with Et2O (100 mL ꢁ 3) and the
ethereal phases were combined, washed with brine (100 mL), dried
over MgSO4, and filtered. The solvent was evaporated under
vacuum and the product was purified by column chromatography
to afford 6,6-dimethoxy-3,5-dimethylhexa-2,4-dienenitrile (6)
(3.12 g, 17 mmol). 1H NMR (200 MHz, CDCl3/TMS) d = 1.84 (s, 3H,
CH3), 2.20 (s, 3H, CH3), 3.34 (s, 6H, 2 ꢁ OCH3), 4.55 (s, 1H, CH),
5.22 (s, 1H, CH), 6.13 (s, 1H, CH).
This product was dissolved in acetone (50 mL) and acidified
with 1 M HCl (to ca. pH 2). The solution was treated with a mixture
of K2CO3 and MgSO4, filtered and evaporated under reduced pres-
sure. The product was purified to afford 3,5-dimethyl-6-oxohexa-
2,4-dienenitrile (6) (2.20 g, 17 mmol) as a light yellow oil. 1H
NMR (300 MHz, CDCl3/TMS) d = 2.01 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 5.53 (s, 1H, CH), 6.76 (s, 1H, CH), 9.50 (s, 1H, CH). 13C NMR
(100 MHz, CDCl3/TMS): d = 11.3 (CH3), 20.0 (CH3), 103.3 (CH),
116.2 (CN), 141.9 (C), 146.4 (CH), 155.3 (C), 195.4 (CHO). HRMS
(calculated for C8H9NO) m/z 135.1632, (obtained) 134.1624.
Preparation of 9-Z-11-methylretinal (1), all-E-11-methylretinal
(1) and 1-(20,60,60-trimethylcyclohex-20-en-10-yl)-6-(buten-200-al-300-
yl)-3,5-dimethylcyclohexa-1,3-diene (7): A solution of b-ionyltriphe-
9-Z-11-Methylretinal 1: 1H NMR (400 MHz, CDCl3/TMS) d = 1.02
(s, 6H, 2 ꢁ CH3), 1.47 (m, 1H, CH2), 1.61 (m, 2H, CH2), 1.69 (s, 3H,
CH3), 1.98 (s, 3H, CH3), 2.01 (t, 2H, CH2), 2.02 (s, 3H, CH3), 2.29
3
(s, 3H, CH3), 5.86 (s, 1H, CH), 5.92 (s, 1H, CH), 5.99 (d, JH–
3
3
H = 8.21 Hz, 1H, CH), 6.29 (d, JH–H = 16 Hz, 1H, CH), 6.48 (d, JH–
3
H = 16 Hz, 1H, CH), 10.07 (d, JH–H = 8.21 Hz, 1H, CHO). 13C NMR
(100 MHz, CDCl3/TMS): d = 18.4 (CH3), 19.2 (CH3), 20.6 (CH3),
21.4 (CH3), 21.8 (CH3), 29.0 (2 ꢁ CH3), 33.9 (CH2), 34.2 (CH2),
39.6 (CH2), 129.7, 129.9, 131.5, 132.1, 132.3, 136.5, 137.9, 141.9,
155.9, 191.3 (CHO).
1-(20,60,60-Trimethylcyclohex-20-en-10-yl)-6-(buten-200-al-300-yl)-3,
5-dimethylcyclohexa-1,3-diene (7): 1H NMR (400 MHz, CDCl3/TMS)
d = 1.00 (s, 3H, CH3), 1.14 (s, 3H, CH3), 1.48 (m, 2H, CH2), 1.50 (s,
3H, CH3), 1.60 (m, 2H, CH2), 1.71 (s, 3H, CH3), 1.74 (s, 3H, CH3),
3
1.90 (m, 2H, CH2), 2.12 (s, 3H, CH3), 2.74 (d, JH–H = 8.21 Hz, 1H,
3
CH), 3.61 (m, 1H, CH), 5.24 (s, 1H, CH), 5.81 (d, JH–H
=
3
8.21 Hz, 1H, CH), 5.85 (s, 1H, CH), 9.96 (d, JH–H = 8.21 Hz, 1H,
CHO). 13C NMR (100 MHz, CDCl3/TMS): d = 19.1, 20.6, 22.3, 23.8,
28.0, 28.7, 33.4, 35.9, 39.8, 41.9, 52.9, 125.5, 125.6, 129.0, 130.0,
132.3, 135.7, 136.5, 162.5, 191.2 (CHO). HRMS (calculated for
C21H30O) m/z 298.2296, (obtained) 298.2273.
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