A Highly Stereoselective Synthesis of 11Z-Retinal Using Tricarbonyliron Complex

Article abstract of DOI:10.1021/jo9916030

A stereoselective synthesis of 11Z-retinal 2, which is the chromophore of visual pigment (rhodopsin), was accomplished from the β-ionylideneacetaldehyde-tricarbonyliron complex 3. The Peterson reaction of 3 using ethyl trimethylsilylacetate smoothly proce

Full text of DOI:10.1021/jo9916030

2438
J . Org. Chem. 2000, 65, 2438-2443
A High ly Ster eoselective Syn th esis of 11Z-Retin a l Usin g
Tr ica r bon ylir on Com p lex†
Akimori Wada,* Naoko Fujioka, Yukiko Tanaka, and Masayoshi Ito*
Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, J apan
Received October 14, 1999
A stereoselective synthesis of 11Z-retinal 2, which is the chromophore of visual pigment (rhodopsin),
was accomplished from the â-ionylideneacetaldehyde-tricarbonyliron complex 3. The Peterson
reaction of 3 using ethyl trimethylsilylacetate smoothly proceeded to afford predominantly the
Z-ester 6. Transformation of the Z-ester 6 to the methyl ketone 19, followed by the Emmons-
Horner reaction of 19 with C2-cyanophosphonate, produced ethyl 11Z,13E-retinonitrile-tricarbo-
nyliron complex 21 as the only product. Decomplexation of 21 with CuCl2 and subsequent DIBAL
reduction gave 11Z-retinal 2 in excellent yield. Mechanistic consideration of Z-selectivity in the
Peterson reaction of the aldehyde-tricarbonyliron complex is also discussed.
It is well-known that retinal 1 is a chromophore of
photosensitive pigments such as rhodopsin, bacterior-
hodopsin, retinochrome, and so on. These pigments
covalently bond to the retinal through a protonated Schiff
base with lysine of the protein opsin and play an
important role as retinal proteins in vital cells. The most
characteristic feature of these compounds is that the
biological activities are dependent upon the stereochem-
istry of the retinal in the protein. For example, the
chromophore of the visual pigment rhodopsin is 11Z-
retinal 2 and those of bacteriorhodopsin and retin-
ochrome, whose functions are a light-driven proton pump
and a regeneration of rhodopsin, are 13Z- and all-E-
retinals, respectively.1,2 Although there are a number of
reports available in the literature for the synthesis of
retinal and related compounds to investigate the biologi-
cal function of these proteins, only a few reports for the
stereoselective synthesis3 have been found, except for the
all-E isomer. Recently, we have developed a novel method
for a stereoselective synthesis of all-E and 9Z-retinoic
acids using the tricarbonyliron complex.4 In continuation
of our study torward the synthesis of retinal and related
compounds, herein we describe a stereoselective synthe-
sis of 11Z-retinal from the â-ionylideneacetaldehyde-
tricarbonyliron complex, including the full account of our
work in the preliminary communication5 (Figure 1)
F igu r e 1. Structure of retinals.
Resu lts a n d Discu ssion
Construction of the Z-stereochemistry in a disubsti-
tuted olefin is essential for the preparation of 11Z-retinal.
To achieve this, there are various methods such as
selective hydrogenation of the acetylene compounds,6
olefination of the aldehyde using phosphonate reagent
having a fluorine atom,7 and a cross-coupling reaction of
vinyl halides with metal olefins in the presence of a
palladium catalyst.8 However, these methods are not
satisfactory for the preparation of 11Z-retinal 2 due to
the low yield, low stereoselectivity, and a difficulty in the
synthesis of the starting materials. Recently, it was
shown that the aldol condensation of aldehyde having
the arene-tricarbonylchromium complex9 or alkyne-
hexacarbonyldicobalt complex10 with silyl enol ether or
silyl ketene acetal exhibits a different stereoselectivity
compared to that of the uncomplexed aldehydes. We also
found that in the dehydration of ethyl acetate adduct of
* To whom correspondence should be addressed. Tel: +81(J apan)-
78-441-7561. Fax: +81(J apan)-78-441-7562. E-mail: a-wada@kobe-
pharma-u.ac.jp.
† Retinoids and Related Compounds. 23. Part 22: Wada, A.; Fujioka,
N.; Ito, M. Chem. Pharm. Bull. 1999, 47, 171.
(1) The Retinoids, 2nd ed., Sporn, M. B., Roberts, A. B., Goodman,
D. S., Eds.; Raven Press, Ltd: New York, 1994.
(2) (a) Ozaki, K.; Terakita, A.; Hara, R.; Hara, T. Vision Res. 1987,
27, 1057. (b) Hara, R.; Hara, T.; Ozaki, K.; Terakita, A.; Eguchi, G,.;
Kodama, R.; Takeuchi, T. Retinal Proteins; VNU Science Press:
Utrecht, 1987. (c) Terakita, A.; Hara, R.; Hara, T. Vision Res. 1989,
29, 639.
(3) For 9Z-retinoic acid: (a) Bennani, Y. L.; Boehm, M. F. J . Org.
Chem. 1995, 60, 1195. For 11Z-retinal; (b) Uenishi, J .; Kawahama,
R.; Yonemitsu, O.; Wada, A.; Ito, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 320. (c) Borhan, B.; Souto, M. L.; Um. J . M.; Zhou, B.; Nakanishi,
K. Chem. Eur. J . 1999, 5, 1172. For 13Z-retinoic acid: (d) Thibonnet,
J .; Abarbri, M.; Ducheˆne, A.; Parrain, J .-L. Synlett 1999, 141.
(4) (a) Wada, A.; Hiraishi, S.; Ito, M. Chem. Pharm. Bull. 1994, 42,
757. (b) Wada, A.; Saeko, H.; Takamura, N.; Date, T.; Aoe, K.; Ito, M.
J . Org. Chem. 1997, 62, 4343.
(6) Oroshnik, W. J . Am. Chem. Soc. 1956, 78, 2651.
(7) (a) Mead, D.; Asato, A. E.; Denny, M.; Liu, R. S. H.; Hanzawa,
Y., Taguchi, T.; Yamada, A.; Kobayashi, N.; Hosoda, A.; Kobayashi,
Y. Tetrahedron Lett. 1987, 28, 259. (b) Trehan, A.; Liu, R. S. H.
Tetrahedron Lett. 1988, 29, 419.
(8) (a) de Lera, A. R.; Torrado A.; Iglesias, B.; Lo´pez, S. Tetrahedron
Lett. 1992, 33, 6205. (b) Torrado, A.; Iglesias, B.; Lo´pez, S.; de Lera,
A. R. Tetrahedron 1995, 51, 2435.
(9) (a) Mukai, C.; Cho, W. J .; Hanaoka, M. Tetrahedron Lett. 1989,
30, 7435. (b) Mukai, C.; Cho, W. J .; Kim, I. J .; Kido, M., Hanaoka, M.
Tetrahedron 1991, 47, 3007.
(10) (a) J u, J .; Reddy, B. R.; Khan, M.; Nicholas, K. M. J . Org. Chem.
1989, 54, 5426. (b) Mukai, C.; Suzuki, K.; Hanaoka, M. Chem. Pharm.
Bull. 1990, 38, 567. (c) Mukai, C.; Suzuki, K.; Nagami, K.; Hanaoka,
M. J . Chem. Soc., Perkin Trans. 1 1992, 141.
(5) Wada, A.; Tanaka, Y.; Fujioka, N.; Ito, M. Bioorg. Med. Chem.
Lett. 1996, 6, 2049.
10.1021/jo9916030 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

Stereoselective Synthesis of 11Z-Retinal
J . Org. Chem., Vol. 65, No. 8, 2000 2439
Sch em e 1
Sch em e 2
â-ionone-tricarbonyliron complex by thionyl chloride, the
Z-olefin was predominantly produced in contrast to the
usual dehydration, in which the thermodynamically most
stable E-olefin was preferentially produced via the E1-
mechanism.11 These findings suggested us that the
aldehyde-tricarbonyliron complex is a strong candidate
for the construction of disubstituted Z-olefin and it would
be a useful substrate for the preparation of 11Z-retinal
2.
were easily prepared from the tricarbonyliron-complex
10a -c14 by the reaction of the lithium salt of acetonitrile
and subsequent DIBAL reduction.15 In these reactions,
a similar migration of tricarbonyliron was observed as
shown for the preparation of 3.4b The Peterson reaction
of ethyl and isopropyl derivatives 11b,c smoothly pro-
ceeded to give predominantly Z-isomers 13b,c in 58% and
56% yields, respectively. The increase in the bulkiness
of the 9-substituent caused a slight decrease in the yield
of the products; however, the Z-stereoselectivity was not
seriously affected. In the case of 11a , which had no alkyl
substituent at the 9-position, the Z-stereoselectivity was
dramatically decreased, and almost the same amount of
E- and Z-isomers was obtained. Furthermore, when the
noncomplexed aldehyde 14 was treated with ethyl tri-
methylsilylacetate, the E-isomer 15 was obtained as the
major product (60%) accompanied by the Z-isomer 16 in
38% yield (Scheme 3).
These facts strongly suggest that both the tricarbonyl-
iron complex and the 9-substituent are essential for the
Z-stereoselectivity during these Peterson reactions. Al-
though the mechanism for this high Z-selectivity is not
clear yet, we tentatively propose the following explana-
tion. It is well-known that in the dienylaldehyde-
tricarbonyliron complex the carbonyl group of the alde-
hyde exists in both the s-cis and s-trans conformations
around the C10-C11 single bond.16 However, if there is a
substituent at the 9-position such as 3 and 11b,c, the
carbonyl group would have the s-trans conformation in
order to avoid the steric interaction between the carbonyl
group of the aldehyde with the C9-substituent (Figure
2).17
First, we attempted numerous olefination reactions of
the â-ionylideneacetaldehyde-tricarbonyliron complex
3,4b which was easily derived from the â-ionone-tricar-
bonyliron complex by the reaction of the lithium salt of
acetonitrile followed by DIBAL reduction. The Wittig
reaction or the Emmons-Horner reaction of 3 using
triphenylcarbethoxymethylene-phosphorane or diethyl
(2-oxopropyl)phosphonate afforded the E-olefinic products
4 and 5 as the sole products in 62% and 49% yields,
respectively (Scheme 1). The geometry of the newly
produced double bond at the 11 position in 4 and 5 was
determined as E from their NMR spectra, in which the
coupling constants between the 11 and 12 positions
exhibited 15 and 15.5 Hz, respectively.12 In the reaction
of 3 with acetone under the basic conditions, the alde-
hyde-tricarbonyl complex 3 was recovered unchanged.
On the contrary, treatment of 3 with the lithium
enolate of ethyl trimethylsilylacetate in THF at -70 °C
afforded the Z-isomer 6 predominantly (77%) accompa-
nied by the 11E-isomer 4 (15%). Similarly, in the reaction
of trimethylsilylacetonitrile, the 11Z-nitrile 8 (59%) was
obtained as the major product in addition to the 11E-
isomer 7 (19%) and trimethylsilylnitrile 9 (16%), which
seemed to be produced by dehydration from the reaction
intermediate. The structure of 9 was determined by
desilylation with tetrabutylammonium fluoride in THF
to yield 8. As the interconversion of the Z-ester 6 to the
E-ester 4 was not found under the reaction conditions
used, we speculated that the stereoselectivity is con-
trolled by formation of kinetically preferred â-hydroxysi-
lane, which is followed by a synchronous syn elimina-
tion13 (Scheme 2).
There are six possible transition states, in which the
lithium enolate approaches the aldehyde from the op-
posite side of the tricarbonyliron complex18 (Scheme 4).
Among these transition states, transition states [A1] and
[B3] may be favorable due to the steric repulsion between
(14) Wada, A.; Fujioka, N.; Ito, M. Chem. Pharm. Bull. 1999, 47,
171.
(15) In the case of 10c, the Z-iosmer of 11c was also obtained in
25% yield.
To confirm the generality of this Z-stereoselectivity,
the Peterson reaction of various aldehyde-tricarbonyl-
iron complexes was investigated. The substrates 11a -c
(16) Gre´e, R. Synthesis 1989, 341.
(17) X-ray analysis of 3 exhibits the s-trans conformation of the
carbonyl group of the aldehyde, and this result will be published in
near future. In the NMR NOE experiment of compound 3, both cross-
peaks between the aldehyde proton and C10-proton (s-cis conformation)
or C9-methyl protons (s-trans conformation) were observed; therefore,
it was impossible to confirm the conformation of the carbonyl group
by NMR.
(11) Lomas, J . S.; Sagatys, D. S.; Dubois, J . E. Tetrahedron Lett.
1971, 599.
(12) For structural comparisons standard retinoid numbering has
been used.
(13) Hudrlik, P. F.; Peterson, D., Rona, R. J . J . Org. Chem. 1975,
40, 2263.
(18) Clinton, N. A.; Lillya, C. P. J . Am. Chem. Soc. 1970, 92, 3058.

2440 J . Org. Chem., Vol. 65, No. 8, 2000
Wada et al.
Sch em e 3
Sch em e 4
F igu r e 2. Conformation of dienylaldehyde-tricarbonyliron
complex.
the 9-alkyl group and the substituent on the enolate.
Thus, in these transition states the hydrogen occupied
the least-hindered position in the reaction intermediate.
In these two transition states, [B3] has a serious interac-
tion between the trimethylsilyl group and the diene-
tricarbonyliron complex compared with that of [A1].
Therefore, the transition state [A1] was preferred to
afford the Z-olefin via syn elimination from the â-hy-
droxysilyl adduct.13
According to the above hypothesis, the more bulky silyl
substituent on the Peterson reagent seems to afford the
higher Z-selectivity in the olefin products. Indeed, in the
reaction of the aldehyde-tircarbonyliron complex 3 with
tert-butyldimethylsilylacetonitrile, the Z-olefin 8 was
obtained exclusively in 30% yield, and this fact strongly
supports our proposed reaction mechanism, although the
yield of product was low due to the steric bulkiness of
the reagent.
ation by the reaction with the Grignard reagent and
subsequent oxidation of magnesium salt by Mukaiyama’s
method19 using 1,1′-(azodicarbonyl)dipiperidine 17.4b To
apply this methodology, the nitrile 8 was converted to
the aldehyde-tricarbonyliron complex 18 by DIBAL
reduction in 84% yield. Treatment of 18 with methyl-
magnesium bromide followed by oxidation with 17 af-
forded the desired ketone 19 and isomerized aldehyde
20 in 27% and 55% yields, respectively. These structures
were determined on the basis of their spectral data. The
aldehyde 20 seemed to be formed by isomerization of the
starting aldehyde 18 under the basic reaction conditions
used, and it is evident that the rate of isomerization was
faster than that of the oxidation of the magnesium salt,
which was generated by the addition of methylmagne-
sium bromide to the aldehyde 18, since the isomerized
aldehyde 20 was obtained as the major product (Scheme
5).
Subsequently, we focused our attention on the trans-
formation of the ester 6 or nitrile 8 to 11Z-retinal 2. A
direct conversion of the nitrile 8 to the C18-ketone-
tricarbonyliron complex 19 using methylmagnesium
bromide was unsuccessful. Recently, we have succeeded
in converting the aldehyde-tricarbonyliron complex to
the ketone-tricarbonyliron complex without decomplex-
On the other hand, the conversion of the ester 6 to 19
by the reported method using triphenylstannylmethyl-
(19) Saigo, K.; Morikawa, A.; Mukaiyama, T. Bull. Chem. Soc. J pn.
1976, 49, 1656.

Stereoselective Synthesis of 11Z-Retinal
J . Org. Chem., Vol. 65, No. 8, 2000 2441
300, or 500 MHz. Column chromatography (CC) under reduced
pressure by aspirator was performed using Merck silica gel
60. Medium pressure CC was carried out using Merck LiChro-
prep Si 60. All reactions were carried out under a nitrogen
atmosphere. THF and ether were purified by distillation from
benzophenone-sodium ketyl under nitrogen. Standard workup
means that the organic layers were finally washed with brine,
dried over anhydrous sodium sulfate (Na2SO4), filtered, and
concentrated in vacuo below 30 °C using a rotary evaporator.
Sch em e 5
Tr ica r bon yl [Eth yl (η4-4,5,6,7)-(2E,4E,6E)-5-Meth yl-7-
(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-2,4,6-h ep ta tr ien oa te]-
ir on (0) (4). A mixture of â-iononylideneacetaldehyde tricar-
bonyliron complex 3 (100 mg, 0.28 mmol) and (carbethoxy-
methylene)triphenylphosphorane (118 mg, 0.34 mmol) in
benzene (20 mL) was heated under reflux for 6 h. After cooling,
the solvent was removed in vacuo, and the residue was purified
by CC (ether/hexane 1:9) to give the ester 4 (74.6 mg, 62%) as
an orange oil: UV-vis 322, 247 nm (sh); IR 2933, 2056, 1995,
1703 cm-1; 1HNMR (300 MHz) δ 1.15 (s, 3H), 1.26 (s, 3H), 1.29
(t, J ) 7 Hz, 3H), 1.4-1.62 (m, 4H), 1.56 (d, J ) 11 Hz, 1H),
1.81 (s, 3H), 1.97-2.09 (m, 2H), 2.11 (d, J ) 11 Hz, 1H), 2.4
(s, 3H), 4.19 (q, J ) 7 Hz, 2H), 5.72 (d, J ) 11 Hz, 1H), 5.98
(d, J ) 15 Hz, 1H), 7.09 (dd, J ) 15, 11 Hz, 1H); 13C NMR
(125 MHz) δ 14.3, 18.9, 20.1, 23.0, 28.8, 29.8, 34.9, 35.2, 42.2,
56.9, 60.2, 62.6, 86.1, 97.3, 119.2, 135.0, 135.4, 145.8, 166.7,
211.8 (C3); HRMS calcd for C22H28FeO5 428.1287, found
428.1295 (M-).
Sch em e 6
Tr ica r b on yl [(η4-5,6,7,8)-(3E,5E,7E)-6-Met h yl-8-(2,6,6-
tr im eth yl-1-cycloh exen -1-yl)-3,5,7-octa tr ien -2-on e]ir on -
(0) (5). To a stirred solution of diethyl(2-oxopropyl)phospho-
nate (97 mg, 0.6 mmol) in THF (5 mL) was added a solution
of n-butyllithium (1.6 M hexane solution, 0.38 mL, 0.6 mmol)
at 0 °C. After the mixture was stirred for 30 min, a solution of
the â-iononylideneacetaldehyde tricarbonyliron complex 3 (70
mg, 0.2 mmol) in THF (5 mL) was added. The resulting
mixture was stirred for an additional 5 h at rt. After addition
of saturated aqueous NH4Cl and evaporation of the solvent,
the organics were extracted with ether followed by standard
workup. The residue was purified by CC (ether/hexane 1:4) to
give the ketone 5 (37.9 mg, 49%) as an orange oil: UV-vis
297 nm; IR 2979, 2040, 1979, 1655, 1591 cm-1; 1H NMR (300
MHz) δ: 1.16 (s, 3H), 1.27 (s, 3H), 1.4-1.6 (m, 4H), 1.56 (d, J
) 11 Hz, 1H), 1.83 (s, 3H), 2.02 (br t, J ) 6.5 Hz, 2H), 2.18 (d,
J ) 11 Hz, 1H), 2.24 (s, 3H), 2.42 (s, 3H), 5.76 (d, J ) 11 Hz,
1H), 6.28 (d, J ) 15.5 Hz, 1H), 6.97 (dd, J ) 15.5, 11 Hz, 1H);
HRMS calcd for C21H26FeO4 398.1182, found 398.1191 (M-).
Tr ica r bon yl [Eth yl (η4-4,5,6,7)-(2E,4E,6E)-5-Meth yl-7-
(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-2,4,6-h ep ta tr ien oa te]-
ir on (0) (4) a n d Tr ica r bon yl [Eth yl (η4-4,5,6,7)- (2Z,4E,6E)-
5-Me t h yl-7-(2,6,6-t r im e t h yl-1-cycloh e xe n -1-yl)-2,4,6-
h ep ta tr ien oa te]ir on (0) (6). To a solution of LDA, prepared
from n-butyllithium (1.6 M hexane solution, 1.93 mL, 3.08
mmol) and diisopropylamine (0.43 mL, 3.08 mmol) in THF (30
mL), was added a solution of ethyl trimethylsilylacetate (0.56
mL, 3.08 mmol) at -78 °C, and the resulting mixture was
stirred for an additional 20 min. A solution of the aldehyde 3
(1 g, 2.79 mmol) in THF (10 mL) was added at -78 °C, and
the mixture was further stirred for 20 min. The reaction was
quenched with saturated aqueous NH4Cl and then extracted
with ether followed by standard workup. The residue was
purified by CC (ether/hexane 1:4) to give the esters of 4 (180
mg, 15%) and 6 (923 mg, 77%) as an orange oil, respectively.
The E-ester 4 was identical with the authentic specimen
obtained by the previous method.
lithium20 smoothly proceeded to give the desired ketone
19 in excellent yield. The Emmons-Horner reaction of
19 with diisopropyl cyanomethylphosphonate using so-
dium hydride as base gave the nitrile 21 as the single
product in 73% yield. After decomplexation of 21 with
copper(II) dichloride,21 the final transformation of 22 to
the 11Z-retinal 2 was achieved by DIBAL reduction in
good yield (Scheme 6).
In summary, we have developed a new method for
stereoselective Z-olefin synthesis by the Peterson reaction
of the aldehyde tricarbonyliron complex and also achieved
the stereoselective synthesis of 11Z-retinal 2 by applying
this methodology. This method would provide a novel
route for the stereoselective synthesis of vitamin A and
related compounds.
11Z-Isom er 6: UV-vis 280 nm; IR 2935, 2041, 1980, 1699,
1614 cm-1;1H NMR (300 MHz) δ 1.17 (s, 3H), 1.28 (s, 3H), 1.29
(t, J ) 7 Hz, 3H), 1.4-1.62 (m, 4H), 1.86 (s, 3H), 1.97-2.09
(m, 2H), 2.34 (d, J ) 11 Hz, 1H), 2.37 (s, 3H), 3.36 (d, J ) 11
Hz, 1H), 4.19 (q, J ) 7 Hz, 2H), 5.50 (d, J ) 11 Hz, 1H), 5.71
(d, J ) 11 Hz, 1H), 6.39 (t, J ) 11 Hz, 1H); 13C NMR (125
MHz) δ 14.4, 18.9, 19.4, 23.1, 28.9, 29.9, 34.9, 35.1, 42.2, 54.1,
59.9, 63.0, 86.4, 97.8, 116.1, 135.1, 135.3, 145.8, 166.8, 212.0
(C3); HRMS calcd for C22H28FeO5 428.1287, found 428.1293
(M-).
Exp er im en ta l Section
All melting points are uncorrected. UV-vis spectra were
recorded in ethanol, IR spectra in chloroform, and 1H NMR
spectra in deuteriochloroform unless otherwise stated at 200,
(20) Sato, T.; Matsuoka, H., Igarashi, T.; Minomura, M.; Murayama,
E. J . Org. Chem. 1988, 53, 1207.
(21) Pearson, A. J .; Lai, Y. S.; Lu, W.; Pinkerton, A. A. J . Org. Chem.
1989, 54, 3882.

2442 J . Org. Chem., Vol. 65, No. 8, 2000
Wada et al.
Tr ica r b on yl [(η4-4,5,6,7)-(2E,4E,6E)-5-Met h yl-7-(2,6,6-
tr im eth yl-1-cycloh exen -1-yl)-2,4,6-h eptatr ien en itr ile]ir on -
(0) (7), Tr ica r bon yl [(η4-4,5,6,7)-(2Z,4E,6E)-5-Meth yl-7-
(2,6,6-t r i m e t h y l-1-c y c lo h e x e n -1-y l)-2,4,6-h e p t a t r i -
en en it r ile]ir on (0) (8), a n d Tr ica r b on yl [(η4-4,5,6,7)-
(2E,4E,6E)-5-Met h yl-7-(2,6,6-t r im et h yl-1-cycloh exen -1-
yl)-2-tr im eth ylsilyl-2,4,6-h ep ta tr ien en itr ile]ir on (0) (9). In
the same manner as described for the preparation of 4 and 6,
the tricarbonyliron complex 3 (1.0 g, 2.79 mmol) was reacted
with trimethylsilylacetonitrile (0.35 mL, 2.52 mmol). The
residue was purified by medium-pressure CC (ether/hexane
1:4) to give the nitriles 7 (61 mg, 19%), 8 (188 mg, 59%), and
9 (60 mg, 16%) as an orange solid, respectively.
mg, 27%) and aldehyde 20 (60 mg, 60%) as a red oil,
respectively.
Keton e 19: UV-vis 290 nm; IR 2933, 2039, 1979, 1673,
1
1576 cm-1; H NMR (300 MHz, C6D6) δ 1.21 (s, 3H), 1.33 (s,
3H), 1.3-1.5 (m, 4H), 1.80 (br t, J ) 6.5 Hz, 2H), 1.83 (s, 6H),
1.90 (s, 3H), 2.59 (d, J ) 11 Hz, 1H), 3.80 (d, J ) 11 Hz, 1H),
5.53 (d, J ) 11 Hz, 1H), 5.60 (d, J ) 11 Hz, 1H), 6.05 (t, J )
11 Hz, 1H); 13C NMR (125 MHz) δ 18.9, 19.1, 23.1, 28.9, 29.9,
31.7, 34.9, 35.2, 42.2, 54.7, 63.7, 86.5, 98.4, 122.3, 135.1, 135.5,
145.1, 198.6, 211.9 (C3); HRMS calcd for C21H26FeO4 398.1182,
found 398.1166 (M-).
Ald eh yd e 20: UV-vis 295 nm; IR 2935, 2041, 1981, 1664
cm-1; 1H NMR (300 MHz, C6D6) δ 1.13 (s, 3H), 1.15 (d, J ) 11
Hz, 1H), 1.25 (s, 3H), 1.3-1.5 (m, 4H), 1.68 (s, 3H), 1.80 (s,
3H), 1.81 (br t, J ) 6 Hz, 2H), 2.02 (d, J ) 11 Hz, 1H), 5.48 (d,
J ) 11 Hz, 1H), 6.10 (dd, J ) 15, 7.5 Hz, 1H), 6.50 (dd, J )
11E-Isom er 7: mp 109-111 °C (ether-n-hexane); UV-vis
281 nm; IR 2936, 2216, 2042, 1981, 1605 cm-1; 1H NMR (300
MHz) δ 1.14 (s, 3H), 1.25 (s, 3H), 1.4-1.6 (m, 4H), 1.44 (d, J
) 11 Hz, 1H), 1.81 (s, 3H), 2.01 (br t, J ) 6 Hz, 2H), 2.17 (d,
J ) 11 Hz, 1H), 2.36 (s, 3H), 5.41 (d, J ) 16 Hz, 1H), 5.73 (d,
J ) 11 Hz, 1H), 6.77 (dd, J ) 16, 11 Hz, 1H); HRMS calcd for
15, 11 Hz, 1H), 9.29 (d, J ) 7.5 Hz, 1H); HRMS calcd for C20H24
-
FeO4 384.1025, found 384.1025 (M-).
20H23FeNO3 381.1028, found 381.1038 (M-).
Con ver sion of 6 to 19. To a stirred solution of Ph3SnCH2I
(688 mg, 1.4 mmol) in dry Et2O (20 mL) was added a solution
of n-butyllithium (1.6 M hexane solution, 0.88 mL, 1.4 mmol)
at -50 °C, and the resulting mixture was stirred for an
additional 10 min. A solution of the ester 6 (200 mg, 0.47
mmol) in dry Et2O (5 mL) was added at -78 °C, and the
mixture was stirred for 2 h at -78 °C. After addition of
saturated aqueous NaCl (10 mL) and evaporation of the
solvent, the organics were extracted with ether followed by
standard workup. The residue was purified by CC (ether/
hexane 1:4) to give the ketone 19 (148 mg, 79%) as an orange
oil. This compound 19 was identical with the authentic
specimen obtained by the previous method.
Tr ica r bon yl[(η4-6,7,8,9)-(2E,4Z,6E,8E)-3,7-Dim eth yl-9-
(2,6,6-tr im eth yl-1-cycloh exen -1-yl)-2,4,6,8-n on atetr aen en -
itr ile]ir on (0) (21). To a solution of sodium hydride (60% oil
dispersion, 40 mg, 1 mmol) in THF (5 mL) was added dropwise
diisopropylcyanomethylphosphonate (0.2 mL, 1 mmol) at 0 °C.
After the solution was stirred for an additional 30 min at rt,
a solution of the ketone 19 (80 mg, 0.2 mmol) in THF (4 mL)
was added at 0 °C. After the solution was stirred for an
additional 24 h at rt, the reaction was quenched with saturated
aqueous NH4Cl and then extracted with ether followed by
standard workup. The residue was purified by CC (ether/
hexane 1:9) to give 21 (62 mg, 73%) as a red oil: UV-vis 317
nm; IR 2934, 2211, 2036, 1973, 1598 cm-1; 1H NMR (300 MHz,
C6D6) δ 1.16 (s, 3H), 1.27 (s, 3H), 1.3-1.5 (m, 4H), 1.68 (s, 3H),
1.74-1.82 (m, 2H), 1.85 (d, J ) 10.5 Hz, 1H), 1.88 (s, 3H),
1.95 (s, 3H), 2.02 (d, J ) 11 Hz, 2H), 4.82 (s, 1H), 5.28 (d, J )
12 Hz, 1H), 5.51 (d, J ) 11 Hz, 1H), 5.58 (br t, J ) 12 Hz, 1H);
13C NMR (125 MHz, C6D6) δ 19.1, 19.2, 20.6, 23.0, 29.0, 29.8,
35.0, 35.2, 42.4, 56.2, 63.2, 85.7, 96.5, 99.6, 117.3, 127.6, 134.5,
135.1, 136.0, 156.6, 212.7 (C3); HRMS calcd for C23H27FeNO3
421.1389, found 421.1354 (M-).
C
11Z-Isom er 8: mp 108-110 °C (ether-n-hexane); UV-vis
280 nm; IR 2935, 2213, 2042, 1984, 1593 cm-1; 1H NMR (300
MHz) δ 1.16 (s, 3H), 1.27 (s, 3H), 1.4-1.6 (m, 4H), 1.85 (s,
3H), 1.89 (d, J ) 11 Hz, 1H), 2.02 (br t, J ) 6 Hz, 2H), 2.37 (s,
3H), 2.41 (d, J ) 11 Hz, 1H), 5.14 (d, J ) 11 Hz, 1H), 5.74 (d,
J ) 11 Hz, 1H), 6.60 (t, J ) 11 Hz, 1H); HRMS calcd for C20H23
-
FeNO3 381.1028, found 381.1033 (M-).
Tr im eth ylsilyl com p ou n d 9: mp 93-96 °C (ether-n-
hexane); UV-vis 291 nm; IR 2933, 2192, 2041, 1983, 1566
cm-1; 1H NMR (300 MHz) δ 0.23 (s, 9H), 1.16 (s, 3H), 1.27 (s,
3H), 1.4-1.6 (m, 4H), 1.85 (s, 3H), 2.08 (br t, J ) 6 Hz, 2H),
2.12 (d, J ) 11 Hz, 1H), 2.38 (s, 3H), 2.44 (d, J ) 11 Hz, 1H),
5.73 (d, J ) 11 Hz, 1H), 6.66 (d, J ) 11 Hz, 1H); HRMS calcd
for C23H31FeNO3Si 453.1424, found 453.1411 (M-).
Con ver sion of 9 to 8. To a stirred solution of silylnitrile 9
(59 mg, 0.13 mmol) in THF (5 mL) was added tetrabutylam-
monium fluoride (0.03 mL, 0.13 mmol) at 0 °C, and the
resulting mixture was stirred for an additional 10 min. The
reaction was quenched with saturated NH4Cl, and then the
reaction mixture was extracted with ether followed by stan-
dard workup. The residue was purified by CC (ether/benzene/
hexane 1:2:7) to give the nitrile 8 (48 mg, 96%). This was
identical with the authentic specimen obtained by the previous
method.
Tr ica r b on yl[(η4-4,5,6,7)-(2Z,4E,6E)-5-Met h yl-7-(2,6,6-
t r im et h yl-1-cycloh exen -1-yl)-2,4,6-h ep t a t r ien a l]ir on (0)
(18). To a solution of the nitrile 8 (200 mg, 0.52 mmol) in dry
CH2Cl2 (15 mL) was added dropwise a solution of DIBAL (0.12
mL, 0.68 mmol) in dry CH2Cl2 (2 mL) at 0 °C. After the solution
was stirred for an additional 30 min at 0 °C, the excess DIBAL
was destroyed by addition of moist silica gel (H2O/SiO2 1:5).
After filtration with Celite, the filtrate was dried over Na2-
SO4. The solvent was evaporated off, and the residue was
purified by CC (ether/hexane 1:4) to afford the aldehyde 18
(168 mg, 84%) as a red oil: UV-vis 294 nm; IR 2935, 2042,
(2E,4Z,6E,8E)-3,7-Dim eth yl-9-(2,6,6-tr im eth yl-1-cyclo-
h exen -1-yl)-2,4,6,8-n on a tetr a en en itr ile (22). To a stirred
solution of nitrile complex 21 (19 m g, 0.045 mmol) in ethanol
(2 mL) was added a solution of copper(II) chloride (30 mg, 0.23
mmol) in ethanol (3 mL) at rt, and the resulting mixture was
stirred for an additional 30 min. After removal of ethanol, the
residue was extracted with ether followed by standard workup.
The residue was purified by CC (ether/hexane 1:9) to give the
decomplexed nitrile 22 (9.4 mg, 72%) as a pale yellow oil. The
1H NMR spectrum is consistent with that of the literature.22
1
1982, 1673, 1608 cm-1; H NMR (300 MHz, C6D6) δ 1.16 (s,
3H), 1.28 (s, 3H), 1.3-1.5 (m, 4H), 1.72 (s, 3H), 1.80 (br t, J )
6 Hz, 2H), 1.81 (s, 3H), 2.32 (d, J ) 11 Hz, 1H), 2.79 (d, J )
11 Hz, 1H), 5.49 (d, J ) 11 Hz, 1H), 5.59 (dd, J ) 11, 4.5 Hz,
1H), 6.11 (t, J ) 11 Hz, 1H), 9.83 (d, J ) 4.5 Hz, CHO); HRMS
calcd for C20H24FeO4 384.1025, found 384.1041 (M-).
Tr ica r b on yl[(η4-5,6,7,8)-(3Z,5E,7E)-6-Met h yl-8-(2,6,6-
tr im eth yl-1-cycloh exen -1-yl)-3,5,7-octa tr ien -2-on e]ir on -
(0) (19) a n d Tr ica r bon yl[(η4-4,5,6,7)-(2E,4E,6E)-5-Meth yl-
7-(2,6,6-t r i m e t h y l-1-c y c lo h e x e n -1-y l)-2,4,6-h e p t a -
tr ien a l]ir on (0) (20). To a solution of the aldehyde 18 (100
mg, 0.26 mmol) in dry Et2O (5 mL) was added isopropylmag-
nesium bromide (1M ether solution, 0.34 mL, 0.34 mmol) at 0
°C, and the resulting mixture was stirred for an additional 30
min. A solution of 1,1-(azodicarbonyl)dipiperidine (78.7 mg,
0.31 mmol) in THF (5 mL) was added at 0 °C. After addition
of saturated aqueous NaCl (10 mL) and evaporation of the
solvent, the organics were extracted with ether and washed
with saturated aqueous NaHCO3. The residue was purified
by CC (ether/benzene/hexane 1:2:11) to give the ketone 19 (28
(2E,4Z,6E,8E)-3,7-Dim eth yl-9-(2,6,6-tr im eth yl-1-cyclo-
h exen -1-yl)-2,4,6,8-n on a tetr a en a l (2). To a solution of nitrile
22 (9 mg, 0.032 mmol) in dry toluene (5 mL) was added
dropwise DIBAL (0.0074 mL, 0.042 mmol) in dry toluene (0.2
mL) at 0 °C. After stirring for an additional 30 min at 0 °C,
the excess DIBAL was destroyed by addition of moist silica
gel (H2O/SiO2 1:5). After removal of toluene, the residue was
extracted with ether followed by standard workup. The residue
(22) Liu, R. S. H.; Asato, A. E. Tetrahedron 1984, 40, 1931.

Stereoselective Synthesis of 11Z-Retinal
J . Org. Chem., Vol. 65, No. 8, 2000 2443
was purified by CC (ether/hexane 1:9) to give the aldehyde 2
(9 mg, 98%) as a yellow oil. The 1H NMR spectrum is consistent
with that of the literature.23
from J apan Private School Promotion Foundation, and
the Chiba-Geigy Foundation (J apan) for the Promotion
of Science.
Ack n ow led gm en t. This research was supported in
part by a Grant-in-Aid for Scientific Research (C, No.
9672292) from the Ministry of Education, Science and
Culture (J apan), the Science Research Promotion Fund
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 11-13, 15, and 16, 1H NMR spectra for compounds
4-9, 12a , 13a , and 18-21, and 13C NMR spectra for com-
pounds 4, 6, 19, and 21. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Wada, A.; Sakai, M.; Imamoto, Y., Shichida, Y.; Yamauchi, M.;
Ito, M. J . Chem. Soc., Perkin Trans. 1 1997, 1773
J O9916030