An expedient stereocontrolled synthesis of 7-cis-retinoids

Article abstract of DOI:10.1081/SCC-100104430

Ethyl (7Z)-retinoate 5 has been efficiently synthesized using as key step the Suzuki coupling of an in situ generated alkenylboronic acid and the geometrically homogeneous tetraenyliodide with (Z)-geometry, itself obtained by yodomethylenation according t

Full text of DOI:10.1081/SCC-100104430

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AN EXPEDIENT STEREOCONTROLLED SYNTHESIS OF 7-
CIS-RETINOIDS
a
a
b
Rosana Alvarez , Beatriz Domínguez & Angel R. de Lera
a
Departamento de Química Orgánica , Universidade de Vigo , Vigo, 36200, Spain
b
Departamento de Química Orgánica , Universidade de Vigo , Vigo, 36200, Spain
Published online: 09 Nov 2006.
To cite this article: Rosana Alvarez , Beatriz Domínguez & Angel R. de Lera (2001) AN EXPEDIENT STEREOCONTROLLED
SYNTHESIS OF 7-CIS-RETINOIDS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:13, 2083-2087, DOI: 10.1081/SCC-100104430
To link to this article: http://dx.doi.org/10.1081/SCC-100104430
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SYNTHETIC COMMUNICATIONS, 31(13), 2083–2087 (2001)
AN EXPEDIENT STEREOCONTROLLED
SYNTHESIS OF 7-CIS-RETINOIDS
Rosana Alvarez, Beatriz Domınguez,
´
and Angel R. de Lera*
Departamento de Quımica Organica,
´ ´
Universidade de Vigo, 36200 Vigo, Spain
ABSTRACT
Ethyl (7Z)–retinoate 5 has been efficientlys yn thesized using
as keystep the Suzuki coupling of an in situ generated alke-
nylboronic acid and the geometrically homogeneous tetra-
enyliodide with (Z)-geometry, itself obtained by
yodomethylenation according to Stork’s conditions.
Functional group manipulation then afforded (7Z)–retinal 7.
The studies on the visual cycle performed by Wald and coworkers in
the earlyfifties highlighted the importance of the retinal side-chain geometry
1
upon its biological activity. Geometric isomers of retinal have since then
been extensivelyused in bioorganic studies aimed at understanding the
stereoselectivityof the binding site in retinal proteins, in particular the
visual pigments. These studies have stimulated the development of synthetic
2
approaches to all sixteen possible geometric isomers of retinal. For the
synthesis of the more hindered 7-cis isomers, Liu developed a general
route which uses a photosensitised isomerization of trans-b-ionyl derivatives
*
Corresponding author.
2
083
Copyright & 2001 byMarcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
´
ALVAREZ, DOMINGUEZ, AND DE LERA
2
084
3
in the presence of 2-acetonaphthone, an effort which culminated in
4
the preparation of the 7-cis isomers, including the highlytwisted all- cis-
4
d
retinal.
We felt that the straightforward approach to 9-cis-retinoids that we
5
recentlydeveloped, based on the Suzuki cross coupling of an in situ gen-
6
erated C -cyclohexenylboronic acid and a C -side chain tetraenyliodide,
9
11
might be extended to the stereocontrolled synthesis of the 7-cis isomers. Two
requisites had to be met, namelythe generation of a tetraen yl iodide with the
desired Z-configuration, and the preservation of that geometryduring the
coupling reaction. The realization of this scheme culminated an efficient
7
synthesis of the sterically hindered 7-cis-retinoids.
Cyclohexenyl boronate was best obtained immediately prior to
the palladium-catalyzed cross-coupling reaction (in order to avoid prema-
6
ꢁ
ture decomposition) bytreatment of iodide 2 with t-BuLi in THF at ꢀ78 C
6
for 30 min, followed byaddition of trimeth yl borate. For the C -function-
alized side chain, the Wittig condensation of trienal ester 3, a common
1
1
2
building block in retinoid synthesis, with iodomethylenetriphenyl-
8
phosphorane according to Stork’s procedure remarkablyprovided the
unstable (Z)-tetraenyliodide ester 4 essentiallyas a single geometric
1
isomer, as shown by H-NMR analysis of the crude reaction mixture.
This iodide 4 was immediatelyadded to the freshlyprepared boronate,
followed bythe sequential addition of 10% aq TlOH and Pd(PPh 3)4.
9
The palladium-catalyzed cross-coupling, accelerated by thallium hydroxide,

ORDER
REPRINTS
7
-CIS-RETINOIDS
2085
took place at room temperature, affording the pentaene ethyl (7Z)-retinoate 5
in 76% yield. A two-step reduction-oxidation sequence without isolation of
the unstable alcohol 6 then afforded 7-cis-retinal 7.
EXPERIMENTAL
Ethyl 7-cis-retinoate 5. Sodium bis-trimethylsilylamide (1.17 mL, 0.6 M
in toluene, 0.7 mmol) was added to a suspension of (Ph PCH I)I (0.397 g,
3
2
0
.75 mmol) in THF (1 mL) and stirred at room temperature for 30 min. The
ꢁ
reaction mixture was cooled to ꢀ60 C, and hexamethyl phosphoramide
(
0.35 mL) was added. After 10 min stirring, the mixture was cooled down
ꢁ
to ꢀ78 C, and a solution of aldehyde 3 (0.104 g, 0.5 mmol) in THF (1 mL)
was added. After stirring for 2 h, the reaction mixture was poured into H O
2
(
extracts were dried over MgSO , concentrated in vacuo and the residue
5 mL) and extracted with hexane (3 ꢂ 5 mL). The combined organic
4
was used in the next step without further purification.
t-BuLi (0.88 mL, 1.7 M in THF, 1.5 mmol) was added dropwise to a
ꢁ
cooled (ꢀ78 C) solution of iodide 4 (0.188 g, 0.75 mmol) in THF (2 mL).
After stirring for 1 h, B(OMe) (0.13 mL, 1.125 mmol) was added and the
3
ꢁ
resulting mixture was stirred at 0 C for 1 h. Then, 10% aqueous TlOH
(
4.9 mL, 2.25 mmol) and a solution of the above residue and Pd(PPh3)4
0.087 g, 0.075 mmol) in THF (3 mL) were added sequentiallyand the mix-
(
ture was stirred at room temperature for 12 h. The reaction was extracted
with ethyl ether (2 ꢂ 10 mL) and the combined organic extracts were washed
with brine (3 ꢂ 10 mL), dried over MgSO and concentrated in vacuo.
4
The residue was purified bychromatography(SiO 2, 97:3 hexane:ethyl acet-
ate) to afford 0.125 g (76%) of ethyl 7-cis-retinoate 5 as a yellow oil.
1
H-NMR (400.14 MHz, CDCl ): d 6.95 (dd, J ¼ 15.3, 12.2 Hz, 1H, H ),
3
11
6
.28 (d, J¼15.3 Hz, 1H, H ), 6.25 (d, J ¼ 12.6 Hz, 1H, H ), 6.13 (d,
1
2
7
J ¼ 12.6 Hz, 1H, H ), 5.96 (d, J ¼ 12.2 Hz, 1H, H ), 5.81 (s, 1H, H ),
8 10 14
4
1
3
.20 (q, J ¼ 7.1 Hz, 2H, OEt), 2.37 (s, 3H, CH ), 1.9–2.0 (m, 1H, 2H ),
3
3
.94 (s, 3H, CH ), 1.7–1.8 (m, 2H, 2H ), 1.6–1.7 (m, 2H, 2H ), 1.55 (s,
3 4 5
1
3
H, CH ), 1.33 (t, J ¼ 7.1 Hz, 3H, OEt), 0.97 (s, 6H, C -2CH ). C-NMR
3
1
3
(
100.62 MHz, CDCl ): d 167.2 (s), 152.7 (s), 140.5 (s), 136.5 (s), 135.3 (s),
3
135.2 (d), 134.5 (d), 131.2 (d), 130.9 (d), 128.8 (d), 118.7 (s), 59.6 (t), 39.2 (t),
3
4.6 (s), 32.1 (t), 29.9 (q, 2x), 28.8 (q), 21.6 (q), 19.2 (t), 14.6 (q), 13.8 (q). IR-
+
FT (NaCl): ꢀ. 3000–2800 (s), 1700 (s), 1580 (w), 1240 (w), 1149 (s). MS (EI )
þ
þ
m/z (%): 329 (M þ 1, 25), 328 (M , 100), 255 (37), 185 (20), 171 (16),
1
45 (14), 133 (14), 119 (16), 109 (16), 105 (19), 91 (17), 69 (21). HMRS
+
1
(EI ): calcd for C H O , 328.2402; found, 328.2404. H-NMR data for
22 32 2
methyl 7-cis-retinoate has been reported.
4
c

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´
ALVAREZ, DOMINGUEZ, AND DE LERA
2
086
7
-cis-retinal 7. To a solution of ethyl 7-cis-retinoate 5 (0.097 g,
ꢁ
0
1
1
.296 mmol) in THF (5 mL) at ꢀ78 C, was added DIBALH (0.734 mL,
M in toluene, 0.734 mmol) and the resulting suspension was stirred for
h at ꢀ78 C. After careful addition of 10% aqueous NH Cl, the mixture
ꢁ
4
was extracted with ethyl ether (3 ꢂ 10 mL). The combined organic layers
were dried over MgSO and concentrated in vacuo. The residue was used
4
in the next step without further purification.
MnO (0.463 g, 5.33 mmol) and Na CO (0.565 g, 5.33 mmol) were
2
2
3
added to a solution of the residue obtained above in CH Cl (10 mL).
2
2
ꢁ
After stirring at 25 C for 12 h, the reaction mixture was filtered through
Celite, and the solvent was removed. The residue was purified byHPLC
Õ
(
8
(
1
Prep. Nova-Pak , HR silica 60A, 19 ꢂ 300 mm; 5:95 ethyl acetate:hexane;
1
mL/min; t ¼28.5 min) to afford 0.075 g (89%) of 7-cis-retinal 7. H-NMR
R
400.14 MHz, CDCl ): d 10.08 (d, J ¼ 8.2 Hz, 1H, H ), 7.04 (dd, J ¼ 15.1,
3 15
1.5 Hz, 1H, H ), 6.31 (d, J ¼ 15.1 Hz, 1H, H ), 6.23 (d, J ¼ 11.5 Hz, 1H,
1
1
12
H ), 6.10 (d, J ¼ 12.6 Hz, 1H, H ), 5.9–6.0 (m, 1H, H þ H ), 2.29 (s, 3H,
10 8 7 14
CH ), 1.91 (s, 3H, CH ), 1.8–1.9 (m, 2H, 2H ), 1.58 (s, 3H, CH ), 1.5–1.6
3
3
3
3
1
3
(
m, 2H, 2H ), 1.49 (s, 3H, CH ), 1.4–1.5 (m, 2H, 2H ). C-NMR
4 3 5
(
100.62 MHz, CDCl ): d 189.8 (s), 152.9 (s), 141.1 (s), 137.9 (s), 136.9 (s),
3
1
3
3
1
35.7 (d), 135.1 (d), 132.1 (d), 131.4 (d), 130.4 (d), 129.9 (d), 39.4 (t), 33.3 (s),
2.3 (t), 29.1 (q), 21.8 (q), 19.6 (t), 14.6 (q), 12.4 (q). IR-FT (NaCl): ꢀ.
+
þ
000–2800 (s), 1660 (s), 1450 (w). MS (EI ) m/z (%): 285 (23), 284 (M ,
00), 173 (36), 159 (18), 145 (18), 133 (18), 131 (14), 119 (30), 107 (16), 105
+
(26), 95 (18), 91 (23), 69 (18). HMRS (EI ): calcd for C H O, 284.2140;
2a
found, 284.2150. H-NMR data for 7-cis-retinal has been reported.
2
0
28
1
ACKNOWLEDGMENTS
We thank MEC (SAF98-0143) and Xunta de Galicia
PGIDT99PX30105B) for financial support, and Dr. M. Klaus
Hoffmann-La Roche, Basel) for a generous gift of compound 3. We also
(
(
thank CACTI (Universidade de Vigo) for providing NMR and MS spectra.
REFERENCES
1
. (a) Wald, G.; Brown, P.K.; Hubbard, R. and Oroshnik, W. Proc. Natl.
Acad. Sci. USA 1956, 42, 578–580. (b) Wald, G.; Brown, P.K.;
Hubbard, R. and Oroshnik, W. Proc. Natl. Acad. Sci. USA 1955, 41,
438–451.

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7
-CIS-RETINOIDS
2087
2
. (a) Liu, R.S.H. and Asato, A.E. Tetrahedron 1984, 40, 1931–1969. (b)
Dawson, M.I. and Hobbs, P.D. The Synthetic Chemistry of Retinoids,
In ‘‘Retinoids, Biology, Chemistry and Medicine’’. Sporn, M.B.;
Roberts, A.B. and Goodman, D.S., Eds.; Raven Press: New York,
1994; chapter 2, pp. 5–178.
3
4
. Ramamurthy, V.; Butt, Y.; Yang, C.; Yang, P. and Liu R.S.H. J. Org.
Chem. 1973, 38, 1247–1249.
. (a) Asato, A.E. and Liu, R.S.H. J. Am. Chem. Soc. 1975, 97,
4128–4130. (b) Ramamurthy, V. and Liu, R.S.H. Tetrahedron 1975,
31, 201–206. (c) Miller, D; Trammell, M.; Kini, A. and Liu, R.S.H.
Tetrahedron Lett. 1981, 22, 409–412. (d) Asato, A.E.; Kini, A.; Denny,
M. and Liu, R.S.H. J. Am. Chem. Soc. 1983, 105, 2923–2924. (e)
Trehan, A. and Liu, R.S.H. Tetrahedron Lett. 1988, 29, 419–422. (f)
Chen, R.-L. and Liu, R.S.H. Tetrahedron Lett. 1994, 35, 6251–6254.
(g) Chen, R.-L. and Liu, R.S.H. Tetrahedron 1996, 52, 7809–7816.
. For recent reviews, see: (a) Martin, A. and Yang, Y. Acta Chem.
Scand. 1993, 47, 221–230. (b) Suzuki, A. Pure Appl. Chem. 1994, 66,
5
213–222. (c) Miyaura, N. and Suzuki, A. Chem. Rev. 1995, 95,
2405–2483.
6
7
. Pazos, Y. and de Lera, A.R. Tetrahedron Lett. 1999, 40, 8287–8290.
. A synthesis of 7-cis-retinol (7-cis-vitamin A) has also been published, in
which the 7-cis geometryresults from Lindlar semih yd rogenation of
the corresponding alkynes, and the retinoid side-chain was completed
bytraditional Wittig-t yp e condensations, with the difficulties of pre-
serving the integrityof the side-chain configuration along the entire
sequence. Soukup, M. and Widmer, E. Tetrahedron Lett. 1991, 32,
4117–4118.
8
9
. Stork, G. and Zhao, K. Tetrahedron Lett. 1989, 30, 2173–2174.
. Uenishi, J.; Beau, J.-M.; Armstrong, R.W. and Kishi, Y. J. Am. Chem.
Soc. 1987, 109, 4756–4758.
Received in the Netherlands September 13, 2000

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