Trienylboronic acid, a versatile coupling tool for retinoid synthesis; Stereospecific synthesis of 13-aryl substituted (11Z)-retinal

Article abstract of DOI:10.1016/S0040-4039(03)00550-1

Trienylboronic acid 1a was prepared from iodotriene 3, which was coupled with (2Z,4Z)-3-aryl-5-iodo-2,4-pentadienol 9 by Suzuki coupling reaction to give geometrically pure 13-aryl substituted (11Z)-retinol 10. Oxidation of 10 gave 13-aryl substituted (11Z)-retinal 11.

Full text of DOI:10.1016/S0040-4039(03)00550-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3093–3096
Trienylboronic acid, a versatile coupling tool for retinoid
synthesis; stereospecific synthesis of 13-aryl substituted
(11Z)-retinal
Jun’ichi Uenishi,a,* Katsuaki Matsuia and Akimori Wadab
aKyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
bKobe Pharmaceutical University, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Received 27 January 2003; revised 17 February 2003; accepted 21 February 2003
Abstract—Trienylboronic acid 1a was prepared from iodotriene 3, which was coupled with (2Z,4Z)-3-aryl-5-iodo-2,4-pentadienol
9 by Suzuki coupling reaction to give geometrically pure 13-aryl substituted (11Z)-retinol 10. Oxidation of 10 gave 13-aryl
substituted (11Z)-retinal 11. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
gated polyenes, including Wittig or Wittig–Horner–
Emmons reaction and Julia olefination reaction have
been reported.3 These methods can be used for the
synthesis of geometrically stable polyenes but were not
suitable for the synthesis of polyenes possessing less
stable (Z)-olefinic bond or large substituent groups on
the olefinic carbons.4 A transition metal-catalyzed
cross-coupling reaction is effective in such cases and has
been used for the geometry control in conjugated
polyene syntheses.5 In fact, some retinoids and their
analogues have been prepared by metal catalyzed cross-
coupling reactions.6 Considering the flexible synthetic
approach for retinoids I–IV (Fig. 1), connection
between a C10 and C11 sigma-bond by a cross-coupling
reaction using trienylmetal species 1 and iododiene is a
favorable and straightforward approach, as shown in
Scheme 1. However, since a few approaches have been
successfully utilized,7 a versatile and reliable C1ꢀC10
trienylmetal reagent is desired as a cross-coupling unit
for general and flexible retinoid synthesis. In this paper,
we describe the preparation of trienylboronic acid 1a as
an isolable trienylmetal reagent and the cross-coupling
reaction for the first synthesis of a 13-aryl substituted
(11Z)-retinal.8
Retinoids play important roles in biological actions in
organisms.1 These stereo-structures, shown in Figure 1,
generally consist of a consecutively conjugated pen-
taene. They are generally unstable and sensitive to light,
acid, base and heat to raise isomerization or polymer-
ization. The stereochemistry of olefinic bonds is highly
important in relation to the biological activities.2 Vari-
ous synthetic methods for the synthesis of such conju-
2. Preparation of 1a and cross-coupling reaction
Figure 1.
Initially, we attempted to prepare trienylstannane 1b
from the known dienyne 29 by stannylmagnesiation,
although it was found to be unstable and rather
difficult to handle.10 We therefore used trienylboronic
acid 1a instead of 1b as a C1ꢀC10 unit (Scheme 2).
Keywords: trienylboronic acid; Suzuki coupling; conjugated pentaene;
11Z-retinal; iododiene.
* Corresponding author. Fax: +81-75-595-4763; e-mail: juenishi@
mb.kyoto-phu.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00550-1

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J. Uenishi et al. / Tetrahedron Letters 44 (2003) 3093–3096
3. Synthesis of 13-aryl substituted (11Z)-retinal
In the recognition process of vision, the first photo-iso-
merization of the (11Z)-retinal chromophore induces
structural change in the light receptor rhodopsin. The
isomerization activates transmembrance G-protein-cou-
pled receptor proteins for the signal communication
path and the signal is eventually transmitted to the
brain.16 The static structure of rhodopsin has recently
been revealed by X-ray crystallographic studies within a
17
,
range of 3.3 A level of resolution. Although the three
dimensional structure of static rhodopsin has been
determined, the dynamic flexibility of opsin may allow
it to take a modified (11Z)-retinal into a pocket of the
protein hole. Such a loose interaction between a ligand
and protein is sometimes observed depending on the
size of the ligand as well as some other interactive
forces between the ligand and protein.18 We were inter-
ested in the case of 13-substituted analogues of (11Z)-
retinal and opsin, and have attempted the synthesis of
13-aryl substituted (11Z)-retinal (Fig. 2).
Scheme 1.
The preparation of the other coupling unit, iododiene
9, is outlined in Scheme 3. Stereoselective introduction
of trimethylsilylacetylene to O-TBDPS protected 3,3-
dibromo-2-propen-1-ol by Sonogashira coupling gave
(Z)-bromoenyne 5 in 87% yield.19 Suzuki coupling of 5
with phenylboronic acid in the presence of 5 mol%
PdCl2(dppf) and sodium carbonate in THF at 55°C
gave (E)-enyne 6a in 90% yield with retention of the
configuration. The stereochemistry was confirmed by
NOE that was observed between the CH2 group and
ortho protons of an aromatic ring. Deprotection of
TMS group and of TBDPS ether by treatment with an
excess of tetrabutylammonium fluoride gave 7a in 86%
yield. Then, iodination of terminal alkyne with iodine
and morpholine in refluxing benzene gave iodoenyne 8a
in a quantitative yield. Finally, partial cis hydrogena-
tion of the alkynyl bond with diimide20 gave (2Z,4Z)-3-
phenyl-5-iodopentadien-1-ol 9a in 39% yield along with
over reduced product and starting material. On the
other hand, Suzuki coupling of 5 with p-formylbenz-
eneboronic acid followed by acetal formation gave 6b
in 79% yield in two steps. The same reaction sequences,
desilylation, iodination and partial hydrogenation as
those for the synthesis of 9a gave 9b in 64% yield in
three steps (Scheme 4).
Scheme 2. Reagents and conditions: (a) i. Bu3SnMgMe, cat.
CuCN, THF then MeI; ii. iodine, CH2Cl2 or i. Cp2ZrCl2,
AlMe3, ClCH2CH2Cl then iodine; (b) i. BuLi, −78°C, THF, ii.
B(OPri)3, −20°C, THF, rt, then purification by silica gel
column chromatography; (c) i. (E)-1-iodohexene, cat.
Pd(PPh3) , aq. KOH, Ag2CO3, THF.
4
Stannylmagnesiation of enyne 211 and quenching the
resultant adduct with iodomethane gave trienylstan-
nane 1b. Immediate iodination of the crude extract gave
trienyliodide 3 in 70% yield.12 Lithium–iodine exchange
of 3 with n-BuLi at −20°C and subsequent metal
exchange with triisopropyl borate gave diisopropyl
trienylborate, which was hydrolyzed by the usual work-
up to give trienylboronic acid 1a. Fortunately, this
boronic acid can be purified by silica gel chromatogra-
phy and is reasonably stable for storage in solution.
However, drying-up of the solvent from the acid gave
rise to decomposition and polymerization, resulting in
rapid loss of its purity.13 We recommended that 1a is
stored in solution. Subsequently, compound 1a was
subjected to coupling reaction with 1-iodohexene in the
presence of Pd(PPh3)4 (5 mol%), KOH, and Ag2CO3 in
THF at room temperature to give tetraene 4 in 53%
yield.14,15
Pd-catalyzed cross-coupling of 1a with iododienes 9a
and 9b was conducted in THF at room temperature in
the presence of silver carbonate and aq. KOH. The
pentaenes 10a and 10b were obtained in 54 and 49%
yields, respectively.21 The observed coupling constant,
11.8 Hz, between C11ꢀH and C12ꢀH in both compounds
Figure 2.

J. Uenishi et al. / Tetrahedron Letters 44 (2003) 3093–3096
3095
Scheme 3. Reagents and conditions: (a) i. trimethylsilylacetylene, cat. PdCl2(dppf), CuI, Pri2NH, benzene; (b) ArB(OH)2, cat.
PdCl2(dppf), Na2CO3, THF; (c) MeOH, cat. TsOH, MgSO4; (d) TBAF, THF; (e) iodine, morpholine, benzene; (f)
KOOCNꢁNCOOK, AcOH, THF.
Acknowledgements
This work was financially supported by the Grant-in-
Aid for Scientific Research on Priority Areas (A) from
the Ministry of Education, Science, Sports and Culture,
Japan, and by a Special Grant from the Nagase Science
and Technology Foundation.
References
1. (a) The Retinoids; Sporn, M. B.; Roberts, A. B.; Good-
man, D. S., Eds.; Raven Press: New York, 1994; (b)
Chemistry and Biology of Synthetic Retinoids; Dawson,
M. L.; Okamura, W. H., Eds.; CRC Press: Boca Raton
Florida, 1990.
Scheme 4.
2. (a) Evans, R. M. Science 1998, 240, 889–895; (b) Hara,
R.; Hara, T.; Ozaki, K.; Terakita, A.; Eguchi, G.;
Kodama, R.; Takeuchi, T. Retinal Proteins; VNU Sci-
ence Press: Utrecht, 1987; (c) Bourquet, W.; Germain, P.;
Gronemeyer, H. Trends Pharmacol. Sci. 2000, 21, 381–
388.
3. The Chemistry of Dienes and Polyenes; Rappoport, Z.,
Ed.; John Wiley & Sons: New York, 1997. Some retinoid
syntheses by olefin forming reactions, see: (a) Ito, M.
Pure Appl. Chem. 1991, 63, 13–22; (b) Otera, J. In
Carotenoids; Briton, G.; Liaaen-Jensen, S.; Pfander, H.,
Eds.; Birkhauser: Boston, 1996, pp. 103–114.
4. A mixture of stereoisomers was obtained generally.
5. (a) Metal-Catalyzed Cross-coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; (b)
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; John Wiley & Sons: New
York, 2002; Vol. 1.
clearly indicated a (11Z)-configuration. Finally, oxida-
tion of 10a by barium manganate in methylene chloride
furnished the synthesis of geometrically pure retinal
11a21 in 30% yield. Similarly, 11b21 was obtained in 23%
yield. These 13-aryl substituted derivatives were less
stable than other (11Z)-retinals. During the oxidation
and purification, they started decomposing gradually
even when all of the operations were carried out under
dark or red-colored lamp conditions.
In conclusion, we have described a novel and efficient
method for the preparation of geometrically pure
trienylboronic acid 1a as an isolable alkenylmetal
reagent, which is found to be a versatile unit for
retinoid synthesis by Pd-catalyzed cross-coupling reac-
tion. The first synthesis of 13-aryl substituted (11Z)-
retinals was accomplished by this methodology.

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J. Uenishi et al. / Tetrahedron Letters 44 (2003) 3093–3096
6. (a) de Lera, A. R.; Torrado, A.; Iglesias, B.; Lo¨pez, S.
hexane (Rf value of the boronic acid was 0.2 on silica gel
TLC developed by 20% EtOAc in hexane). This boronic
acid was used as THF solution in the next cross coupling
reaction.
Tetrahedron Lett. 1992, 33, 6205–6208; (b) Torrado, A.;
Iglesias, B.; Lo¨pez, S.; De Lera, A. R. Tetrahedron 1995,
51, 2435–2453; (c) Uenishi, J.; Kawahama, R.; Yone-
mitsu, O.; Wada, A.; Ito, M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 320–323; (d) Borhan, B.; Souto, M. L.;
Um, J. M.; Zhou, B.; Nakanishi, K. Chem. Eur. J. 1999,
5, 1172–1175.
14. Compound 1a was usually used 2–3 equiv. for
iodoalkene.
15. Lera et al. reported Suzuki coupling of 9-demethyltrienyl-
bronoic acid using TlOH conditions in Ref. 6a.
16. Recent literature: (a) Sakmar, T. P. Prog. Nucleic Acid
Res. Mol. Biol. 1998, 59, 1–34; (b) Borhan, B.; Souto, M.
L.; Imai, H.; Shichida, Y.; Nakanishi, K. Science 2000,
288, 2209–2212.
17. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.;
Motoshima, H.; Fox, B. A.; Trong, I. L.; Teller, D. C.;
Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano,
M. Science 2000, 289, 739–745.
18. For the case of 9-alkyl substituted (11Z)-retinal, see:
Wada, A.; Fujioka, N.; Imai, H.; Shichida, Y.; Ito, M.
Bioorg. Med. Chem. Lett. 1998, 8, 423–426.
19. Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353–
4355.
7. (a) By Negishi et al. using bistrienylzinc reagent 1c for the
synthesis of all trans retinal, see: Negishi, E.; Zbyslaw, O.
Tetrahedron Lett. 1991, 32, 6683–6686; (b) By Duchere
and Parrain et al., using trienylstannane reagent 1b for
the synthesis of all trans retinoic acid, see: Thibonnet, J.;
Abarbri, M.; Duchene, A.; Parrain, J.-L. Synlett 1999,
141–143.
8. Stereodefined synthesis of (11Z)-retinal; see, Refs 6c,d
and also Wada, A.; Fujioka, N.; Tanaka, Y.; Ito, M. J.
Org. Chem. 2000, 65, 2438–2443. The report for 13-aryl
substituted all trans retinal, see: Danshina, S. V.;
Drachev, A. L.; Eremin, S. V.; Kaulen, A. D.; Khitrina,
L. V.; Mitsner, B. I.; Belozerskii, A. N. Arch. Biochem.
Biophys. 1990, 279, 225–231.
9. Negishi, E.; King, O. Org. Synth. 1985, 64, 44–49.
10. Stannylmagnesiation of enyne; Uenishi, J.; Kawahama,
R.; Tanio, A.; Wakabayashi, S. Chem. Commun. 1993,
1438–1439. After work-up and successive purification by
silica gel column chromatography, hardly separable
proto-destannylated product and reagent derived by-
products were largely contaminated with trienylstannane.
In addition, it was found that the cross-coupling of 1b
with 9 under the Stille conditions gave a mixture of
geometric isomers at least by our hands.
20. Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91–155.
1
21. 10a; oil; Rf=0.33 (40% Et2O in hexane); H NMR (300
MHz, C6D6) l 7.24–7.05 (5H, m), 6.48 (1H, t, J=11.8
Hz), 6.26 (1H, d, J=16.1 Hz), 6.16 (1H, d, J=11.8 Hz),
6.12 (1H, d, J=11.8 Hz), 6.06 (1H, d, J=16.1 Hz), 5.98
(1H, t, J=6.8 Hz), 3.98 (2H, d, J=6.8 Hz), 1.96 (2H, t,
J=6.2 Hz), 1.83 (3H, s), 1.75 (3H, s), 1.64–1.54 (2H, m),
1.51–1.45 (2H, m), 1.11 (6H, s). 10b; oil; Rf=0.23 (40%
1
Et2O in hexane); H NMR (300 MHz, C6D6) l 7.54 (2H,
d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 6.48 (1H, t,
J=11.8 Hz), 6.24 (1H, d, J=16.2 Hz), 6.16 (1H, d,
J=11.8 Hz), 6.14 (1H, d, J=11.8 Hz), 6.02 (1H, d,
J=16.2 Hz), 5.98 (1H, t, J=6.7 Hz), 5.41 (1H, s), 3.97
(2H, d J=6.7 Hz), 3.23 (6H, s), 1.95 (2H, t, J=6.1 Hz),
1.83 (3H, s), 1.73 (3H, s), 1.66–1.54 (2H, m), 1.51–1.44
(2H, m), 1.08 (6H, s). 11a; oil; Rf=0.73 (40% Et2O in
hexane); 1H NMR (300 MHz, C6D6) l 9.73 (1H, d,
J=8.1 Hz), 7.30–6.95 (5H, m), 6.51 (1H, t, J=12.1 Hz),
6.34 (1H, d, J=8.1 Hz), 6.29 (1H, d, J=15.8 Hz), 5.94
(1H, d, J=12.1 Hz), 5.89 (1H, d, J=15.8 Hz), 5.77 (1H,
d, J=12.1 Hz), 1.94 (2H, t, J=5.8 Hz), 1.71 (3H, s), 1.68
(3H, s), 1.62–1.51 (2H, m), 1.49–1.41 (2H, m), 1.07 (6H,
s). 11b; oil; Rf=0.57 (40% Et2O in hexane); 1H NMR
(300 MHz, C6D6) l 9.73 (1H, d, J=8.1 Hz), 7.43 (2H, d,
J=8.1 Hz), 7.06 (2H, d, J=8.1 Hz), 6.52 (1H, t, J=12.1
Hz), 6.35 (1H, d, J=8.1 Hz), 6.27 (1H, d, J=15.8 Hz),
5.94 (1H, d, J=12.1 Hz), 5.86 (1H, d, J=15.8 Hz), 5.81
(1H, d, J=12.1 Hz), 5.35 (1H, s), 3.19 (6H, s), 1.93 (2H,
t, J=6.2 Hz), 1.71 (3H, s), 1.67 (3H, s), 1.63–1.50 (2H,
m), 1.47–1.41 (2H, m), 1.04 (6H, s).
11. The example to dienyne, see: Uenishi, J.; Kawahama, R.;
Yonemitsu, O. J. Org. Chem. 1997, 62, 1691–1701.
12. The compound 3 was also prepared by the Negishi’s
method using Cp2ZrCl2 and trimethylaluminum in the
similar yield.
13. The yield of 1a is estimated to be 60–70% approximately.
Polymerization and/or protonation were observed during
the decomposition process. An immediate use of 1a is of
course recommended. However, as long as it is kept in
solution, the boronic acid is fairly stable during a day.
When the acid can be stored in frozen benzene at −20°C,
it survives at least for a week, but is gradually decom-
posed after a month. Preparation of 1a: To a mixture of
iodotriene (1.0 mmol) in THF (5 ml) BuLi was added
dropwise (1.6 M in hexane, 2.2 mmol) at −78°C, and the
mixture was stirred for 10 min. After the reaction com-
pleted, triisopropyl borate (5 mmol) was added to the
mixture and it was stirred for an additional 30 min at
room temperature. After the mixture was diluted with
hexane, the whole mixture was directly charged on silica
gel column chromatography eluted by 20% EtOAc in