Synthetic Scheme for the Preparation of 13C-Labeled 3,4-Didehydro-Retinal
FULL PAPER
a suspension of washed NaH (0.29 g, 7.3 mmol) in dry THF at 0
3 H, 5-CH3), 1.9 (m, 1 H, 3-Heq), 2.32 (s, 3 H, 9-CH3), 2.70 (br. s,
°C, was reacted with 3-methyl-5-(4-hydroxy-2,6,6-trimethylcy-
1 H, -OH), 3.99 (br. s, 1 H, 4-H), 5.92 (d, J ϭ 7.9 Hz, 10-H), 6.23
clohex-1-enyl)-penta-2,4-dienal (0.75 g, 3.2 mmol). After workup (d, J ϭ 16.0 Hz, 1 H, 8-H), 6.70 (d, J ϭ 16.0 Hz, 1 H, 7-H), 10.11
and purification (silica gel, 60% ether/PE), 3,7-dimethyl-9-(4-
hydroxy-2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenenitrile
(0.65 g, 2.2 mmol, 69%) was obtained as a mixture of isomers. H
(d, J ϭ 7.9 Hz, 1 H, 11-H). 13C NMR (75 MHz, CDCl3): δ
(ppm) ϭ 12.8 (9-CH3), 18.4 (5-CH3), 27.4/28.2 (1-CH3), 28.7 (C-
3), 34.4 (C-2), 34.6 (C-1), 69.6 (C-4), 129.0 (C-10), 132.3 (C-5),
1
NMR (300 MHz, CDCl3): δ (ppm) ϭ 1.03/1.08 (2s, 6 H, 1-CH3), 134.8 (C-7), 136.6 (C-8), 140.3 (C-6), 154.5 (C-9), 191.3 (C-11).
1.4 (m, 1 H, 2-Hax), 1.73 (s, 3 H, 5-CH3) 1.8 (m, 1 H, 2-Heq), 2.01
(s, 3 H, 9-CH3), 2.1 (m, 1 H, 4-Hax), 2.20 (s, 3 H, 13-CH3), 2.4 (m,
C5-Phosphonate 12 (0.63 g, 2.9 mmol) in dry THF (10 mL) was
added to a suspension of NaH (0.22 g, 5.6 mmol) in dry THF at 0
1 H, 4-Heq), 2.99 (br. s, 1 H, -OH), 3.96 (m, 1 H, 3-H), 5.20 (s, 1
°C. After 30 min at r.t., 3-methyl-5-(3-hydroxy-2,6,6-trimethylcy-
H, 14-H), 6.13 (d, J ϭ 11.6 Hz, 1 H, 10-H), 6.14 (d, J ϭ 16.0 Hz,
clohex-1-enyl)-2,4-pentadienal (0.57 g, 2.4 mmol) in THF was ad-
ded and the mixture was stirred overnight at r.t. After workup and
purification by column chromatography (60% ether/PE), 3,7-di-
1 H, 8-H), 6.27 (d, J ϭ 16.0 Hz, 1 H, 7-H), 6.31 (d, J ϭ 15.0 Hz,
1 H, 12-H), 6.96 (dd, J ϭ 15.0/11.6 Hz, 1 H, 11-H). 13C NMR
(75 MHz, CDCl3): δ (ppm) ϭ 12.8 (9-CH3), 16.4 (13-CH3), 21.4
methyl-9-(3-hydroxy-2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-
(5-CH3), 28.5/30.0 (1-CH3), 36.8 (C-1), 42.2 (C-4), 48.0 (C-2), 64.2
tetraenenitrile (0.60 g, 2.0 mmol, 83%) was obtained as a mixture
(C-3), 96.3 (C-14), 117.2 (C-15), 127.1 (C-5), 128.4 (C-7), 131.3 (C-
1
of isomers. H NMR (300 MHz, CDCl3): δ (ppm) ϭ 1.02/1.06 (2s,
10), 132.3 (C-11), 133.2 (C-12), 137.1 (C-6), 137.5 (C-8), 140.8 (C-
6 H, 1-CH3), 1.43 (m, 1 H, 2-Heq), 1.69 (m, 1 H, 2-Hax), 1.72 (m,
9), 156.9 (C-13).
1 H, 3-Hax), 1.84 (s, 3 H, 5-CH3), 1.90 (m, 1 H, 3-Heq), 2.01 (s, 3
H, 9-CH3), 2.20 (s, 3 H, 13-CH3), 3.12 (br. s, 1 H, -OH), 4.00 (m,
1 H, 4-H), 5.20 (s, 1 H, 14-H), 6.09 (d, J ϭ 11.5 Hz, 1 H, 10-H),
6.18 (d, J ϭ 16.3 Hz, 1 H, 8-H), 6.28 (d, J ϭ 16.3 Hz, 1 H, 7-H),
6.31 (d, J ϭ 15.1 Hz, 1 H, 12-H), 6.95 (dd, J ϭ 15.1/11.5 Hz, 1 H,
11-H). 13C NMR (75 MHz, CDCl3): δ (ppm) ϭ 12.7 (9-CH3), 16.3
(13-CH3), 20.7 (5-CH3), 27.3/28.7 (1-CH3), 28.2 (C-3), 34.4 (C-2),
34.5 (C-1), 69.7 (C-4), 96.4 (C-14), 117.8 (C-15), 128.5 (C-7), 129.2
(C-10), 129.2 (C-12), 130.5 (C-5), 131.4 (C-11), 137.7 (C-8), 140.6
(C-9), 140.9 (C-6), 156.7 (C-13).
The C20-nitrile (0.54 g, 1.8 mmol) was reduced to the correspond-
ing aldehyde 3 with Dibal-H (4.5 mL, 4.5 mmol) in dry toluene,
using the same procedure as described before. After purification on
a silica-gel column (60% ether/PE), 3-hydroxy-retinal (3) (0.48 g,
1.6 mmol, 89%) was obtained as a mixture of isomers. 1H NMR
(600 MHz, CDCl3): δ (ppm) ϭ 1.03/1.08 (2s, 6 H, 1-CH3), 1.50 (t,
J ϭ 12.0 Hz, 1 H, 2-Hax), 1.74 (s, 3 H, 5-CH3), 1.79 (t, J ϭ 4.1 Hz,
1 H, 2-Heq), 2.03 (s, 3 H, 9-CH3), 2.08 (t, J ϭ 10.3 Hz, 1 H, 4-Hax),
2.33 (s, 3 H, 13-CH3), 2.40 (d, J ϭ 5.2 Hz, 1 H, 4-Heq), 2.90 (br. s,
1 H, -OH), 4.00 (m, 1 H, 3-H), 5.97 (d, J ϭ 8.2 Hz, 1 H, 14-H),
6.16 (d, J ϭ 16.1 Hz, 1 H, 8-H), 6.20 (d, J ϭ 11.5 Hz, 1 H, 10-H),
6.29 (d, J ϭ 16.1 Hz, 1 H, 7-H), 6.38 (d, J ϭ 15.0 Hz, 1 H, 12-H),
7.15 (dd, J ϭ 15.0/11.5 Hz, 1 H, 11-H), 10.08 (d, J ϭ 8.2 Hz, 1 H,
15-H). 13C NMR (150 MHz, CDCl3): δ (ppm) ϭ 12.7 (9-CH3), 12.9
(13-CH3), 21.4 (C-18), 28.5/30.0 (1-CH3), 36.8 (C-1), 42.3 (C-4),
48.0 (C-2), 64.3 (C-3), 127.3 (C-5), 128.5/128.7 (C-7/C-14), 129.6
(C-10), 132.3 (C-11), 134.5 (C-12), 137.1 (C-6), 137.4 (C-8), 140.8
(C-9), 154.8 (C-13), 191.0 (C-15)
By using the procedure described above for (2), reduction of the 4-
hydroxy-C20-nitrile (0.60 g, 2.0 mmol) in dry toluene with Dibal-
H (5.0 mL, 5.0 mmol) gave, after purification (60% ether/PE), the
corresponding 4-hydroxyretinal 4 (0.53 g, 1.8 mmol, 87%) as a mix-
ture of isomers. 1H NMR (400 MHz, CDCl3): δ (ppm) ϭ 1.03/1.06
(2s, 6 H, 1-CH3), 1.43 (m, 1 H, 2-Heq), 1.68 (m, 1 H, 2-Hax), 1.73
(m, 1 H, 3-Hax), 1.85 (s, 3 H, 5-CH3), 1.89 (m, 1 H, 3-Heq), 2.03
(s, 3 H, 9-CH3), 2.33 (s, 3 H, 13-CH3), 2.90 (br. s, 1 H, -OH), 4.02
(m, 1 H, 4-H), 5.97 (d, J ϭ 8.1 Hz, 1 H, 14-H), 6.19 (d, J ϭ
16.0 Hz, 1 H, 8-H), 6.21 (d, J ϭ 11.3 Hz, 1 H, 10-H), 6.31 (d, J ϭ
16.0 Hz, 1 H, 7-H), 6.38 (d, J ϭ 15.1 Hz, 1 H, 12-H), 7.14 (dd, J ϭ
15.1/11.3 Hz, 1 H, 11-H), 10.07 (d, J ϭ 8.1 Hz, 1 H, 15-H). 13C
NMR (100 MHz, CDCl3): δ (ppm) ϭ 12.7 (9-CH3), 12.8 (13-CH3),
18.4 (5-CH3), 27.4/28.7 (1-CH3), 28.2 (C-3), 34.4 (C-2), 34.4 (C-1),
69.6 (C-4), 128.6/128.7 (C-14/C-7), 129.5 (C-10), 130.7 (C-5), 132.2
(C-11), 134.6 (C-12), 137.7 (C-8), 140.5/140.7 (C-6/C-9), 154.7 (C-
13), 190.9 (C-15).
(4RS)-Hydroxyretinal (4)
3-Methyl-5-(3-hydroxy-2,6,6-trimethylcyclohex-1-enyl)penta-2,4-
dienal: In a similar way to that described above, C5-phosphonate
12 (1.14 g, 5.3 mmol) was deprotonated with NaH (0.4 g,
10.1 mmol) and coupled to 3-hydroxy-2,6,6-trimethylcyclohex-1-
enecarbaldehyde 9 (0.74 g, 4.4 mmol). After purification (50%
ether/PE), 3-methyl-5-(3-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-
penta-2,4-dienenitrile (0.82 g, 3.6 mmol, 81%) was obtained as a
mixture of isomers. 1H NMR (300 MHz, CDCl3): δ (ppm) ϭ 1.01/
1.04 (2s, 6 H, 1-CH3), 1.4 (m, 1 H, 2-Heq), 1.7 (m, 2 H, 2-Hax/3-
Hax), 1.81 (s, 3 H, 5-CH3), 1.9 (m, 1 H, 3-Heq), 2.20 (s, 3 H, 9-
CH3), 2.64 (br. s, 1 H, -OH), 3.99 (br. s, 1 H, 4-H), 5.21 (s, 1 H,
10-H), 6.17 (d, J ϭ 16.0 Hz, 1 H, 8-H), 6.52 (d, J ϭ 16.0 Hz, 1 H,
7-H). 13C NMR (75 MHz, CDCl3): δ (ppm) ϭ 15.9 (9-CH3), 18.0
(5-CH3), 27.0/27.8 (1-CH3), 28.3 (C-3), 34.0 (C-2), 34.0 (C-1), 69.1
(C-4), 96.6 (C-10), 117.1 (C-11), 131.8 (C-5), 133.1 (C-7), 134.5 (C-
8), 139.4 (C-6), 156.3 (C-9).
Acknowledgments
The authors wish to thank Kees Erkelens and Fons Lefeber for
their help in recording the NMR spectra.
[1]
L. Zechmeister, in: cis-trans Isomeric Carotenoids, Vitamins A
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[2]
O. Isler, in: Carotenoids, Birkhäuser Verlag, Basel, 1971.
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Y. Katsuta, K. Yoshihara, Tetrahedron Lett. 1994, 35,
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M. Sedou, M. Sugahara, H. Uchiyama, K. Hiraki, T. Ham-
By using the procedure described before, 3-methyl-5-(3-hydroxy-
[4]
2,6,6-trimethylcyclohex-1-enyl)penta-2,4-dienenitrile
(0.60 g,
anaka, M. Michinomae, K. Yoshihara, Y. Kito, J. Comp. Phys.
1990, A166, 769Ϫ773.
S. Matsui, M. Seidou, I. Uchiyama, N. Sekiya, K. Hiraki, K.
2.6 mmol) in dry toluene was reduced with Dibal-H (6.0 mL,
6.0 mmol). After purification on a silica-gel column (60% ether/
PE), 3-methyl-5-(3-hydroxy-2,6,6-trimethylcyclohex-1-enyl)penta-
2,4-dienal (0.57 g, 2.4 mmol, 94%) was obtained as a mixture of
[5]
Yoshihara, Y. Kito, Biochim. Biophys. Acta 1988, 966,
370Ϫ374.
1
[6]
isomers. H NMR (300 MHz, CDCl3): δ (ppm) ϭ 1.03/1.06 (2s, 6
K. Vogt, K. Kirschfeld, Naturwissenschaften 1984, 71,
211Ϫ213.
H, 1-CH3), 1.4 (m, 1 H, 2-Heq), 1.7 (m, 2 H, 2-Hax/3-Hax), 1.84 (s,
Eur. J. Org. Chem. 2003, 863Ϫ868
867