Isomers of 10-fluoro-20-13C-retinal and the corresponding rhodopsin analogs

Article abstract of DOI:10.1016/S0040-4039(01)00082-X

The doubly-labeled 10-fluoro-20-¹³C-retinal has been prepared. Five isomers have been isolated and two isomeric rhodopsin analogs prepared. The latter are intended for REDOR distance measurements.

Full text of DOI:10.1016/S0040-4039(01)00082-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1643–1644
Isomers of 10-fluoro-20-13C-retinal and the corresponding
rhodopsin analogs
Jiahong Ni, Jin Liu, Leticia U. Colmenares and Robert S. H. Liu*
Department of Chemistry, University of Hawaii, Honolulu, HI 96822, USA
Received 29 August 2000; accepted 11 September 2000
Abstract—The doubly-labeled 10-fluoro-20-13C-retinal has been prepared. Five isomers have been isolated and two isomeric
rhodopsin analogs prepared. The latter are intended for REDOR distance measurements. © 2001 Elsevier Science Ltd. All rights
reserved.
The visual pigment rhodopsin is an integral membrane
protein in the disk membrane of vertebrate rod cells. It
contains the hindered 11-cis retinal isomer as a chro-
mophore, bound to Lys296 through a protonated Schiff
base linkage.1 The exact twisted conformation of the
polyene chromophore has been of concern to many
research groups. This is due to its effect on the follow-
ing properties of the visual pigment, e.g. the absorption
maxima,2 its chirality as a result of the helical twist,3
and the enhanced photoreactivity.4
nuclear parameters are likely to allow larger distances
(up to 11 A) to be measured. In this paper, we report
the successful combination of the synthetic techniques
developed for the preparation of fluorinated7 and 13C
isotopically-labeled8 retinals for the synthesis of the first
19F,13C doubly-labeled retinal, i.e. the title compound,
10-fluoro-20-13C-retinal.
5
,
A modification of the established 13+2+3+2 strategy in
vitamin A synthesis9 is shown in Scheme 1. The steps
for introducing the labels are the following. The 10-F
substituent was introduced following the established
procedure of reaction of b-ionone with ethyl
diethylphosphonofluoroacetate in the presence of
NaH.7 The 13C label was introduced in the manner
established by Lugtenburg et al.,8 i.e. via the intermedi-
acy of C-17-methoxymethylamide 3 reacting with a
labeled methyl Grignard. The two isomers (9-cis to
all-trans ꢀ4:1) of amide 3 are readily separated by
column chromatography. Therefore, subsequent chain-
extension reactions were carried out with the separated
Solid-state NMR, using singly or doubly 13C-enriched
samples, has provided a wealth of structural informa-
tion about the retinal chromophore and its interaction
with the opsin binding site.5 More recently, the devel-
opment of new pulse sequences in rotational echo dou-
ble-resonance (REDOR) methods allow measurement
of heteronuclear dipole couplings, which in turn yields
information concerning distances between the nuclei of
concern.5,6 The coupling between 19F and 13C is of
particular interest because it is recognized that their
Scheme 1. (a) (EtO)2POCFHCO2Et+NaH; (b) DIBAL-H, MnO2, (EtO)2POCH2CO2Et+NaH, HN(OMe)Me+n-BuLi; (c)
13CH3MgI; (d) (EtO)2POCH2CN+n-BuLi; (e) DIBAL-H.
* Corresponding author. Tel.: 808-956-5723; fax: 808-956-5908; e-mail: rliu@gold.chem.hawaii.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00082-X

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J. Ni et al. / Tetrahedron Letters 42 (2001) 1643–1644
isomers, yielding two sets of readily-separable isomers
of retinal (9-cis and 9,13-di-cis; 13-cis and all-trans).7
The data from the NMR spectra of all these isomers
are listed10 and they were found to be identical to those
reported for 10-fluororetinal,7 with the only exception
being the large 13C–H coupling constant (ꢀ128 Hz) for
13-Me. Additionally, the 11-cis isomer, characterized by
its UV spectrum,7 was also obtained from irradiation of
the synthetic mixture in acetonitrile.9
4. Yoshizawa, T.; Kandori, H. Prog. Retin. Res. 1991, 11,
33.
5. Smith, S. O.; Aschheim, K.; Groesbeek, M. Q. Rev.
Biophys. 1996, 29, 395.
6. Groesbeek, M.; Smith, S. O. J. Org. Chem. 1997, 62,
3638.
7. (a) Asato, A. E.; Matsumoto, H.; Denny, M.; Liu, R. S.
H. J. Am. Chem. Soc. 1978, 100, 5957; (b) Liu, R. S. H.;
Asato, A. E. In Chemistry and Biology of Synthetic
Retinoids; Dawson, M.; Okamura, W. H., Eds.; CRC
Press: Boca Raton, FL, 1990; p. 51.
8. (a) Groesbeek, M.; Rood, G. A.; Lugtenburg, J. Recl.
Trav. Chim. Pays-Bas 1992, 111, 149; (b) Jansen, F. S.;
Lugtenburg, J. In Carotenoids; Britton, G.; Liaaen-
Jensen, S.; Pfander, H., Eds.; Birkha¨user: Basel, 1995;
Vol. 1A, p. 233.
We have also prepared the rhodopsin pigment analogs
in good yields (>50%) from the 11-cis and 9-cis isomers
of 1. Expectedly, their absorption maxima (502 and 486
nm, respectively) are identical to those reported earlier7
for the singly-labeled isomers.
In summary, a convenient method has been devised for
the synthesis of a doubly-labeled retinal, which led to
the isolation of four isomers of 10-fluoro-20-13C-retinal.
The resultant rhodopsin analogs now await detailed
REDOR NMR analyses. The 11-cis pigment will be an
independent test for the helical twist obtained recently
with doubly-labeled 13C samples,11 and the 9-cis isomer,
with a longer distance between the C,F nuclei, will offer
a meaningful independent test for the method.
9. Liu, R. S. H.; Asato, A. E. Tetrahedron 1984, 40, 1931.
10. Partial 1H and 19F NMR data for four isomers of 1.
1
All-trans: H NMR (300 MHz, CDCl3): l 10.14 (d, 1H,
J=8.1 Hz, H-15), 6.88 (dd, 1H, J=26.6 and 15.4, H-11),
6.69 (d, 1H, J=16.4, H-7), 6.65 (dd, 1H, J=15.4 and 4.9,
H-12), 6.33 (d, 1H, J=16.4, H-8), 6.06 (t, 1H, J=8.1,
H-14), 2.32 ppm (d, 3H, J=127.9 Hz, 13CH3-13); 19F
NMR (376.4 MHz, CDCl3): −124.5 ppm (d, J=26.8 Hz).
1
13-cis: H NMR: l 10.27 (d, 1H, J=8.3 Hz, H-15), 7.54
(dd, 1H, J=15.1 and 5.4, H-12), 6.80 (dd, 1H, J=26.9
and 15.1, H-11), 6.73 (d, 1H, J=16.2, H-7), 6.36 (d, 1H,
J=7.2, H-14), 2.16 (d, 3H, J=127.7 Hz, 13CH3-13); 19F
NMR: −124.66 ppm (d, J=26.8). 9-cis: 1H NMR: l
10.14 (d, 1H, J=8.0 Hz, H-15), 6.98 (dd, 1H, J=26.9
and 15.3, H-11), 6.63 (dd, 1H, J=15.3 and 4.6, H-12),
6.39 (d, 1H, J=15, H-7), 6.31 (d, 1H, J=15.1, H-8), 6.09
(t, 1H, J=7.8, H-14), 2.34 (d, 3H, J=127.9 Hz, 13CH3-
Acknowledgements
The work was supported by a grant from the US Public
Health Services (DK-17806). Helpful discussion with
Dr. A. E. Asato is much appreciated.
1
13); 19F NMR: −119.8 ppm (d, J=26.7). 9,13-di-cis: H
NMR: l 10.27 (d, 1H, J=8.0 Hz, H-15), 7.51 (dd, 1H,
J=15.1 and 5.4, H-12), 6.87 (dd, 1H, J=26.9 and 15.1,
H-11), 6.38 (d, 1H, J=15.4, H-7), 6.31 (d, 1H, J=15.4,
H-8), 5.94 (t, 1H, J=7.4, H-14), 2.16 (d, 3H, J=127.7
Hz, 13CH3-13); 19F NMR: −120.1 ppm (d, J=26.7).
11. Verdegen, P. J. E.; Bovce-Geurts, P. H. M.; deGrip, W.
J.; Lugtenburg, J.; deGroot, H. J. M. Biochemistry 1999,
38, 11316.
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