Synthesis of Retinals Fluorinated at Odd-Numbered Side-Chain Positions and of the Corresponding Fluorobacteriorhodopsins

Article abstract of DOI:10.1021/jo961355x

Conventional Horner-Wadsworth-Emmons and Wittig condensations were used to fluorinate the odd-numbered positions of the retinal side chain past C₇. The stereochemically labile cis-fluororetinals were easily converted into the most stable trans-fluororetinals, which were incubated with bacterio-opsin. Contrary to expectations, the fluorinated retinals provided artificial pigments with near normal absorption properties, showing that any electrostatic interactions between the fluorine atoms and protein groups were insufficient to prevent normal binding. The new artificial pigments had smaller opsin shifts than did native bacteriorhodopsin, which is interpreted as due either to greater electrostatic interaction between the protonated imine and its counterion, or to local interactions between the fluorine substituents and nearby polar protein groups.

Full text of DOI:10.1021/jo961355x

310
J . Org. Chem. 1997, 62, 310-319
Syn th esis of Retin a ls F lu or in a ted a t Od d -Nu m ber ed Sid e-Ch a in
P osition s a n d of th e Cor r esp on d in g F lu or oba cter ior h od op sin s
Andre´s Francesch, Rosana Alvarez, Susana Lo´pez, and Angel R. de Lera*,†
Departamento de Qu´ımica Orga´nica, Universidade de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received J uly 17, 1996X
Conventional Horner-Wadsworth-Emmons and Wittig condensations were used to fluorinate the
odd-numbered positions of the retinal side chain past C7. The stereochemically labile cis-
fluororetinals were easily converted into the most stable trans-fluororetinals, which were incubated
with bacterio-opsin. Contrary to expectations, the fluorinated retinals provided artificial pigments
with near normal absorption properties, showing that any electrostatic interactions between the
fluorine atoms and protein groups were insufficient to prevent normal binding. The new artificial
pigments had smaller opsin shifts than did native bacteriorhodopsin, which is interpreted as due
either to greater electrostatic interaction between the protonated imine and its counterion, or to
local interactions between the fluorine substituents and nearby polar protein groups.
In tr od u ction
bacterio-opsin. The factors determining the absorption
wavelength of BR are thought certainly to include both
ring-chain coplanarization (i.e. adoption of the 6-s-trans
conformation) and the existence of a weak interaction
between the Schiff base and its counterion.4a In addition,
the large bathochromic opsin shift of the BR analogue
containing 13,14-dehydroretinal strongly suggests that
for BR and BR analogues in general other factors may
also be involved, such as a lowering of the energy of the
excited state due to interactions between the polyene
chain and polar or polarizable side chains on the protein.4b
The light-transducing protein bacteriorhodopsin (BR)
is found in nature in the purple outer membrane of
Halobacterium salinarium1 and has been used in opto-
electronic devices.2 Its chromophore is the protonated
Schiff base (PSB) formed by trans-retinal (1) and the
Lys216 residue of the apoprotein, bacterio-opsin. In the
bacterial cell, absorption of a quantum of light induces
trans/ cis isomerization of the retinal to the 13-cis-retinal
configuration (2),1 followed by loss of the iminium proton
to an aspartate residue located to the extracelular side
of the chromophore. The apoprotein then undergoes a
conformational change that exposes the chromophore to
a protonated aspartate residue on its cytoplasmic side,
and reprotonation of the chromophore is followed by back-
isomerization; the photocycle closes with the reversion
of the apoprotein to its initial conformation. The net
result is to pump a proton across the membrane.
While the gross geometrical changes of the BR reti-
nylidene chromophore in the primary photochemical step
are well stablished,1 little is known about retinal-
apoprotein interactions other than the imino bond, or
about how such interactions are related to the changes
in apoprotein structure that enable proton transport.
Efforts to understand these interactions have often
attempted to interpret the effects of modifying retinal on
the “opsin shift”,3 the difference between the wavenum-
bers of the absorption maximum of the model PSB formed
with n-butylamine and that of the pigment formed with
We recently reported the preparation of retinal ana-
logues with relocated side-chain methyl groups.5 Their
incubation with bacterio-opsin failed to produce a BR
analogue if the retinal modification affected the region
near the terminal CHO, and ab initio calculations on
corresponding model PSBs suggested that the importance
of the C-13 methyl group lies in its narrowing the C12-
C13-C14 bond angle, which ensures proper placement
of the cyclohexene relative to the imino group.
We have now addressed the issue of possible interac-
tions between retinal and polar residues in the BR
molecule by using fluorine as a retinal-bound reporter
group with high electronegativity and no steric demands.
(For other recent applications of vinylic fluorine and
fluorinated olefins, see refs 6-8). The polyolefinic nature
of retinal allows incorporation of fluorine at virtually any
position of the side chain.9 In fact, trans-retinal ana-
logues with fluorine substituents at even numbered
† Present address: Departamento de Qu´ımica Pura e Aplicada,
Universidade de Vigo, As Lagoas-Marcosende, 36200 Vigo, Spain.
Phone: 34-86-812316; fax: 34-86-812382. e-mail: qolera@uvigo.es
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) For reviews, see: (a) Birge, R. R. Annu. Rev. Biophys. Bioeng.
1981, 10, 315. (b) Stoeckenius, W.; Bogomolni, R. A. Annu. Rev.
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1992, 24, 147. (d) Oesterhelt, D., Tittor, J .; Bamberg, E. J . Bioenerg.
Biomembr. 1992, 24, 181. (e) Ebrey, T. In Thermodynamics of
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Boca Raton, FL, 1993; pp 353-387. (f) Lanyi, J . K. Biochim. Biophys.
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(6) A recent MNDO study shows the similarity (bond distances,
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Honig, B. J . Am. Chem. Soc. 1980, 102, 7945. (b) Lugtenburg, J .;
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Chem. Soc. 1986, 108, 3104.
S0022-3263(96)01355-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Fluorinated Retinals
J . Org. Chem., Vol. 62, No. 2, 1997 311
Resu lts a n d Discu ssion
1. Syn th esis of Retin a l An a logs 7-10. The use of
fluorinated biomolecules in biological research has stimu-
lated the development, mostly in recent years,12 of a
number of stereoselective approaches to functionalized
fluoroolefins. When we began this work, the fluorinated
versions of the classical Peterson,12e Refortmatsky,12f and
Horner-Wadsworth-Emmons (HWE)12h reactions were
well known. For this work we chose the HWE reaction
because of its mild conditions and the existence of
precedents of its use for other fluororetinoids.10 However,
since the conditions used in these latter syntheses have
usually led to an approximately 3:1 mixture of E and Z
isomers with respect to the newly formed double bond,10
we instead used conditions that had been reported to
allow highly stereoselective preparation of (E)-R-fluoro-
R,â-unsaturated esters by condensation of fluorinated
HWE reagents with either presynthesized aldehydes12h
or aldehydes obtained in situ by DIBALH reduction of
the corresponding esters.12d We envisaged that the
stereochemically pure cis compounds so obtained would
easily be isomerizable to their more stable trans isomers13
and would additionally provide cis-fluororetinoids of
interest for research on the biological activities of this
type of compounds (13-cis-retinal in relation to BR,1,14 11-
cis-retinal for rhodopsin,14 and 9-cis-retinoic acid for
research on retinoid receptors14,15).
F igu r e 1. Natural chromophores in BR and side-chain
fluorinated retinal analogues.
carbons (3-6) have already been synthesized10 and
successfully reacted with bacterio-opsin to form BR
analogues.10c-h In this work we synthesized, and formed
models PSBs with, retinals with fluorines at odd-
numbered side-chain carbons, namely 9-demethyl-9-
fluororetinal 7, 11-fluororetinal 8, 13-demethyl-13-
fluororetinal 9, and 9,13-didemethyl-9,13-difluororetinal
10. In these fluororetinals, unlike those previously
studied (3-6)10c-h the fluorine atoms are located at
positions which in the native pigment are conjugated
with the electron-withdrawing iminium ion of the BR
PSB. It has been predicted, on the basis of studies of
BR analogues and their model PSBs,11 that these posi-
tions must share the positive charge of the PSB base
proton through delocalization along the polyene side
chain. We hoped that alterations, by the fluorine atoms,
of any interactions between the polyene side-chain and
polar bacterio-opsin side chains might show up as
alterations of the absorption properties of the pigment
and/or of its opsin shift with respect to model PSBs.
The synthesis of the desired retinals was based on
Wittig reaction16 between a cyclohexene moiety bearing
a functionalized side chain and a fluorinated fragment
that was itself prepared by reaction of a fluorinated HWE
reagent with the appropriate aldehyde representing an
even-numbered carbon of the final side chain (Scheme
1). Condensation of diethyl (fluorocarbethoxymethyl)-
phosphonate12h with aldehydes 1217a and 1617b (n-BuLi,
THF, -78 °C, and then room temperature)12d,h provided
the anticipated (E)-R-fluoro-R,â-unsaturated esters 13
and 17, respectively, in excellent yield. For their conver-
sion to 15 and 19, the reagents used in the subsequent
Wittig reactions, in situ reduction, and olefination12d
worked poorly, but conversion via the alcohols 14 and
18, respectively, was satisfactory.
(8) (a) McCarthy, J . R.; J arvi, E. T.; Matthews, D. P.; Edwards, M.
L.; Prakash, N. J .; Bowlin, T. L.; Mehdi, S.; Sunkara, P. S.; Bey, P. J .
Am. Chem. Soc. 1989, 111, 1127. (b) Allmendinger, T.; Felder, E.;
Hungerbu¨ller, E. Tetrahedron Lett. 1990, 31, 7301. (c) Boros, L. G.;
DeCorte, B.; Gimi, R. H.; Welch, J . T.; Wu, Y.; Handschumacher, R.
E. Tetrahedron Lett. 1994, 33, 6033. (d) Bartlett, P. A.; Otake, A. J .
Org. Chem. 1995, 60, 3107. (e) Welch, J . T.; Lin, J . Tetrahedron 1996,
52, 291.
(9) (a) For the nomenclature and numbering of the retinoid struc-
ture, see: IUPAC-IUB J oint Commission on Biochemical Nomenclature
(J CBN). Eur. J . Biochem. 1982, 129, 1. (b) To avoid terminological
confusion, we use the trivial designations cis and trans to indicate the
stereochemistry of the double bonds relative to the polyene chain as
present in the native system (1) (Figure 1) regardless of the presence
of non-native substituents. The stereochemical designations E and
Z, however, conform to the priority rules.
(10) (a) Machleidt, H.; Wessendorf, R. J ustus Liebigs Ann. Chem.
1964, 679, 20. (b) Machleidt, H.; Strehlke, G. J ustus Liebigs Ann.
Chem. 1965, 681, 21. (c) Asato, A. E.; Matsumoto, H.; Denny, M.; Liu,
R. S. H. J . Am. Chem. Soc. 1978, 100, 5957. (d) Liu, R. S. H.;
Matsumoto, H.; Asato, A. E.; Denny, M.; Shichida, Y.; Yoshizawa, T.;
Dahlquist, F. W. J . Am. Chem. Soc. 1981, 103, 7195. (e) Asato, A. E.;
Liu, R. S. H. Tetrahedron Lett. 1986, 27, 3337. (f) Asato, A. E.; Denny,
M.; Matsumoto, H.; Mirzadegan, T.; Ripka, W. C.; Crescitelli, F.; Liu,
R. S. H. Biochemistry 1986, 25, 7021. (g) Liu, R. S. H.; Crescitelli, F.;
Denny, M.; Matsumoto, H.; Asato, A. E. Biochemistry 1986, 25, 7026.
(h) Tierno, M. E.; Mead, D.; Asato, A. E.; Liu, R. S. H.; Sekiya, N.;
Yoshihara, K.; Chang, C.-W.; Nakanishi, K.; Govindjee, R.; Ebrey, T.
G. Biochemistry 1990, 29, 5948. For fluororetinoic acid and fluoroa-
rotinoids, see: (i) Pawson, B. A.; Chan, K.-K.; DeNoble, J .; Han, R.-J .
L.; Piermattie, V.; Specian, A. C.; Srisethnil, S.; Trown, P. W.;
Bohoslawec, O.; Machlin, L. J .; Gabriel, E. J . Med. Chem. 1979, 22,
1059. (j) Chan, K.-K.; Specian, A. C.; Pawson, B. A. J . Med. Chem.
1981, 24, 101. (k) Lovey, A. J .; Pawson, B. A. J . Med. Chem. 1982, 25,
71.
(12) (a) McCarthy, J . R.; Huber, E. W.; Le, T.-B.; Laskovics, F. M.;
Matthews, D. P. Tetrahedron 1996, 52, 45. (b) Allmendinger, T.
Tetrahedron 1991, 47, 4905. (c) Pirrung, M. C.; Rowley, E. G.; Holmes,
C. P. J . Org. Chem. 1993, 58, 5683. (d) Thenappan, A.; Burton, D. J .
J . Org. Chem. 1990, 55, 4639. (e) Welch, J . T.; Herbert, R. W. J . Org.
Chem. 1990, 55, 4782. (f) Ishihara, T.; Kuroboshi, M. Chem. Lett. 1987,
1145. (g) Controt, P.; Grison, C.; Sauve`tre, R. J . Organomet. Chem.
1987, 332, 1. (h) Etemad-Moghadam, G.; Seyden-Penne, J . Bull. Chim.
Soc. Fr. 1985, 448. (i) Bessie`re, Y.; Savary, D. N.-H.; Schlosser, M.
Helv. Chim. Acta 1977, 60, 1739. (j) Normant, J . F.; Foulon, J . P.;
Masure, D.; Sauve`tre, R. Villieras, J . Synthesis 1975, 122.
(13) (a) Rando, R. R.; Chang, A. J . Am. Chem. Soc. 1983, 105, 2879.
(b) Lukton, D.; Rando, R. R. J . Am. Chem. Soc. 1984, 106, 258. (c)
Lukton, D.; Rando, R. R. J . Am. Chem. Soc. 1984, 106, 4525.
(14) (a) Dawson, M. I.; Okamura, W. H., Eds. Chemistry and Biology
of Synthetic Retinoids; CRC Press: Boca Raton, FL, 1990. (b) Sporn,
M. B., Roberts, A. B., Goodman, D. S., Eds. The Retinoids: Biology,
Chemistry and Medicine, 2nd ed.; Raven Press: New York, 1993.
(15) For recent reviews, see: (a) Pfahl, M. Retinoid Response
Pathways, In From Basic Science to Clinical Applications; Livrea, M.
A., Vidali, G., Eds.; Birkha¨user: Basel, 1994; pp 115-126. (b) Man-
gelsdorf, D. J .; Evans, R. M. Cell 1995, 83, 841.
(16) For reviews on the Wittig (and WHE) reaction, see: (a)
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (b) Vedejs, E.;
Peterson, M. J . Top. Stereochem. 1994, 21, 1.
(17) (a) For an alternative synthesis of 12, see: Nicolaou, K. C.; Liu,
J .-J .; Yang, Z.; Ueno, H.; Sorensen, E. J .; Claiborne, C. F.; Guy, R. K.;
Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J . Am. Chem. Soc. 1995,
117, 634. (b) Torrado, A.; Iglesias, B.; Lo´pez, S.; de Lera, A. R.
Tetrahedron 1995, 51, 2435.
(11) For an INDO/CI/SOS study of the charge distribution in both
the ground state and the excited state of model protonated Schiff bases
of retinal, see: Hendrickx, E.; Clays, K.; Persoons, A.; Dehu, C.; Bre´das,
J . L. J . Am. Chem. Soc. 1995, 117, 3547.

312 J . Org. Chem., Vol. 62, No. 2, 1997
Francesch et al.
from phosphonium salt 32.22 Generation of the phos-
phorane with n-BuLi at -78 °C, followed by addition of
fluoroaldehyde 19 at -78 °C and additional stirring at
room temperature for 5 h, provided a 57% yield of the
(9E)-TBDPS-protected 11-fluororetinol 33 as the only
isomer, which was deprotected with n-Bu4NF,19 to afford
the alcohol 34 (Scheme 3); the stereoselectivity of the
coupling with fluoroaldehyde 19 is strikingly different23
from that achieved when the phosphonium salt 32 is
coupled with aldehydes,24 which provides ∼3:2 mixtures
of E and Z stereoisomers at the newly formed trisubsti-
tuted double bond. Treatment of 34 with MnO2 and Na2-
Sch em e 1a
20a
CO3 provided the (9E)-11-fluororetinal 35 in 80% yield,
which slowly converted into 8 on manipulation. Alter-
natively, BaMnO4 treatment of alcohol 34 provided in
94% yield the desired trans-11-fluororetinal 8.
Syn t h esis of 13-Dem et h yl-13-flu or or et in a l (9).
Wittig condensation between the phosphonium salt 36
(derived from â-ionone)25 and the enal 15 (Scheme 1) is
the key step leading to retinal analogue 9. Treatment
of 36 with n-BuLi at -78 °C, followed by addition of
aldehyde 15 and stirring at room temperature for 5 h,
provided protected 13-demethyl-13-fluororetinol in 69%
yield as a 60:40 mixture of the (11E) and (11Z) stereo-
isomers 37 and 38, respectively (Scheme 4). Deprotec-
tion19 and HPLC separation afforded fluororetinols 39
a
Reagents and conditions: (a) ClTBDPS, imidazole, DMF, 25
°C, 12 h; (b) O3, MeOH/CH2Cl2 (50:50), -78 °C, then Ph3P; (c)
diethyl (fluorocarbethoxymethyl)phosphonate, n-BuLi, THF, -78
°C, then 25 °C, 3 h; (d) DIBALH, THF, -78 °C, then 0 °C, 1 h; (e)
BaMnO4, CH2Cl2, 25 °C, 12 h.
20a
and 40. Whereas oxidation of 39 with MnO2/Na2CO3
Syn th esis of 9-Dem eth yl-9-flu or or etin a l (7). Treat-
ment of aldehyde 15 with the phosphonium salt 20
(derived from â-cyclocitral18) under the conditions de-
scribed above12d provided the (2E,4E)-fluorinated silyl
ether 21 as a precursor of C9-fluorinated retinoids
(Scheme 2). Aldehyde 23 was prepared by standard
n-Bu4NF deprotection19 of 21 and MnO2 oxidation of the
resulting alcohol 22 under basic conditions (MnO2/Na2-
CO3 in CH2Cl220a). Aldehyde 23 was coupled (n-BuLi,
DMPU, -78 °C, and then 0 °C, 10 h)21a to phosphonate
2421b to afford a 74% yield of ethyl 9-demethyl-9-fluo-
roretinoate (25) as the anticipated all-(E)-isomer (as
shown by the coupling constants of the vinylic hydrogens;
see below). DIBALH reduction of 25, followed by allylic
oxidation with MnO2 in the presence of Na2CO3 in CH2-
Cl2,20a gave the aldehyde 26 in 54% overall yield. Despite
careful manipulation in the dark, compound 26 was
slowly converted into its isomer 7, which is trans (9Z)
with respect to the C-9-C-10 double bond.
An alternative route to 7 was based on the finding that
stereomutation of the terminal double bond of 22 was
easily induced by treatment with HBr‚Ph3P. Coupling
of aldehyde 1617b with the â-fluoroallyl phosphorane
anion derived from phosphonium salt 27 afforded a 68:
32 mixture of the polyene isomers 28 and 29. After
deprotection19 of the mixture and separation of the
retinols 30 and 31 by HPLC, the desired (9Z,11E)-9-
demethyl-9-fluororetinal (7) was obtained in 88% yield
by oxidation of 30 with BaMnO4.20b,c
afforded a mixture of 41 and 9 in a ca. 4:1 ratio, the
desired 13-trans isomer 9 was obtained under barium
manganate oxidation conditions.20b,c
Syn th esis of 9,13-Did em eth yl-9,13-d iflu or or etin a l
(10). Coupling between aldehyde 15 and the fluorophos-
phonium salt 27 (obtained as in Scheme 2), carried out
by the general procedure described above, provided a 89%
yield of a 75:25 mixture of 42 and 43, the (11E)- and
(11Z)-isomers of protected 9,13-didemethyl-9,13-difluo-
roretinol (Scheme 5). Treatment of the unseparated
mixture with n-Bu4NF,19 followed by HPLC separation,
provided alcohols 44 and 45 in 76% yield. Allylic oxida-
tion of fluororetinol 44 afforded, under basic MnO2
conditions,20a the 9,13-didemethyl-9,13-difluororetinal
isomers 46 and 10 in ca. 4:1 ratio, whereas treatment
with BaMnO4 took place with isomerization of the
terminal double bond to the desired (13Z)-isomer 10 in
92% yield. Despite our precautions, isomerization of the
(13E)-13-fluororetinals of both series (41 and 46) to the
most stable (13Z)-isomers (9 and 10) always occurred
upon manipulation (e.g. after NMR spectroscopy follow-
ing HPLC separation, evaporation of the solvent gave rise
to extensive isomerization).
1
2. Str u ctu r e Deter m in a tion . The H NMR data of
the fluororetinal isomers are listed in Table 1. Assign-
1
ment rests on the H NMR chemical shifts and coupling
constants for the hydrogens of the retinal polyene chain26a
and, for the configuration of the fluoroolefin isomers, on
the magnitude of the three bond H-F coupling constants
Syn th esis of 11-F lu or or etin a l (8). The synthesis of
this analogue was envisaged as the result of Wittig
condensation between aldehyde 19 and the anion derived
(22) (a) Olive´, J .-L.; Mousseron-Canet, M.; Dornand, J . Bull. Soc.
Chim. Fr. 1969, 3247. (b) Eschenmoser, W.; Eugster, C. H. Helv. Chim.
Acta 1978, 61, 822.
(18) Dawson, M. I.; Hobbs, P. D.; Chan, R. L.-S.; Chao, W.-R. J . Med.
Chem. 1981, 24, 1214.
(23) For other cases of stereochemical reversal of Wittig reactions
involving fluorinated ketones, see: (a) Ruban, G.; Zobel, D.; Kobmehl,
G.; Nuck, R. Chem. Ber. 1980, 113, 3384. (b) Eguchi, T.; Aoyama, T.;
Kakinuma, K. Tetrahedron Lett. 1992, 33, 5545.
(24) Sueiras, J .; Okamura, W. H. J . Am. Chem. Soc. 1980, 102, 6255.
(25) Curley J r., R. W.; DeLuca, H. F. J . Org. Chem. 1984, 49, 1941.
(26) (a) Liu, R. S. H.; Asato, A. E. Tetrahedron 1984, 40, 1931. (b)
Bovey, F. A., Ed. NMR Data Tables for Organic Compounds; Inter-
science: NY, 1969. (c) Kemp, W., Ed. NMR in Chemistry; MacMillan
Education: London, 1986; pp 170-175. (d) Reference 6c, pp 577-594.
(19) Hanessian, S.; Lavalle´e, P. Can. J . Chem. 1975, 53, 2975.
(20) (a) Fatiadi, A. J . Synthesis 1976, 65. (b) Firouzabadi, H.;
Mostafavipoor, Z. Bull. Chem. Soc. J pn. 1983, 56, 914. (c) Hollinshead,
D. M.; Howell, S. C.; Ley, S. V.; Mahon, M.; Ratcliffe, N. M.;
Worthington, P. A. J . Chem. Soc., Perkin Trans. 1 1983, 1579.
(21) (a) Bennani, Y. L.; Boehm, M. F. J . Org. Chem. 1995, 60, 1195.
(b) Fujiwara, K.; Takahashi, H.; Ohta, M. Bull. Chem. Soc. J pn. 1962,
35, 1743.

Synthesis of Fluorinated Retinals
J . Org. Chem., Vol. 62, No. 2, 1997 313
Sch em e 2a
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C, then aldehyde 15, 25 °C, 7 h; (b) n-Bu4NF, Et2O, 25 °C, 2 h; (c) MnO2, Na2CO3,
CH2Cl2, 25 °C, 10 h; (d) n-BuLi, DMPU, THF, -78 °C; then aldehyde 23, 0 °C, 5 h; (e) DIBALH, THF, -78 °C, then 0 °C, 1 h; (f) HBr.Ph3P,
MeOH, 25 °C, 48 h; (g) n-BuLi, 16, THF, -78 °C, then 25 °C, 6 h; (h) BaMnO4, CH2Cl2, 25 °C, 10 h.
Sch em e 3a
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C, then aldehyde 19, 25 °C, 5 h; (b) n-Bu4NF, Et2O, 25 °C, 1 h; (c) MnO2, Na2CO3,
CH2Cl2, 25 °C, 8 h; (d) BaMnO4, CH2Cl2, 25 °C, 10 h.
Sch em e 4a
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C, then aldehyde 15, 25 °C, 5 h; (b) n-Bu4NF, Et2O, 25 °C, 1 h; (c) MnO2, Na2CO3,
CH2Cl2, 25 °C, 6 h; (d) BaMnO4, CH2Cl2, 25 °C, 7 h.
3
(3J HF (cis) ∼ 20-25 Hz, J HF (trans) ∼ 30-40 Hz).26b-d
Schiff bases were prepared by reacting each retinal
analogue (∼0.5 mg) with n-butylamine (40 µL) in ether
(1 mL) in the presence of 4 Å molecular sieves at room
temperature for 30 min. Filtration and evaporation of
solvent and excess amine under vacuum provided the
desired Schiff base,27 which was dissolved in methanol
Additionally, for the retinals with fluorine at C-13, the
aldehydes with (13E) geometry showed a significant J HF
∼ 4 Hz, which was absent (or very small) in the
corresponding (13Z) isomers. The stereochemistry of the
trisubstituted double bonds was further confirmed by
NOESY experiments.
4
3. P r ep a r a tion of Mod el Sch iff Ba ses (SBs), P r o-
ton a ted Sch iff Ba ses (P SBs), a n d P igm en ts. Model
(27) de Lera, A. R.; Reischl, W.; Okamura, W. H. J . Am. Chem. Soc.
1989, 111, 4051.

314 J . Org. Chem., Vol. 62, No. 2, 1997
Francesch et al.
Sch em e 5a
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C, then aldehyde 15, 25 °C, 5 h; (b) n-Bu4NF, Et2O, 25 °C, 1 h; (c) MnO2, Na2CO3,
CH2Cl2, 25 °C, 6 h; (d) BaMnO4, CH2Cl2, 25 °C, 10 h.
Ta ble 1. Selected 1H NMR Ch em ica l Sh ifts (in CDCl3) a n d 1H-1H Cou p lin g Con sta n ts (19F -1H Cou p lin g Con sta n ts in
P a r en th eses) of F lu or or etin a lsa
C-5 C-9
CH3 CH3
C-13
CH3
fluororetinal
H7
H8
H10
H11
H12
H14
5.95
H15
10.11
J 7,8 J 10,11 J 11,12 J 14,15
trans-9-demethyl-
9-fluororetinal (7)
9-cis-9-demethyl-
9-fluororetinal (26)
trans-11-
fluororetinal (8)
11-cis-11-
1.75
1.79
-
-
2.32
2.31
6.67 5.89 (26.2) 5.57 (32.9) 7.10 6.33
6.70 6.30 (27.1) 5.92 (18.8) 6.86 6.24
15.9 11.4 15.6
15.8 11.7 15.2
8.1
8.1
8.1
7.7
8.0
7.0
8.0
6.8
5.96
10.10
10.06
9.84
1.76 2.11 2.43 (3.0) 6.41 6.08
5.74 (30.0)
6.08 (26.8)
6.19
-
-
5.44 (36.3) 5.99
5.53 (22.2) 5.97
16.0
15.8
-
-
-
-
1.62 1.69 2.08
6.42 6.17
6.47 6.21
6.47 6.25
fluororetinal (35)b
trans-13-demethyl-
13-fluororetinal (9)
13-cis-13-demethyl-
13-fluororetinal (41)
trans-9,13-didemethyl-
9,13-difluororetinal (10)
13-cis-9,13-didemethyl-
9,13-difluororetinal (46)
1.75 2.09
1.76 2.09
-
-
-
-
7.42 6.09 (26.6) 5.47 (32.8) 10.08
7.43 6.83 (29.0) 5.76 (18.3) 9.97 (3.7) 16.0 12.0 14.9
16.2 11.4 15.4
16.0 12.0 14.9
6.20
1.76
1.77
-
-
6.79 5.92 (27.2) 5.58 (32.8) 7.36 6.03 (26.8) 5.51 (26.0) 10.06
6.80 5.94 (26.0) 5.64 (32.3) 7.37 6.79 (28.7) 5.77 (18.0) 9.92 (4.0) 16.1 11.6 15.1
a
b
Chemical shifts in ppm, coupling constants in hertz. For signal assignments, see text. In C6D6.
Ta ble 2. Absor p tion Ma xim a (in n m ) of F lu or or etin a ls, Th eir Un p r oton a ted (SB) a n d P r oton a ted (P SB) N-Bu tyl Sch iff
Ba ses, a n d th e P igm en ts F or m ed u p on In cu ba tin g Th em w ith Ba cter io-Op sin . Also Sh ow n Ar e th e Cor r esp on d in g
Opsin Sh ifts (OS), th e Differ en ce betw een th e Absor p tion Wa ven u m ber s of Mod el P SB a n d P igm en t. F or Com p a r ison ,
Va lu es Cor r esp on d in g to Un flu or in a ted Retin a l Ar e Also Sh ow n 10h
retinal
λmax (retinal)
λmax (SB)
λmax (PSB)
λmax pigment
OS (cm-1
)
trans-retinal (1)a
380
360
443
455
567
587
680
548
591
540
562
518
530
520
600
4940
4940
7270
4170
5450
4520
4830
4060
4550
4080
4790
14-F-retinal (6)a
13-demethyl-13-F-retinal (9)b
12-F-retinal (5)a
382
370
368
372
362
354
355
355
446
447
434
442
428
427
429
466
11-F-retinal (8)b
10-F-retinal (4)a
9-demethyl-9-F-retinal (7)b
8-F-retinal (3)a
9,13-didemethyl-9,13-diF-retinal (10)b
13-demethyl-13,14-diF-retinala
a
b
Taken from ref 10h. This work.
for UV spectroscopy. Protonation of the SB was effected
in the UV cell by addition of trichloroacetic acid10h to this
solution. The wavelengths of the absorption maxima of
the trans-retinals and their SBs and PSBs are listed in
Table 2, together with values reported for PSBs derived
from retinals fluorinated at the even-numbered carbons.10h
It is generally accepted that strongly electronegative
groups on the retinal polyene side chain increase the
energy of the excited state relative to that of native
retinal. However, from the values of the absorption
maxima of retinals 7-10 and their SBs listed on Table 2
it can be concluded that the overall effect of the substitu-
tion of methyl (or hydrogen) by fluorine is negligible for
9 and very small for 7, 8, and 10. It seems likely that
fluorine compensates the destabilization of a neighboring
positive charge due to its inductive effect with its ability
to stabilize the charge through n-π back donation.28 The
small hypsochromic shifts exhibited by the retinal ana-
logues and their SBs with respect to that of native retinal,
with values increasing with the distance of the fluorine
atom from the polar group, should be interpreted as due
to reduction of delocalization along the polyene side chain
by the presence of the electron-withdrawing group.
Table 2 shows that this trend is indeed followed both
among PSBs fluorinated at even-numbered carbons and
among PSBs fluorinated at odd-numbered carbons, but
the latter invariably absorb at shorter wavelengths than
PSBs fluorinated at neighboring even-numbered carbons.
Furthermore, placing a fluorine atom at C-13 (in retinal
9 and its derivatives) does not seem to alter the absorp-
tion properties of the native system.
The above difference between the series of PSBs
fluorinated at odd- and even-numbered carbons may be
attributed to a difference with regard to the distribution
(28) Gassman, P. G.; Tidwell, T. T. Acc. Chem. Res. 1983, 16, 279.

Synthesis of Fluorinated Retinals
J . Org. Chem., Vol. 62, No. 2, 1997 315
Ta ble 3. INDO Tota l Ch a r ge Distr ibu tion P er Atom (in
|e|) in th e Gr ou n d Sta te a n d in th e F ir st Excited Sta te
for Selected Ca r bon s of tr a n s-Retin a l P r oton a ted
N-Bu tyl Sch iff Ba se Sid e Ch a in 11
proton charge along the retinal polyene chain. In the
same way as for model compounds, charge delocalization
in the pigments derived from analogues 7-10 should be
reduced by the presence of a fluorine atom at odd-
numbered positions of the retinal side chain, as indicated
by the opsin shift values in Table 2. Therefore, the
smaller opsin shifts of the new BR analogues compared
to the native BR may be due to the PSB-counterion
interaction being greater in the analogues than in native
BR. Other interpretations cannot yet be ruled out, such
as conformational changes induced by the protein or
additional interactions of the fluorine atoms with charged
or polar protein side-chain groups. In particular, it has
been suggested30 that the presence of a positive charge
rather more than 3 Å from C-7 and C-9 would explain
the 13C NMR data of BR.
Finally we note that whereas the BR analogues based
on compounds 7-10 all absorb at shorter wavelengths
than native BR, the analogues with fluorines at C-12 and
C-14 absorb at longer wavelengths. In the case of the
14-fluorinated analogue, a minor absorption peak at 680
nm has been attributed to an all-trans,15-cis conforma-
tion which allows electrostatic interaction with a nearby
carboxylate; this conformer decays into the major form
absorbing at 587 nm.10h
atom
charge
charge
number
ground state
excited state
C-15
C-14
C-13
C-12
C-11
C-10
C-9
0.264
-0.078
0.150
-0.057
0.129
0.144
0.001
-0.074
0.096
-0.069
0.108
0.008
-0.056
0.113
C-8
-0.043
0.057
of the positive charge of the PSB proton over the polyene
side-chain positions in both the ground and the excited
state. Table 3 lists the values of charge distribution
along the polyene side chain in the ground and the first
excited state computed (INDO) for the protonated N-
butylamine retinal Schiff base. Although in the ground
state the positive charge is mostly localized on the region
close to the protonated imino group (C-11- - - -NH+) in
the first excited state the charge is delocalized more along
the molecule. The excited state therefore shows a weaker
charge separation than the ground state. Furthermore,
odd- and even-numbered carbons invert their charge
upon excitation (i.e. C-13 changes from +0.150 in the
ground state to -0.074 in the excited state, whereas C-12
changes from -0.057 to +0.096). Accordingly, electro-
negative fluorine substituents at an even-numbered
carbon of the retinal PSB side chain should stabilize the
excited state, thus contributing to charge delocalization
and as a consequence the absorption maxima should shift
to longer wavelengths. The opposite effect must prevail
for PSBs of retinals 7-10 with fluorine atoms positioned
at odd-numbered carbons, although the effect of shorten-
ing the absorption wavelength is somehow balanced by
the greater stabilization of the ground state.
When retinals 7-10, previously dissolved in ethanol,
were incubated with bacterio-opsin in 0.02 M phosphate
buffer of pH 7.0, all formed the expected artificial
pigments. Their absorption peak wavelengths (UV-vis
absorption spectra were recorded using bleached purple
membrane as the reference29 ) show the same pattern as
those of the PSBs: shortening of absorption wavelength
(a) as the fluorine atom moves toward the cyclohexene
ring, and (b) with respect to BRs in which the retinal is
fluorinated at neighboring even-numbered positions. The
fact that within the series 7-10 trend a shows the same
regular dependence on fluorine positions as among the
corresponding PSBs suggests that there can be no strong
electrostatic interaction between the fluorine atom and
polar or charged groups on protein side chains, since any
such interaction ought to depend on the position of the
fluorine atom and hence disrupt the regularity of the
shift.
Con clu sion s
In this work we synthesized retinals with fluorine
atoms at the odd-numbered side-chain positions past C-7.
The retinal structure was assembled by means of Wittig
reactions between building blocks, one or more of which
had been selectively functionalized by HWE condensa-
tion. The resulting (E)-cis-fluororetinals were converted
into the more stable corresponding (Z)-trans-fluororeti-
nals, which were (a) reacted with n-butylamine to form
model PSBs, and (b) incubated with bacterio-opsin to
form BR analogues. The successful formation of the
latter, which is concluded from the similarity between
their absorption properties and those of native BR, show
that any electrostatic interaction between protein groups
and the fluororetinal fluorine atoms is not sufficient to
prevent the fluororetinal from docking in the bacterio-
opsin binding site.
Hypsochromic shifts with respect to native BR and its
model PSB are exhibited by the BR analogues and model
PSBs of all the new retinals except 13-demethyl-13-
fluororetinal (9); the BR analogue of 9 exhibits this shift,
but not its model PSB. The fact that the new BR
analogues have smaller opsin shifts than native BR may
be due to the PSB-counterion interaction being greater
in the analogues than in native BR, or to local interac-
tions between the fluorine substituents and nearby polar
protein groups.
It is hoped that more information on the conformation
of compounds 7-10 in their BR analogues will be
provided by 19F NMR spectroscopy, which has recently
afforded evidence of restricted rotation of opsin-bound 11-
The opsin shift of native BR is thought to be due largely
to the PSB-counterion interaction being weaker in BR
than for its model PSB in solution. This weakening,
which is attributed to the orientation and distance of the
counterion (the carboxylate group of an aspartate resi-
due) being such that water molecules can bridge between
counterion and PSB,30-32 allows delocalization of the PSB
(31) (a) Livnah, N.; Sheves, M. J . Am. Chem. Soc. 1993, 115, 351.
(b) Gat, Y.; Sheves, M. J . Am. Chem. Soc. 1993, 115, 3772.
(32) Kandori, H.; Yamazaki, Y.; Sasaki, J .; Needleman, R.; Lanyi,
J . K.; Maeda, A. J . Am. Chem. Soc. 1995, 117, 2118.
(33) (a) Colmenares, L. U.; Asato, A. E.; Denny, M.; Mead, D.;
Zingoni, J . P.; Liu, R. S. H. Biochem. Biophys. Res. Commun. 1991,
179, 1337. (b) Colmenares, L. U.; Liu, R. S. H. Photochem. Photobiol.
1992, 56, 101. (c) Colmenares, L. U.; Liu, R. S. H. J . Am. Chem. Soc.
1992, 114, 6933. (d) Colmenares, L. U.; Liu, R. S. H. Tetrahedron 1996,
52, 109.
(29) Oesterhelt, D.; Stoeckenius, W. Methods Enzymol. 1974, 31,
667.
(30) Albeck, A.; Livnah, N.; Gottlieb, H.; Sheves, M. J . Am. Chem.
Soc. 1992, 114, 2400.

316 J . Org. Chem., Vol. 62, No. 2, 1997
Francesch et al.
OH) cm-1. HMRS: calcd for ([C20H25FO2Si] - [C4H9 (t-Bu)]):
287.0904; found, 287.0909.
cis-fluororetinal aromatic analogue around the C-6-C-7
bond in the visual pigment rhodopsin.33
(2E )-4-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-2-flu or ob u t -2-
en a l (15). The following oxidation procedure is representative.
BaMnO4 (10.4 g, 90%, 0.041 mol) was added in one portion to
a solution of alcohol 14 (1.4 g, 4.1 mmol) in CH2Cl2 (40 mL).
After stirring at 25 °C for 12 h, the reaction mixture was
filtered through Celite, and the solvents were removed. The
residue was purified by chromatography (silica, 90:10 hexane/
ethyl acetate) to provide aldehyde 15 (1.3 g, 93%) as a colorless
oil. 1H NMR (250.13 MHz, CDCl3): δ 1.09 (9H, s), 4.60 (2H,
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es.5,34 [(ter t-Bu tyl-
d ip h en ylsilyl)oxy]eth a n a l (12). tert-Butylchlorodiphenyl-
silane (10.6 g, 38.5 mmol) was added dropwise at 0 °C to a
solution of (Z)-but-2-ene-1,4-diol (11; 1.54 g, 17.5 mmol) and
imidazole (2.62 g, 38.5 mmol) in DMF (40 mL). The solution
was stirred at 25 °C for 12 h, diluted with H2O (50 mL), and
extracted with hexane (4 × 50 mL). The combined organic
layers were washed with H2O (2 × 50 mL), dried (MgSO4),
and concentrated. The resulting residue was purified by
distillation (180 °C/1 mmHg) to afford 9.69 g (98%) of the crude
silyl ether as a colorless oil which was used in the next step
without further purification.
A fraction of the crude silyl ether (6.51 g, 11.5 mmol) was
dissolved in MeOH/CH2Cl2 (50:50, 200 mL) and treated with
O3 at -78 °C for 20 min. The reaction was quenched with
Ph3P (4.53 g, 17.7 mmol) at -78 °C, and the resulting mixture
was allowed to warm to 25 °C. After stirring at 25 °C for 0.5
h, the solvent was removed and the residue was purified by
chromatography (silica, 85:15 hexane/ethyl acetate) to afford
6.54 g (95%) of aldehyde 12 as a colorless oil. 1H NMR (250.13
MHz, CDCl3): δ 1.16 (9H, s), 4.26 (2H, s), 7.4-7.5 (6H, m),
7.7-7.8 (4H, m), 9.75 (1H, s). 13C NMR (62.89 MHz, CDCl3):
δ 19.1, 26.6 (3×), 69.9, 127.9 (4×), 130.0 (2×), 132.5 (2×), 135.5
(4×), 201.5. IR (NaCl): υ 1740 (s, CdO) cm-1. HMRS: calcd
for C18H22O2Si, 298.1389; found, 298.1388.
4
3
dd, J H-H ) 6.4 Hz, J H-F ) 3.3 Hz), 6.25 (1H, dt, J H-F ) 18.2
Hz, J H-H ) 6.4 Hz), 7.4-7.5 (6H, m), 7.6-7.7 (4H, m), 9.66
3
(1H, d, J H-F ) 15.5 Hz). 13C NMR (62.89 MHz, CDCl3): δ
18.9, 26.6 (3×), 57.7 (3J C-F ) 10.1 Hz), 124.7 (2J C-F ) 17.0
Hz), 127.9 (2×), 130.1 (4×), 132.4 (2×), 135.4 (4×), 153.4 (1J C-F
) 257.9 Hz), 183.1 (2J C-F ) 29.0 Hz). IR (NaCl): υ 1712 (s,
CdO) cm-1. HRMS: calcd for ([C20H23FO2Si] - [C4H9(t-Bu)]),
285.0747; found, 285.0751.
Eth yl (2E,4E)-6-[(ter t-Bu tyld ip h en ylsilyl)oxy]-2-flu or o-
4-m eth ylh exa -2,4-d ien oa te (17). Ester 17 was obtained as
a colorless oil in 92% yield by the procedure described for 13.
1H NMR (250.13 MHz, CDCl3): δ 1.08 (9H, s), 1.31 (3H, t, J )
7.2 Hz), 1.67 (3H, s), 4.27 (2H, q, J ) 7.2 Hz), 4.33 (2H, d, J )
6.1 Hz), 5.49 (1H, tt, 3J H-H ) 6.1 Hz, 5J H-F ) 4J H-H ) 1.2 Hz),
3
6.37 (1H, d, J H-F ) 22.5 Hz), 7.4-7.5 (6H, m), 7.7-7.8 (4H,
m). 13C NMR (75.47 MHz, CDCl3): δ 14.0, 16.3, 19.1, 26.7
(3×), 61.1, 61.4, 123.7 (2J C-F ) 23.7 Hz), 127.6 (3J C-F ) 9.3
Hz), 127.7 (4×), 129.7 (2×), 133.5 (2×), 134.1 (4J C-F ) 5.0 Hz),
135.5 (4×), 146.7 (1J C-F ) 253.1 Hz), 160.6 (2J C-F ) 36.4 Hz).
IR (NaCl): υ 1736 (s, CdO) cm-1. HRMS: calcd for ([C25H31
FO3Si] - [(C4H9 (t-Bu)]), 369.1322; found, 369.1328.
-
Eth yl (2E)-4-[(ter t-Bu tyldiph en ylsilyl)oxy]-2-flu or obu t-
2-en oa te (13). The following olefination procedure is repre-
sentative. n-BuLi (10.6 mL, 1.6 M in hexane, 16.9 mmol) was
added with a syringe to a cooled (-78 °C) solution of diethyl
(fluorocarbethoxymethyl)phosphonate (4.11 g, 16.9 mmol) in
THF (30 mL). After stirring for 30 min at -78 °C, a solution
of aldehyde 12 (4.6 g, 15.4 mmol) in THF (15 mL) was added
dropwise with a cannula. After stirring the resulting solution
for 1 h at -78 °C and 3 h at 25 °C, a solution of 10% HCl was
added until pH was neutral, and the resulting mixture was
extracted with Et2O (3 × 25 mL). The combined organic layers
were washed with H2O and brine, dried (MgSO4), and concen-
trated. Purification by chromatography (silica, 90:10 hexane/
ethyl acetate) afforded ester 13 (6.20 g, 95%) as a yellowish
oil. 1H NMR (250.13 MHz, CDCl3): δ 1.07 (9H, s), 1.21 (3H,
(2E ,4E )-6-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-2-flu or o-4-
m eth ylh exa -2,4-d ien -1-ol (18). Alcohol 18 was obtained as
a colorless oil in 90% yield, by the general procedure. 1H NMR
(250.13 MHz, CDCl3): δ 1.07 (9H, s), 1.58 (3H, s), 4.29 (2H, d,
3
3
J ) 6.3 Hz), 4.27 (2H, d, J H-F ) 25.6 Hz), 5.55 (1H, tt, J H-H
5
4
3
) 6.3 Hz, J H-F ) J H-H ) 1.2 Hz), 5.76 (1H, d, J H-F ) 21.3
Hz), 7.4-7.5 (6H, m), 7.7-7.8 (4H, m). 13C NMR (75.47 MHz,
CDCl3): δ 16.7, 19.1, 26.7 (3×), 57.9 (2J C-F ) 30.0 Hz), 60.8,
114.3 (2J C-F ) 25.3 Hz), 127.7 (4×), 129.3 (3J C-F ) 12.0 Hz),
129.7 (2×), 130.4 (4J C-F ) 3.2 Hz), 133.7 (2×), 135.6 (4×), 158.5
(1J C-F ) 251.3 Hz). IR (NaCl): υ 3500-3100 (br, OH) cm-1
.
HRMS: calcd for C23H29FO2Si, 384.1922; found, 384.1924.
(2E ,4E )-6-[(t er t -Bu t yld ip h e n ylsilyl)oxy]-2-flu or o-4-
m eth ylh exa -2,4-d ien a l (19). Aldehyde 19 obtained as a
colorless oil in 90% yield, by the general procedure, was used
in the next step without further purification. 1H NMR (250.13
MHz, C6D6): δ 1.17 (9H, s), 1.21 (3H, s), 4.12 (2H, d, J ) 6.0
t, J ) 7.2 Hz), 4.16 (2H, q, J ) 7.2 Hz), 4.68 (2H, dd, J H-H
)
)
5.7 Hz, 4J H-F ) 3.4 Hz), 6.11 (1H, dt, 3J H-F ) 19.8 Hz, J H-H
5.7 Hz), 7.4-7.5 (6H, m), 7.6-7.7 (4H, m). 13C NMR (62.89
MHz, CDCl3): δ 13.8, 19.1, 26.7 (3×), 59.1 (3J C-F ) 6.8 Hz),
61.5, 124.0 (2J C-F ) 18.0 Hz), 127.8 (4×), 129.8 (2×), 133.3
(2×), 135.6 (4×), 145.6 (1J C-F ) 255.8 Hz), 160.5 (2J C-F ) 35.7
3
5
Hz), 5.59 (1H, tt, J H-H ) 6.0 Hz, J H-F
)
4J H-H ) 1.3 Hz),
3
6.11 (1H, d, J H-F ) 17.8 Hz), 7.2-7.3 (6H, m), 7.7-7.8 (4H,
m), 9.40 (1H, d, 3J H-F ) 20.0 Hz). IR (NaCl): υ 1692 (s, CdO)
Hz). IR (NaCl): υ 1735 (s, CdO) cm-1
. HMRS: calcd for
([C22H27FO3Si] - [C4H9(t-Bu)]), 329.1009; found, 329.1006.
cm-1
.
(2E,4E)-ter t-Bu t yld ip h en ylsilyl 3-F lu or o-5-(2,6,6-t r i-
m eth ylcycloh ex-1-en -1-yl)p en ta -2,4-d ien -1-yl Eth er (21).
Following the general procedure for olefination, treating
phosphonium salt 20 (0.7 g, 1.46 mmol) in THF (8 mL) with
n-BuLi (0.91 mL, 1.6 M in hexane, 1.46 mmol) and adding
aldehyde 15 (0.45 g, 1.32 mmol) in THF (5 mL) provided, after
7 h, a residue which was purified by chromatography (silica,
first with 50:50 hexane/Et2O, and then on a second column
with 99:1 hexane/Et2O) to give silyl ether 21 (0.54 g, 89%) as
a yellow oil. 1H NMR (250.13 MHz, CDCl3): δ 0.98 (6H, s),
1.04 (9H, s), 1.4-1.6 (4H, m), 1.61 (3H, s), 1.99 (2H, t, J ) 6.0
(2E)-4-[(ter t-Bu tyld ip h en ylsilyl)oxy]-2-flu or obu t-2-en -
1-ol (14). The following reduction procedure is representative.
To a solution of ester 13 (5.2 g, 13.4 mmol) in THF (10 mL) at
-78 °C was added DIBALH (28.2 mL, 1 M in hexane, 28.2
mmol), and the resulting suspension was stirred for 1 h at 0
°C. After careful addition of H2O, the mixture was extracted
with ether (3 × 40 mL). The combined organic layers were
dried (MgSO4) and concentrated. The residue was purified by
chromatography (silica, 85:15 hexane/ethyl acetate) to afford
alcohol 14 (4.36 g, 94%) as a colorless oil. 1H NMR (250.13
4
3
Hz), 4.25 (2H, dd, J H-H ) 7.5 Hz, J H-F ) 1.3 Hz), 5.31 (1H,
MHz, CDCl3): δ 1.04 (9H, s), 4.03 (2H, dd, J H-F ) 19.7 Hz,
3
3
4
dt, J H-F ) 20.4 Hz, J H-H ) 7.5 Hz), 5.89 (1H, dd, J H-F
)
J H-H ) 5.1 Hz), 4.21 (2H, dd, J H-H ) 7.3 Hz, J H-F ) 2.0 Hz),
3
17.2 Hz, J H-H ) 16.0 Hz), 6.48 (1H, d, J ) 16.0 Hz), 7.3-7.5
(6H, m), 7.6-7.7 (4H, m). 13C NMR (62.89 MHz, CDCl3): δ
19.0, 19.1, 21.5, 26.7 (3×), 28.8 (2×), 33.0, 34.0, 39.5, 58.5
(3J C-F ) 14.8 Hz), 106.5 (2J C-F ) 22.3 Hz), 120.3 (2J H-F ) 22.0
Hz), 127.8 (4×), 129.7 (2×), 130.1 (3J C-F ) 5.1 Hz), 130.9 (2×),
133.5, 135.6 (4×), 136.8, 157.0 (1J C-F ) 242.6 Hz). HRMS:
calcd for C30H39FOSi, 462.2754; found, 462.2749.
5.41 (1H, dt, J H-F ) 20.1 Hz, J H-H ) 7.3 Hz), 7.4-7.5 (6H,
m), 7.6-7.7 (4H, m). 13C-NMR (75.47 MHz, CDCl3): δ 19.6,
26.6 (3×), 57.5 (2J C-F ) 30.5 Hz), 58.4 (3J C-F ) 13.4 Hz), 107.9
(2J C-F ) 20.1 Hz), 127.7 (4×), 129.8 (2×), 133.0 (2×), 135.5
(4×), 159.7 (1J C-F ) 254.5 Hz). IR (NaCl): υ 3600-3070 (br,
(34) The purity of all new compounds was judged by a combination
of HPLC and 1H and 13C NMR analysis before mass spectral were
recorded and is indicated in the supporting information by copies of
the 1H NMR /13C NMR spectra of selected compounds.
(2E,4E)-3-F lu or o-5-(2,6,6-tr im eth ylcycloh ex-1-en -1-yl)-
p en ta -2,4-d ien -1-ol (22). The following procedure for depro-
tection is general. Tetrabutylammonium fluoride (0.97 mL,

Synthesis of Fluorinated Retinals
J . Org. Chem., Vol. 62, No. 2, 1997 317
1.0 M in THF, 0.97 mmol) was added to a solution of silyl ether
21 (0.39 g, 0.85 mmol) in Et2O (3 mL). After stirring at 25 °C
for 2 h, ether (15 mL) was added, the resulting solution was
washed with saturated NaHCO3 and brine and dried (MgSO4),
and the solvent was removed. The residue was purified by
chromatography (silica, 70:30 hexane/ether) to afford alcohol
22 (0.91 g, 100%) as an orange oil. 1H NMR (250.13 MHz,
C6D6): δ 1.05 (6H, s), 1.4-1.6 (4H, m), 1.70 (3H, s), 1.91 (2H,
t, J ) 6.0 Hz), 2.66 (1H, broad), 4.02 (2H, d, J ) 7.9 Hz), 5.37
1. IR (NaCl): υ 1654 (s, CdO) cm-1. UV (MeOH): λmax 288,
306, 320 nm. HRMS: calcd for C19H25FO, 288.1889; found,
288.1890.
(2Z,4E)-[3-F lu or o-5-(2,6,6-tr im eth ylcycloh ex-1-en -1-yl)-
p en ta -2,4-d ien yl]tr ip h en ylp h osp h on iu m Br om id e (27). A
solution of alcohol 22 (1.1 g, 4.9 mmol) in MeOH (20 mL) was
added through a cannula to a suspension of triphenylphos-
phine hydrobromide (1.69 g, 4.9 mmol) in MeOH (17 mL). After
stirring at 25 °C for 48 h, the solvent was removed under
vacuum and the residue was crystallized to provide phospho-
nium salt 27 (2.46 g, 93%) as yellow crystals (mp 76-78 °C).
1H NMR (250.13 MHz, CDCl3): δ 0.93 (6H, s), 1.4-1.6 (4H,
m), 1.61 (3H, s), 1.96 (2H, t, J ) 6.0 Hz), 4.7-5.0 (3H, m),
3
3
(1H, dt, J H-F ) 20.0 Hz, J H-H ) 7.9 Hz), 6.24 (1H, dd, J H-F
) 17.8 Hz, J H-H ) 16.0 Hz), 6.81 (1H, d, J ) 16.0 Hz). 13C
NMR (62.89 MHz, C6D6): δ 19.4, 21.5, 28.8 (2×), 33.2, 34.2,
39.7, 56.6 (3J C-F ) 13.3 Hz), 107.1 (2J C-F ) 21.9 Hz), 120.4
(2J C-F ) 22.0 Hz), 130.7 (3J C-F ) 5.1 Hz), 131.4, 137.1, 158.6
3
5.70 (1H, dd, J H-F ) 26.3 Hz, J H-H ) 15.9 Hz), 6.29 (1H, d, J
(1J C-F ) 247.5 Hz). IR (NaCl): υ 3510-3040 (br, OH) cm-1
HRMS: calcd for C14H21FO, 224.1576; found, 224.1578.
.
) 15.9 Hz), 7.7-7.9 (15H, m). HRMS: calcd for ([C32H35BrFP]
- [Br]), 469.2461; found, 469.2468.
(2E,4E)-3-F lu or o-5-(2,6,6-tr im eth ylcycloh ex-1-en -1-yl)-
p en ta -2,4-d ien a l (23). To a solution of alcohol 22 (0.4 g, 1.78
mmol) in CH2Cl2 (30 mL) were added, in one portion, 2.79 g
(32.12 mmol) of MnO2 and 3.41 g (32.12 mmol) of Na2CO3.
After stirring at 25 °C for 10 h, the reaction mixture was
filtered through Celite and the solvents were removed. The
residue was purified by chromatography (silica, 95:5 hexane/
ethyl acetate) to provide aldehyde 23 (0.34 g, 86%) as a yellow
oil, accompanied by the 2Z isomer (0.04 g, 9%). 1H NMR
(250.13 MHz, CDCl3): δ 1.08 (6H, s), 1.4-1.6 (4H, m), 1.80
(7E,9Z,11E,13E)- a n d (7E,9Z,11Z,13E)-ter t-Bu t yld i-
p h en ylsilyl 9-Dem eth yl-9-flu or or etin yl Eth er s (tr a n s-
a n d 11-cis-ter t-b u t yld ip h en ylsilyl 9-d em et h yl-9-flu o-
r or et in yl et h er s) (28 a n d 29). Following the general
procedure described above for 13, a mixture of 28 and 29 was
prepared from phosphonium salt 27 (0.42 g, 0.76 mmol) in THF
(10 mL), n-BuLi (0.48 mL, 1.6 M in hexane, 0.76 mmol), and
aldehyde 1617b (0.24 g, 0.69 mmol) in THF (5 mL). The residue
obtained after chromatography (0.30 g, 83%, 68:32 11E/11Z
isomer ratio) was used in the next step without further
purification.
3
(3H, s), 2.08 (2H, t, J ) 6.0 Hz), 5.72 (1H, dd, J H-F ) 18.4
3
Hz, J H-H ) 7.1 Hz), 6.72 (1H, dd, J H-F ) 27.3 Hz, J H-H
)
(7E,9Z,11E,13E)- a n d (7E,9Z,11Z,13E)-9-Dem et h yl-9-
flu or or etin ols (tr a n s- a n d 11-cis-9-d em eth yl-9-flu or or et-
in ols) (30 a n d 31). Application of the general procedure to a
mixture of the silyl ethers 28 and 29 (0.30 g, 0.56 mmol)
afforded, after chromatography (silica, 70:28:2 hexane/ether/
triethylamine), the corresponding mixture of alcohols (0.12 g,
70%). The 11E and 11Z fluororetinol isomers 30 and 31 were
separated by HPLC (83:17 hexane/ethyl acetate, tR (11Z) )
26 min, tR (11E) ) 34 min). (7E,9Z,11E,13E)-9-Dem eth yl-
9-flu or or etin ol (tr a n s-9-d em eth yl-9-flu or or etin ol) (30).
1H NMR (250.13 MHz, C6D6): δ 1.10 (6H, s), 1.4-1.6 (4H, m),
1.58 (3H, s), 1.73 (3H, s), 1.93 (2H, t, J ) 6.0 Hz), 4.03 (2H, d,
16.0 Hz), 7.08 (1H, d, J ) 16.0 Hz), 9.92 (1H, dd, J H-H ) 7.1
Hz, J H-F ) 3.4 Hz). 13C NMR (62.89 MHz, CDCl3): δ 18.7,
4
21.6, 28.7 (2×), 33.6, 34.1, 39.6, 108.9 (2J C-F ) 20.2 Hz), 118.1
(2J C-F ) 18.5 Hz), 136.4, 136.5, 138.8 (3J C-F ) 6.6 Hz), 172.1
(1J C-F ) 274.8 Hz), 188.8 (3J C-F ) 20.1 Hz). IR (NaCl): υ 1684
(s, CdO) cm-1. HRMS: calcd for C14H19FO, 222.1420; found,
222.1420.
E t h yl (7E,9E,11E,13E)-9-Dem et h yl-9-flu or or et in oa t e
(eth yl 9-cis-9-dem eth yl-9-flu or or etin oate) (25). To a cooled
(-78 °C) solution of phosphonate 2421b (0.16 g, 0.535 mmol)
in THF (4 mL) were added n-BuLi (0.22 mL, 2.7 M in hexane,
0.594 mmol, via a syringe) and DMPU (0.14 mL, 1.1 mmol).
After stirring at -78 °C for 30 min, a solution of aldehyde 23
(0.066 g, 0.298 mmol) in THF (5 mL) was added through a
cannula. After stirring the resulting solution at -78 °C for 1
h and at 0 °C for 5 h, a solution of saturated NH4Cl was added,
and the resulting mixture was extracted with ether (3 × 25
mL). The combined organic layers were washed with H2O and
brine, dried (MgSO4), and concentrated. Purification by chro-
matography (silica, 95:5 hexane/ethyl acetate) afforded ester
25 (0.073 g, 74%) as a yellow oil. 1H NMR (500.13 MHz,
CDCl3): δ 1.06 (6H, s), 1.29 (3H, t, J ) 7.0 Hz), 1.4-1.6 (4H,
m), 1.78 (3H, s), 2.06 (2H, t, J ) 6.0 Hz), 2.33 (3H, s), 4.17
3
J ) 6.4 Hz), 5.41 (1H, dd, J H-F ) 34.4 Hz, J H-H ) 11.2 Hz),
5.65 (1H, t, J ) 6.4 Hz), 5.92 (1H, dd, 3J H-F ) 26.5 Hz, J H-H
)
16.0 Hz), 6.25 (1H, d, J ) 15.5 Hz), 6.82 (1H, d, J ) 16.0 Hz),
6.85 (1H, dd, J ) 15.5, 11.2 Hz). IR (NaCl): υ 3570-3220
(br, OH) cm-1. HRMS: calcd for C19H27FO, 290.2046; found,
290.2052. (7E,9Z,11Z,13E)-9-Dem eth yl-9-flu or or etin ol (11-
cis-9-dem eth yl-9-flu or or etin ol) (31). 1H NMR (250.13 MHz,
C6D6): δ 1.07 (6H, s), 1.4-1.6 (4H, m), 1.64 (3H, s), 1.66 (3H,
s), 1.90 (2H, t, J ) 5.7 Hz), 3.98 (2H, d, J ) 6.6 Hz), 5.67 (1H,
t, J ) 6.6 Hz), 5.83 (1H, d, J ) 11.2 Hz), 5.90 (1H, dd, 3J H-F
)
26.5 Hz, J H-H ) 16.0 Hz), 6.12 (1H, dd, 3J H-F ) 33.4 Hz, J H-H
) 12.2 Hz), 6.64 (1H, t, J ) 11.9 Hz), 6.83 (1H, d, J ) 16.0
Hz). 13C NMR (62.89 MHz, C6D6): δ 16.6, 19.4, 21.6, 28.8 (2×),
3
(2H, q, J ) 7.0 Hz), 5.77 (1H, s), 5.89 (1H, dd, J H-F ) 18.8
Hz, J H-H ) 11.8 Hz), 6.24 (1H, d, J ) 15.2 Hz), 6.28 (1H, dd,
3J H-F ) 27.4 Hz, J H-H ) 15.9 Hz), 6.64 (1H, d, J ) 15.9 Hz),
6.71 (1H, dd, J ) 15.2 Hz, 11.8 Hz). 13C NMR (62.89 MHz,
CDCl3): δ 13.7, 14.3, 19.0, 21.7, 28.9 (2×), 33.2, 34.2, 39.5,
59.7, 109.5 (2J C-F ) 30.2 Hz), 119.1, 119.3 (2J C-F ) 20.9 Hz),
127.1 (3J C-F ) 11.4 Hz), 131.6 (4J C-F ) 4.5 Hz), 132.4, 135.1
33.3, 34.3, 39.8, 59.2, 107.1 (3J C-F ) 11.7 Hz), 120.4 (4J C-F
)
6.8 Hz), 124.7 (2J C-F ) 22.2 Hz), 129.6 (3J C-F ) 4.8 Hz), 131.6
(2J C-F ) 29.9 Hz), 133.6, 133.7, 135.4, 137.3, 158.3 (1J C-F
257.7 Hz). UV (MeOH): λmax (ꢀ) 322 (6 800) nm.
)
(7E,9Z,11E,13E)-9-Dem et h yl-9-flu or or et in a l (tr a n s-9-
d em eth yl-9-flu or or etin a l) (7). Following the general pro-
cedure described for oxidation of alcohol 14, retinol 30 (0.11
g, 0.38 mmol) was reacted with BaMnO4 (1.12 g, 90%, 3.9
mmol) in CH2Cl2 (5 mL), affording retinal 7 (0.10 g) in 88%
yield as an orange solid (mp 60-62 °C; hexane/ethyl acetate).
HPLC (96:4, hexane/ethyl acetate; tR) 34.5 min). 1H NMR
(300.13 MHz): Table 1. IR (NaCl): υ 1660 (s, CdO) cm-1. UV
3
(dd, J C-F ) 9.6 Hz), 137.1, 151.9, 160.0 (1J C-F ) 272.8 Hz),
167.2. HRMS: calcd for C21H29FO2, 332.2151; found, 332.2150.
(7E,9E,11E,13E)-9-Dem et h yl-9-flu or or et in a l (9-cis-9-
d em eth yl-9-flu or or etin a l) (26). DIBALH (0.45 mL, 1 M in
hexane, 0.45 mmol) was added to a solution of ester 25 (0.070
g, 0.211 mmol) in THF (5 mL) at -78 °C, and the resulting
suspension was stirred for 1 h at 0 °C. After careful addition
of H2O, the mixture was extracted with ether (10 × 3 mL).
The combined organic layers were dried (MgSO4) and concen-
trated. The residue was purified by chromatography (silica,
85:15 hexane/ethyl acetate) to afford the corresponding alcohol
(0.037 g, 60%) as a yellow oil. This compound (0.037 g, 0.127
mmol) in CH2Cl2 (5 mL) was oxidized with MnO2 (0.198 g, 2.28
mmol) and Na2CO3 (0.246 g, 2.28 mmol) at 25 °C for 6 h.
Workup and purification as described above (silica 90:10
hexane/ether) provided aldehyde 26 (0.033 g, 90%). A sample
for analysis was obtained by HPLC purification (98:2 hexane/
ethyl acetate, tR ) 33.1 min). 1H NMR (250.13 MHz): Table
(MeOH): λmax (ꢀ) 368 (8 200) nm. HRMS: calcd for C19H25
FO, 288.1889; found, 288.1880.
-
(7E,9E,11E,13E)-ter t-Bu tyld ip h en ylsilyl 11-F lu or or eti-
n yl Eth er (11-cis-ter t-bu tyld ip h en ylsilyl 11-flu or or etin yl
eth er ) (33). Following the general procedure for Wittig
olefination, the title compound was obtained in 57% yield, after
HPLC purification (99.9:0.1 hexane/ethyl acetate; tR ) 38 min).
1H NMR (250.13 MHz, CDCl3): δ 1.02 (6H, s), 1.04 (9H, s),
1.4-1.6 (4H, m), 1.59 (3H, s), 1.68 (3H, s), 2.00 (2H, t, J ) 6.4
3
Hz), 2.08 (3H, s), 4.29 (2H, d, J ) 6.2 Hz), 5.64 (1H, d, J H-F
) 22.2 Hz), 5.65 (1H, d, J ) 6.2 Hz), 6.07 (1H, d, J ) 15.8 Hz),
3
6.20 (1H, d, J H-F ) 20.8 Hz), 6.27 (1H, d, J ) 15.8 Hz), 7.3-

318 J . Org. Chem., Vol. 62, No. 2, 1997
Francesch et al.
7.4 (6H, m), 7.6-7.7 (4H, m). 13C NMR (75.47 MHz, CDCl3):
δ 14.1 (4J C-F ) 10.1 Hz), 17.0, 19.1, 19.2, 21.6, 26.7 (3×), 28.8
(2×), 32.9, 34.2, 39.5, 61.1, 114.9 (2J C-F ) 30.6 Hz), 118.4 (2J C-F
) 20.4 Hz), 127.6, 127.7 (4×), 127.9 (3J C-F ) 12.1 Hz), 128.9,
129.6 (2×), 130.7 (4J C-F ) 5.1 Hz), 133.8 (2×), 134.8, 135.6
(4×), 137.7, 139.0 (3J C-F ) 3.3 Hz), 157.5 (1J C-F ) 245.6 Hz).
HRMS: calcd for C36H47FOSi, 542.3380; found, 542.3383.
(7E,9E,11E,13E)-11-F lu or or etin ol (11-cis-11-flu or or et-
in ol) (34). Application of the general procedure to silyl ether
33 afforded a 74% yield of alcohol 34 after HPLC purification
(87:13, hexane/ethyl acetate; tR ) 28.9 min). 1H NMR (250.13
MHz, C6D6): δ 1.09 (6H, s), 1.4-1.6 (4H, m), 1.53 (3H, s), 1.73
(3H, s), 1.95 (2H, t, J ) 6.0 Hz), 2.20 (3H, s), 3.90 (2H, d, J )
mmol) in CH2Cl2 (10 mL) was treated with activated MnO2
(0.17 g, 1.98 mmol) and Na2CO3 (0.21 g, 1.98 mmol). After
stirring at 25 °C for 3 h, the mixture was filtered through
Celite, and the solvents were removed in vacuo, to afford a
mixture of retinals 41 and 9 (0.025 g, 80%) in a 4:1 ratio, which
were separated by HPLC (98:2 hexane/ethyl acetate, tR (13E)
) 23.6 min, tR (13Z) ) 32.4 min). (7E,9E,11E,13E)-13-
Dem eth yl-13-flu or or etin a l (13-cis-13-d em eth yl-13-flu o-
r or etin a l) (41). 1H NMR (500.13 MHz): Table 1. HRMS:
calcd for C19H25FO, 288.1889; found, 288.1885. (7E,9E,11E,-
13Z)-13-Dem et h yl-13-flu or or et in a l (tr a n s-13-d em et h yl-
13-flu or or etin a l) (9). 1H NMR (500.13 MHz): Table 1. IR
(NaCl): υ 1669 (s, CdO) cm-1. UV (MeOH): λmax (ꢀ) 382 (10
600) nm. HRMS: calcd for C19H25FO: 288.1889; found,
288.1890.
(7E,9Z,11E,13E)- a n d (7E,9Z,11Z,13E)-ter t-Bu t yld i-
p h en ylsilyl 9,13-Did em eth yl-9,13-d iflu or or etin yl Eth er s
(13-cis- a n d 11,13-d i-cis-ter t-bu tyld ip h en ylsilyl 9,13-d i-
d em eth yl-9,13-d iflu or or etin yl eth er s) (42 a n d 43). The
general procedure effected coupling between phosphonium salt
27 (0.67 g, 1.23 mmol), treated at -78 °C with n-BuLi (0.77
mL, 1.6 M en hexane, 1.23 mmol), and aldehyde 15 (0.38 g,
1.12 mmol). Chromatography of the resulting crude on silica,
first with 50:50 hexane/ether, and a second column with 99:1
hexane/ether, afforded an 89% yield (0.53 g) of a 75:25 mixture
of the 11E and 11Z isomers 42 and 43, which was used in the
next step without separation.
5
6.6 Hz), 5.58 (1H, dt, J H-H ) 6.6 Hz, J H-F ) 1.2 Hz), 5.79
3
(1H, d, J H-F ) 22.9 Hz), 6.27 (1H, d, J ) 16.0 Hz), 6.34 (1H,
d, 3J H-F ) 29.3 Hz), 6.39 (1H, d, J ) 16.0 Hz). 13C NMR (62.89
MHz, C6D6): δ 14.3 (4J C-F ) 10.1 Hz), 16.7, 19.5, 21.7, 28.9
(2×), 33.1, 34.4, 39.7, 59.2, 115.5 (2J C-F ) 30.4 Hz), 119.1 (2J C-F
) 20.3 Hz), 127.3, 129.4, 131.4 (4J C-F ) 5.1 Hz), 131.7 (3J C-F
) 12.1 Hz), 137.9, 138.1, 139.6 (3J C-F ) 3.4 Hz), 158.0 (1J C-F
) 245.6 Hz). IR (NaCl): υ 3500-3100 (br, OH) cm-1
HRMS: calcd for C20H29FO, 304.2202; found, 304.2208.
.
(7E,9E,11E,13E)-11-F lu or or etin a l (11-cis-11-flu or or eti-
n a l) (35). Following the general procedure, a solution of 11-
fluororetinol 34 (0.04 g, 0.14 mmol) in CH2Cl2 (5 mL) was
treated for 8 h with MnO2 and Na2CO3 at 25 °C to afford, after
chromatography, retinal 35 (32 mg, 80%). Purification by
HPLC (97:3 hexane/ethyl acetate, tR ) 31.9 min) provided a
sample for analysis. 1H NMR (250.13 MHz, C6D6): Table 1.
HRMS: calcd for C20H27FO, 302.2046; found, 302.2052.
(7E,9E,11Z,13E)-11-F lu or or etin a l (tr a n s-11-flu or or eti-
n a l) (8). In accordance with the general procedure, a solution
of 11-fluororetinol 34 (0.072 g, 0.23 mmol) in CH2Cl2 (5 mL)
was treated for 10 h with BaMnO4 (0.61 g, 90%, 2.14 mmol)
at 25 °C to afford, after chromatography, retinal 8 (0.067 g,
(7E,9Z,11E,13E)- a n d (7E,9Z,11Z,13E)-9,13-Did em eth yl-
9,13-d iflu or or etin ols (13-cis- a n d 11,13-d i-cis-9,13-d id e-
m eth yl-9,13-d iflu or or etin ols) (44 a n d 45). The general
procedure afforded a residue which was purified (silica, 75:25
hexane/ether) to afford 0.091 g (76%) of a mixture of the 11E
and 11Z isomers 44 and 45, which were separated by HPLC
(85:15, hexane/ethyl acetate; tR
(11Z) ) 34 min, tR (11E) ) 42
min). (7E,9Z,11E,13E)-9,13-Did em et h yl-9,13-d iflu or o-
r etin ol (13-cis-9,13-d id em eth yl-9,13-d iflu or or etin ol) (44).
1H NMR (250.13 MHz, C6D6): δ 1.07 (6H, s), 1.4-1.6 (4H, m),
1.70 (3H, s), 1.91 (2H, t, J ) 6.0 Hz), 3.81 (2H, d, J ) 7.7 Hz),
94%). Purification by HPLC (97:3, hexane/ethyl acetate; tR
34.0 min) provided a sample for analysis. 1H NMR (250.13
MHz): Table 1. IR (NaCl): 1660 (s, CdO) cm-1
UV
)
.
3
5.1-5.3 (2H, m), 5.88 (1H, dd, J H-F ) 26.0 Hz, J H-H ) 16.1
(MeOH): λmax (ꢀ) 370 (11 800) nm. HRMS: calcd for C20H27
FO, 302.2046; found, 302.2044.
-
Hz), 6.10 (1H, dd, 3J H-F ) 27.4 Hz, J H-H ) 15.5 Hz), 6.83 (1H,
d, J ) 16.1 Hz), 7.35 (1H, dd, J )15.5, 11.6 Hz). 13C NMR
(62.89 MHz, C6D6): δ 19.3, 21.5, 28.8 (2×), 33.4, 34.3, 39.9,
(7E,9E,11E,13E)- a n d (7E,9E,11Z,13E)-ter t-Bu t yld i-
p h en ylsilyl 13-Dem eth yl-13-flu or or etin yl Eth er s (13-cis-
a n d 11,13-d i-cis-ter t-bu tyld ip h en ylsilyl 13-d em eth yl-13-
flu or or etin yl eth er s) (37 a n d 38). The yellow oil afforded
by the general procedure was a 69% combined yield of a 60:40
mixture of the 11E and 11Z isomers 37 and 38, which were
used in the next step without separation.
(7E,9E,11E,13E)- a n d (7E,9E,11Z,13E)-13-Dem eth yl-13-
flu or or etin ols (13-cis- a n d 11,13-d i-cis-13-d em eth yl-13-
flu or or etin ols) (39 a n d 40). Application of the general
procedure described above for 22 to a 60:40 mixture of the silyl
ethers 37 and 38 (0.34 g, 0.56 mmol, E/Z mixture) afforded,
after chromatography (silica, 80:18:2 hexane/ether/triethyl-
amine), the corresponding mixture of alcohols 39 and 40 (0.17
g, 93%) which were separated by HPLC (87:13 hexane/ethyl
56.8 (3J C-F ) 13.5 Hz), 108.7 (2J C-F ) 21.0 Hz), 109.3 (2J C-F
)
13.6 Hz), 118.6 (2J C-F ) 23.7 Hz, 4J C-F ) 3.4 Hz), 123.8 (3J C-F
) 11.7 Hz), 123.9 (2J C-F ) 13.7 Hz), 130.8 (3J C-F ) 4.3 Hz),
132.2, 137.2, 147.7 (1J C-F ) 252.2 Hz), 158.7 (1J C-F ) 247.5
Hz). IR (NaCl): υ 3520-3150 (br, OH) cm-1. HRMS: calcd
for C18H24F2O, 294.1795; found, 294.1793. (7E,9Z,11Z,13E)-
9,13-Did em eth yl-9,13-d iflu or or etin ol (11,13-d i-cis-9,13-
d id em eth yl-9,13-d iflu or or etin ol) (45). 1H NMR (250.13
MHz, C6D6): δ 1.03 (6H, s), 1.4-1.6 (4H, m), 1.60 (3H, s), 1.87
(2H, t, J ) 6.1 Hz), 3.72 (2H, d, J ) 7.7 Hz), 5.24 (1H, dt,
3
3J H-F ) 21.3 Hz, J H-H ) 7.7 Hz), 5.66 (1H, dd, J H-F ) 34.2
3
Hz, J H-H ) 10.9 Hz), 5.80 (1H, dd, J H-F ) 26.7 Hz, J H-H
)
16.3 Hz), 6.48 (1H, dd, 3J H-F ) 32.0 Hz, J H-H ) 12.3 Hz), 6.64
(1H, t, J )11.6 Hz), 6.86 (1H, d, J ) 16.3 Hz).
acetate, tR (11Z)
) 23.5 min, tR (11E) ) 37 min).
(7E,9Z,11E,13Z)-9,13-Did em eth yl-9,13-d iflu or or etin a l
(tr a n s-9,13-d id em eth yl-9,13-d iflu or or etin a l) (10). Retinol
44 (26 mg, 88.3 mmol) was oxidized with BaMnO4 (0.25 g, 90%,
0.88 mmol) and Na2CO3 (93 mg, 0.88 mmol) for 7 h at 25 °C.
Purification of the residue (silica, 90:10 hexane/ether) provided
23 mg (92%) of retinal 10 as a solid (mp 58-60 °C, hexane/
ethyl acetate) which was further purified by HPLC (96.5:3.5,
hexane/ethyl acetate; tR ) 33.5 min). 1H NMR (250.13 MHz):
Table 1. IR (NaCl): υ 1675 (s, CdO) cm-1. UV (MeOH): λmax
(ꢀ) 372 (6 500) nm. HRMS: calcd for C18H22F2O, 292.1639;
found, 292.1636.
(7E,9Z,11E,13E)-9,13-Did em eth yl-9,13-d iflu or or etin a l
(13-cis-9,13-d id em eth yl-9,13-d iflu or or etin a l) (46). This
isomer was obtained as the major component in the MnO2/
Na2CO3 oxidation (75% yield) of alcohol 44. 1H NMR (250.13
MHz): Table 1. UV (MeOH): λmax (ꢀ) 370 (16 800) nm.
Gen er a l P r oced u r e for Sch iff Ba se a n d P r ot on a t ed
Sch iff Ba se F or m a tion . n-Butylamine (3 mL, 30.9 µmol)
was added at 25 °C to a solution of fluororetinal (8.1 mg, 28.1
µmol) in Et2O (2 mL) containing 4 Å molecular sieves. After
(7E,9E,11Z,13E)-13-Dem eth yl-13-flu or or etin ol (11,13-d i-
cis-13-d em eth yl-13-flu or or etin ol) (40). 1H NMR (250.13
MHz, CDCl3): δ 1.02 (6H, s), 1.4-1.6 (4H, m), 1.71 (3H, s),
1.96 (3H, s), 2.02 (2H, t, J ) 6.2 Hz), 4.22 (2H, d, J ) 7.0 Hz),
3
5.40 (1H, dt, J H-F ) 20.6 Hz, J H-H ) 7.0 Hz), 5.90 (1H, dd,
3J H-F ) 32.5 Hz, J H-H ) 11.4 Hz), 6.15 (1H, d, J ) 16.1 Hz),
6.29 (1H, d, J ) 16.1 Hz), 6.55 (1H, t, J ) 11.6 Hz), 6.70 (1H,
d, J ) 12.0 Hz). IR (NaCl): υ 3600-3100 (br, OH) cm-1
.
HRMS: calcd for C19H27FO, 290.2046; found, 290.2049.
(7E,9E,11E,13E)-13-Dem eth yl-13-flu or or etin ol (13-cis-13-
d em et h yl-13-flu or or et in ol) (39). 1H NMR (250.13 MHz,
CDCl3): δ 1.02 (6H, s), 1.4-1.6 (4H, m), 1.71 (3H, s), 1.98 (5H,
3
m), 4.23 (2H, d, J ) 7.5 Hz), 5.40 (1H, dt, J H-F ) 20.5 Hz,
J H-H ) 7.5 Hz), 6.10 (1H, d, J ) 11.6 Hz), 6.11 (1H, d, J )
15.9 Hz), 6.25 (1H, dd, 3J H-F ) 27.8 Hz, J H-H ) 15.0 Hz), 6.28
(1H, d, J ) 15.9 Hz), 7.00 (1H, dd, J ) 15.0, 11.6 Hz). HRMS:
calcd for C19H27FO, 290.2046; found, 290.2050.
(7E,9E,11E,13E)- a n d (7E,9E,11E,13Z)-13-Dem eth yl-13-
flu or or etin a ls (13-cis- a n d 13-tr a n s-13-d em eth yl-13-flu o-
r or etin a ls) (41 a n d 9). A solution of retinol 39 (0.032 g, 0.011

Synthesis of Fluorinated Retinals
J . Org. Chem., Vol. 62, No. 2, 1997 319
stirring at 25 °C for 30 min, the solids were filtered out, and
the solvent and excess amine were removed under vacuum.
The resulting Schiff base was dissolved in MeOH (3 mL) for
UV spectroscopy. The Schiff base was protonated in the same
solvents by addition of trichloroacetic acid (4.6 mg, 28.1 µmol).
P r ep a r a tion of Ba cter io-op sin . Purple membrane was
obtained from H. salinarium strain S9 as described.29 Purple
membrane in 4M NaCl, 1 M NH2OH‚HCl of pH 8.0 (BR
concentration, 2 mg/mL) was illuminated at room temperature
with filtered light (520 nm cut-off), under continuous stirring,
until the suspension became colorless. It was then washed
three times with water and resuspended in the appropriate
buffer.
Francesch), and the University of Santiago de Compos-
tela (fellowship to R. Alvarez) and was assisted by a
generous gift of native BR and use of the research
facilities provided by the Biophysics group at UAB (Prof.
E. Padro´s), and enlightening discussions with Prof.
Milos Hudlicky during his Fulbright stay at the Uni-
versity of Santiago de Compostela.
Su p p or tin g In for m a tion Ava ila ble: Complete spectro-
scopic characterization, including reproduction of the 1H or 13C
NMR spectra of selected compounds described in the text (40
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t . This work received finan-
cial support from FIS (Contract 95/1534), the Xunta de
Galicia (grant XUGA20904B95, fellowship to A.
J O961355X