9-CF3 and 13-CF3-β-carotene, canthaxanthin and related carotenoids. Synthesis, characterization and electrochemical data

Article abstract of DOI:10.1016/S0022-1139(99)00045-7

The preparation and characterization of the following trifluoromethylated carotenoids are reported: 9-CF₃-, 13-CF₃-, 9,9′-bis-CF₃-, 13,13′-bis-CF₃-β-carotene, 9-CF₃- and 13-CF₃-canthaxanthi

Full text of DOI:10.1016/S0022-1139(99)00045-7

Journal of Fluorine Chemistry 97 (1999) 165±171
9-CF3 and 13-CF3±b-carotene, canthaxanthin and
related carotenoids. Synthesis, characterization
and electrochemical data
Dorothee Hoischen, Leticia U. Colmenares, Inna Koukhareva,
Melissa Ho, Robert S.H. Liu*
Department of Chemistry, University of Hawaii, Honolulu, HI 96822, USA
Received 18 November 1998; received in revised form 19 December 1998; accepted 19 December 1998
Dedicated to Prof. Yoshiro Kobayashi on the occasion of his 75th birthday
Abstract
The preparation and characterization of the following tri¯uoromethylated carotenoids are reported: 9-CF3±, 13-CF3±, 9,90-bis-CF3±,
13,130-bis-CF3±b-carotene, 9-CF3± and 13-CF3±canthaxanthin, 130-CF3± and, 90-CF3±4-oxo-b-carotene, 130-CF3±adonirubin and 3-
dehydro-130-CF3±canthaxanthin. The CF3 group exhibits a strong cis-directing effect leading primarily to the cis isomer (near the CF3
group, i.e., all-E) in the synthetic mixtures. The minor all-trans isomer could be enriched by sensitized irradiation; however, they were
found to be only marginally stable at room temperature. The CF3 group also exhibits a stabilizing effect towards oxidation reactions.
Spectral data and oxidation potentials of these ¯uorinated carotenoids are reported. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Tri¯uoromethylated carotenoids; Synthesis; Spectral data; Oxidation potentials
1. Introduction
carotenoids, their isolation, characterization and some of
their properties.
Carotenoids are naturally occurring pigments. Because of
their involvement in light initiated biological processes (e.g.,
light harvesting and protection in the photosynthetic appa-
ratus) as well as their nutritional and health values, their
isolation, characterization and synthesis have attracted much
attention of researchers in recent decades.1 Fluorinated
carotenoids, in contrast to the analogous retinoids [2±4],
on the other hand attracted little attention in spite of poten-
tial bene®ts such as the possible use of F-atoms as NMR
reporting labels2, being more lipophilic3 and as an effective
perturbing unit on UV±Vis absorption properties of the
polyene chromophore [8,9]. Recently, we reported the pre-
paration of several vinyl ¯uoroastaxanthins [10] and forma-
tion of ¯uorinated a-crustacyanins [11]. Now, we would like
to report the preparation of several tri¯uoromethylated
2. Results and discussion
In the early stage of developing synthetic methodo-
logies to tri¯uoromethylated carotenoids, we encountered
unexpected dif®culties arising from the high sensitivity
of the polyene chromophore especially in cases of
simultaneous presence of the CF3 group and the 4-keto
functionality under the alkaline conditions used in Wittig
ylide formation. Neither were we successful in preparing
the key tri¯uoromethylated central C10 unit by following
sequences of reactions similar to those used for the
parent systems [11±13]. Therefore, instead of the
C15‡C10‡C15 route, successfully applied to the synthesis
of several vinyl ¯uoro-carotenoids [10], we now describe
results in applying the C20‡C20 or the C20‡C5‡C15 strategy
to the tri¯uoromethylated carotenoids. These results illus-
trate the possible preparation and stability of such com-
pounds.
*Corresponding author. Tel.: +1-808-956-5723; fax: +1-808-956-5908;
e-mail: rliu@gold.chem.hawaii.edu
1See e.g., [1].
2See e.g., [5,6].
3See e.g., [7].
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 4 5 - 7

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D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
2.1. Trifluoromethylated-b-carotenes
isomer in the product mixture was the 9-cis (all-E) isomer,
again retaining the preferred cis (9E) stereochemistry during
ole®nation.
By way of McMurry coupling reaction [15] of 9-cis-9-
CF3±retinal, 9-cis,90-cis-9,90-bis-CF3±b-carotene (all-E), 3,
was prepared. And, starting with 13-CF3±retinal, 13-cis,130-
cis-13,130-bis-CF3±b-carotene (all-E), 4, was prepared.
13-cis-13-CF3±b-carotene4 (1) was prepared by reaction
of the C20 Wittig salt with 13-cis-13-CF3±retinal [14]. The
13-cis (13E) geometry, a result of the cis-directing property
of the CF3 group, was retained during the coupling reaction
giving primarily the 13-cis (all-E) isomer (ꢀ80% based
on F NMR) of the carotenoid, which was subsequently
puri®ed by preparative hplc. Starting with 9-cis-9-CF3±
retinal and following a similar C20‡C20 coupling reaction,
9-CF3±b-carotene (2) was also prepared.5 The predominant
2.2. Oxygenated tri¯uoromethylated carotenoids
2.2.1. 90-cis-90-CF3±4-oxo-b-carotene (5) and
9-cis-9-CF3±canthaxanthin (6)
Oxidation of b-carotene by sodium hypochlorite was
reported to be an effective procedure for its conversion to
canthaxanthin [16]. When the reaction was applied to 9-
CF3±b-carotene, a more complex mixture of products was
obtained from which the mono and bis-oxidized products
were isolated (readily separated by column chromatogra-
phy). The ring closer to the CF3 group was found to be less
reactive because only one mono-oxidized product was
isolated with its H NMR spectrum (chemical shifts of H8
and H80) being consistent with the structure shown. This
4The cis, trans designations used in this paper conform to the accepted
nomenclature for carotenoids, i.e., according to the disposition of the
substituents that constitute a continuation of the main polyene chain: see
B.C.L. Weeden, G.P. Mass, in: G. Britton, S. Liaaen-Jensen, H. Pfander
(Eds.), Carotenoids 1A, Isolation and Analysis, Birkhauser, Basel, 1995, p.
34.
5Compound 2 was found to be surprisingly sensitive to molecular
oxygen, undergoing allylic oxidation upon standing in NMR solvents to a
product that was subsequently characterized to be 4-oxo-b-carotene 5 (see
below).

D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
167
selectivity also accounts for the low yield (slow rate of
formation) of the bis-oxidized product and to the formation
of other unidenti®ed degradation products by prolonging the
reaction time.
tenal with the C15-Wittig salt. In addition to the major 13-
cis (all-E) isomer (70%), three other isomers were also
present. Two of them were isolated by preparative hplc.
They were identi®ed as 13-cis, 130-cis- (130-Z, 20%) and all-
2.2.2. 130-cis-130-CF3±4-oxo-b-carotene (7)
trans (13-Z, <5%) (see below for spectral data).
The compound was prepared from reaction of the C15
Wittig salt with the 13-cis-13-CF3±C25-apocarotenal. The
latter was prepared in turn by reaction of the protected C5
Wittig salt 10 (see Section 3) with 13-cis-13-CF3±retinal.
The product mixtures contained primarily the 13-cis (all-E)
isomer. It was isolated by preparative hplc.
2.2.4. 130-CF3±Adonirubin, 3-hydroxy-130-CF3±
canthaxanthin (9)
The compound was prepared from a Wittig reaction
similar to that for 8, using instead the 3-hydroxy-4-keto-
C15-Wittig salt. Under normal phase conditions for hplc
separation, compound 9 was found to undergo ready dehy-
dration, as indicated by the H NMR spectrum of the
collected product: the disappearance of the 4.3 ppm signal
for H3 and the appearance of a new set of two coupled vinyl
hydrogens. The remaining vinyl hydrogen signals were
nearly identical to those of 8 (Table 1). As a result, com-
pound 9 had to be puri®ed under reverse phase hplc con-
ditions.
2.2.3. 13-cis-13-CF3±canthaxanthin (8)
The compound was prepared from reaction of the C5-
Wittig salt 10 (see Section 3) with 13-cis-13-CF3±4-oxo-
retinal followed by coupling of the resulting C25-apocaro-

168
D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
Table 1
Partial (vinyl region) H NMR data of isomers of trifluoromethylated carotenoidsa
Compound
H7
H8
H10
H11
H12
H14
H15
H150
H140
H120
H110
H100
H80
H70
13C,13-CF3±b-car., 1 b
9C,9-CF3±b-carotene, 2 b
9,90C-bis-CF3±b-car., 3 b
9,90C-bis-CF3±b-car., 3
13,130C-bis-CF3±b-car, 4
6.28
6.29
6.73
6.45
6.33
6.17
6.43
6.54
6.29
6.18
6.29
6.55
6.57
6.51
6.50
6.17
6.37
6.34
6.37
6.30
6.55
6.17
c
6.90
6.72
6.80
6.61
6.99
6.61
6.73
6.56
6.63
7.00
6.90
6.91
7.22
6.92
7.21
6.73
6.59
c
6.66
c
6.73
c
6.93
c
6.30
c
6.38
c
6.79
c
6.17
6.16
6.15
6.14
6.24
6.21
6.31
6.70
6.18
6.67
6.33
6.78
6.79
6.41
6.17
6.31
6.12
6.29
6.11
6.33
6.76
6.67
6.58
6.68
6.78
6.31
6.69
6.40
6.59
6.67
6.58
6.67
6.57
6.78
6.17
6.39
6.68
6.42
6.28
6.30
6.44
6.28
6.67
6.72
6.21
6.72
6.21
6.28
6.55
6.74
6.99
6.68
6.69
6.71
6.68
6.73
6.76
6.76
6.56
6.76
6.58
6.69
90C-9-CF3-4-oxo-b-c., 5 b 6.44
6.75
6.57
6.56
6.78
6.56
6.93
6.96
6.58
6.96
6.56
6.57
6.32
6.23
6.25
6.32
6.33
6.32
6.34
6.71
6.34
6.70
6.23
6.45
6.47
6.48
6.45
6.48
6.46
6.46
6.40
6.46
6.41
6.47
6.72
6.72
6.73
6.73
6.70
6.79
6.80
6.74
6.80
6.72
6.72
6.29
6.26
6.27
6.29
6.27
6.30
6.30
6.22
6.30
6.21
6.26
6.37
6.36
6.36
6.37
6.36
6.37
6.37
6.31
6.37
6.28
6.36
6.28
6.14
6.15
6.28
6.15
6.29
6.31
6.10
6.31
6.04
6.14
90C-9-CF3-4-oxo-b-c., 5
9-C,9-CF3±canthax., 6
9-C-9-CF3±canthax., 6 b
all-t-9-CF3±canthax., 6a
6.81
6.64
6.51
6.07
130C,130-CF3-4-oxo-b, 7 b 6.30
13C,13-CF3±canthax., 8 b
13C,13-CF3±canthax., 8
130C,130-CF3±adon., 9 b
130C,130-CF3±adon., 9
13C0,130-CF3-3-dhc., 11
6.34
6.16
6.34
6.10
6.81
a In C6D6, unless otherwise specified.
b In CD2Cl2.
c Overlapping signals.
Table 2
2.3. Enrichment of the all-trans isomer
Oxidation potentials, UVabsorption maxima and calculated HOMO levels
of trifluoromethylated carotenoids
Because of the potential use of such carotenoids in studies
of caroteno±protein complexes where the all-trans isomer is
required6, we have carried out exploratory photochemical
experiments to seek for conditions to enrich the all-trans
isomer of the CF3-substituted carotenoids. For 9-CF3±
canthaxanthin, the all-trans isomer was present in 4.6%
of the synthetic mixture. Direct irradiation (light > 430 nm)
of either the 9-cis isomer or the synthetic mixture resulted in
doubling the amount of the trans isomer (according to F
NMR). The amount was further increased (to ꢀ20%) when
the compound was subjected to triplet sensitization (Rose
Bengal using light > 530 nm)6. The latter conditions were
employed to enrich the all-trans isomer of 13-CF3±canthax-
anthin, 9-CF3±canthaxanthin as well as 130-CF3±adonirubin
and subsequently its isolation by hplc was attempted. How-
ever, the all-trans isomer was found only to be marginally
stable at room temperature. Under the usual conditions of
hplc separation (room temperature and storage at 08C),
ꢀ40% of all-trans 9-CF3±canthaxanthin (9Z) was found
to have reverted back to the 9-cis isomer (all-E); while
>90% of the 13-CF3±canthaxanthin and the 130-CF3±ado-
nirubin reverted to the 13-cis isomer. All-trans-9-CF3±
canthaxanthin (9Z) was eventually isolated in pure form
when hplc fractions were kept at 08C and the NMR solvent
was pre-treated with K2CO3 for the removal of any possible
acidic impurities.
a
1
Compound
Eox
EHOMO
ꢀmax
(nm)
(mV)
(eV)
All-trans-b-carotene
13-cis-13-CF3±, 1
570
698
820 b
940
815 c
730
739
722
860
940
827
795
7.66
8.96
7.88
8.20
8.22
7.84
461
451
9-cis-9-CF3±, 2
448
9-cis,90-cis-9,90-bis-CF3±, 3
13-cis,130-cis-13,130-bis-CF3±, 4
All-trans-canthaxanthin
9-cis-
436
452
477 d
472 d
468 d
474 d
451, 470 d
453
13-cis-
9-cis-9-CF3±, 6
8.07
8.16
8.025
7.97
13-cis-13-CF3±, 8
90-cis-90-CF3-4-oxo-b-carot., 5
130-cis-130-CF3-4-oxo-b-carot., 7
130-cis-130-CF3±adonirubin, 9
All-trans-130-CF3±adonirubin
452, 464 d
462 e
467 e
a In hexane.
b A broad band that began to resolve into two waves at a slower scan-rate.
c The beginning of four overlapping oxidative waves.
d CH2Cl2.
e 80:10:10 (acetonitrile:ethyl acetate:methanol).
in Table 2. Initial assignment of proton signals was aided by
comparison with the corresponding data of either the parent
b-carotene or canthaxanthin7 or the corresponding C25-apo-
b-carotenals and by selective decoupling. Thus, the magni-
tude of the trans coupling constants helped identify those
signals corresponding to H8, H12 and H14 (larger near the
end of the chain) [19]; and the broader width of the signals
for H7 and H10 (long range coupling). The chemical shift of
the vinyl hydrogen on the carbon adjacent to the CF3-
substituted carbon (H8 for 9-CF3 and H12 for 13-CF3) is
2.4. Spectroscopic properties
The H NMR data of the ¯uorinated carotenoids are
tabulated in Table 1 and the UV±Vis absorption maxima
6See e.g., [17].
7See e.g., [18].

D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
169
at unusually high ®eld as noted before [14,20] for retinoids
although such signals for the cis isomer exhibit the same
down®eld shift from the trans isomer as in retinoids. Final
peak assignments were aided by spectral simulation.
The F NMR chemical shift (see Section 3) is a sensitive
measure of the cis/trans (E/Z) geometry where the CF3
group is located. For the trans (Z) isomer, the F chemical
shift is usually ꢀ6 ppm down®eld from that of the cis (E).
The UV±Vis absorption spectra of the ¯uorinated carote-
noids (Table 2) exhibit the general trend of blue shift from
that of the parent systems.
removing an electron for these ¯uorinated carotenoids
parallels with the calculated values (by AM1) of the HOMO
energy levels and the absorption maxima (Table 2), a
feature also discussed by Kispert and Jeevarajan [22]. Third,
a general trend was observed in that electron withdrawing
group on the b-carotene chain increases the dif®culty of di-
cation formation vis-a-vis ®rst oxidation step. First reported
by Kispert and coworkers, we concur that increasing gap
between the two oxidation waves take place as in the b-
carotene, 9-CF3± and 13-CF3±carotene and 4-keto series.
However, in the canthaxanthin series, the trend is reversed.
Addition of more electron withdrawing groups to the poly-
ene chain decreases the gap between the two oxidation steps
(believed to involve the two keto groups), especially when
the CF3 group is located near the middle of the chain.
In conclusion, 9-CF3± and 13-CF3±b-carotenes and
canthaxanthins can be prepared. The cis directing properties
of the CF3 group and the sensitivity of the compounds under
strong basic conditions, however, made preparation of the
all-E isomer dif®cult. The isolated isomers of CF3±carote-
noids exhibit spectroscopic and electrochemical properties
characteristic of those polyenes with strong electron with-
drawing groups. The increased oxidation potentials of the
CF3-substituted carotenoids agree with the noted preferen-
tial oxidation of the ring with no nearby CF3-group in the
preparation of 90-CF3±4-keto-canthaxanthin.
2.5. Oxidation potentials
Because of the recent interest in oxidation processes of
carotenoids [21], we have carried out electrochemical
experiments to determine the oxidation potentials of several
of these tri¯uoromethylated carotenoids. The cyclic vol-
tammograms of two substituted b-carotenes along with that
of the parent hydrocarbon is shown in Fig. 1 as representa-
tive examples. The oxidation potential data for these ¯uori-
nated carotenoids are summarized in Table 2.
There are three obvious features general to all these
¯uorinated carotenoids. First, unlike b-carotene and
canthaxanthin, the ¯uorinated carotenoids do not exhibit
reversible oxidative waves, as evidenced by the near zero
amplitude of the reductive waves in all cases. We suspect
that ¯uoro-substituents have introduced new (yet to be
identi®ed) reactions to the radical cation (or di-cation) of
the carotenoids. Second, there is a noticeable increase of the
®rst oxidation potential from that of the unsubstituted
carotenoids (b-carotene and canthaxanthin) (see Table 2).
This is an expected consequence when the highly electron-
withdrawing CF3 group is introduced onto the polyene
chain, a feature pointed out by Kispert and Jeevarajan
[22] in their extensive electrochemical studies of other
electronegatively substituted carotenoids (e.g., the values
of canthaxanthins are much higher than that of b-carotene)
[22±24]. It is noteworthy that the degree of dif®culty in
3. Experimental
3.1. General procedures
In general, normal phase hplc conditions were used for
separation of isomers of ¯uorinated carotenoids: 5 m,
4.6Â25 mm Si column (Rainin Microsorb). Solvent condi-
tions were: 0.125±0.25% ether in hexane for ¯uorinated b-
carotenes and 5% acetone in hexane for ¯uorinated canthax-
anthins. UV±Vis spectra were recorded on a PE l-19
spectrometer. H NMR spectra were recorded either on a
400 (Varian Inova 400 WB) or a 500 MHz (GE Omega GN-
500) spectrometer; F NMR spectra recorded on the Varian
Inova spectrometer (376 MHz), using tri¯uorotrichloro-
ethane ( 82.2 ppm) as external standard. Simulation of
H NMR spectra was carried out using gNMR software v
3.6. AM1 (Austin Model 1). Calculations were performed
using HyperChem software with an AST Bravo PC.
For photosensitized irradiation, a catalytic amount of
Rose Bengal was introduced to an acetonitrile solution of
a carotenoid. The solution was deoxygenated by bubbling
argon gas through the sample tube and irradiated with a
200 W Hanovia Hg lamp, using a Corning 3-70 ®lter plate.
3.2. Electrochemistry
Cyclic voltammetry measurements were carried out in a
single compartment cell with a 2 mm diameter glassy
Fig. 1. Cyclic voltammograms for trifluoromethylated-b-carotenes: (a) 9-
cis-9-CF3, (b) 13-cis-13-CF3, along with that of all-trans-b-carotene.

170
D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
carbon disk electrode as a working electrode, a platinum
wire as an auxiliary electrode and Ag/AgCl as a reference
electrode.
THF and 3 ml of CH2Cl2 yielded 20 mg of the bis-CF3±
carotene-4 (68% yield). F NMR (CD2Cl2): 53.9 ppm.
Methylene chloride of hplc grade (Fisher Co.) was kept
over CaH2 under argon. The needed amount of solvent was
distilled just before use. The supporting electrolyte, tetra-n-
butylammonium hexa¯uorophosphate (TBAHFP) was used
as supplied by Fluka and kept in the vacuum dessicator over
Drierite. All carotenoids were puri®ed by hplc before use.
A 0.1 M solution of TBAHFP in CH2Cl2 was employed
with ca. 0.1±0.3 mM of the carotenoid with scan speed
ranging from 50 to 1000 mV s 1. During the measurements
the electrochemical cell was purged by dry argon gas.
All the measurements were performed employing a Prin-
ceton Applied Research Potentiostat/Galvanostat Model
273 run by Model 250-270 Electrochemical Research soft-
ware.
3.3.5. 90-cis-90-CF3±4-oxo-b-carotene (5) and 9-cis-9-
CF3±canthaxanthin (6)
A mixture of 110 mg of 9-CF3±b-carotene in 3 ml of
CH2Cl2, acatalytic amount of I2 and 550 mg of NaClO3 in
1 ml of H2O was stirred at room temperature for 3 h. After
usual workup and column chromatography, two carotenoids
were isolated: 90-CF3±4-oxo-b-carotene (30 mg, 26% yield)
and 9-CF3±canthaxanthin (46 mg, 38%). The major (ꢀ80%)
9-cis isomer for each compound was isolated by preparative
hplc. F NMR (CD2Cl2): 64.0 and 63.9 ppm, respec-
tively.
3.3.6. 13-cis-13-CF3±canthaxanthin (8)
To a dry THF solution of 13-CF3±4-oxo-retinal (200 mg)
and the protected C5-phosphonium salt 10 (380 mg) [25]
was added at 788C 0.2 ml of 2.5 M BuLi. Standard
workup and chromatography (silica gel, 15% ether/hexane)
yielded 170 mg of the C25 13-CF3±4-oxo-apocarotenal.
Reaction of the above C25-apocarotenal (30 mg) and 4-
oxo-C15-triphenylphosphonium salt (40 mg) in the same
manner as described above yielded 32 mg of 13-cis-13-
CF3±canthaxanthin (70% yield). The major 13-cis isomer
was isolated by preparative hplc. HRMS: Calc. for
C40H49F3O2ˆ618.3695, found 618.3695. F NMR (CD2Cl2):
13-cis, 63.6 ppm; all-trans, 59.1 ppm.
3.3. Materials
b-Carotene was generously supplied by Hoffmann La-
Roche and Co. Canthaxanthin was prepared by oxidation of
b-carotene according to published procedure [16].
3.3.1. 13-CF3±b-carotene (1)
To a methylene chloride (2 ml) solution of 100 mg of 13-
cis-13-CF3±retinal and 200 mg C20-Wittig salt was added at
08C a methanol solution of sodium methoxide. Standard
workup and chromatography on silica gel with 15% ether/
hexane yielded 168 mg of 13-cis-13-CF3±b-carotene. The
major 13-cis isomer (80%) was puri®ed by hplc. NMR
signals for the vinylic protons are listed in Table 1. HRMS:
calculated for C40H53F3ˆ590.4102, foundˆ590.4096. F
NMR (CD2Cl2): 63.5 ppm.
3.3.7. 130-cis-130-CF3±4-oxo-b-carotene (7)
3.3.2. 9-cis-9-CF3±b-carotene (2)
Starting with 120 mg of 13-cis-13-CF3±retinal and
0.208 g of the protected C5-phosphonium salt 10 and fol-
lowing the same procedure as above, 136 mg (90% yield) of
13-CF3±C25-apocarotenal was prepared. Reaction of 20 mg
of the apocarotenal with 30 mg of 4-oxo-C15-triphenyl-
phosphonium bromide gave 27 mg of 13-CF3±4-oxo-b-
carotene (88% yield). The major 13-cis isomer was isolated
by preparative hplc. F NMR (CD2Cl2): 63.6 ppm.
Following the same procedure as above, the coupling of
9-CF3±retinal (80 mg) and C20-triphenylphosphonium bro-
mide (200 mg) yielded 140 mg of the desired product. The
major 9-cis isomer (80%) was isolated by preparative hplc.
F NMR: 64.1 ppm. Photosensitized (with Rose Bengal)
isomerization resulted in formation of the all-trans isomer
(ꢀ20%). F NMR: 59.1 ppm.
3.3.3. 9-cis,90-cis-9,90-bis-CF3±b-carotene (3)
3.3.8. 130-CF3±Adonirubin (9)
Under argon, 30 mg of 9-cis-9-CF3±retinal was added to a
slurry of 68 mg TiCl4, 12 mg Zn, 3 ml THF, 3 ml CH2Cl2.
After 2 h, extraction and chromatography of the product
mixture yielded 26 mg of the bis-CF3±carotene (90% yield).
The major (95%) dicis isomer was isolated by preparative
hplc. HRMS: Calc. for C40H50F6ˆ644.3829, found
644.3811. F NMR (CD2Cl2): 65.0 ppm.
Reaction of 20 mg of the 13-CF3±C25-apocarotenal above
with 33 mg of 3-hydroxy-4-oxo-C15-triphenylphosphonium
bromide in the same manner as described above gave 22 mg
of the CF3±adonirubin 9 (72% yield). HRMS: calculated for
C40H49F3O3ˆ634.3636, foundˆ634.3641. A ®rst attempt to
purify the 13-cis isomer by preparative hplc on a normal
phase silica gel column (10% acetone in hexane) resulted in
a mixture of four major components. The principal compo-
nent, 11, (ꢀ50%) gave a H NMR spectrum (Table 2)
consistent with that of the cross-conjugated dienone end
group from dehydration of the starting material (130-cis-3-
3.3.4. 13-cis,130-cis-13,130-bis-CF3±b-carotene (4)
Under the same conditions as above, 30 mg of 13-cis-13-
CF3±retinal with 68 mg of TiCl4, 12 mg of Zn in 3 ml of

D. Hoischen et al. / Journal of Fluorine Chemistry 97 (1999) 165±171
171
dehydro-130-CF3±canthaxanthin).
63.5 ppm. Puri®cation by reverse phase hplc (C30 col-
umn) using acetonitrile:ethyl acetate:methanol (80:10:10)
F
NMR (CD2Cl2):
[8] R.S.H. Liu, E. Krogh, X.-Y. Li, D. Mead, L.U. Colmenares, J.R.
Thiel, J. Ellis, D. Wong, A.E. Asato, Photochem. Photobiol. 58
(1993) 701.
[9] L.U. Colmenares, Ph.D. Dissertation, University of Hawaii, 1991.
[10] J. Liu, L.U. Colmenares, R.S.H. Liu, Tetrahedron Lett. 38 (1997)
8495.
gave 13-cis-9. F NMR (CD2Cl2):
63.7, (CD3CN):
63.1 ppm. The all-trans isomer was isolated from mix-
tures obtained from photosensitized irradiation. F NMR
(CD3CN): 4. 58.8 ppm.
[11] D. Hoischen, L.U. Colmenares, J. Liu, C.J. Simmons, G. Britton,
R.S.H. Liu, Bioorg. Chem. 26 (1998) 365.
[12] H. Mayer, O. Isler, in: O. Isler (Ed.), Carotenoids, Birkhauser Verlag,
Basel, 1971, p. 325.
[13] K. Bernhard, in: N. Krinsky, M.M. Mathews-Roth, R.F. Taylor
(Eds.), Carotenoids, Chemistry and Biology, Plenum Press, New
York, 1984, p. 337.
Acknowledgements
The work was supported by a grant from the US Public
Health Services (DK-17806) and partially by the NSF-REU
program (CHE-9531532). We thank Dr. J. Paust of BASF
for the generous supply of intermediates for carotenoid
synthesis and Drs. Hengartner and Bernhard of Hoff-
mann-La Roche for a sample of b-carotene.
[14] D. Mead, A.E. Asato, M. Denny, R.S.H. Liu, Y. Hanzawa, T.
Taguchi, A. Yamada, N. Kobayashi, A. Hosoda, Y. Kobayashi,
Tetrahedron Lett. 28 (1987) 259.
[15] J.E. McMurry, M.P. Fleming, J. Am. Chem. Soc. 96 (1974) 4708.
[16] J. Paust, J. Schneider, H. Jaedicke, Ger Pat. 2 534 805, 1975; J. Paust,
in: G. Britton, S. Liaaen-Jensen, H. Pfander (Eds.), Carotenoids, vol
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[17] G. Britton, G.M. Armitt, S.Y.M. Lau, A.K. Patel, C.C. Stone, in: G.
Britton, T.W. Goodwin (Eds.), Carotenoids, Chemistry and Bio-
chemistry, Pergamon Press, Oxford, 1982, p. 237.
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