A stereoselective synthesis of ethyl 9-cis-7,8-didehydro-19-trifluoromethylretinoate

Article abstract of DOI:10.1016/S0022-1139(99)00186-4

The design and synthesis of ethyl 9-cis-7,8-didehydro-19-trifluoromethylretinoate was described. The key step is the Sonogashira reaction of ethyl 3-iodo-4,4,4-trifluoro-2(Z)-butenoate 2 with terminal alkyne 3.

Full text of DOI:10.1016/S0022-1139(99)00186-4

Journal of Fluorine Chemistry 101 (2000) 31±33
A stereoselective synthesis of ethyl
9-cis-7,8-didehydro-19-tri¯uoromethylretinoate
Feng-Ling Qing*, Jieweng Ying, Yanmei Zhang
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 27 April 1999; accepted 29 July 1999
Abstract
The design and synthesis of ethyl 9-cis-7,8-didehydro-19-tri¯uoromethylretinoate was described. The key step is the Sonogashira
reaction of ethyl 3-iodo-4,4,4-tri¯uoro-2(Z)-butenoate 2 with terminal alkyne 3. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Tri¯uoromethylated; Retinoids
1. Introduction
cyclocitral with tri¯uoromethylated bromo C5 ester
(BrCH2(CF3)C=CHCO2R) in the key step [8], but the yield
of this reaction was low (30% yield). Following our previous
work describing the regio- and stereo-speci®c preparation of
ethyl 3-iodo-4,4,4-tri¯uoro-2(Z)-butenoate 2 [9,10], we
decided to employ 2 as building block for the preparation
of 1 (Scheme 1). The Sonogashira reaction of 2 with
terminal alkyne 3 afforded the conjugated (2Z)-en-ynoic
acid derivative containing a tri¯uoromethyl group 4 in 85%
yield. This ester underwent dehydration with phosphorus
oxychloride in pyridine to the diene-yne ester 5. The ester 5
was converted to the aldehyde 6 by DIBAL-H reduction and
subsequent MnO2 oxidation. The con®guration of trisub-
stituted double bond in 6 was assigned by 19F NMR spectro-
scopy (ꢀF ˆ 9.8 ppm for tri¯uoromethyl group in 6 (using
CF3CO2H as an external standard, up®eld positive)). The ꢀF
Retinoids, natural and synthetic analogs of vitamin A, are
potent molecules that can effect a variety of fundamental
biological processes including cell differentiation and pro-
liferation and apoptosis [1,2]. The nuclear receptors, the
RARs and RXRs have retinoic acid (RA) and 9-cis-retinoic
acid (9-cis RA) as ligand molecules, respectively. Current
research efforts in this ®eld have focused on searching for
conformationally restricted retinoids in order to elucidate
the biological functions of each receptor [3,4]. With a view
towards replacing the disubstituted double bonds with
alkynes to provide rigidity [5] and to explore the effect of
a tri¯uoromethyl group on chemical and physical properties
[6,7], we were interested in designing and preparing of ethyl
9-cis-7,8-didehydro-19-tri¯uoromethylretinoate 1.
2. Results and discussion
value for the CF3 group was close to 10.0 ppm which is
diagnostic for the CF3 group and CHO group being trans
oriented. Under classical conditions using n-butyl lithium as
base [11], the reaction of 6 with the C5-phosphonate 7 did
not proceed satisfactorily. The Emmons-Hoener reaction
was carried out successfully using LDA to give the target
Liu et al. have reported the synthesis of 9-cis-19,19,19-
tri¯uororetinal by using the Reformatsky reaction of
*Corresponding author. Fax: ‡86-2164166128.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 8 6 - 4

32
F.-L. Qing et al. / Journal of Fluorine Chemistry 101 (2000) 31±33
Scheme 1. Synthesis of 1.
molecule 1 and its 13-Z isomer (1 : 13-Z ˆ 1 : 1), which can
be separated by column chromatography. The stereochem-
istry (E-form) of the 11,12-double bond in 1 and its 13-Z
isomer was determined on the basis of the coupling con-
stants of the 11-H signal in the NMR spectrum.
3.2. Preparation of compound 5
The hydroxyalkynoate 4 (0.55 g, 1.6 mmol) was added to
a solution of phosphorus oxychloride (0.38 g, 2.5 mmol) in
pyridine (8 ml) at room temperature. After 15 min of stir-
ring at room temperature and 7 h at re¯ux, the reaction was
cooled to 08C and saturated aqueous sodium bicarbonate
was added (10 ml). After extraction with ether, the com-
bined organic layers were washed with 10% aqueous hydro-
chloric acid and brine, dried (Na2SO4), and evaporated in
vacuo to give, after ¯ash chromatography (petroleum±ethyl
acetate ˆ 50 : 1) 5 (0.31 g, 62%). 19F NMR (CDCI3)
3. Experimental
19F NMR spectra (56.4 Hz) were recorded on a Varian-
360A instrument using CF3CO2H as an external standard,
up®eld positive. 1H NMR spectra were recorded on a
300 MHz spectrometer with tetramethylsilane as the inter-
nal standard. All chemical shifts are expressed in ppm. The
mass spectra were recorded on a Finnigan-MAT-8430 mass
spectrometer. IR spectra were recorded as KBr discs on a
Shimadzu IR-440 Spectrometer. Terminal alkyne 3 was
prepared by a literature procedure [12]. Light petroleum
ether refers to the fraction with distillation range 60±908C.
1
ꢀ: 10.0 (s); H NMR (CDCI3) ꢀ: 1.15 (s, 6H), 1.30 (t,
J ˆ 7.0 Hz, 3H), 1.47±1.52 (m, 2H), 1.57±1.67 (m, 2H),
2.00 (s, 3H), 2.09(t, J ˆ 7.0 Hz, 2H), 4.26 (q, J ˆ 7.0 Hz,
‡
‡
2H), 6.48 (s, 1H). MS (m/e): 315 (M ‡ 1,21.0), 313 (M ,
17.3), 299 (26.0), 285 (100.0), 271 (42.0) 163 (40.0). IR:
2963, 2937, 2870, 2184, 1730, 1634, 1602, 1459, 1462,
1364, 1286, 1255, 1196 cm 1. HRMS Calcd for C17H21-
F3O2: 314.1494, Found: 314.1476.
3.1. Preparation of compound 4
3.3. Preparation of compound 6
To a three-necked, round-bottomed ¯ask were added
ethyl 3-iodo-4,4,4-tri¯uoro-2(Z)-butenoate
2
(360 mg,
DIBAL-H (3.0 ml, 5.7 mmol, 1.5 M in toluene) was
added to a solution of 5 (0.7 g, 2.23 mmol) in toluene
(5 ml) at 788C. After 30 min of stirring at room tempera-
ture, the reaction was cooled to 08C and 20% aqueous
hydrochloric acid (10 ml) was added. After extraction with
ether, the combined organic layers were washed with brine,
dried (Na2SO4), and evaporated in vacuo to give the alcohol
which was used in the next reaction without further pur-
i®cation. A mixture of the alcohol (0.44 g, 1.06 mmol),
activated MnO2 (1.0 g) and dichloromethane (16 ml) was
stirred at room temperature for 6 h under nitrogen. Then the
reaction mixture was diluted with dichloromethane and
®ltered. The inorganic solid was washed with dichloro-
methane. The combined ®ltrates were evaporated in vacuo
1.2 mmol), alkyne 3 (220 mg, 1.3 mmol), CuI (13 mg,
0.07 mmol), PdCl2(PPh3)2 (15 mg, 0.03 mmol) and triethy-
lamine (5 ml) under nitrogen. The reaction mixture was
stirred at room temperature for 24 h. Diethyl ether (10 ml)
and 5% aqueous HCI (10 ml) were added to the ¯ask. The
organic layer was washed with brine (2 Â 20 ml), dried
(Na2SO4), and ¯ash chromatographed (petroleum±ethyl
acetate ˆ 20 : 1) to yield 4 (330 mg, 85%). 19F NMR
(CDCI3) ꢀ: 10.0 (s); 1H NMR (CDCI3) ꢀ: 1.00±1.58
(m, 15H), 1.29 (t, J ˆ 7.0 Hz, 3H), 1.90±1.93 (m, 1H),
2.65 (br, 1H), 4.25 (q, J ˆ 7.0 Hz, 2H), 6.58 (s, 1H); MS
‡
(m/e): 332 (M , 17.0), 303 ( 25.0), 259 (66.9), 69 (100.0), 55
(90.8); IR: 3495, 2934, 2873, 2217, 1733, 1635, 1464, 1370,
1328, 1307, 1287, 1259, 1191, 1030 cm 1; HRMS Calcd for
C17H23F3O3; 332.1599, Found: 332.1599.
1
to give pure 6. 19F NMR (CDCI3) ꢀ: 9.8 (s): H NMR
(CDCI3) ꢀ: 1.12 (s, 6H), 1.51 (t, J ˆ 5.7 Hz, 2H), 1.60±1.68

F.-L. Qing et al. / Journal of Fluorine Chemistry 101 (2000) 31±33
33
(m, 2H), 1.94 (s, 3H), 21.11 (t, J ˆ 6.0 Hz, 2H), 6.58 (d,
J ˆ 7.8 Hz, 1H), 10.19 (d, J ˆ 7.8 Hz, 1H). MS (m/e): 271
1264, 1226, 1159, 1133, 1049, 801, 706 cm 1. HRMS:
Calcd for C22H27F3O2: 380.1973, Found: 380.1974.
‡
‡
(M ‡ 1, 24.3), 270 (M , 42.2), 255 (100.0), 241 (29.7),
200 (71.2). IR: 2694, 2871, 1693, 1590, 1364, 1262, 1194,
1154 cm 1. HRMS Calcd for C15H17F3O: 270.1231, Found:
270.1232.
Acknowledgements
We thank National Natural Science Foundation of China
for funding this work.
3.4. Preparation of compound 1
References
To a solution of triethyl 3-methyl-4-phosphonocrotonate
(184 mg, 0.69 mmol) in THF (10 ml) at 788C was added
LDA (0.7 ml, 0.7 mmol, 1 M in THF). After stirring for
15 min, the solution containing the ylide of triethyl phos-
phonocrotonate was added to a solution of 6 (150 mg,
0.55 mmol) in THF (10 ml) at 788C. The reaction mixture
was warmed to room temperature, and quenched with
saturated aqueous NH4CI (15 ml). After extraction with
ether, the combined organic layers were washed with water
and brine, dried (Na2SO4), and evaporated in vacuo to give,
after ¯ash chromatography (petroleum-ether ˆ 50 : 1) 1
(95 mg). 19F NMR (CDCI3) ꢀ: 12.0 (s); 1H NMR (CDCI3)
ꢀ: 1.25 (s, 6H), 1.29 (s, 3H), 1.32 (t, J ˆ 7.0 Hz, 3H), 1.48±
1.53 (m, 2H), 1.59±1.68 (m, 2H), 1.95, (s, 3H), 2.05±2.11
(m, 2H), 2.32 (s, 3H), 4.19 (q, J ˆ 7.0 Hz, 2H), 5.90 (s, 1H),
6.58 (d, J ˆ 15.3 Hz, 1 h), 6.89 (d, J ˆ 11.0 Hz, 1H), 7.11
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