New, regioselective, one-pot synthesis of (all-E)-retinoic acid and analogues from enaminodiester synthons

Article abstract of DOI:10.1002/ejoc.200300029

A one-pot synthesis of (all-E)-retinoic acid and related compounds from new enamino diester synthons is described. The enamino diesters was produced nearly quantitatively from methyl propylidene- and isopropylidenemalonate and DMF-DMA. This easy process allowed retinoic acid to be produced in 1 d and appeared advantageous to current industrial syntheses. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200300029

FULL PAPER
New, Regioselective, One-Pot Synthesis of (all-E)-Retinoic Acid and Analogues
from Enaminodiester Synthons
[a]
[a]
Dominique Cartier,[a] Alain Valla,*[a,b] Regis Le Guillou, Roger Labia, and
´
Pierre Potier[c]
Keywords: Enamino diesters / (all-E)-Retinoic acid
A one-pot synthesis of (all-E)-retinoic acid and related com- produced in 1 d and appeared advantageous to current in-
pounds from new enamino diester synthons is described. The
enamino diesters was produced nearly quantitatively from
methyl propylidene- and isopropylidenemalonate and
DMF−DMA. This easy process allowed retinoic acid to be
dustrial syntheses.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Natural retinoids have been found to be active in the Aventis joined a C15 component with an added C5 unit, and
regulation and differentiation of many cell types, the best HoffmannϪLa Roche a C14 constituent with a further C6
effects having been achieved with retinol, retinaldehyde, unit. For the construction of the C1ϪC7 or C7ϪC8 bonds,
(13Z)-retinoic acid and (all-E)-retinoic acid.[1,2] This last Aventis coupled a C9 unit with a C11 component while Su-
has selective biological activity for normal growth and epi- mitomo combined two C10 synthons.
thelial differentiation. Retinoic acid receptors (RARs) have
a high affinity both for (all-E)-retinoic acid and its (9Z)
isomer, the latter being the natural ligand of the retinoid X
receptors (5RXRs).[3] These transcription factors (RARα,
RARβ, RARγ and RXRα, RXRβ, RXRγ) activate tran-
scription by interaction with their target genes through
Scheme 1
specific DNA-binding domains. It was recently found that
retinoic acid induced apoptosis in leukaemia cells was me-
For these regioselective syntheses, ethylenic partners with
diated by paracrine action of a tumour necrosis factor re-
lated apoptosis-inducing ligand.[4]
the required stereochemistry were needed and, furthermore,
large numbers of steps or purifications were necessary.
With the intention of synthesising the economically most
important retinoids by a single pathway, we recently pre-
pared enamino diesters synthons 1a and 1b, which could be
easily obtained and directly coupled with β-ionone. Thus,
condensation of methyl alkylidenemalonates and N,N-di-
methylformamide dimethyl acetal (DMFϪDMA) directly
afforded the desired intermediates 1a and 1b in excellent
yields (Scheme 2).
These important biological activities have prompted an
intensive search to obtain the required stereochemistry of
the ethylenic linkage.
The industrial synthetic routes were based on the pro-
cedures of Wittig[5] (BASF AG), Julia[6] (Aventis) and
Isler[7] (HoffmannϪLa Roche). A range of recent examples,
using tricarbonyliron complexes[8] and palladium-catalysed
cross-coupling reactions such as the Negishi reaction,[9] Su-
zuki coupling,[10] Stille reaction,[11] Heck reaction[12] and
Sonogashira coupling[13] etc. have been investigated.
The major strategies are illustrated in Scheme 1.[14] Each
pathway has been achieved by two approaches. For the con-
struction of the C10ϪC11 or C11ϪC12 bonds, BASF AG and
Scheme 2. a: R1 ϭ Me, R2 ϭ H; b: R1 ϭ H, R2 ϭ Me
[a]
Laboratoire de Chimie et Biologie des Substances Naturelles 6,
´
Rue de l’Universite, 29000 Quimper, France
In series a, the synthon 1a allowed a one-pot synthesis
of (all-E)-retinoic acid.[15] The step-by-step sequence of the
synthesis is described in Scheme 3. The lithium enolate of
β-ionone was treated with the enamino diester 1a to give
the addition product 4a [(all-E)/(12Z)ϭ 80:20; 65%] via an
Fax: (internat.) ϩ 33-2/98641948
E-mail: valla@iutquimp.univ-brest.fr
[b]
[c]
´
`
VA R&D Pepiniere d’Entreprises 140,
Boulevard de Creac’h Gwen, 29561 Quimper Cedex, France
UPR 2301 CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
2250
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300029
Eur. J. Org. Chem. 2003, 2250Ϫ2253

(all-E)-Retinoic Acid and Analogues from Enaminodiester Synthons
FULL PAPER
intermediate unstable compound 2a, which spontaneously any detectable amounts of the expected isomer 7a
underwent elimination of dimethylamine to provide 3a, (Scheme 5).
which was further protonated. The Grignard reaction be-
tween MeMgBr and compound 4a required an excess of
reagent, 1 equiv. serving to regenerate the anion 3a. The
presence of this delocalized negative charge between the
two ester groups should protect them from being attacked
by MeMgBr. The Grignard reagent therefore reacted only
with the ketone to give intermediate 5a and, after pro-
tonation and dehydration, the (methoxycarbonyl)-retro-reti-
noate 6a [(12E)/(12Z) ϭ 75:25; 69%]. This, after saponifi-
cation and concomitant decarboxylation, afforded mainly
the (all-E)-retinoic acid (7a) [(all-E)/(13Z) ϭ 83:17; 80%].
The (all-E) isomer was purified by rapid column chroma-
tography with CH2Cl2/MeOH (98:2) as eluent, followed by
crystallisation from acetonitrile (Scheme 3). Compounds of
series b were obtained by the same route, via enamino dies-
ter 1b [4b: (all-E)/(12Z) ϭ 80:20; 57%; 6b: (all-E)/(12Z) ϭ
80:20; 48%; 7b: (all-E)/(12Z) ϭ 80:20; 50%].
Scheme 5
Conversely, by the step-by-step procedure, starting with
α-ionone and synthon 1a, very poor yields of diester 11a
were obtained (18%, compared with 69% in the case of dies-
ter 6a, Scheme 6).
Scheme 6
This suggested an alternate mechanism for α-ionone in
the one-pot procedure, but this mechanism is also credible
in the one-pot procedure for β-ionone, as illustrated in
Scheme 6. We may note that this mechanism does not in-
volve a (methoxycarbonyl)-retro-retinoate 6a, which can be
isolated in the case of β-ionone, but not with α-ionone. On
the other hand, the first mechanism implies a vacant proton
for the dehydration process in position 4 or 6. In the α-
ionone series, the proton at C4 is ethylenic and the proton
at C6 poorly accessible due to steric hindrance.
This procedure offers an alternative, inexpensive method
for the production of other important related products such
as vitamin A[17,18] and β-carotene[19] via a single synthon
1a and β-ionone. Syntheses of these compounds could be
completed in 2Ϫ3 d from (all-E)-retinoic acid (obtained in
61% overall yield from β-ionone) by established procedures.
Scheme 3
A one-pot procedure for the synthesis of retinoic acid
(7a), depicted in Scheme 3, was desirable from both an
economic and an ecological point of view. It was feasible
because the reaction conditions for each successive step are
compatible (i. LDA, 1a; ii. MeMgBr; iii. KOH/EtOH/H2O).
The intermediary malonic acid corresponding to compound
5 in Scheme 3 was thus spontaneously decarboxylated, and
coupling of the obtained monoacid preferentially afforded
the (all-E) isomer. This one-pot process was accomplished
in 1 d and (all-E)-retinoic acid was obtained with an in-
creased overall yield [(all-E)/(13Z) ϭ 87:13; 70%].
The other compound 7b [(all-E)/(13Z) ϭ 85:15; 55%] was
also obtained by the same one-pot route (Scheme 4).
Experimental Section
General: All experiments were carried out under argon. All starting
products were purchased from SigmaϪAldrich. Melting points
were measured with a Leitz 350 heated-stage microscope and are
not corrected. IR spectra were recorded with a Bruker IFS 55 spec-
trometer. 1H and 13C NMR spectra were determined with a Bruker
Avance DPX 400 spectrometer (1H: 400 MHz; 13C: 100 MHz).
Chemical shifts (δ) are expressed in ppm downfield from internal
TMS. J values are given in Hz. The traditional retinoid numbering
system[20] is used for identification and spectroscopic data
Scheme 4. a: R1 ϭ Me, R2 ϭ H; b: R1 ϭ H, R2 ϭ Me
A possible alternate mechanism: Surprisingly, when start-
ing with α-ionone and synthon 1a, the one-pot synthesis
gave the retinoic acid 10a with, in this case, favourable
(13Z) regioselectivity [(all-E)/(13Z) ϭ 35:65] but without (Scheme 3). Chemical Abstracts nomenclature is used below.
Eur. J. Org. Chem. 2003, 2250Ϫ2253
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2251

D. Cartier, A. Valla, R. Le Guillou, R. Labia, P. Potier
FULL PAPER
Dimethyl 2-[(2E)-3-(Dimethylamino)-1-methyl-2-propenylidene]ma-
(CO); 145.5, 143.1, 130.1, 128.6, 126.9, 51.8 (CH); 39.8.1, 34.1, 20.4
lonate (1a): A mixture of dimethyl isopropylidenemalonate (43 g, (CH2); 53.0, 28.8, 21.9, 12.9 (CH3) ppm. C22H30O5 (374.47): calcd.
250 mmol) and DMFϪDMA (40 mL, 1.2 equiv.) was heated at 95 C 70.56, H 8.07; found C 70.39, H 8.19.
°C for 18 h with removal of the MeOH (DeanϪStark) and then
heated at reflux for 2 h. After elimination of the excess of
DMFϪDMA under reduced pressure, the enamino ester was crys-
Methyl 14-(Methoxycarbonyl)-retro-retinoate (6a): A solution of
MeMgBr (3  in THF, 7.5 mL, 2.8 equiv.) was added at Ϫ10 °C
to 4a (2.98 g, 8 mmol) in THF (30 mL). The chilled bath was re-
moved and, 30 min later, the crude mixture was quenched with a
tallized from pentane/diethyl ether. Yellow crystals, m.p. 113 °C
(54 g, 95%). IR (KBr): ν˜ ϭ 1716, 1686, 1619, 1539, 1433, 1399,
satd. solution of NH4Cl and extracted with diethyl ether. After
1330, 1191, 1115, 1068, 995, 959 cmϪ1 1H NMR (CDCl3): δ ϭ
.
conventional workup, the crude, oily product was purified by col-
umn chromatography (SiO2; CH2Cl2). Yellow oil [2.05 g, 69%; (all-
E)/(12Z) ϭ 75:25]. IR (film): ν˜ ϭ 2955, 2915, 2847, 1736, 1436,
6.93 (d, J ϭ 13.2 Hz, 1 H, 4-H), 6.07 (d, J ϭ 13.2 Hz, 1 H, 5-H),
3.71 (s, 6 H, COOCH3), 2.91 [s, 6 H, N(CH3)2], 2.10 (s, 3 H, 3-
CH3) ppm. 13C NMR (CDCl3): δ ϭ 168.5, 167.3 (CO); 148.8, 97.4
(CH); 52.0, 51.9, 41.0, 16.7 (CH3) ppm. C11H17NO4 (227.26): calcd.
C 58.14, H 7.54, N 6.16; found C 58.02, H 7.58, N 6.28.
1306, 1279, 1204, 1142, 1020, 958, 877, 733 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 6.75 (d, J ϭ 12.30 Hz, 1 H, 10-H), 6.41Ϫ6.22 (m, 3
H, 7-H ϩ 11-H ϩ 12-H), 6.22 (d, J ϭ 6.2 Hz, 1 H, 8-H), 5.79 (t,
J ϭ 5.50 Hz, 1 H, 4-H), 4.73 (s, 1 H, 14-H), 3.77 (s, 3 H, OCH3),
2.22 (m, 2 H, 2-CH2), 1.96, 1.91, 1.91, (3 s, 9 H, 5-CH3, 9-CH3,
13-CH3), 1.51 (m, 2 H, 3-CH2), 1.29 (s, 6 H, 1-CH3) ppm. 13C
NMR: δ ϭ 168.3, 168.1 (CO); 139.6, 134.2, 132.0, 128.6, 122.5,
119.7 (CH); 40.5, 22.8 (CH2); 53.5, 52.4, 28.8, 21.4, 21.3, 11.9
(CH3) ppm. C23H32O4 (372.50): calcd. C 74.16, H 8.66; found C
74.01, H 8.76.
Dimethyl 2-[(2E)-3-(Dimethylamino)-2-methyl-2-propenylidene]ma-
lonate (1b): This compound was obtained by the same procedure,
from dimethyl propylidenemalonate (34.4 g, 200 mmol). Orange
crystals, m.p. 91Ϫ93 °C (33.5 g, 77%). IR (KBr): ν˜ ϭ 1724, 1678,
1619, 1536, 1426, 1390, 1371, 1233, 1169, 1126, 1082, 1023, 918,
881, 761, 726 cmϪ1 1H NMR (CDCl3): δ ϭ 7.31 (s, 1 H, 5-H),
.
6.79 (s, 1 H, 3-H), 3.82 and 3.75 (2 s, 6 H, N(CH)3], 3.08 (s, 6 H,
OCH3), 1.83 (s, 3 H, CH3) ppm. 13C NMR (CDCl3): δ ϭ 169.3,
166.9 (CO); 155.0, 154.1 (CH); 51.8, 51.5, 43.3, 13.5 (CH3) ppm.
C11H17NO4 (227.26): calcd. C 58.14, H 7.54, N 6.16; found C
58.03, H 7.64, N 6.13.
Dimethyl 2-[(1E,3E,5E,7Z)-2,5-Dimethyl-7-(2,6,6-trimethyl-2-cyclo-
hexen-1-ylidene)-1,3,5-heptatrienyl]malonate (6b): This compound
was obtained as a yellow oil by the same method, from 8 mmol of
4b (column chromatography: SiO2; CH2Cl2); yield 1.43 g [48%; (all-
E)/(12Z) ϭ 80:20]. IR (film): ν˜ ϭ 2956, 2936, 2868, 1736, 1661,
Dimethyl 2-[(1E,3E,6E)-1-Methyl-5-oxo-7-(2,6,6-trimethyl-1-cyclo-
hexen-1-yl)-1,3,6-heptatrienyl]malonate (4a): A solution of BuLi
(1.6  in hexanes, 13.2 mL, 21 mmol) was added at Ϫ25 °C to
iPr2NH (3.1 mL, 22 mmol) in DME (20 mL), and β-ionone (3.85 g,
20 mmol) in DME (20 mL) was then slowly added at Ϫ30/Ϫ40 °C.
After the mixture had been kept at Ϫ30 °C for 20 min, 1a (4.77 g,
1.05 equiv.) in DME (50 mL) was quickly added. The refrigerated
bath was then removed and the mixture was allowed to warm to
room temperature. After 10 min, the crude mixture was heated at
reflux for 2 h (until the evolution of Me2NH had ceased). The solu-
tion was quenched at 0 °C with HCl in water (1 ⁾ and extracted
with diethyl ether. After conventional workup, the crude product
was purified by column chromatography (SiO2; CH2Cl2) to yield a
yellow oil [4.86 g, 65%; (all-E)/(12Z) ϭ 80:20). IR (film): ν˜ ϭ 2954,
2931, 2866, 1739, 1653, 1627, 1598, 1435, 1364, 1310, 1263, 1201,
1153, 1080, 1029, 983 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.49 (dd, J ϭ
15.1, J ϭ 11.4 Hz, 1 H, 11-H), 7.35 (d, J ϭ 16.1 Hz, 1 H, 7-H),
6.44 (d, J ϭ 15.1 Hz, 1 H, 10-H), 6.28 (d, J ϭ 16.1 Hz, 1 H, 8-H),
6.18 (d, J ϭ 11.4 Hz, 1 H, 12-H), 4.14 (s, 1 H, 14-H), 3.68 (s, 6 H,
OMe), 1.99 (m, 2 H, 4-CH2), 1.98 (s, 3 H, 13-CH3), 1.69 (s, 3 H,
5-CH3), 1.55 (m, 2 H, 3-CH2), 1.40 (m, 2 H, 2-CH2), 1.00 (s, 6 H,
1-CH3) ppm. 13C NMR: δ ϭ 189.2, 167.6 (CO); 143.3, 137.4, 130.2,
130.2, 130.0 (CH); 40.1, 34.0, 19.2 (CH2); 60.9, 53.1, 29.2, 22.2,
16.6 (CH3) ppm. C22H30O5 (374.47): calcd. C 70.56, H 8.07; found
C 70.41, H 8.26.
1436, 1313, 1272, 1197, 1149, 1020, 911, 730 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 6.77 (d, J ϭ 12.30 Hz, 1 H, 10-H), 6.37Ϫ6.35 (m, 2
H, 7-H ϩ 11-H), 5.79Ϫ5.75 (m, 2 H, 4-H ϩ 13-H), 4.44 (d, 1 H,
13-H), 3.75 (s, 3 H, OCH3), 2.10 (m, 2 H, 2-CH2), 1.90, 1.90, 1.89,
(3 s, 9 H, 5-CH3, 9-CH3, 12-CH3), 1.50 (m, 2 H, 3-CH2), 1.30 (s, 6
H, 1-CH3) ppm. 13C NMR: δ ϭ 168.6 (CO); 130.5, 130.3, 128.2,
121.2, 119.9, 51.5 (CH); 35.6, 34.2 (CH2); 53.7, 28.9, 27.9, 21.7,
13.1 (CH3) ppm. C23H32O4 (372.50): calcd. C 74.16, H 8.66; found
C 73.99, H 8.81.
Retinoic Acid (7a): A solution of retro-retinoate 6a (10.38 g,
25 mmol) in ethanol (250 mL) was saponified with an aqueous
ethanolic solution of KOH (8.4 g, 6 equiv.) in water (150 mL) at 40
°C for 45 min. The solvents were distilled under reduced pressure
and the crude mixture was acidified with cold HCl (2 ⁾. After
extraction with ethyl acetate and conventional workup, the oily
product was purified by column chromatography (SiO2; CH2Cl2/
MeOH, 98:2) to yield 5 g of (all-E)- and 1.05 g of (13Z)-retinoic
acid. The physicochemical properties were identical to those of a
reference product (SIGMA).
12-Methyl-13-demethylretinoic Acid (7b): This compound was ob-
tained by the same route from 6b (5 mmol) and purified by column
chromatography (SiO2; CH2Cl2/MeOH, 99:1) to produce (all-E)-7b
(0.76 g, 51%). Yellow crystals, m.p. 97 °C (pentane/ether). IR (film):
ν˜ ϭ 3447, 2970, 2943, 2875, 1708, 1675, 1446, 1381, 1265, 1170,
1061, 972, 733 cmϪ1. 1H NMR (CDCl3): δ ϭ 7.50 (d, J ϭ 15.50 Hz,
1 H, 13-H), 6.93, (d, J ϭ 12.0 Hz, 1 H, 11-H), 6.71 (d, J ϭ 15.8 Hz,
1 H, 7-H), 6.36 (d, J ϭ 15.8 Hz, 2 H, 8-H), 6.30 (d, J ϭ 12.0 Hz,
1 H, 10-H), 5.83 (d, J ϭ 15.5 Hz, 1 H, 14-H), 2.08 (s, 3 H, 12-
CH3), 1.94 (s, 3 H, 9-CH3), 1.86 (m, 2 H, 4-CH2), 1.76 (s, 3 H, 2-
CH3), 1.66 (m, 2 H, 3-CH2), 1.50 (m, 2 H, 2-CH2), 1.16 (s, 3 H, 1-
CH3) ppm. 13C NMR: δ ϭ 175.0 (CO); 151.6, 141.4, 137.6, 132.7,
125.4, 114.6 (CH); 39.5, 34.2, 19.1 (CH2); 30.9, 28.9, 21.7, 12.7,
12.3 (CH3) ppm. C20H28O2 (300.44): calcd. C 79.96, H 9.39; found
C 79.81, H 9.56.
Dimethyl 2-[(1E,3E,6E)-2-Methyl-5-oxo-7-(2,6,6-trimethyl-1-cyclo-
hexen-1-yl)-1,3,6-heptatrienyl]malonate (4b): This compound was
obtained by the same procedure, from 1b and β-ionone (0.96 g,
5 mmol). Yellow oil, purified by column chromatography (SiO2;
CH2Cl2); yield 1.07 g [57%; (all-E)/(12Z) ϭ 80:20]. IR (film): ν˜ ϭ
2976, 2940, 1752, 1635, 1703, 1436, 1320, 1262, 1220, 1196 cmϪ1
.
1H NMR (CDCl3): δ ϭ 7.46 (d, J ϭ 16.0 Hz, 1 H, 11-H), 7.32 (d,
J ϭ 15.8 Hz, 1 H, 7-H), 6.46 (d, J ϭ 16.0 Hz, 1 H, 10-H), 6.46 (d,
J ϭ 15.8 Hz, 1 H, 8-H), 6.20 (d, J ϭ 9.6 Hz, 1 H, 13-H), 4.48 (s, 1
H, 14-H), 3.79 (s, 6 H, OMe), 2.09 (m, 2 H, 4-CH2), 1.92 (s, 3 H,
12-CH3), 1.82 (s, 3 H, 5-CH3), 1.64 (m, 2 H, 3-CH2), 1.50 (m, 2 H, One-Pot Procedure. Retinoic Acid (7a): Butyllithium (1.6  in hex-
2-CH2), 1.10 (s, 6 H, 1-CH3) ppm. 13C NMR: δ ϭ 189.3, 167.9
anes, 100 mL, 160 mmol) was added at Ϫ25 °C to diisopropylamine
2252
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2250Ϫ2253

(all-E)-Retinoic Acid and Analogues from Enaminodiester Synthons
(23 mL, 1.1 equiv.) in DME (120 mL). β-Ionone (30.5 mL, 129.8, 129.2, 121.4, 115.9, 54.9 (CH); 30.9, 23.5, 19.1 (CH2); 27.7,
FULL PAPER
150 mmol) in DME (120 mL) was then slowly added at Ϫ30 to
Ϫ40 °C. The mixture was stirred at this temp. for 20 min, and en-
amino ester 1a (35.8 g, 1.05 equiv.) in DME (350 mL) was then
added. The refrigerating bath was removed and, after 10 min, the
solution was refluxed for 1 h. The temp. was allowed to rise to Ϫ10
to 0 °C, and methylmagnesium bromide (3  in THF, 115 mL, 2.3
equiv.) was added. The refrigerating bath was removed and, after
30 min, ethanol (150 mL) and then KOH (50.5 g, 6 equiv.) in water
(450 mL) were added at 0 °C. After 30 min, the solution was heated
at 40 °C for 45 min. The solvents were distilled under reduced
pressure and the crude mixture was acidified with cold HCl (2 ⁾.
The oily product was extracted and purified as reported above;
yield 27.6 g (61%) of the (all-E) isomer and 5.6 g (12%) of the
(13Z) isomer.
27.0, 23.0, 21.2, 13.3 (CH3) ppm. C20H28O2 (300.44): calcd. C
79.96, H 9.39; found C 79.77, H 9.57.
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12-Methyl-13-demethylretinoic Acid (7b): This compound was ob-
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yield 2.1 g (47%).
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hexen-1-yl)-1,3,6-heptatrienyl]malonate (9a): This compound was
obtained as a yellow oil, purified by column chromatography (SiO2;
CH2Cl2); yield 4.87 g [65%; (all-E)/(12Z) ϭ 80:20] by the same
method as used for 4a [from 20 mmol (3.85 g) of α-ionone]. IR
(film): ν˜ ϭ 2956, 2915, 2868, 1736, 1661, 1627, 1586, 1436, 1365,
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J. K. Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508Ϫ524.
R. F. Heck, J. P. Nolley, J. Org. Chem. 1972, 37, 2320Ϫ2322.
K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 4467Ϫ4470.
[11]
[12]
[13]
1286, 1211, 1150, 1040, 979 cmϪ1 1H NMR (CDCl3): δ ϭ 7.51
.
(dd, J ϭ 15.1, J ϭ 11.0 Hz, 1 H, 11-H), 6.72 (dd, J ϭ 15.6, J ϭ
9.8 Hz, 1 H, 7-H), 6.48 (d, J ϭ 15.1 Hz, 1 H, 10-H), 6.25 (d, J ϭ
15.6 Hz, 1 H, 8-H), 6.21 (d, J ϭ 12.05 Hz, 1 H, 12-H), 5.49 (m, 1
H, 4-H), 4.17 (s, 1 H, 14-H), 3.75 (s, 6 H, OMe), 2.30 (d, J ϭ
9.8 Hz, 1 H, 6-H), 2.03 (s, 3 H, 13-CH3), 2.02 (m, 2 H, 3-CH2),
1.48 (s, 3 H, 5-CH3), 1.43 and 1.20 (2 s, 6 H, 1-CH3) ppm.13C
NMR: δ ϭ 189.1, 167.6 (CO); 148.9, 139.2, 131.9, 129.5, 128.9,
122.5, 60.6, 52.1 (CH); 32.5, 22.7 (CH2); 53.4, 53.3, 27.8, 26.7, 22.9,
16.2 (CH3) ppm. C22H30O5 (374.47): calcd. C 70.56, H 8.07; found
C 70.37, H 8.19.
[14]
For recent C1ϪC7/C7ϪC8 strategies, see: [14a] Y. Pazos, B. Igles-
[14b]
ias, A. De Lera, J. Org. Chem. 2001, 66, 8483Ϫ8489.
T.
Takahashi, A. Furutani, S. Seko, PCT 059860, 12.10.2000. [14c]
T. Takahashi, S. Seko, E. P. 1120398, 01.08.2001. [14d] T. Takah-
ashi, A. Furutani, S. Seko, PCT 024713, 04.05.2000. For recent
C10ϪC11/C11ϪC12 strategies, see: [14e]D. Cahard, M. Mammeri,
J.-M. Poirier, L. Duhamel, Tetrahedron Lett. 2000, 41,
[14f]
3619Ϫ3622.
J.-E. Ancel, P. Meilland, PCT 00 02854,
20.01.2000. [14g] M. Salman, V. K. Kaul, J. S. Babu, N. Kumar,
PCT 009089, 08.10.2001. [14h]A. Laurent, V. Prat, A. Valla, Z.
4,5-Didehydro-5,6-dihydroretinoic Acid (α-Retinoic Acid) (10a): This
compound was obtained by the same method as used for the one-
pot route [from 1.92 g (10 mmol) of α-ionone]. Yellow oil purified
by column chromatography (SiO2; CH2Cl2/MeOH, 99:1); yield
0.53 g of (all-E), 0.98 g of (13Z) (together 50%). (all-E) Isomer:
Yellow crystals, m.p. 161 °C (pentane/ether). IR (film): ν˜ ϭ 2963,
Andriamialisoa, M. Giraud, R. Labia, P. Potier, Tetrahedron
Lett. 2000, 41, 7221Ϫ7224.
Z. Andriamialisoa, M. Giraud, R. Labia, P. Potier, Eur. J. Org.
Chem. 2001, 1731Ϫ1734.
Z. Andriamialisoa, D. Cartier, M. Giraud, R. Labia, P. Potier,
Tetrahedron Lett. 2001, 42, 4795Ϫ4797.
A. Laurent, Z. Andriamialisoa, C. Cartier, R. Labia, P. Potier,
Synth. Commun. 2001, 31, 3219Ϫ3223.
A. Laurent, Z. Andriamialisoa, D. Cartier, M. Giraud, R. La-
bia, P. Potier, Helv. Chim. Acta 2001, 84, 3423Ϫ3427.
Wada, K. Fukunaga, M. Ito, Synlett 2001, 800Ϫ802.
[14i]
A. Valla, V. Prat, A. Laurent,
[14j]
A. Valla, A. Laurent, V. Prat,
[14k]
A. Valla, V. Prat,
1
2915, 2861, 1680, 1586, 1443, 1252, 1190, 965, 904, 727 cmϪ1. H
[14l]
NMR (CDCl3): δ ϭ 6.99 (dd, J ϭ 15.0, J ϭ 11.4 Hz, 1 H, 11-H),
6.28, (d, J ϭ 15.0 Hz, 1 H, 12-H), 6.11 (2d, 2 H, J ϭ 15.5, J ϭ
11.4, 10-H ϩ 8-H), 5.77 (s, 1 H, 14-H), 5.64 (dd, J ϭ 15.5, J ϭ
9.5 Hz, 1 H, 7-H), 5.4 (s, 1 H, 4-H), 2.35 (s, 3 H, 13-CH3), 2.18 (d,
J ϭ 9.5 Hz, 1 H, 6-H), 2.00 (m, 2 H, 3-CH2), 1.93 (s, 3 H, 9-CH3),
1.56 (s, 3 H, 5-CH3), 1.43 and 1.21 (2 m, 2 H, 2-CH2), 0.89 and
0.80 (2 s, 3 H, 1-CH3) ppm. 13C NMR: δ ϭ 172.0 (CO); 135.6,
134.8, 133.2, 131.6, 128.9, 121.0, 117.8, 55.1 (CH); 30.7, 30.2, 26.9
(CH2); 27.5, 26.9, 23.3, 13.9, 13.1 (CH3) ppm. C20H28O2 (300.44):
calcd. C 79.96, H 9.39; found C 79.79, H 9.54. (13Z) Isomer: Yellow
crystals, m.p. 149 °C (pentane/ether). IR (film): ν˜ ϭ 2961, 2920,
2864, 1673, 1590, 1445, 1251, 1182, 967, 822, 725. 1H NMR
(CDCl3): δ ϭ 7.75 (d, J ϭ 15.3 Hz, 1 H, 12-H), 7.11, (dd, J ϭ 15.3,
J ϭ 11.4 Hz, 1 H, 11-H), 6.25 (d, J ϭ 11.4 Hz, 1 H, 10-H), 6.15
(d, J ϭ 15.4 Hz, 1 H, 8-H), 5.65 (dd, J ϭ 15.4, J ϭ 9.3 Hz, 1 H5,
7-H), 5.42 (s, 1 H, 4-H), 2.20 (d, J ϭ 9.35 Hz, 1 H, 6-H), 2.08 (s,
3 H, 13-CH3), 2.02 (m, 2 H, 3-CH2), 1.94 (s, 3 H, 9-CH3), 1.58 (s,
3 H, 5-CH3), 1.45 and 1.19 (2 m, 2 H, 2-CH2), 0.92 and 0.83 (2 s,
3 H, 1-CH3) ppm. 13C NMR: δ ϭ 171.8 (CO); 135.9, 133.2, 132.9,
A. Valla, V. Prat,
[14m]
A.
[15]
[16]
[17]
A. Valla, D. Cartier, R. Labia, P. Potier, PCT 0234710,
02.05.2002; Fr. Pat. 13726, 26.10.2002.
A. Valla, Z. Andriamialisoa, V. Prat, M. Giraud, A. Laurent,
P. Potier, Tetrahedron Lett. 1999, 40, 9235Ϫ9237.
From acyl chloride: H. O. Huisman, A. Smit, P. H. van
Leeuwen, J. H. van Rij, Recl. Trav. Chim. Pays-Bas 1956, 75,
977Ϫ1006.
From alkyl esters:
[18]
[18a]
O. Schwarzkopf, H. J. Cahnann, A. D.
Lewis, J. Swidinsky, H. M. Wuest, Helv. Chim. Acta 1949, 32,
[18b]
443Ϫ452.
C. D. Robeson, J. D. Cawley, L. Weisler, M. H.
Stern, C. C. Eddinger, A. J. Chechak, J. Am. Chem. Soc. 1955,
77, 4111Ϫ4119.
[19]
[20]
G. Britton, S. Liaaen-Jensen, H. Pfander, Carotenoids, vol.2
(‘‘Synthesis’’), Birkhäuser, Basel, 1996, p. 329.
IUPAC: Nomenclature of carotenoids, Pure Appl. Chem. 1975,
41, 406Ϫ431.
Received January 22, 2003
Eur. J. Org. Chem. 2003, 2250Ϫ2253
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2253