A new one-pot synthesis of all E-retinoic acid via a new enaminodiester synthon

Article abstract of DOI:10.1016/S0040-4039(03)01431-X

A 'one-pot' synthesis of all E-retinoic acid from a new enaminodiester was described. The enaminodiester was easily produced from methyl isopropylidenemalonate and DMF-DMA.

Full text of DOI:10.1016/S0040-4039(03)01431-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5789–5790
A new one-pot synthesis of all E-retinoic acid via a new
enaminodiester synthon
a
a,b,
a
a
c
Dominique Cartier, Alain Valla, * Roger Labia, R e´ gis Le Guillou and Pierre Potier
a
Chimie et Biologie des Substances Naturelles 6, rue de l’Universit e´ , 29000 Quimper, France
b
VA R&D P e´ pini e` re d’Entreprises, 140 boulevard de Creac’h Gwen, 29561 Quimper, France
c
UPR 2301 CNRS Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Received 2 June 2003; revised 5 June 2003; accepted 7 June 2003
Abstract—A ‘one-pot’ synthesis of all E-retinoic acid from a new enaminodiester was described. The enaminodiester was easily
produced from methyl isopropylidenemalonate and DMF-DMA.
©
2003 Elsevier Ltd. All rights reserved.
All E-retinoic acid (RA) and some of its isomers inhibit
required stereochemistry, which increased the purifica-
tion problems and/or the number of steps.
some cancer cell growth in culture and in animal mod-
1
els. All E-RA and its 9Z and 13Z isomers have some
efficacy against certain human leukemia and several
skin cancers. Retinoids have been shown to affect
With a new concise route in mind for the synthesis of
all E retinoic acid, we recently synthesized a new C-6
2
15
multiple signal transduction pathways, including regu-
lation and differentiation and the best effects were
achieved with retinol, retinaldehyde, 13Z-RA and all
enaminodiester 1, which could be easily obtained and
directly condensed with b-ionone. Thus, dimethyl iso-
propylidenemalonate and dimethylformamide dimethyl-
acetal (DMF-DMA) directly provided this compound,
in nearly quantitative yield (Dean–Stark, 90°C, 18 h
then reflux, 2 h) (Scheme 1).
3
,4
E-RA. It has been shown that retinoic acid receptors
RARs) have a high affinity for both RA-retinoic acid
(
and its 9Z isomer, the latter was the natural ligand of
the retinoid X receptors (5RXRs). It was found
5
recently that the retinoic acid-induced apoptosis in
leukemia cells was mediated by the paracrine action of
tumor-selective death ligand trail (tumor necrosis fac-
The ‘one-pot’ procedure is illustrated in Scheme 2. The
lithium enolate of b-ionone was reacted with enam-
inodiester 1 to give the ketoester 3 via an intermediate
2 which, by heating, underwent elimination of dimethyl-
amine (LDA, DME, −25°C, then b-ionone in DME, 20
min, −25°C then 1, DME, −25°C to rt then reflux, 1 h).
Addition of the methyl Grignard reagent led to com-
pound 4 (MeMgBr, THF, −20°C then rt) which, after
saponification and further decarboxylation ((1) KOH, 5
6
tor-related apoptosis-inducing ligand).
The traditional and industrial synthetic routes of
retinoids have been so far based on three procedures:
7
8
Wittig (BASF), Julia (Aventis: ex. Rh oˆ ne-Poulenc)
9
and Isler (Hoffmann-La Roche). All make use of
b-ionone as the starting material. More recently, new
stereoselective approaches have been exhaustively
explored using palladium-catalyzed cross-coupling reac-
equiv., EtOH, H O, 40°C, 45 min, (2) HCl 2 M),
2
afforded regioselectively the all E retinoic acid 5 (all
E/13Z: 87/13, 70%). The physicochemical properties
were identical to those of a standard purchased from
Sigma (Scheme 2).
10
tions such as: the Negishi reaction, the Suzuki cou-
1
1
12
13
pling, the Stille reaction, the Heck reaction, and
1
4
the Sonogashira coupling.
In order to obtain stereoselective syntheses, these strate-
gies implied the use of polyethylenic partners with the
Keywords: all E retinoic acid; enaminodiester.
*
Corresponding author. Tel.: +33-2-98-64-19-22; fax: +33-2-98-64-
9-48; e-mail: valla@univ-brest.fr
1
Scheme 1.
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01431-X

5
790
D. Cartier et al. / Tetrahedron Letters 44 (2003) 5789–5790
Scheme 2.
The one-pot route was needed from both economical
and ecological points of view. This process was viable
because the reaction conditions of the successive steps
were compatible: thus the Grignard reagent could react
with the ketone because the negative charge of 3 was
stabilized by the two esters at the C14 position. After
hydrolysis of the esters and acidification, the malonic
acid obtained spontaneously decarboxylates, regioselec-
tively to all E retinoic acid. This synthesis was con-
cluded in 1 day with more than 70% yield from
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. Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746–
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. (a) Isler, O.; Huber, W.; Ronco, A.; Kofler, M. Helv.
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b-ionone on a 100 g scale.
1
1
0. (a) Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun.
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6. 1. Beige crystals, mp=113°C. IR (KBr): 1716; 1686;
619; 1539; 1433; 1399; 1330; 1191; 1115; 1068; 995; 959.
0
1
1
H NMR (CDCl ): 6.93 (d, 1H, J=13.2, H ); 6.07 (d, 1H,
2
000, 19, 1457–1465; (d) Lin, B.; Chen, G.; Xiao, D.;
3
4
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5
3
13
(
CH ) ); 2.10 (s, 3H, 3-CH ). C NMR (CDCl ) (CO):
3 2
3
3
167.3 (CH); 148.8; 97.4 (CH
); 52.0; 51.9; 41.0; 16.7.
3