New synthetic analogs of retinoids: Synthesis of aromatic analogs of 9-methylidene- and 13-demethyl-9-methylidene-retinol, -retinal, and ethyl 13-demethyl-9-methylideneretinoate

Article abstract of DOI:10.1002/1522-2675(20011114)84:11<3423::AID-HLCA3423>3.0.CO;2-C

Aromatic analogs of 9-methylidene and 13-demethyl-9-methylideneretinol, -retinal, and ethyl 13-demethyl-9-methylideneretinoate were synthesized via a new β-methylidene-aldehyde synthon.

Full text of DOI:10.1002/1522-2675(20011114)84:11<3423::AID-HLCA3423>3.0.CO;2-C

Helvetica Chimica Acta Vol. 84 (2001)
3423
New Synthetic Analogs of Retinoids: Synthesis of Aromatic Analogs of 9-
Methylidene- and 13-Demethyl-9-methylidene-retinol, -retinal, and Ethyl 13-
Demethyl-9-methylideneretinoate
by Alain Valla*1), Virginie Prat, Alain Laurent, Zo Andriamialisoa, Dominique Cartier, Michel Giraud,
Roger Labia
¬
Chimie et Biologie des Substances Naturelles, FRE 2125 CNRS, 6, rue de l−Universite,
F-29000 Quimper
and Pierre Potier
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS Avenue de la Terrasse,
F-91198 Gif-sur-Yvette Cedex
Aromatic analogs of 9-methylidene and 13-demethyl-9-methylideneretinol, -retinal, and ethyl 13-
demethyl-9-methylideneretinoate were synthesized via a new b-methylidene-aldehyde synthon.
Introduction. Retinoids are known to modulate proliferation and differentiation
of various cell types through activation of their intracellular receptors [1 3]. Presently,
several aromatic retinoids are used for the treatment of cancers and skin diseases
[3][4]. The search for new analogs with better therapeutic indices is still of current
interest.
Standard methodologies for the preparation of synthetic retinoids have generally
been based on established methods or on previously reported compounds rather than
on development of new synthons.
We recently reported the synthesis of b-methylidenealdehyde synthons, and their
use in the synthesis of (13Z)- or (13E)-retinoic acids [5][6] (Scheme 1).
Results and Discussion. Use of b-methylidene aldehyde A as an alternative to b-
ionylideneacetaldehyde [7 9] enabled synthesis of the standard substituted chain of
retinoids (Scheme 1). Moreover, the −9-methylidene× configuration could be preserved
under Horner-Emmons conditions, prompting us to synthesize the new aromatic 9-exo-
methylidene retinoids via the new b-methylidene aldehyde 1 (Scheme 2).
This new synthon 1 was synthesized from (E)-4-phenylbut-3-en-2-one (2).
Formylation (MeONa, HCOOMe, pentane) and acetalization of Na salt of the
hydroxymethylidene compound 3 (MeOH, H2SO4) furnished the b-acetal 4. Wittig
‡
reaction (t-BuOK, (C6H5)3P CH3 BrÀ, cyclohexane) and mild acidic hydrolysis of the b-
methylideneacetal 5 (HCOOH, pentane), provided the b-methylidene aldehyde 1
(20% from 2).
1
)
E-mail: Valla@iutquimp.univ-brest.fr; fax: (33)298908048

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Helvetica Chimica Acta Vol. 84 (2001)
Scheme 1
Scheme 2
Reaction of compound 1 with ethyl (E)-4-(diethoxyphosphoryl)but-2-enoate
(NaH, DME, À608) afforded the 9-methylidene derivative 6a (Scheme 3). Thus, this
Horner-Emmons-based synthesis led stereoselectively (99%) to the new
(7E,11E,13E)-13-demethyl-9-methylidene analog of ethyl retinoate. Under the same

Helvetica Chimica Acta Vol. 84 (2001)
3425
conditions, reaction of 1 with ethyl (E)-4-(diethoxyphosphoryl)-3-methylbut-2-enoate
(or the mixture (E)/(Z) 50 :50) led to the aromatic 9-methylidene analog of ethyl
retinoate 6b, as a mixture of (13E)- and (13-Z)-isomers (50 :50).
The retinol analogs 7 could be easily obtained from the latter by reduction
(DIBAL-H, À58, the room temperature, 30 min.). Oxidation of alcohols 7 (MnO2,
pentane, room temperature, 12 h) then afforded the retinal analogs 8 (Scheme 3).
Scheme 3
The new aromatic 9-methylidene and 13-demethyl-9-methylidene analogs of
retinol, retinal, and ethyl retinoate were obtained with no detectable amounts of
conjugated isomers.
Experimental Part
General. All reactions were carried out under Ar. Pure anal. samples of compounds 6 8 were obtained by
anal. TLC performed on Merck silica gel (60 F254) plates. IR Spectra: Bruker IF-55 spectrometer. 1H- and
13C-NMR spectra were recorded at 400 and 100 MHz, resp., on a Bruker Avance DPX-400 instrument. The
chemical shifts (d) are reported in ppm relative to TMS (J in Hz).
(E)-3-Methylidene-5-phenylpent-4-enal (1). Yellow oil (20% from 4-phenylbut-3-en-2-one). IR (film):
1722. 1H-NMR (CDCl3): 9.70 (t, J ˆ 2.4, CHO); 7.44 (d, J ˆ 7.3, HÀC(2), HÀC(6) of Ph); 7.35 (t, J ˆ 7.3,
HÀC(3), HÀC(5) of Ph); 7.25 (m, HÀC(4) of Ph); 6.93, 6.50 (2d, J ˆ 16.3, HÀC(4), HÀC(5)); 5.47, 5.27 (2s,
CH2); 3.41 (d, J ˆ 2.4, CH2(10). 13C-NMR (CDCl3): 199.9 (C(1); 137.3, 136.4 (C(1) of Ph, C(3)); 130.0, 129.8,
128.6, 127.9, 126.5 (C(2), C(3), C(4), C(5), C(6) of Ph, and C(4) and C(5)); 120.8 (CH2ˆ); 47.4 (C(10)). Anal.
calc. for C12H12O: C 83.69, H 7.02, O 9.29; found: C 83.53, H 7.12, O 9.35.
Compounds 6a and 6b: Typical Procedure. To a suspension of NaH (5.8 mmol) in 1,2-dimethoxyethane
(DME, 10 ml) was added at À108 a DME soln. (20 ml) of ethyl (E)-4-(diethoxyphosphoryl)but-2-enoate (for
6a) or ethyl (E)/(Z)-4-(diethoxyphosphoryl)-3-methylbut-2-enoate (for 6b) (50 :50; 5.8 mmol). The soln. was
stirred for 15 min, and a DME solution (20 ml) of 1 (5.8 mmol) was added slowly at À608. The mixture was then
warmed to r.t. and hydrolyzed with aq. sat. NH4Cl soln. The mixture was extracted with Et2O, and the org. layers
were washed with H2O and dried (MgSO4). The residue was purified by chromatography on silica gel, eluting
with CH2Cl2/cyclohexane 60 :40 to provide compounds 6a or 6b as yellow oils.
Ethyl 7-Methylidene-9-phenylnona-2,4,8-trienoate (6a). Yield 35%. IR (film): 1710, 1642. 1H-NMR
(C6D6)2): 7.57 (dd, J ˆ 15.4, 10.8, HÀC(13)); 7.37 (d, J ˆ 7.4, HÀC(2), HÀC(6)); 7.24 (t, J ˆ 7.4, HÀC(3),
HÀC(5)); 7.17 (t, J ˆ 7.4, HÀC(4)); 6.86 (2d, J ˆ 16.2, HÀC(7), HÀC(8)); 6.04 (dd, J ˆ 15.2, 10.8, HÀC(12));
5.99 (d, J ˆ 15.4, HÀC(14)); 5.90 (dt, J ˆ 15.2, 6.7, HÀC(11)); 5.17, 5.00 (2s, CH2ˆ)); 4.18 (q, J ˆ 7.1, MeCH2);

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Helvetica Chimica Acta Vol. 84 (2001)
2.90 (d, J ˆ 6.7, CH2(10)); 1.11 (t, J ˆ 7.1, MeCH2). 13C-NMR (CDCl3)2): 167.0 (C(15)); 144.3, 140.8, 130.1, 129.8,
128.8, 128.5, 127.6, 126.4, 120.0 (C(2), C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12), C(13), C(14)); 143.3,
136.9 (C(1), C(9)); 117.8 (CH2ˆ); 60.1 (MeCH2); 35.5 (C(10)); 14.2 (MeCH2). Anal. calc. for C18H20O2: C
80.56, H 7.51, O 11.93; found: C 80.43, H 7.63, O 11.94.
Ethyl 3-Methyl-7-methylidenenona-2,4,8-trienoate (6b; (13E)/(13Z) 50 : 50). Yield 40%. Yellow oil. Anal.
calc. for C19H22O2: C 80.82, H 7.85, O 11.33; found: C 80.68, H 7.86, O 11.46.
Data of (13E)-6b: IR (film): 1712, 1636, 1612. 1H-NMR (D6)DMSO)2): 7.52 (d, J ˆ 7.3, HÀC(2), HÀC(6));
7.35 (t, J ˆ 7.3, HÀC(3), HÀC(5)); 7.25 (t, J ˆ 7.3, HÀC(4)); 6.98, 6.69 (2d, J ˆ 16.4, HÀC(7), and HÀC(8));
6.36 (d, J ˆ 15.6, HÀC(12)); 6.28 (dt, J ˆ 15.6, 6.3, HÀC(11)); 5.79 (s, HÀC(14)); 5.29, 5.12 (2s, CH2ˆ); 4.08 (q,
J ˆ 7.1, MeCH2); 3.21 (d, J ˆ 6.3, CH2(10)); 2.22 (s, MeÀC(13)); 1.20 (t, J ˆ 7.1, MeCH2). 13C-NMR (CDCl3)2):
167.1 (C(15)); 152.0, 143.7, 137.0 (C(1), C(9), C(13)); 135.1, 134.0, 130.3, 128.7, 128.5, 127.5, 126.4, 118.3 (C(2),
C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12), C(14)); 117.6 (CH2ˆ); 59.6 (MeCH2); 35.5 (C(10)); 14.2, 13.8
(MeÀC(13), MeCH2).
Data of (13Z)-6b: IR (film): 1707, 1636, 1603. 1H-NMR ((D6)DMSO)2): 7.59 (d, J ˆ 15.8, HÀC(12)); 7.51
(d, J ˆ 7.4, HÀC(2), and HÀC(6)); 7.35 (t, J ˆ 7.4, HÀC(3), HÀC(5)); 7.25 (t, J ˆ 7.4, HÀC(4)); 6.98, 6.69 (2d,
J ˆ 16.4, HÀC(7), HÀC(8)); 6.31 (dt, J ˆ 15.8, 6.8, HÀC(11)); 5.68 (s, HÀC(14)); 5.30, 5.13 (2s, CH2ˆ); 4.08 (q,
J ˆ 7.1, MeCH2); 3.23 (d, J ˆ 6.8, CH2(10)); 1.98 (s, MeÀC(13)); 1.19 (t, J ˆ 7.1, MeCH2). 13C-NMR (CDCl3)2):
166.2 (C(15)); 150.7, 143.9, 137.1 (C(1), C(9), C(13)); 135.7, 130.3, 129.3, 128.8, 128.5, 127.5, 126.4, 116.4 (C(2),
C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12), and C(14)); 117.5 (CH2ˆ); 59.6 (MeCH2); 36.0 (C(10)); 21.0,
14.2 (MeÀC(13), MeCH2).
Compounds 7a and 7b: Typical Procedure. DIBAL-H (20% in toluene, 10 mmol) was slowly added at À58
to 5 mmol of 6a or 6b in toluene (10 ml). After stirring 30 min at À58, the reaction was quenched with aq. sat.
NH4Cl soln. The resulting crude product was extracted with Et2O. The org. layers were washed with H2O and
dried (MgSO4). The combined extracts were concentrated, and the oily product was purified by chromatog-
raphy on silica gel eluting with CH2Cl2 (for 7a) or CH2Cl2/MeOH: 98 :2 (for 7b) to furnish the alcohols 7a or 7b
as yellow oils.
7-Methylidene-9-phenylnona-2,4,8-trien-1-ol (7a). Yield 60%. Anal. calc. for C16H18O: C 84.91, H 8.02, O
1
7.07; found: C 84.76, H 8.08, O 7.16. IR (film): 3302. H-NMR (CDCl3)2): 7.45 (d, J ˆ 7.3, HÀC(2), HÀC(6));
7.35 (t, J ˆ 7.3, HÀC(3), HÀC(5)); 7.26 (t, J ˆ 7.3, HÀ(4)); 6.87, 6.61 (2d, J ˆ 16.3, HÀC(7), HÀC(8)); 6.29, 6.19
(2dd, J ˆ 15.0, 10.4, HÀC(12), HÀC(13)); 5.86 (dt, J ˆ 15.0, 6.8, HÀC(11)); 5.80 (dt, J ˆ 15.0, 6.0, HÀC(14));
5.23, 5.11 (2s, CH2ˆ); 4.19 (d, J ˆ 6.0, HÀC(15)); 3.16 (d, J ˆ 6.8, CH2(10)). 13C-NMR (CDCl3)2): 144.2, 137.1
(C(1), C(9)); 132.1, 131.5, 131.0, 130.4, 130.2, 128.6, 128.5, 127.4, 126.4 (C(2), C(3), C(4), C(5), C(6), C(7),
C(8), C(11), C(12), C(13), and C(14)); 117.3 (CH2ˆ); 63.3 (C(15)); 35.2 (C(10)).
3-Methyl-7-methylidene-9-phenylnona-2,4,8-trien-1-ol (7b; (13E)/(13Z) 50 :50). Yield 70%. Anal. calc. for
C17H20O: C 84.96, H 8.39, O 6.66; found: C 84.83, H 8.44, O 6.73.
Data of (13E)-7b: IR (film): 3356. 1H-NMR (CDCl3)2): 7.45 (d, J ˆ 7.3, HÀC(2), HÀC(6)); 7.35 (t, J ˆ 7.3,
HÀC(3), HÀC(5)); 7.26 (t, J ˆ 7.3, HÀC(4)); 6.87, 6.63 (2d, J ˆ 16.3, HÀC(7), and HÀC(8)); 6.21 (d, J ˆ 15.6,
HÀC(12)); 5.83 (dt, J ˆ 15.6, 6.8, HÀC(11)); 5.64 (t, J ˆ 6.9, HÀC(14)); 5.22, 5.11 (2s, CH2ˆ); 4.30 (d, J ˆ 6.9,
CH2(15)); 3.18 (d, J ˆ 6.8, CH2(10)); 1.83 (s, Me). 13C-NMR (CDCl3)2): 144.5, 137.2, 136.2 (C(1), C(9), C(13));
135.6, 130.5, 128.6, 128.5, 128.4, 127.4, 127.2, 126.4 (C(2), C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12),
C(14)); 117.2 (CH2ˆ); 59.3 (C(15)); 35.4 (C(10)); 12.6 (Me).
Data of (13Z)-7b: IR (film): 3384. 1H-NMR (CDCl3)2): 7.45 (d, J ˆ 7.3, HÀC(2), HÀC(6)); 7.35 (t, J ˆ 7.3,
HÀC(3), HÀC(5)); 7.26 (t, J ˆ 7.3, HÀC(4)); 6.90, 6.63 (2d, J ˆ 16.2, HÀC(7), HÀC(8)); 6.57 (d, J ˆ 15.5,
HÀC(12)); 5.92 (dt, J ˆ 15.5, 6.8, HÀC(11)); 5.54 (t, J ˆ 7.0, HÀC(14)); 5.24, 5.12 (2s, CH2ˆ); 4.32 (d, J ˆ 7.0,
CH2(15)); 3.21 (d, J ˆ 6.8, CH2(10)); 1.90 (s, Me). 13C-NMR (CDCl3)2): 144.3, 137.1, 135.4 (C(1), C(9), C(13));
130.5, 129.6, 128.6, 128.5, 128.0, 127.4, 126.8, 126.4 (C(2), C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12), and
C(14)); 117.3 (CH2ˆ); 58.3 (C(15)); 35.7 (C(10)); 20.5 (Me).
Compounds 8a and 8b: Typical Procedure. A mixture of alcohol 7a or 7b (10 mmol) and 100 mmol of MnO2
in 60 ml of pentane was stirred at r.t. for 3 h. After filtration, the org. layer was concentrated, and the oily
product was purified by chromatography on silica gel eluting with CH2Cl2 to provide the aldehydes 8 as yellow
oils.
7-Methylidene-9-phenylnona-2,4,8-trienal (8a). Yield 65%. Anal. calc. for C16H16O: C 85.68, H 7.19, O 7.13;
found: C 85.50, H 7.35, O 7.14. IR (film): 1687, 1637. 1H-NMR (CDCl3)2): 9.57 (d, J ˆ 8.0, HÀC(15)); 7.45 (d, J ˆ
2
)
For C-atom numbering, see formula 6 in Scheme 3.

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7.3, HÀC(2), HÀC(6)); 7.36 (t, J ˆ 7.3, HÀC(3), HÀC(5)); 7.27 (t, J ˆ 7.3, HÀC(4)); 7.14 (dd, J ˆ 15.3, 10.0,
HÀC(13)); 6.87, 6.58 (2d, J ˆ 16.3, HÀC(7), HÀC(8)); 6.45 (m, HÀC(11), HÀC(12)); 6.13 (dd, J ˆ 15.3, 8.0,
HÀC(14)); 5.29, 5.13 (2s, CH2ˆ); 3.29 (d, J ˆ 5.2, CH2(10)). 13C-NMR (CDCl3)2): 193.8 (C(15)); 152.0, 143.5,
130.6, 130.0, 129.9, 129.0, 128.6, 127.7, 126.4 (C(2), C(3), C(4), C(5), C(6), C(7), C(8), C(11), C(12), C(13), and
C(14)); 142.9, 136.8 (C(1), C(9)); 118.1 (CH2ˆ); 35.7 (C(10)).
3-Methyl-7-methylidene-9-phenylnona-2,4,8-trienal (8b; (13E)/(13Z) 50 :50): Yield 70%. Anal. calc. for
C17H18O: C 85.67, H 7.60, O 6.71; found C 85.50, H 7.62, O 6.88.
Data of (13E)-8b: IR (film): 1666, 1632. 1H-NMR (CDCl3)2): 10.13 (d, J ˆ 8.2, CHO); 7.45 (d, J ˆ 7.3,
HÀC(2), HÀC(6)); 7.36 (t, J ˆ 7.3, HÀ(C3), HÀC(5)); 7.27 (t, J ˆ 7.3, HÀC(4); 6.88, 6.60 (2d, J ˆ 16.3,
HÀC(7), HÀC(8)); 6.42 (dt, J ˆ 15.8, 6.4, HÀC(11)); 6.33 (d, J ˆ 15.8, HÀC(12)); 5.95 (d, J ˆ 8.2, HÀC(14));
5.28, 5.13 (2s, CH2ˆ); 3.27 (d, J ˆ 6.4, CH2(10)); 2.28 (s, Me). 13C-NMR (CDCl3)2): 191.4 (C(15)); 154.3, 143.3,
136.9 (C(1), C(9), C(13)); 136.2, 134.8, 130.1, 128.9, 128.8, 128.6, 127.6, 126.4 (C(2), C(3), C(4), C(5), C(6),
C(7), C(8), C(11), C(12), C(14); 117.9 (CH2ˆ); 35.7 (C(10)); 13.0 (Me).
Data of (13Z)-8b: IR (film): 1666, 1633. 1H-NMR (CDCl3)2): 10.20 (d, J ˆ 8.1, CHO); 7.45 (d, J ˆ 7.3,
HÀC(2), HÀC(6)); 7.36 (t, J ˆ 7.3, HÀC(3), HÀC(5)); 7.27 (t, J ˆ 7.3, HÀC(4)); 7.22 (d, J ˆ 15.4, HÀC(12));
6.88, 6.61 (2d, J ˆ 16.3, HÀC(7), HÀC(8)); 6.33 (dt, J ˆ 15.4, 6.7, HÀC(11)); 5.87 (d, J ˆ 8.1, HÀC(14)); 5.29,
5.14 (2s, CH2ˆ); 3.31 (d, J ˆ 6.7, CH2(10)); 2.11 (s, Me). 13C-NMR (CDCl3)2): 191.1 (C(15)); 154.4, 143.2, 136.8
(C(1), C(9), C(13)); 137.3, 130.1, 128.9, 128.6, 127.8, 127.6, 126.8, 126.4 (C(2), C(3), C(4), C(5), C(6), C(7),
C(8), C(11), C(12), C(14)); 117.9 (CH2ˆ); 35.9 (C(10)); 21.3 (Me).
We are indebted to Dr. R. H. Dodd for helpful discussions.
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Received May 19, 2001