Stereoselective synthesis of 9-methylene-13-demethyl analogs of natural retinoids

Article abstract of DOI:10.1081/SCC-100106030

9-Methylene-13-demethyl analogs of retinol, retinal and retinoic acid, methyl ester were synthesised via new synthons β-methylenealdehydes.

Full text of DOI:10.1081/SCC-100106030

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STEREOSELECTIVE SYNTHESIS OF 9-METHYLENE-13-
DEMETHYL ANALOGS OF NATURAL RETINOIDS
Alain Valla a , Virginie Prat a , Alain Laurent a , Zo Andriamialisoa a , Dominique Cartier a
, Roger Labia a & Pierre Potier b
a rue de 1'Université , Chimie et Biologie des Substances Naturelles, FRE 2125 CNRS 6,
Quimper, 29000, France
b Institut de Chimie des Substances Naturelles , UPR 2301 CNRS Avenue de la Terrasse,
Gif-sur-Yvette, Cedex, 91198, France
Published online: 20 Aug 2006.
To cite this article: Alain Valla , Virginie Prat , Alain Laurent , Zo Andriamialisoa , Dominique Cartier , Roger Labia &
Pierre Potier (2001) STEREOSELECTIVE SYNTHESIS OF 9-METHYLENE-13-DEMETHYL ANALOGS OF NATURAL RETINOIDS,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:21,
3219-3223, DOI: 10.1081/SCC-100106030
To link to this article: http://dx.doi.org/10.1081/SCC-100106030
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SYNTHETIC COMMUNICATIONS, 31(21), 3219–3223 (2001)
STEREOSELECTIVE SYNTHESIS
OF 9-METHYLENE-13-DEMETHYL
ANALOGS OF NATURAL RETINOIDS
Alain Valla,1, Virginie Prat,1 Alain Laurent,1
*
Zo Andriamialisoa,1 Dominique Cartier,1
Roger Labia,1 and Pierre Potier2
1Chimie et Biologie des Substances Naturelles
FRE 2125 CNRS 6, rue de 1’Universite –
29000 Quimper, France
2Institut de Chimie des Substances Naturelles,
UPR 2301 CNRS Avenue de la Terrasse 91198
Gif-sur-Yvette Cedex, France
ABSTRACT
9-Methylene-13-demethyl analogs of retinol, retinal and reti-
noic acid, methyl ester were synthesised via new synthons
b-methylenealdehydes.
Retinoids have various biological activities, including cellular differ-
entiation, apoptosis and also act as modulators of inflammatory and immu-
nological events.1,2 Although retinoids are thought to have great therapeutic
potential, the wide range of toxic effects has often limited their clinical use.3
*Corresponding author. Fax: (33) 2 98908048; E-mail: Valla@iutquimp.univ-brest.fr
3219
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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VALLA ET AL.
Figure 1.
We recently reported the synthesis of a novel class of synthons,
b-methylenealdehydes, and their use in the synthesis of 13 Z retinoic
acids.4 Noteworthy, only a few examples of synthesis and use of b-methy-
lenealdehydes in organic chemistry were reported.5–11
Nevertheless, the stereochemistry of C-9 (9-methylene) could be pre-
served and we report here the syntheses of 9-methylene-13-demethyl analogs
of retinols, retinals and methyl retinoate via the b-methylenealdehydes 1a
and 1b (Figure 1).
Scheme 1.
These new synthons 1(a, b) were respectively synthesised from
b-ionone 2a and a-ionone 2b. Formylation (CH3ONa, HCOOCH3, pentane)
and acetalisation of the sodium salts of hydroxymethylenic compounds 3
(a, b) (CH3OH, H2SO4) furnished the b-ketoacetals 4 (a, b). Witting reaction
(t-ButOK, (C6H5)3Pþ-CH3 BrÀ, cyclohexane) and mild acidic hydrolysis of
the b-methyleneacetals 5 (a, b) (HCOOH, pentane), produce the b-methyle-
nealdehydes 1 (35% from 2a and 30% from 2b)4 (Scheme 1).
Reaction of compounds 1 with 4-(diethoxyphosphoryl)-but-2-enoic
acid, methyl ester (NaH, DME, À60ꢀC), affords the 9-methylene derivatives
6a (40%) and 6b (45%), with no detectable conjugated isomers. Thus,
this Horner-Emmons synthesis of compounds 1 with 4-(diethoxyphos-
phoryl)-but-2E-enoic acid, methyl ester, led stereoselectively (ꢁ 99%) to
the new 7E, 11E, 13E-9-methylene-13-demethyl analogs of retinoic acid,
methyl esters.12

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Scheme 2.
The retinol analogs 7 (7a, 65%, 7b, 70%) could be easily obtained
from these latter by reduction (DIBAL-H, À5ꢀC, then rt, 30 min), and the
retinal analogs 8 (8a, 60%, 8b, 70%) by MnO2 oxidation of alcohols 7
(MnO2, pentane, rt, 12 h) (Scheme 2).
ACKNOWLEDGMENT
We thank Prof. M. Giraud for his support of this research.
REFERENCES
1. Orfanos, C.E.; Ehlert, R.; Gollnick, H. Drugs 1987, 34, 459–503.
2. Linney, E. Current Topics in Developmental Biology, Academic Press,
Orlando, FL, 1992, pp. 309–350.
3. The retinoids, Biology, Chemistry and Medicine, 2nd ed.; Raven Press
Ltd., New York, 1994, pp. 545–572.
4. Giraud, M.; Valla, A.; Andriamialisoa, Z.; Potier, P. French Patent
1994, 9415189. BOPI 1996, 25, 2728260.
5. Huche, M. Tetrahedron Lett. 1976, 30, 2607.
6. Cresson, P.C.R. Hebd. Seances Acad. Sci. Ser. C 1974, 279, 859.
7. Kritchevsky, D. J. Amer. Chem. Soc. 1943, 65, 487.
8. Ansell, F.; Hancock, J.W.; Hickinbottom, W.H. J. Chem. Soc.
1956, 911.
9. Stella, L. Tetrahedron Lett. 1984, 25, 3457.
10. Cardillo, G.; Contento, M.; Sandri, S. J. Chem. Soc. Perkins Trans. 1
1979, 1729
11. Cardillo, G.; Contento, M.; Sandri, S. Tetrahedron Lett. 1974, 2215.
12. 6a: Yellow oil (40%). Anal. Calc. pour C20H28O2: C, 79.96; H, 9.39; O,
10.65. Found: C, 79.83; H, 9.43; O, 10.74. IR (film): 1721, 1644 cmÀ1
.

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VALLA ET AL.
1H NMR (400 Mz, C6D6): 7.55 (dd, 1H, J ¼ 15.5, J ¼ 10.8, C13-H); 6.24
(s, 2H, C7-H and C8-H); 6.06 (dd, 1H, J ¼ 15.2, J ¼10.8, C12-H); 5.96
(d, 1H, J ¼ 15.5, C14-H); 5.94 (dt, 1H, J ¼ 15.2, J ¼ 6.5, C11-H); 5.09
and 4.94 (2s, 2H, C9-CH2); 3.54 (s, 3H, CO2CH3); 2.94 (d, 2H, J ¼ 6.5,
C10-H); 2.02 (t, 2H, J ¼ 6.3, C3-H); 1.81 (s, 3H, C2-CH3); 1.67 (m, 2H,
C4-H); 1.54 (m, 2H, C5-H); 1.16 (s, 6H, C6-CH3). 13C NMR (100 Mz,
CDCl3); 167.5 (C15); 144.8, 141.7, 134.0, 129.5, 128.1 and 119.2 (C7, C8,
C11, C12, C13 and C14); 143.5, 137.2 and 129.1 (C1, C2 and C9); 115.6
(C9-CH2); 51.3 (CO2CH3); 39.3, 35.8, 32.7 and 19.1 (C3, C4, C5 and
C10); 34.0 (C6); 28.7 and 21.5 (C2-CH3 and C6-CH3).
6b: Yellow oil (45%). Anal. Calc. pour C20H28O2: C, 79.96; H, 9.39; O,
10.65. Found: C, 79.78; H, 9.45; O, 10.77. IR (film): 1721, 1644 cmÀ1
.
1H NMR (C6D6): 7.50 (dd, 1H, J ¼ 15.6, J ¼ 10.8, C13-H); 6.15 and
5.93 (2d, 2H, J ¼ 15.6, C8-H and C14-H); 6.00 (dd, 1H, J ¼ 15.2,
J ¼ 10.8, C12-H); 5.89 (dt, 1H, J ¼ 15.2, J ¼ 6.3, C11-H); 5.56 (dd, 1H,
J ¼ 15.6, J ¼ 9.5, C7-H); 5.51 (m, 1H, C3-H); 5.06 and 4.89 (2s, 2H,
C9-CH2); 3.54 (s, 3H, CO2CH3); 2.86 (d, 2H, J ¼ 6.3, C10-H); 2.20 (d,
1H, J ¼ 9.5, C1-H); 2.07 (m, 2H, C4-H); 1.73 (s, 3H, C2-CH3); 1.51 (dt,
1H, J ¼ 13.2, J ¼ 8.0, C5-H); 1.22 (dt, 1H, J ¼ 13.2, J ¼5.0, C5-H); 1.00
and 0.92 (2s, 6H, C6-CH3). 13C NMR (CDCl3): 167.5 (C15); 144.8,
141.6, 132.4, 132.2. 129.5, 120.9 and 119.1 (C3, C7, C8, C11, C12, C13
and C14); 143.2 and 133.9 (C2 and C9); 115.1 (C9-CH2); 54.5 and 51.4
(C1 and CO2CH3); 35.9, 31.7 and 22.9 (C4, C5 and C10); 32.3 (C6); 27.3,
26.9 and 22.8 (C2-CH3 and C6CH3).
7a: Yellow oil (65%). Anal. Calc. pour C19H28O: C, 83.77; H, 10.36; O,
5.87. Found: C, 83.59; H, 10.52; O, 5.89. IR (film): 3334 cmÀ1
.
1H NMR: (CDCl3): 6.27 and 6.14 (2dd, 2H, J ¼ 15.0, J ¼ 10.6, C12-H
and C13-H); 6.15 and 6.06 (2d, 2H, J ¼ 16.0, C7-H and C8-H); 5.81 (dt,
1H, J ¼ 15.0, J ¼ 6.7, C11-H); 5.75 (dt, 1H, J ¼ 15.0, J ¼ 6.0, C14-H);
5.00 and 4.95 (2s, 2H, C9-CH2); 4.17(d, 2H, J ¼ 6.0, C15-H); 3.07 (d,
2H, J ¼ 6.7, C10-H); 2.01 (t, 2H, J ¼ 6.2, C3-H); 1.70 (s, 3H, C2-CH3);
1.62 (m, 2H, C4-H); 1.47 (m, 2H, C5-H); 1.01 (s, 6H, C6-CH3).
13C NMR (CDCl3); 144.6, 137.4 and 128.9 (C1, C2 and C9); 134.4,
132.5, 131.5, 130.8, 130.0 and 127.7 (C7, C8, C11, C12, C13 and C14);
114.9 (C9-CH2); 63.2 (C15); 39.3, 35.4, 32.7 and 19.1 (C3, C4, C5, and
C10); 34.1 (C6); 28.7 and 21.5 (C2-CH3 and C6-CH3).
7b: Yellow oil (70%). Anal. Calc. pour C19H28O: C, 83.77; H, 10.36; O,
5.87. Found: C, 83.62; H, 10.51; O, 5.87. IR (film): 3331 cmÀ1
.
1H NMR (CDCl3): 6.23 and 6.09 (2dd, 2H, J ¼ 15.0, J ¼ 10.5, C12-H
and C13-H); 6.07 (d, 1H, J ¼ 15.6, C8-H); 5.76 (dt, 1H, J ¼ 15.0, J ¼ 6.7,
C11-H); 5.72 (dt, 1H, J ¼ 15.0, J ¼ 6.0, C14-H); 5.52 (dd, 1H, J ¼ 15.6,
J ¼ 9.5, C7-H); 5.42 (m, 1H, C3-H); 4.98 and 4.90 (2s, 2H, C9-CH2);

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9-METHYLENE-13-DEMETHYL ANALOGS
3223
4.14 (d, 2H, J ¼ 6.0, C15-H); 3.00 (d, 2H, J ¼6.7, C10-H); 2.16 (d, 1H,
J ¼9.5, C1-H); 2.02 (m, 2H, C4-H); 1.59 (s, 3H, C2-CH3); 1.43 (dt, 1H,
J ¼ 13.0, J ¼ 8.0. C5-H); 1.19 (dt, 1H, J ¼ 13.0, J ¼ 4.8. C5-H); 0.91 and
0.82 (2s, 6H, C6-CH3).13C NMR (CDCl3): 144.8 and 134.6 (C2 and C9);
133.3, 132.8, 132.3, 131.9, 131.4, 130.5 and 121.4 (C3, C7, C8, C11, C12,
C13, and C14); 114.9 (C9-CH2); 63.6 (C15); 55.1 (C1); 36.1, 32.3 and 23.5
(C4, C5 and C10); 32.8 (C6); 27.8, 27.5 and 23.4 (C2-CH3 and C6-CH3).
8a: Yellow oil (60%). Anal. Calc. pour C19H26O: C, 84.39; H, 9.69; O,
5.92. Found: C, 84.25; H, 9.77; O, 5.98. IR (film): 1723, 1683,
1
1638 cmÀ1. H NMR (C6D6): 9.48 (d, 1H, J ¼7.8, C15-H); 6.51 (dd,
1H, J ¼ 15.4, J ¼ 9.9, C13-H); 6.26 (s, 2H, C7-H and C8-H); 6.02 (dd,
1H, J ¼ 15.4, J ¼ 7.8, C14-H); 5.95 (m, 2H, C11-H and C12-H); 5.12 and
4.92 (2s, 2H, C9-CH2); 2.95 (d, 2H, J ¼ 5.3, C10-H); 2.03 (t, 2H, J ¼ 6.2,
C3-H); 1.82 (s, 3H, C2-CH3); 1.67 (m, 2H, C4-H); 1.56 (m, 2H, C5-H);
1.17 (s, 6H, C6-CH3). 13H NMR (CDCl3): 193.8 (C15); 152.2, 144.2,
133.9, 130.4, 129.7 and 128.3 (C7, C8, C11, C12, C13 and C14); 143.2,
137.1 and 129.3 (C1, C2 and C9); 115.9 (C9-CH2); 39.3, 36.0, 32.7 and
19.1 (C3, C4, C5 and C10); 34.7 (C6); 28.7 and 21.5 (C2-CH3 and
C6-CH3).
8b: Yellow oil (70%). Anal. Calc. pour C19H26O: C, 84.39; H, 9.69; O,
5.92. Found: C, 84.33; H, 9.74; O, 5.93. IR (film): 1683, 1640 cmÀ1
.
1H NMR (C6D6): 9.46 (d, 1H, J ¼7.9, C15-H); 6.56 (dd 1H, J ¼ 15.5,
J ¼ 10.0, C13-H); 6.16 (d, 1H, J ¼15.5, C8-H); 6.00 (dd, 1H,
J ¼ 15.2, J ¼ 7.9, C14-H); 5.95 (m, 2H, C11-H and C12-H); 5.57 (dd,
1H, J ¼ 15.5, J ¼ 9.5, C7-H); 5.52 (m, 1H, C3-H); 5.08 and 4.92 (2s,
2H, C9-CH2); 2.88 (d, 2H, J ¼ 5.2, C10-H); 2.21 (d, 1H, J ¼9.5, C1-H);
2.07 (m, 2H, C4-H); 1.72 (s, 3H, C2-CH3); 1.51 (dt, 1H, J ¼ 13.0,
J ¼ 8.0, C5-H); 1.23 (dt, 1H, J ¼ 13.0, J ¼ 4.8. C5-H); 1.01 and 0.92
(2s, 6H, C6-CH3). 13C NMR (CDCl3): 193.8 (C15); 152.2, 144.1,
132.4, 132.2, 130.3, 129.7 and 121.0 (C3, C7, C8, C11, C12, C13, and
C14); 142.8 and 133.8 (C2 and C9); 115.5 (C9-CH2); 54.5 (C1); 36.2, 31.7
and 22.9 (C4, C5 and C10); 32.3 (C6); 27.3, 26.9 and 22.8 (C2-CH3 and
C6-CH3).
Received in the UK November 1, 2000

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