Synthesis of new ethyl 9-methylene-13E and 13Z-retinoates via the Julia olefination reaction

Article abstract of DOI:10.1016/S0040-4039(01)00845-0

Synthesis of new ethyl 9-methylene-13E and 13Z-retinoates via the 9-methylene C-15 sulphone 5 is reported. The Julia olefination strategy was used for building the C-20 skeleton.

Full text of DOI:10.1016/S0040-4039(01)00845-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4795–4797
Synthesis of new ethyl 9-methylene-13E and 13Z-retinoates via
the Julia olefination reaction
Alain Valla,a,* Alain Laurent,a Virginie Prat,a Zo Andriamialisoa,a Dominique Cartier,a
Michel Giraud,a Roger Labiaa and Pierre Potierb
aChimie et Biologie des Substances Naturelles, FRE 2125, rattache´e au CNRS 6, rue de l’Universite´, 29000 Quimper, France
bInstitut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 18 April 2001; accepted 18 May 2001
Abstract—Synthesis of new ethyl 9-methylene-13E and 13Z-retinoates via the 9-methylene C-15 sulphone 5 is reported. The Julia
olefination strategy was used for building the C-20 skeleton. © 2001 Elsevier Science Ltd. All rights reserved.
Retinoids are metabolites, derivatives and synthetic
analogues of vitamin A which exert biological effects by
binding to and activating nuclear retinoid receptors.
The therapeutic actions of retinoids are due to their
ability to regulate cellular processes such as cellular
differentiation, proliferation and modulation of apop-
tosis.1–3 The search for new analogues which minimise
the wide range of toxic effects is therefore of current
interest and prompted us to synthesise the 9 and 13-
methylenic analogues of retinal,4 using b-methyl-
enealdehyde as synthon.5,6
cance of this reaction is reflected by its widespread use
in the total synthesis of natural products such as
retinoic acid11 (Scheme 1).
We report herein on a synthesis of new 13Z and 13E
ethyl 9-methylene retinoates via a new 9-methylene
C-15 sulphone 5. The required sulphone was prepared
as follows: O-silylation of the lithium enolate of b-
ionone 1 with Me3SiCl gave the trimethylsilylenol ether
2. Catalytic condensation (ZnBr2) of enol 2 with
chloromethyl phenyl sulphide led to the b-ketosulphide
3. Peterson olefination of 3 furnished the methylenic
sulphide 4. Oxidation of crude 4, using bis (trimethylsil-
yl) peroxide12 afforded the 9 methylene-C-15 sulphone
5 without any detectable oxidation of the CꢀC double
bonds (Scheme 2).
It is noteworthy that a few synthetic retinoids possess
an exo-methylenic sub-structure on the polyene chain.7–10
The Julia reaction is by far the most important type of
sulphone elimination process and the synthetic signifi-
Scheme 1. (a) EtONa; (b) methyl (2E)-4-bromo-3-methyl-2-butenoate; (c) KOH/EtOH; (d) H3O+.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00845-0

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A. Valla et al. / Tetrahedron Letters 42 (2001) 4795–4797
Scheme 2. Reagents and conditions: (a) LDA, −70°C/THF, 30 min; (b) Me3SiCl/−70°C, 30 min to 0°C, 1 h (95%); (c)
C6H5SCH2SCl/CH2Cl2/ZnBr2 (0.1 equiv), rt, 12 h (55%); (d) Me3SiCH2MgCl/ether, 0°C, 30 min then rt, 1 h (85%); (e) bis
(trimethylsilyl) peroxide/C6H6 80°C, 18 h (70%).
Scheme 3. Reagents and conditions: (a) BuLi/THF, −70°C, 30 min; (b) ethyl 4-bromo-3-methyl-2-butenoate (2E/2Z: 50/50)/THF,
−70°C, 90 min (75%); (c) EtONa (5 equiv.)/cyclohexane, 90 min, rt (95%).
The Julia strategy permitted to build the C-20 skeleton
with no detectable amounts of conjugated isomers.
Thus, anionisation of the sulphone 5 using BuLi, fol-
lowed by treatment with ethyl 4-bromo-3-methyl-2-
butenoate (2E/2Z: 50/50) led to the sulphone-ester 6, as
a mixture of E and Z isomers (E/Z: 50/50). Elimination
of the sulfonyl residue to form ethyl 9-methylene-
retinoates 7 was performed by treating the crude ester 6
mixture with EtONa in cyclohexane, to form 7 as a
mixture of 13E and 13Z isomers (E/Z: 50/50) (Scheme
3). Pure analytical samples of compounds 7 (13E) and
7 (13Z) were obtained by analytical chromatography
performed on Merck silica gel (60 F254) plates, using
CH2Cl2 as eluent.13
3. Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. In The
Retinoids: Biology, Chemistry and Medicine. The retinoid
receptors., 2nd ed.; Raven Press Ltd: New York, 1994;
pp. 319–349.
4. Laurent, A.; Prat, V.; Valla, A.; Andriamialisoa, Z.;
Giraud, M.; Labia, R.; Potier, P. Tetrahedron Lett. 2000,
41, 7221–7224.
5. Valla, A.; Andriamialisoa, Z.; Prat, V.; Laurent, A.;
Giraud, M.; Labia, R.; Potier, P. Tetrahedron 2000, 56,
7211–7215.
6. Valla, A.; Andriamialisoa, Z.; Giraud, M.; Prat, V.;
Laurent, A.; Potier, P. Tetrahedron Lett. 1999, 40, 9235–
9237.
7. Tanaka, H.; Kagechika, H.; Kawachi, E.; Fukasawa, H.;
Hashimoto, Y.; Shudo, K. J. Med. Chem. 1992, 35,
567–572.
Acknowledgements
8. Mandai, T.; Iuchi, Y.; Suzuki, Y.; Kawada, M.; Otera, J.
Tetrahedron Lett. 1982, 23, 4721–4724.
9. Cardillo, G.; Contendo, M.; Sandri, S. J. Chem. Soc.,
Perkin Trans. 1 1979, 1729–1733.
10. Cardillo, G.; Contendo, M.; Sandri, S. Tetrahedron Lett.
1974, 15, 2215–2216.
We are indebted to Dr. R. H. Dodd for helpful
discussions.
11. Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 746–
750.
References
12. Kocienski, P.; Todd, M. J. Chem. Soc. 1982, 1078–1079.
1
13. Compound 2: yellow oil. IR (film): 1610. H NMR (400
1. Orfanos, C. E.; Ehlert, R.; Gollnick, H. Drugs 1987, 34,
459.
2. Linney, E. Current Topics in Developmental Biology; Aca-
demic Press: Orlando, FL, 1992; pp. 309–350.
MHz, CDCl3): 6.42 and 5.89 (2d, 2H, J=15.8, C7-H and
C8-H); 4.34 and 4.32 (2s, 2H, C10-H); 2.02 (t, 2H, J=6.2,
C3-H); 1.72 (s, 3H, C2-CH3); 1.62 (m, 2H, C4-H); 1.48 (m,

A. Valla et al. / Tetrahedron Letters 42 (2001) 4795–4797
4797
2H, C5-H); 1.03 (s, 6H, C6-CH3); 0.27 (s, 9H, Si(Me)3).
13C NMR (100 MHz, CDCl3): 155.2, 136.7 and 129.6 (C9,
C2 and C1); 129.9 and 128.1 (C8 and C7); 95.3 (C10); 39.5
(C5); 34.0 (C6); 32.9 (C3); 28.7 (C6-CH3); 22.0 (C2-CH3);
19.1 (C4); 0.0 (Si(Me)3).
6.14 and 6.04 (2d, 2H, J=16.4, C7-H and C8-H); 5.74 (s,
1H, C14-H); 5.07 and 4.99 (2s, 2H, H2Cꢀ); 4.08 (q, 2H,
J=7.1, CO2-CH2-CH3); 3.15 (d, 2H, J=6.2, C10-H); 2.20
(s, 3H, C13-CH3); 1.97 (m, 2H, C3-H); 1.64 (s, 3H,
C2-CH3); 1.56 (m, 2H, C4-H); 1.41 (m, 2H, C5-H); 1.20 (t,
3H, J=7.1, CO2-CH2-CH3); 0.95 (s, 6H, C6-CH3). 13C
NMR (DMSO-d6): 166.6 (C15); 152.3, 144.1, 137.4 and
128.9 (C13, C9, C2 and C1); 135.6 (C11); 134.8 (C12); 134.4
and 128.1 (C8 and C7); 117.9 (C14); 116.4 (H2Cꢀ); 59.6
(CO2-CH2-CH3); 39.3 (C5); 35.7 (C10); 34.1 (C6); 32.6
(C3); 28.9 (C6-CH3); 21.7 (C2-CH3); 19.1 (C4); 14.5 (CO2-
CH2-CH3); 13.8 (C13-CH3).
1
Compound 3: yellow oil. IR (film): 1665; 1604; 1585. H
NMR (CDCl3): 7.39–7.20 (m, 6H, Ph and C7-H); 6.10 (d,
1H, J=16.3, C8-H); 3.25 (t, 2H, J=7.6, C11-H); 2.94 (t,
2H, J=7.6, C10-H); 2.10 (t, 2H, J=6.2, C3-H); 1.77 (s,
3H, C2-CH3); 1.63 (m, 2H, C4-H); 1.49 (m, 2H, C5-H);
1.07 (s, 6H, C6-CH3). 13C NMR (CDCl3): 198.9 (C9);
143.2, 130.4, 129.8, 129.4 and 126.6 (C8, C7 and Ph);
137.4, 136.3 and 136.2 (C2, C1 and q Ph); 40.3 and 40.1
(C11 and C10); 34.5 (C6); 34.0 (C5); 29.2 (C6-CH3); 28.4
(C3); 22.2 (C2-CH3); 19.2 (C4).
Compound 7: (13E) yellow oil. UV (EtOH) umax: 264 nm.
1
IR (film): 1714; 1603. H NMR (DMSO-d6): 7.57 (d, 1H,
J=15.9, C12-H); 6.25 (dt, 1H, J1=15.9, J2=6.6, C11-H);
6.13 and 6.03 (2d, 2H, J=16.4, C7-H and C8-H); 5.66 (s,
1H, C14-H); 5.08 and 5.01 (2s, 2H, H2Cꢀ); 4.06 (q, 2H,
J=7.1, CO2-CH2-CH3); 3.17 (d, 2H, J=6.6, C10-H); 1.98
(m, 5H, C13-CH3 and C3-H); 1.64 (s, 3H, C2-CH3); 1.56
(m, 2H, C4-H); 1.41 (m, 2H, C5-H); 1.19 (t, 3H, J=7.1,
CO2-CH2-CH3); 0.94 (s, 6H, C6-CH3). 13C NMR
(DMSO-d6): 165.6 (C15); 150.9, 144.1, 137.4 and 128.8
(C13, C9, C2 and C1); 137.1 (C11); 134.3 and 128.2 (C8 and
C7); 128.7 (C12); 116.5 (H2Cꢀ); 116.2 (C14); 59.5 (CO2-
CH2-CH3); 39.3 (C5); 36.2 (C10); 34.1 (C6); 32.6 (C3); 28.9
(C6-CH3); 21.7 (C2-CH3); 20.8 (C13-CH3); 19.1 (C4); 14.5
(CO2-CH2-CH3).
1
Compound 5: yellow oil. IR (film): 1603, 1586, 1151. H
NMR (CDCl3): 7.97–7.58 (m, 5H, Ph); 5.96 (s, 2H, C7-H
and C8-H); 4.98 and 4.92 (2s, 2H, H2Cꢀ); 3.30 (m, 2H,
C11-H); 2.68 (m, 2H, C10-H); 1.99 (t, 2H, J=6.3, C3-H);
1.65 (s, 3H, C2-CH3); 1.60 (m, 2H, C4-H); 1.45 (m, 2H,
C5-H); 0.96 (s, 6H, C6-CH3). 13C NMR (CDCl3): 142.1,
138.8, 136.9 and 129.6 (C9, C2, C1 and q Ph); 133.7,
133.2, 129.3, 128.0 and 127.7 (C8, C7 and Ph); 115.6
(H2Cꢀ); 55.3 (C11); 39.3 (C5); 34.0 (C6); 32.7 (C3); 28.8
(C6-CH3); 25.3 (C10); 21.5 (C2-CH3); 19.0 (C4).
Compound 7: (13Z) yellow oil. UV (EtOH) umax: 264 nm.
1
IR (film): 1708; 1613. H NMR (DMSO-d6): 6.30 (d, 1H,
J=15.7, C12-H); 6.22 (dt, 1H, J1=15.7, J2=6.2, C11-H);
.