Syntheses of new 9- and 13-methylene isomers of retinal

Article abstract of DOI:10.1016/S0040-4039(00)01240-5

Syntheses of new 9- and 13-methylene isomers of retinal via the '9-methylene-C-18 ketone' 1 or 'C-18 ketone' 2 are reported. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01240-5

Tetrahedron Letters 41 (2000) 7221±7224
Syntheses of new 9- and 13-methylene isomers of retinal
Alain Laurent,a Virginie Prat,a Alain Valla,a,* Zo Andriamialisoa,a Michel Giraud,a
Roger Labiaa and Pierre Potierb
a
Â
Â
Chimie et Biologie des Substances Naturelles, FRE 2125, rattachee 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 23 June 2000; accepted 21 July 2000
Abstract
Syntheses of new 9- and 13-methylene isomers of retinal via the `9-methylene-C-18 ketone' 1 or `C-18
ketone' 2 are reported. # 2000 Published by Elsevier Science Ltd.
To our knowledge, only one methylene derivative of retinoids has been reviewed as 13-methylene
isomer of retinoic acid1. Herein, we describe the syntheses of new isomers of retinal, 9- and 13-
methylene using the new C-18 (9-methylene) ketone 1 and the well-known C-18 ketone 22
(Scheme 1).
Scheme 1.
* Corresponding author. Fax: 33 2 98 90 80 48; e-mail: valla@iutquimp.univ-brest.fr
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01240-5

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The synthesis of methylene-ketone 1 (11 E>99%) was achieved by condensation of the
b-methylenealdehyde 3 with diethyl (2-oxopropyl) phosphonate: (1) NaH/DME/phosphonate,
0ꢀC; (2) 3/DME, ^10ꢀC, 51%, a€ording 1. The aldehyde 3 was synthesised by a Peterson's reaction
with the b-ketoacetal, followed by acidic hydrolyse, giving the b-methylenealdehyde 3. This
procedure increased the yield obtained by Wittig's procedure:3 (1) Me3SiCH2MgCl/ether/acetal/
0ꢀC then rt, 1 h; (2) HCOOH/cyclohexane, rt, 1 h, 60%. Condensation of ketone 1 with the anion
derived of N-ethylidenecyclohexylamine:4 (1) LDA/N-ethylidenecyclohexylamine/^78ꢀC /1/THF;
(2) (COOH)2 1%/THF, 0ꢀC, 10 min then 65ꢀC, 12 h, 40% a€ords the 9-methylene retinals 45 (13
E: 80/13 Z: 20) (Scheme 2).
Scheme 2. (a) Me3SiCH2MgCl, ether, 0ꢀC then addition of b-ketocetal, 0ꢀC to rt, 1 h. (b) HCOOH, cyclohexane, rt, 90
min (60%). (c) (EtO)2POCH2COMe, DME, NaH, 0ꢀC, 1 h then addition of 3, DME, ^10ꢀC to rt, 15 min (55%). (d)
LDA, MeCHˆNC6H11, THF, ^30ꢀC to 0ꢀC, 1 h then addition of 8, THF, ^78ꢀC, 1 h. (e) 1% (COOH)2, H2O, THF,
0ꢀC, 10 min then re¯ux 12 h (40%)
Synthesis of ketones 2 (9E: 80/9Z: 20) was performed by condensation of b-ionylidene-
acetaldehydes 5 (9E: 80/9Z: 20) with acetone.6,7 Formylation of ketones 2 (HCOOCH3/CH3ONa/
pentane) and concomitant ketalisation (H2SO4/CH3OH, 75%) a€orded the b-ketoacetals 6 (9E:
80/9Z: 20). Wittig reaction (t-BuOK/(C6H5)3P+CH3 Br^/cyclohexane) followed by acidic hydrolysis
of the b-methyleneketals 7 (HCOOH/cyclohexane) produced the 9E and the 9Z-13-methylene
retinals 8 separated by column chromatography8 (SiO2/CH2Cl2 9E: 80/9Z: 20) (Scheme 3).
These procedures avoid the conjugation of aldehydes 4 and 8 to their a,b-unsaturated analogs.
Scheme 3. (a) Refs. 6 and 7. (b) MeONa, pentane, 0ꢀC then addition of 2, 0ꢀC to rt, 2 h. (c) MeOH, H2SO4, 0ꢀC then
rt, 12 h. (d) t-BuOK, cyclohexane, (C6H5)3P+CH3, Br^, re¯ux 1 h then addition of 6, 10ꢀC to rt. (e) HCOOH, H2O
(60:40), rt, 10 min

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References
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572.
2. Andriamialisoa, Z.; Valla, A.; Zennache, S.; Giraud, M.; Potier, P. Tetrahedron Lett. 1993, 34, 8091±8092.
3. Giraud, M.; Valla, A.; Andriamialisoa, Z.; Potier, P. European Pat. 1996, 964008429 (PCT/FR).
4. Wittig, G.; Hesse, A. Org. Synth. Coll. 1988, 6, 901±904.
5. 1 (11 E). Oil, IR (®lm): 1699, 1674 cm^1. 1H NMR [400 MHz] (DMSO D-6): 6.91 (dt, 1H, J=16.0, J=6.4,
C11 H); 6.12 and 6.05 (2d, 2H, J=16.3, C7 H and C8 H); 6.08 (d, 1H, J=16.0, C12 H); 5.12 and 5.03 (2s, 2H,
C9 CH2); 3.22 (d, 2H, J=6.4, C10 H); 2.19 (s, 3H, C14 H); 1.97 (t, 2H, J=6.0, C3 H); 1.64 (s, 3H, C2 CH3);
1.56 (m, 2H, C4 H); 1.42 (m, 2H, C5 H); 0.95 (s, 6H, C6 CH3). 13CNMR [100 MHz] (CDCl3): 198.3 (C13); 145.9
(C11); 142.7, 137.1 and 129.4 (C1, C2 and C9); 133.8 and 128.4 (C7 and C8); 132.2 (C12); 116.1 (C9 CH2); 39.3 (C5);
35.3 (C10); 34.7 (C6); 32.7 (C3); 28.7 (C6 CH3); 26.8 (C14); 21.5 (C2 CH3); 19.1 (C4). 1 (11 Z). Oil, IR (®lm): 1694
cm^1. 1H NMR (CDCl3): 6.25 (d, 1H, J=11.4, C12 H); 6.14 (dt, 1H, J=11.4, J=6.7, C11 H); 6.07 (m, 2H,
C7 H and C8 H); 5.01 and 4.98 (2s, 2H, C9 CH2); 3.64 (d, 2H, J=6.7, C10 H); 2.25 (s, 3H, C14 H); 2.00 (t,
2H, J=6.3, C3 H); 1.69 (s, 3H, C2 CH3); 1.62 (m, 2H, C4 H); 1.46 (m, 2H, C5 H); 0.99 (s, 6H, C6 CH3).
13C NMR (CDCl3): 199.2 (C13); 146.6, 134.2, 128.3 and 126.8 (C7, C8, C11 and C12); 144.5, 137.3 and 129.1 (C1, C2
and C9); 115.1 (C9 CH2); 39.3, 32.7, 32.6 and 19.1 (C3, C4, C5 and C10); 34.0 (C6); 31.6, 28.7 and 21.5 (C2 CH3,
C6 CH3 and C14). 4 (11 E, 13 E). Oil, IR (®lm): 1668 cm^1. 1H NMR (CDCl3): 10.13 (d, 1H, J=8.0, C15 H); 6.40
(dt, J=15.7, J=6.4, C11 H); 6.30 (d, 1H, J=15.7, C12 H); 6.14 and 6.07 (2d, 2H, J=16.3, C7 H and C8 H);
5.92 (d, 1H, J=8.0, C14 H); 5.06 and 4.98 (2s, 2H, C9 CH2); 3.20 (d, 2H, J=6.4, C10 H); 2.28 (s, 3H,
C13 CH3); 2.00 (m, 2H, C3 H); 1.70 (s, 3H, C2 CH3); 1.62 (m, 2H, C4 H); 1.46 (m, 2H, C5 H); 0.99 (s, 6H,
C6 CH3). 13C NMR (CDCl3): 191.4 (C15); 154.4, 143.6, 137.1 and 129,2 (C1, C2, C9 and C13); 136.9 (C11); 134.5
(C12); 134.0 and 128.3 (C7 and C8); 128.6 (C14); 115.6 (C9 CH2); 39.3 (C5); 36.0 (C10); 34.1 (C6); 32.7 (C3); 28.7
(C6 CH3); 21.5 (C2 CH3); 19.1 (C4); 12.9 (C13 CH3). 4 (11 E, 13 Z). Oil, IR (®lm): 1669 cm^1. 1H NMR
(CDCl3): 10.19 (d, 1H, J=8.1, C15 H); 7.18 (d, 1H, J=15.5, C12 H); 6.30 (dt, J=15.5, J=6.6, C11 H); 6.15 and
6.08 (2d, 2H, J=16.3, C7 H and C8 H); 5.85 (d, 1H, J=8.1, C14 H); 5.08 and 5.00 (2s, 2H, C9 CH2); 3.24 (d,
2H, J=6.6, C10 H); 2.09 (s, 3H, C13 CH3); 2.01 (m, 2H, C3 H); 1.70 (s, 3H, C2 CH3); 1.62 (m, 2H, C4 H);
1.46 (m, 2H, C5 H); 0.99 (s, 6H, C6 CH3). 13CNMR (CDCl3): 190.1 (C15); 154.5, 143.6, 137.1 and 129.3 (C1, C2,
C9 and C13); 137.9 (C11); 133.9 and 128.3 (C7 and C8); 127.6 (C14); 126.4 (C12); 115.7 (C9 CH2); 39.2 (C5); 36.2
(C10); 34.1 (C6); 32.7 (C3); 28.7 (C6 CH3); 21.4 (C2 CH3); 21.2 (C13 CH3); 19.1 (C4).
6. Mousseron-Canet, M.; Olive, J. L. Bull. Soc. Chim. 1969, 3242±3246.
7. Liu, R. S. H.; Asato, A. E. Tetrahedron 1984, 40, 1931±1969.
1
8. 6 (9 E, 11 E). Oil, IR (®lm): 1655 cm^1. H NMR [400 MHz] (CDCl3): 7.65 (dd, 1H, J1=15.1, J2=11.9, C11 H);
6.45 and 6.19 (2d, 2H, J=16.0, C8 H and C7 H); 6.22 (d, 1H, J=15.1, C12 H); 6.18 (d, 1H, J=11.9, C10 H);
4.88 (t, 1H, J=5.6, C15 H); 3.40 (s, 6H, O CH3); 2.91 (d, 2H, J=5.6, C14 H); 2.08 (s, 3H, C9 CH3); 2.05 (t,
2H, J=5.7, C3 H); 1.73 (s, 3H, C2 CH3); 1.63 (m, 2H, C4 H); 1.49 (m, 2H, C5 H); 1.05 (s, 6H, C6 CH3). 13C
NMR [100 MHz](CDCl3): 196.7 (C13); 146.1, 137.3 and 131.0 (C9, C2 and C1); 139.4, 136.6, 131.4, 128.5 and 127.6
(C12, C11, C10, C8 and C7); 102.2 (C15); 54.0 (O CH3); 44.7 (C14); 39.5 (C5); 34.1 (C6); 33.0 (C3); 28.8 (C6 CH3);
1
21.7 (C2 CH3); 19.0 (C4); 13.0 (C9 CH3). 6 (9 E, 11 Z). Oil, IR (®lm): 1651 cm^1. H NMR (CDCl3): 7.73 (dd,
J1=15.0, J2=11.9, C11 H); 6.74 and 6.42 (2d, 2H, J=15.9, C8 H and C7 H); 6.16 (d, 1H, J=15.0, C12 H);
6.10 (d, 1H, J=11.9, C10 H); 4.87 (t, 1H, J=5.56, C15 H); 3.41 (s, 6H, O CH3); 2.90 (d, 2H, J=5.56, C14 H);
2.06 (s, 3H, C9 CH3); 2.05 (t, 2H, J=5.2, C3 H); 1.74 (s, 3H, C2 CH3); 1.66 (m, 2H, C4 H); 1.49 (m, 2H,
C5 H); 1.05 (s, 6H, C6 CH3). 13C NMR (CDCl3): 196.8 (C13); 145.0, 137.6 and 130.8 (C9, C2 and C1); 138.2,
132.4, 129.1, 127.9 and 126.1 (C12, C11, C10, C8 and C7); 102.3 (C15); 54.0 (O CH3); 44.8 (C14); 39.3 (C5); 34.1
(C6); 32.9 (C3); 28.8 (C6 CH3); 21.7 and 21.0 (C6 CH3 and C2 CH3); 19.0 (C4). 7 (9 E, 11 E). Oil, IR (®lm): 1630
1
cm^1. H NMR (CDCl3): 6.68 (dd, 1H, J1=15.3, J2=11.2, C11 H); 6.32 (d, 1H, J=15.3, C12 H); 6.20 and 6.12
(2d, 2H, J=16.2, C8 H and C7 H); 6.10 (d, 1H, J=11.2, C10 H); 5.16 and 5.11 (2s, 2H, H2Cˆ); 4.60 (t, 2H,
J=5.5, C14 H); 3.38 (s, 6H, O CH3); 2.62 (d, 1H, J=5.5, C14 H); 2.03 (t, 2H, J=6.2, C3 H); 1.97 (s, 3H,
C9 CH3); 1.72 (s, 3H, C2 CH3); 1.63 (m, 2H, C4 H); 1.48 (m, 2H, C5 H); 1.04 (m, 6H, C6 CH3). 13C NMR
(CDCl3): 141.6, 137.7, 136.5 and 129.2 (C13, C9, C2 and C1); 137.5, 134.2, 129.8, 126.9 and 125.4 (C12, C11, C10, C8
and C7); 117.6 (H2Cˆ); 103.4 (C15); 53.1 (O CH3); 39.5 (C5); 35.9 (C14); 34.1 (C6); 32.9 (C3); 28.8 (C6 CH3); 21.6
1
(C2 CH3); 19.1 (C4); 12.6 (C9 CH3). 7 (9 E, 11 Z). Oil, IR (®lm): 1633 cm^1. H NMR (CDCl3): 6.78 (dd, 1H,
J1=15.3, J2=11.3, C11 H); 6.65 and 6.21 (2d, 2H, J=16.0, C7 H and C8 H); 6.25 (d, 1H, J=15.3, C12 H);

7224
6.02 (d, 1H, J=11.3, C10 H); 5.15 and 5.11 (2s, 2H, H2Cˆ); 4.60 (t, 2H, J=5.6, C15 H); 3.37 (s, 6H, O CH3);
2.60 (d, 2H, J=5.6, C14 H); 2.06 (t, 3H, J=6.0, C3 H); 1.98 (s, 3H, C9 CH3); 1.75 (s, 3H, C2 CH3); 1.65 (m,
2H, C4 H); 1.50 (m, 2H, C5 H); 1.05 (s, 6H, C6 CH3). 13C NMR (CDCl3): 141.5, 137.9, 135.2 and 129.5 (C1, C2,
C9 and C13); 133.4, 129.7, 128.6, 128.3 and 124.3 (C12, C11, C10, C8 and C7); 117.5 (H2Cˆ); 103.5 (C15); 53.1
(O CH3); 39.4 (C5); 35.8 (C14); 34.1 (C6); 32.9 (C3); 28.8 (C6 CH3); 21.7 and 20.6 (C9 CH3 and C2 CH3); 19.1
(C4). 8 (9 E, 11 E). Oil, IR (®lm): 1725 cm^1. 1H NMR (CDCl3): 9.63 (t, 1H, J=2.5, CHO); 6.55 (dd, 1H, J1=15.3,
J2=11.1, C11 H); 6.39 (d, 1H, J=15.3, C12 H); 6.22 and 6.12 (2d, 2H, J=16.1, C8 H and C7 H); 6.10 (d, 1H,
J=11.1, C10 H); 5.32 and 5.16 (2s, 2H, H2Cˆ); 3.34 (d, 2H, J=2.5, C14 H); 2.03 (t, 2H, J=6.2, C3 H); 1.95 (s,
3H, C9 CH3); 1.72 (s, 3H, C2 CH3); 1.62 (m, 2H, C4 H); 1.48 (m, 2H, C5 H); 1.03 (s, 6H, C6 CH3). 13C NMR
(CDCl3): 200.2 (CHO); 137.7, 137.6 and 129.4 (C13, C9, C2 and C1); 137.2, 132.9, 129.2, 127.6 and 127.0 (C12, C11,
C10, C8 and C7); 119.6 (H2Cˆ); 47.6 (C14); 39.5 (C5); 34.1 (C6); 32.9 (C3); 28.8 (C6 CH3); 21.6 (C2 CH3); 19.1
(C4); 12.7 (C9 CH3). 8 (9 E, 11 Z). Oil, IR (®lm): 1723 cm^1. 1H NMR (CDCl3): 9.62 (t, 1H, J=2.5, CHO); 6.64
(dd, 1H, J1=15.3, J2=11.3, C11 H); 6.59 and 6.23 (2d, 2H, J=16.0, C8 H and C7 H); 6.33 (d, 1H, J=15.3,
C12 H); 6.00 (d, 1H, J=11.3, C10 H); 5.32 and 5.14 (2s, 2H, H2Cˆ); 3.32 (d, 2H, J=2.5, C14 H); 2.07 (t, 2H,
J=6.3, C3 H); 1.98 (s, 3H, C9 CH3); 1.77 (s, 3H, C2 CH3); 1.65 (m, 2H, C4 H); 1.50 (m, 2H, C5 H); 1.05 (s,
6H, C6 CH3). 13C NMR (CDCl3): 200.1 (CHO); 137.7, 136.4 and 129.9 (C13, C9, C2 and C1); 132.2, 129.9, 129.4,
127.6 and 125.8 (C12, C11, C10, C8 and C7); 47.5 (C14); 39.4 (C5); 34.1 (C6); 33.0 (C3); 28.9 (C6 CH3); 21.7 and 20.6
(C9 CH3 and C2 CH3); 19.6 (C4).