Synthesis of new cyclic retinoids via base induced self-condensation of C-13, C-14 and C-15 units

Article abstract of DOI:10.1016/S0040-4039(00)00414-7

New cyclic retinoids from β-ionone and C-14 and C-15 derivatives were synthesised by self-condensation promoted by strong bases. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00414-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3359–3362
Synthesis of new cyclic retinoids via base induced
self-condensation of C-13, C-14 and C-15 units
Alain Valla,∗ Zo Andriamialisoa and Roger Labia
FRE 2125, rattachée au CNRS 6, rue de l’Université, 29000 Quimper, France
Received 24 February 2000; accepted 5 March 2000
Abstract
New cyclic retinoids from β-ionone and C-14 and C-15 derivatives were synthesised by self-condensation
promoted by strong bases. © 2000 Published by Elsevier Science Ltd. All rights reserved.
The past decade of retinoid synthesis has witnessed the emergence of novel structures far removed from
that of the natural product, and some of them have totally lost the terpenoid structure.1 In relation to the
success of vitamin A and related compounds, especially all trans retinoic acid (ATRA) for the treatment
of skin disorders, novel synthetic derivatives were sought.2 Moreover, new molecules are desired to
improve and expand the treatment of malignant diseases. Novel molecules are also needed to overcome
ATRA-resistance which usually occurs during treatment of acute promyelocytic leukemia (APL).3
In previous years, we have been involved in the development of useful synthons for vitamin A
synthesis.4–7 In this work, we have synthesised new retinoids with olefinic moieties incorporated into
a ring. These compounds are obtained from β-ionone 1 and related C-14 and C-15 derivatives 2, 36,7 and
44 (Fig. 1).
Fig. 1.
∗
Corresponding author. Fax: 02 98 90 80 48.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00414-7
tetl 16694

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Starting from β-ionone 1, the new cyclohexenone 5 could be obtained by Michael addition of the
ionone enolate to a second molecule of ionone [(a) MeONa, pentane, 0°C then rt; (b) HCl N]. After
rearrangement of the intermediary 5-keto-enolate to the less hindered enolate, internal ring closure by
aldol condensation and dehydration (Robinson annulation),8 the cyclohexenone 5 is obtained nearly
quantitatively (Fig. 2).
Fig. 2.
The unstable hydroxymethylenic derivative of β-ionone 2 [(a) 1+MeONa, pentane, 0°C, >90%; (b)
CH3COOH], leads to the corresponding triacylbenzene 6 (50%). The formation of the triacylbenzene
could be explained by successive base-induced condensations followed by dehydration of the inter-
mediate trihydroxy cyclohexane (Fig. 3).
Fig. 3.
In cases 3 and 4, the reaction plausibly first proceeds by partial conjugation of the aldehyde or nitrile
[(a) t-but-OK, ether, −10°C, 50%; (b) HCl N]. Michael addition of the β-methylenic enolate to a second
molecule leads to a dimeric intermediate. Ring closure takes place as in the first case and is followed by
concomitant dehydration to the aldehyde 7 and tautomeric rearrangement to the aminonitrile 89 (Figs. 4
and 5).
These new compounds are under biological evaluation.
References
1. Biology, Chemistry and Medicine; Sporn, M. B.; Roberts, A. B.; Goodman, D. S., Ed. The retinoids. Raven Press: New
York, 1994.
2. Traité de chimie thérapeutique 1995, 4, 745–826. La vitamine A et les rétinoïdes.

3361
Fig. 4.
Fig. 5.
3. Sato, A.; Imaizumi, M.; Saito, T.; Yoshinari, M.; Suzuki, H.; Hayashi, Y.; Iinuma, K. Leuk. Res. 1999, 9, 827–832.
4. Andriamialisoa, Z.; Valla, A.; Zennache, S.; Giraud, M.; Potier, P. Tetrahedron Lett. 1993, 34, 8091–8092.
5. Giraud, M.; Andriamialisoa, Z.; Valla, A.; Zennache, S.; Potier, P. Tetrahedron Lett. 1994, 35, 3077–3080.
6. Valla, A.; Andriamialisoa, Z.; Giraud, M.; Prat, V.; Laurent, A.; Potier, P. Tetrahedron Lett. 1999, 40, 9235–9237.
7. Giraud, M.; Valla, A.; Andriamialisoa, Z.; Potier, P. French Patent, 1994, 9415189; BOPI 1996, 25, 2728260.
8. Gawley, R. E. Synthesis 1976, 777–794; Junk, M. E. Tetrahedron 1976, 32, 3–31.
1
9. Compound 5: IR (KBr): 1662 cm− . 1H NMR [300 MHz, CDCl3, J (Hz)]: 6.58 (d, 1H, J=16, H7), 6.15 (d, 1H, J=16, H8),
5.75 (s, 1H, C-10-H), 2.80 (m, 3H, C-12-Ha, C-13-H and C-14-Ha), 2.50 (dd, 1H, J=12, J0=<1, C-12-Hb), 2.32 (d, 1H,
J=12, <1, C-14-Hb), 2.05 and 1.95 (m, 2H, C-3-H and C-30-H), 1.71 and 1.70 (s, 6H, C-2-CH3 and C-20-CH3), 1.82 (m,
4H, C-4-H and C-40-H), 1.30 (m, 4H, C-5-H and C-50-H), 0.95, 0.90, 0.87 and 0.85 (s, 12H, C-6-CH3 and C-60-CH3). 13
C
NMR (CDCl3): 200.8 (C-11), 157.6 (C-1), 138.1 and 137.0 (C-10 and C-2), 134.7 and 133.6 (C-7 and C-10), 132.3 and
129.6 (C-20 and C-9), 126.1 (C-8), 42.3 (C-12), 39.8 and 39.3 (C-3 and C-30), 36.0 (C-60), 34.7 (C-6), 34.3 (C-13), 34.1 and
33.1 (C-4 and C-40), 30.1 (C-14), 28.8 and 28.7 (C-2-CH3 and C-20-CH3), 22.0 and 21.7 (C-6-CH3 and C-60-CH3), 19.2 and
19.0 (C-5 and C-50). Compound 6: IR (KBr) 1659 cm−1. 1H NMR [300 MHz, CDCl3, J (Hz)]: 1.13 s, 6H, 2CH3-C-6), 1.53
(m, 2H, CH2-5), 1.64 (m, 2H, CH2-4), 1.86 (s, 3H,CH3-2), 2.12 (t, 2H, J=6.1, CH2-3), 7.03 (d, 1H, J=15.8, H-8), 7.68 (d,
2H, J=15.8, H-7; 8.64, 1H, H-Ar). 13C NMR (CDCl3) 19.0 (CH2-5), 22.15 (CH3-C-6), 29.09 (CH3-C2), 34.14 (CH2-C-4),
34.27 (CH-6), 40.03 (CH2-C-3), 125.4 (CH-8), 131.6 (CH-7), 136.9 (C-1), 136.6 (C-2), 139.4 (C-10), 146.2 (CH-Ar), 189.6
(CO). Compound 7: IR (KBr): 1674 cm−1. 1H NMR [400 MHz, CDCl3, J (Hz)]: 9.51 (s, 1H, CHO), 6.86 (d, 1H, J=6, H11),

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0
0
0
6.54 and 6.23 (2d, 2H, J=16.2), 5.66 and 5.36 (2d, 2H, J=16.1) (H7+H8+H7 +H8 ), 6.13 (dd, 1H, J=5.9, J =1.8, H12), 2.69
0
0
0
0
(d, 1H, J=17) and 2.42 (dd, 1H, J=17, J =1.8) (C14), 2.05, 1.92, 1.63, 1.60, 1.49 (m, 12H) (C3+C4+C5+C3 +C4 +C5 ), 1.73,
1.57 (2s, 6H, 2-CH3+20-CH3), 1.44 (s, 2H, 9-CH3), 1.05, 1.04, 0.89, 0.88 (4s, 12H, 6-CH3+60-CH3). 13C NMR (CDCl3):
CHO: 192.7; HC_: 145.2, 137.6, 13.2, 132.0, 125.0, 122.0; CH3: 29.4, 29.3, 29.0, 25.5, 22.2, 21.5; CH2: 39.9, 39.6, 38.2,
33.6, 32.9, 19.7, 19.5. Compound 8: IR (KBr): 2170, 1637 cm−1. 1H NMR [400 MHz, CDCl3, J (Hz)]: 6.45 (d, 1H, J=16,
0
0
1), 6.13 (d, 1H, J=16, 1), 5.76 (d, 1H, J=16), 5.23 (d, 1H, J=16) (C7+C8+C7 +C8 ), 5.72 (s, 1H, H12), 4.34 (s, 2H, NH2),
0
0
0
2.61 and 2.33 (2d, 2H, J=17C14), 2.05, 1.94, 1.67, 1.6, 1.5, 1.44 (m, 12H) (C3+C4+C5+C3 +C4 +C5 ), 1.70, 1.58 (2s, 6H,
2-CH3+20-CH3), 1.38 (s, 2H, 9-CH3), 1.02, 1.01, 0.93, 0.92 (4s, 12H, 6-CH3+60-CH3). 13C NMR (CDCl3): HC_: 138.8,
133.6, 132.0, 125.4, 119; CN: 79.5; CH3: 29.3, 29.2, 29.0, 28.9, 27.6; CH2: 39.8, 39.6, 37.0, 33.5, 32.8, 19.7, 19.5.