3542
J . Org. Chem. 1996, 61, 3542-3544
Notes
An Efficien t a n d Ster eoselective Syn th esis
of 9-cis-Retin oic Acid
Youssef L. Bennani†
Department of Retinoid Chemistry,
Ligand Pharmaceuticals, Inc., 10255 Science Center Drive,
San Diego, California 92121
Received December 11, 1995
F igu r e 1.
In tr od u ction
the acid-sensitive trisubstituted 9,10-cis double bond in
an efficient manner and preserving its geometric integ-
rity, (2) securing the trans-geometry of the 13,14-double
bond, and (3) utilizing readily available, inexpensive
starting materials and reagents, as well as avoiding the
use of chromatography in order to simplify the process
for large scale production. Compound 2 has previously
been prepared on a kilogram scale in six steps starting
from â-cyclocitral with an overall yield of ∼11%.7a It has
also been prepared on milligram scale by photoisomer-
ization of ATRA in a low 5% yield.8
We wish to describe herein an efficient approach for
the preparation of 9-cis-RA (2) starting from commer-
cially available and inexpensive â-ionone (Scheme 1). The
key step in this synthesis relies on the geometrically
highly selective introduction of a cis trisubstituted double
bond via a 1,4-conjugate addition of dimethyl cuprate to
acetylenic nitrile 5, to give almost exclusively the crucial
and desired 9,10-cis double bond. Thus, readily available
â-ionone 3 was converted to dieneyne 4 in 80% yield after
distillation according to the reliable Negishi procedure.9
Treatment of 4 with n-BuLi in THF at -78 °C followed
by the addition of phenyl cyanate10 gave, after basic
workup, nitrile 5 in 95% yield. 1,4-Conjugate addition
of dimethyl cuprate to 5, in THF at -78 °C, afforded in
nearly quantitative yield trienenitrile 6, with a high level
of stereocontrol (>98:2 cis:trans).11,12 Reduction of nitrile
6 to the trienealdehyde 7 using Dibal, in hexanes at -78
°C, proceeded in 95% yield, accompanied by about 10%
isomerization to the undesired trans-aldehyde (Scheme
1). Homologation of aldehyde 7 (as a 9:1 2-cis:2-trans
Retinoids are metabolites, derivatives, and synthetic
analogues of vitamin A which exert numerous biological
effects in vivo by binding to and activating nuclear
retinoid receptors, which results in the alteration of gene
expression.1 all-trans-Retinoic acid (ATRA, 1) (Figure 1)2
is known to modulate proliferation and differentiation
of a variety of cell types and has proved useful for the
treatment of dermatological diseases and certain can-
cers.3 Recently, 9-cis-retinoic acid (9-cis-RA, 2) was
identified as a novel endogenous hormone in mammalian
tissues.4 It has been shown to play an important role as
a modulator of nuclear transcription of cells through the
retinoic acid receptors (RARR,â,γ) as well as retinoid X
receptors (RXRR,â,γ).5 9-cis-RA (ALRT1057) is in phase
II clinical trials for the treatment of several cancers
including renal cell carcinoma, non-Hodgkin’s lymphoma,
and acute promyelocytic leukemia, among others.6 As a
result of its biological profile and importance, we needed
to prepare this compound in large quantities, which
prompted us to devise several synthetic schemes for its
preparation.7
The synthesis of 9-cis-RA (2) presented some chal-
lenges, among which were the following (1) introducing
†Present address: Abbott Laboratories, Abbott Park, IL 60064.
(1) (a) Orfanos, C. E.; Ehlert, R.; Gollnick, H. The Retinoids, A
Review of Their Clinical Pharmacology and Therapeutic Use. Drugs
1987, 34, 459. (b) Vokes, E. E.; Weichselbaum, R. R.; Lippman, S. M.;
Hong, W. K. Head and Neck Cancer. N. Engl. J . Med. 1993, 328, 184.
(c) Dawson, M. I.; Okamura, W. H. Chemistry and Biology of Synthetic
Retinoids; CRC Press: Boca Raton, 1990.
(2) The traditional retinoid numbering system is being used in the
text when referring to 9-cis-RA (2) and all-trans-RA (1). The IUPAC
nomenclature was used in the Experimental Section.
(3) (a) Mangelsdorf, D. J .; Umesono, K.; Evans, R. M. The Retinoids
Receptors. In The Retinoids, 2nd ed. Sporn, M. B., Roberts, A. B.,
Goodman, D. S., Eds.; Raven Press, Ltd.: New York, 1994; p 319. (b)
Leid, M.; Kastner, P.; Chambon, P. Trends Biochem. Sci. 1992, 17,
427.
(4) Heyman, R. A.; Mangelsdorf, D. J .; Dyck, J . A.; Stein, R. B.;
Eichelle, G.; Evans, R. M.; Thaller, C. Cell 1992, 68, 397.
(5) (a) Yang, N.; Schule, R.; Mangelsdorf, D. J .; Evans, R. M. Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 3559. (b) Allenby, G.; Bocquel, M.-
T.; Saunders, M.; Kazmer, S.; Speck, T.; Rosenberger, M.; Lovey, A.;
Kastner, P.; Grippo, J . F.; Chambon, P.; Levin, A. A. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 30. (c) Boehm, M. F.; Zhang, L., Zhi, L.; McLurg,
M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J .
A.; Heyman, R. A.; Nadzan, A. M. J . Med. Chem. 1995, 38, 3146 and
references cited therein.
(6) (a) Miller, W. H.; J akubowski, A.; Tong, W. P.; Miller, V.; Rigas,
J . R.; Benedetti, F.; Gill, G.; Truglia, J .; Ulm, E.; Shirley, M.; Warrell,
R. P. Blood 1995, 55, 3021. (b) Smith, M. A.; Parkinson, D. R.; Cheson,
B. D.; Friedman, M. A. Retinoids in Cancer Therapy J . Clin. Oncol.
1992, 10, 839.
(7) (a) White, S. K.; II, Winn, D.; Hwang, C.-K. Patent Application
U.S. Serial No. 08/052,042). (b) White S. K. et al. Manuscript in
preparation. For the preparation of the corresponding carboxylic acid
analogue of nitrile 6, through a lactone intermediate, see: (c) Cainelli,
G.; Cardillo, G.; Orena, M. J . Chem. Soc., Perkin Trans. 1 1979, 1597.
(d) Dugger, R. W.; Heathcock, C. H. J . Org. Chem. 1980, 45, 1181. For
the preparation of aldehyde 7 through a lactol intermediate, see ref
7a,b and: (e) Bennani, Y. L.; Boehm, M. F. J . Org. Chem. 1995, 60,
1195.
(8) Dawson, M. I.; Hobbs, P. D.; Cameron, J . F.; Rhee, S. W. J .
Labelled Compd. Radiopharm. 1993, 33, 245.
(9) (a) Negishi, E. I.; King, A. O; Klima, W. L., Silveira, A., J r. J .
Org. Chem. 1980, 45, 2526. (b) Negishi, E. I.; King, A. O; Tour, J . M.
Organic Synthesis; Wiley: New York, 1990; Collect. Vol. VII, p 63.
(10) (a) Murray, R. E., Zweifel G. Synthesis 1980, 150. (b) Martin,
D.; Bauer, M. Organic Synthesis; Wiley: New York, 1990; Collect. Vol.
VII, p 435.
(11) Ratio determined by 400 MHz 1H-NMR.
(12) For 1,4-addition to acetylenic esters: (a) Corey, E. J .; Katzenel-
lenbogen, J . A. J . Am. Chem. Soc. 1969, 91, 1851. (b) Ernst, L.; Hopf,
H.; Krause, N. J . Org. Chem. 1987, 52, 398. For 1,4-addition to
acetylenic nitriles: (c) Westmijze, H.; Vermeer, P. Westmijze, H.,
Kleijn, H., Vermeer, P. Tetrahedron Lett. 1979, 3327; Synthesis 1978,
454 and references cited therein. For the preparation of a mixture of
nitriles: (d) Cainelli, G.; Cardillo, G.; Contento, M.; Grasselli, P. Umani
Ronchi A. Gazz. Chim. Ital. 1973, 103, 117. (e) Andriamialisoa, Z.;
Valla, A.; Zennache, S.; Giraud, M.; Potier, P. Tetrahedron Lett. 1993,
34, 8091.
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