The suzuki coupling reaction in the stereocontrolled synthesis of 9-cis-retinoic acid and its ring-demethylated analogues

Article abstract of DOI:10.1021/jo010711v

The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 and cyclohexenyl boronate 18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction are better reacted immediately after generation from their precursors, tetraenylstannane 10 and cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized by a stereoselective Horner - Wadsworth - Emmons reaction. On the other hand, easily available cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones, hydrazones were converted to cyclohexenyl iodides. Iodine - lithium exchange and trapping with B(OMe)₃ then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated intermediate obtained upon treating the trisylhydrazone with n-BuLi (Shapiro reaction). None of the above procedures allowed the generation of the more substituted organolithium from 2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-1,1-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild conditions, and the preservation of the retinoid side-chain geometry was therefore secured.

Full text of DOI:10.1021/jo010711v

J . Org. Chem. 2001, 66, 8483-8489
8483
Th e Su zu k i Cou p lin g Rea ction in th e Ster eocon tr olled Syn th esis
of 9-cis-Retin oic Acid a n d Its Rin g-Dem eth yla ted An a logu es†,1
Yolanda Pazos, Beatriz Iglesias, and Angel R. de Lera*
Departamento de Quı´mica Orga´nica, Facultade de Ciencias, Universidade de Vigo 36200 Vigo, Spain
qolera@uvigo.es
Received J uly 16, 2001
The thallium-accelerated Suzuki coupling reaction of tetraenyl iodide 19 and cyclohexenyl boronate
18 afforded ethyl 9-cis-retinoate (12) in high yield. Both coupling partners of the Suzuki reaction
are better reacted immediately after generation from their precursors, tetraenylstannane 10 and
cyclohexenyl iodide 13. The geometrically homogeneous tetraenylstannane 10, comprising the
polyenic side chain of ethyl 9-cis-retinoate and its ring-demethylated analogues, was synthesized
by a stereoselective Horner-Wadsworth-Emmons reaction. On the other hand, easily available
cyclohexanones are ideal starting materials for preparation of the cyclohexenyl boronates required
for the synthesis of the ring-modified 9-cis-retinoic acid analogues. For hindered cyclohexanones,
hydrazones were converted to cyclohexenyl iodides. Iodine-lithium exchange and trapping with
B(OMe)3 then afforded the cyclohexenyl boronates. If the precursor cyclohexanone has secondary
carbons, the alkenyllithium species was conveniently formed by elimination of the C,N-dilithiated
intermediate obtained upon treating the trisylhydrazone with n-BuLi (Shapiro reaction). None of
the above procedures allowed the generation of the more substituted organolithium from
2-methylcyclohexanone. However, the alternative Stille cross-coupling of 34 and 10 afforded 9-cis-
1,1-bisdemethylretinoic acid 7. Both Suzuki and Stille coupling reactions took place under mild
conditions, and the preservation of the retinoid side-chain geometry was therefore secured.
In tr od u ction
Retinoids, i.e., the natural and synthetic analogues of
vitamin A,2,3 act as modulators of nuclear transcription
by binding to and activating two subfamilies of nuclear
receptors,4 namely the RXRs,5 which use 9-cis-retinoic
acid (2, Figure 1) as native ligand, and the RARs,6
* Corresponding author. Phone: + (34) 986 812316. Fax: + (34)
986 812382.
† Abbreviations: PPAR, peroxisome proliferator-activated receptor;
RAR, retinoic acid receptor; RXR, retinoid X receptor; TR, thyroid
receptor; VDR, vitamin D3 receptor.
(1) Part of this work has already been published in preliminary
form: Pazos, Y.; de Lera, A. R. Tetrahedron Lett. 1999, 40, 8287-8290.
(2) (a) The Retinoids; Sporn, M. B., Roberts, A. B., Goodman, D. S.,
Eds.; Academic Press: New York, 1984; Vols. 1 and 2. (b) The
Retinoids: Biology, Chemistry and Medicine, 2nd ed.; Sporn, M. B.,
Roberts, A. B., Goodman, D. S., Eds.; Raven: New York, 1993. (c)
Retinoids: New Trends in Research and Therapy; Saurat, J . H., Ed.;
Karger: Basel, 1985. (d) Retinoids and Cell Differentiation; Sherman,
M. I., Ed.; CRC Press: Boca Raton, FL, 1986. (e) Chemistry and Biology
of Synthetic Retinoids; Dawson, M. L., Okamura, W. H., Eds.; CRC
Press: Boca Raton, FL, 1990. (f) Methods in Enzymology; Packer, L.,
Ed.; Academic Press: New York, 1990; Vol. 89, Retinoids Part A. (g)
Methods in Enzymology; Packer, L., Ed.; Academic Press: New York,
1991; Vol. 90, Retinoids Part B. (h) From Molecular Biology to
Therapeutics; Pharmacol. Skin; Bernard, B. A., Shroot, B., Eds.;
Karger: Basel, 1993. (i) Retinoids: From Basic Science to Clinical
Applications; Livrea, M. A., Vidali, G., Eds.; Karger: Basel, 1994.
(3) For details on the nomenclature and numbering of retinoids,
see: IUPAC-IUB J oint Commission on Biochemical Nomenclature
(J CBN). Eur. J . Biochem. 1982, 129, 1-5.
(4) (a) Mangelsdorf, D. J .; Thummel, C.; Beato, M.; Herrlich, P.;
Schu¨tz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark, M.;
Chambon, P.; Evans, R. M. Cell 1995, 83, 835-839. (b) Mangelsdorf,
D. J .; Evans, R. M. Cell 1995, 83, 841-850. (c) Weatherman, R. V.;
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Eichele, G.; Evans, R. M.; Thaller, C. Cell 1992, 68, 397-406.
(6) Petkovich, M.; Brand, N. J .; Kurst, A.; Chambon, P. Nature 1987,
330, 444-450.
F igu r e 1. Retinoid receptor native ligands (1, 2) and ana-
logues of 9-cis-retinoic acid modified on the cyclohexenyl ring.
activated by both 9-cis-retinoic acid (2) and trans-retinoic
acid (1). Genetic studies in mouse confirmed earlier in
vitro findings, indicating that the functional unit trans-
ducing the retinoid signal was in fact a dimeric associa-
tion of both nuclear receptors (RXR-RAR heterodimers).4
It was then postulated that, upon activation by binding
the retinoid ligands and subsequent conformational
change, the heterodimers activate other components of
the transcription machinery, a step also coupled to the
dissociation from corepressors. This sequence of events
results in the regulation of important gene networks
which control fundamental processes of cell differentia-
tion, homeostasis, morphogenesis, growth, development,
and immune function.2
10.1021/jo010711v CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/15/2001

8484 J . Org. Chem., Vol. 66, No. 25, 2001
Pazos and Iglesias
The described mechanism of gene regulation through
the formation of RAR-RXR heterodimers is shared by
other members of the nuclear receptor superfamily (VDR,
PPAR, TR) which also heterodimerize with RXR.4 The
finding that RXR is the receptor playing the central role
in gene regulation by lipophilic hormones (retinoids,
eicosanoids, vitamin D3, etc.) makes the design and
clinical evaluation of RXR agonists and antagonists an
active area of research. The first objective is now at reach
since the crystal structure of the human RXRR ligand
binding domain bound to its cognate ligand 9-cis-retinoic
acid has recently been disclosed.7 In this regard, some
synthetic retinoid structures barely resembling that of
the cognate ligand have shown RXR agonist8 and an-
tagonist activity.9 It is rather surprising that no studies
have been carried out on the biological activity of close
structural analogues of the native ligand. We therefore
set out to study the binding affinities of analogues with
minor modifications (methyl group deletions) in the
hydrophobic region of 9-cis-retinoic acid (2), while keeping
the polyene skeleton C7-C15 intact (demethylated ana-
logues 3-7). It was expected that those structural
alterations, transmitted to the protein through confor-
mational and hydrophobic interactions, would result in
biological profiles that might help to understand the
“natural selection” of the RXR ligand. Since only the 9-cis
isomers were of interest in this study, we planned to
stereoselectively build the polyene skeketon by direct
C6-C7 single-bond construction. For this purpose, we
turned our attention to palladium-catalyzed cross-
coupling reactions,10 a process which we have found
highly reliable to access fully conjugated polyenes.11 This
approach to Csp2-Csp2 bond construction has indeed
been successfully implemented for the synthesis of the
native RXR ligand, 9-cis-retinoic acid (2),1 using a Suzuki
cross-coupling reaction12 that attaches the intact C7-C15
polyene side-chain (retinoid numbering) to the cyclohex-
enyl fragment. The cyclohexenyl boronic acid was in turn
synthesized by trapping the alkenyllithium reagent
resulting from iodine-lithium exchange with a trialkyl-
borate (see Scheme 3). We subsequently found that the
less-hindered analogues could be most conveniently
obtained through a combined Shapiro13-Suzuki process,
starting from the corresponding trisylhydrazones. We
report here a full account of this approach to 2 and its
ring-demethylated analogues 3-6, as well as the prepa-
ration of retinoid 7 using the alternative Stille cross-
coupling.14
Resu lts a n d Discu ssion
At the outset, and based on our recently reported
procedure for direct retinoid synthesis using the Stille
reaction between tetraalkenyl stannanes and cyclohex-
enyl triflates,11g,h which successfully provided ethyl trans-
retinoate (8 + 9 f 11) and the entire series of derivatives
modified at the hydrophobic ring (the ethyl esters of the
trans isomers of compounds 3-7), we considered coupling
of stannane 10 and cyclohexenyl triflate 8 to be the most
direct approach to the desired ring-modified analogues
with 9-cis geometry (Scheme 1).
Tetraenyl stannane 10 was obtained in high yield from
the condensation of aldehyde 15 (prepared by oxidation
of known stannyl dienol 1415) and the carbanion derived
from diethyl 3-(ethoxycarbonyl)-3-methylprop-2-enylphos-
phonate in the presence of DMPU16a (Scheme 2). Exten-
sive experimentation revealed that the E/Z ratio of the
newly formed double bond was critically dependent upon
the temperature at which the condensation was per-
formed. Therefore, temperatures of -115 °C were re-
quired to provide in a highly stereoselective manner
tetraenyl stannane 10 in 94% yield.
As a drawback of the C9 + C11 Stille approach to
retinoids (8 + 9, Scheme 1), we found that coupling
temperatures increased with the steric hindrance of the
cyclic electrophile.11g Under optimal experimental condi-
tions [Farina’s Pd2(dba)3, AsPh3, NMP, 40 °C],17 mixtures
of product 12 and the trans isomer 11 were invariably
obtained in the reaction of triflate 8 and stannane 10
(Scheme 1). The more reactive10 cyclohexenyl iodide 13
coupled with tetraenyl stannane 10 at a lower reaction
temperature (25 °C), but conversions were unacceptably
slow (ca. 25% conversion after 24 h).
Previous studies have shown that the Suzuki reaction
is more tolerant than the Stille coupling to the steric
hindrance of the coupling partners.18 The use of alkenyl
boronic acids has been previously explored in our retinoid
program for the formation of the C10-C11 bond.11b In
our experience, the main limitation of this approach to
(7) (a) Egea, P. F.; Mitschler, A.; Rochel, N.; Ruff, M.; Chambon, P.;
Moras, D. EMBO J . 2000, 19, 2592-2601 (RXRR-holo-LBD). (b) Wurtz,
J .-M.; Bourguet, W.; Renaud, J .-P.; Vivat, V.; Chambon, P.; Moras, D.;
Gronemeyer, H. Nature Struct. Biol. 1996, 3, 87-94 (canonical
structure). (c) Renaud, J .-P.; Rochel, N. F.; Ruff, M.; Vivat, V.;
Chambon, P.; Gronemeyer, H.; Moras, D. Nature 1995, 378, 681-689
(RARγ-holo-LBD). (d) Bourguet, W.; Ruff, M.; Chambon, P.; Gronem-
eyer, H.; Moras, D. Nature 1995, 375, 377-382 (hRXRR-apo-LBD).
(8) Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, 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, 3146-3155.
(9) Lala, D. S.; Mukherjee, R.; Schulman, I. G.; Canan-Koch, S. S.;
Dardashti, L. J .; Nadzan, A. M.; Croston, G. E.; Evans, R. M.; Heyman,
R. A. Nature 1996, 383, 450-453.
(10) Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang,
P. J ., Eds.; Wiley-VCH: Weinheim, 1998.
(13) (a) Shapiro, R. H. Org. React. 1976, 23, 405. (b) Chamberlin,
A. R.; Bloom, S. H. Org. React. 1990, 39, 1-83.
(14) (a) Mitchell, T. N. in ref 10; chapter 4, pp 167-202. (b) Stille,
J . K. Pure Appl. Chem. 1985, 57, 1771-1780. (c) Stille, J . K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 508-524. (d) Farina, V. In Compre-
hensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Elsevier: Oxford, 1995; Vol. 12, chapter 3.4, pp
161-241. (e) Farina, V.; Roth, G. P. In Advances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; J AI Press: New York, 1996; Vol. 5,
pp 1-53. (f) Farina, V.; Krishnamurthy, V.; Scott, W. J . Organic
Reactions; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1997;
Vol. 50, chapter 1, pp 1-652. (g) Farina, V.; Krishnamurthy, V. The
Stille Reaction; Wiley: New York, 1999.
(11) (a) Torrado, A.; Lo´pez, S.; AÄ lvarez, R.; de Lera, A. R. Synthesis
1995, 285-293. (b) Torrado, A.; Iglesias, B.; Lo´pez, S.; de Lera, A. R.
Tetrahedron 1995, 51, 2435-2454. (c) de Lera, A. R.; Iglesias, B.;
Rodr´ıguez, J .; AÄ lvarez, R.; Lo´pez, S.; Villanueva, X.; Padro´s, E. J . Am.
Chem. Soc. 1995, 117, 8220-8231. (d) AÄ lvarez, R.; Lo´pez, S.; de Lera,
A. R. Nat. Prod. Lett. 1995, 6, 127-132. (e) AÄ lvarez, R.; Herrero, M.;
Lo´pez, S.; de Lera, A. R. Tetrahedron 1998, 54, 6793-6810. (f) AÄ lvarez,
R.; de Lera, A. R. Tetrahedron: Asymmetry 1998, 9, 3065-3072. (g)
Dom´ınguez, B.; Iglesias, B.; de Lera, A. R. J . Org. Chem. 1998, 63,
4135-4139. (h) Dom´ınguez, B.; Pazos, Y.; de Lera, A. R. J . Org. Chem.
2000, 65, 5917-5925.
(15) (a) Yokokawa, F.; Hamada, Y.; Shiori, T. Tetrahedron Lett.
1993, 34, 6559-6562. (b) Betzer, J .-F.; Delagoge, F.; Muller, B.;
Pancrazi, A.; Prunet, J . J . Org. Chem. 1997, 62, 7768-7780.
(16) For other stereoselective approaches to 9-cis-retinoic acid (2),
see: (a) Bennani, Y. L. J . Org. Chem. 1995, 60, 1195-1200. (b) Wada,
A.; Hirashi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J . Org. Chem.
1997, 62, 4343-4348. (c) de Lera, A. R.; Castro, A.; Torrado, A.; Lo´pez,
S. Tetrahedron Lett. 1998, 39, 4575-4578.
(17) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9595.
(18) Anderson, J . C.; Namli, H.; Roberts, C. A. Tetrahedron 1997,
53, 15123-15134.
(12) (a) Suzuki, A. in ref 10; chapter 2, pp 49-97. (b) Suzuki, A. J .
Organomet. Chem. 1999, 576, 147-168.

Synthesis of 9-cis-Retinoic Acid
J . Org. Chem., Vol. 66, No. 25, 2001 8485
Sch em e 1a
a
(a) Pd2(dba)3, AsPh3, NMP, 40 °C.
Sch em e 2a
to the proven instability of polyenyl iodides. The solvent
was then removed and replaced by THF, and this solution
was immediately added dropwise to a THF solution of
Pd(PPh3)4 and the organoborane 18, freshly prepared
from 13. After stirring for 10 min at room temperature,
10% aqueous TlOH22 was added, and stirring was con-
tinued for 3 h. Workup and purification provided ethyl
9-cis-retinoate 12 in a satisfactory 84% combined yield
from starting components 13 and 10.23 Last, basic hy-
drolysis of 12 yielded the desired 9-cis-retinoic acid (2)16
(Scheme 3).
a
(a) MnO2, K2CO3, CH2Cl2, 0 to 25 °C, 2 h, 92%. (b) diethyl
3-(ethoxycarbonyl)-3-methylprop-2-enylphosphonate,
DMPU, THF, -115 to -40 °C, 94%.
n-BuLi,
This new synthetic approach to 9-cis-retinoic acid (2)
based on the Suzuki coupling to construct the C6-C7
bond does not require the isolation of organoboranes and
other unstable intermediates and proceeds under mild
reaction conditions compatible with the lability of the cis
isomers. Since cyclohexenyl boronic ester 18 is ultimately
derived from cyclohexanone 16, the synthetic scheme
should be easily adapted to the preparation of the ring-
demethylated analogues.
Despite the failure to induce a Shapiro reaction start-
ing from the highly hindered ketone 16, we felt that the
demethylated cyclohexanones should more easily be
converted into the alkenyllithium derivatives through
Shapiro reaction of the corresponding arenesulfonylhy-
drazones.24 For the implementation of the Shapiro-
Suzuki sequence, trisylhydrazones were selected due to
reports of fast decomposition (approximately 2 min at 0
°C) of the dianion formed upon treatment with n-BuLi,
a reaction that can be performed in THF.13b Trisylhy-
drazones are usually prepared by mixing equimolecular
amounts of both reactants, the ketone and trisylhydra-
zine, dissolved in methanol, ethanol,25a or diethyl ether25b
(in the presence of an acid catalyst such as hydrochloric
acid) allowing the reaction to proceed at 25 °C. The
trisylhydrazone is isolated in good yield by filtration of
the precipitate obtained upon cooling the reaction mix-
retinoids11a-c and other sensitive polyenes11e,f is the
difficult handling and tedious purification of the boronic
acid (or ester) intermediates. Keay et al.19a overcome this
drawback using the boronic acid immediately after its
generation by trapping the alkenyllithium precursor with
B(OMe)3. Moreover, since alkenyllithium derivatives can
be conveniently prepared by Shapiro reaction starting
from the corresponding hydrazones, both reactions (Sha-
piro-Suzuki) were combined to induce coupling of Csp2
fragments without isolation of the intermediates.19b This
variant for boronic acid formation was particularly ap-
pealing because the precursor hydrazone could itself be
derived from the cyclohexanone, the same starting mate-
rial employed in the preparation of the cyclohexenyl
triflates required for the synthesis of the trans retinoids
by Stille reaction (Scheme 1).11g,h Unfortunately, we faced
the lack of reactivity of the common hydrazones derived
from 2,6,6-trimethylcyclohexanone 16 (trisyl, tosyl, and
even the unsubstituted hydrazone 17, Scheme 3) under
Shapiro’s conditions. Since hydrazones are also precur-
sors of alkenyl iodides,20 cycloalkenyllithium derivatives
could alternatively result from iodine-lithium exchange.
In the event, cyclohexenyl iodide 13 was obtained by a
modification of Barton’s method20a using a solution of I2
in ether in the presence of DBN.20b Iodine-lithium
exchange using t-BuLi in THF at -78 °C for 30 min,
followed by trapping the organolithium with B(OMe)3,19a
provided the putative boronic ester 18 (Scheme 3).
(22) Uenishi, J .; Beau, J .-M.; Armstrong, R. W.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 4756-4758.
(23) An alternative, less efficient synthesis of 9-cis-retinoic acid (2),
based on a Suzuki cross-coupling of the in situ generated alkenyl
boronic ester 18 and a shorter polyenic component (a dienyl iodide),
has been previously published by our group (see ref 1). This sequence,
although stereoselective, faced the limitation of the low yields obtained
in both the Suzuki coupling and the HWE steps, requiring moreover
the difficult handling of sensitive trienol and dienol intermediates.
(24) Keay, B. A.; Maddaford, S. P.; Cristofoli, W. A.; Andersen, N.
G.; Passafaro, M. S.; Wilson, N. S.; Nieman, J . A. Can. J . Chem. 1997,
75, 1163-1171.
The second component, tetraenyl iodide 19, had to be
acquired immediately prior to use, by titration of 10 with
a solution of iodine in dichloromethane21 (Scheme 3), due
(19) (a) Maddaford, S. P.; Keay, B. A. J . Org. Chem. 1994, 59, 6501-
6503. (b) Passafaro, M. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 429-
432.
(20) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J .-L. Tetrahedron
1988, 44, 147-162. (b) Di Grandi, M. J .; J ung, D. K.; Krol, W. J .;
Danishefsky, S. J . J . Org. Chem. 1993, 58, 4989-4992.
(21) Friesen, R. W.; Loo, R. W. J . Org. Chem. 1991, 56, 4821-4823.
(25) (a) Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R. J .
Org. Chem. 1980, 45, 3017-3028. (b) Bertz, S. H.; Dabbagh, G. J . Org.
Chem. 1983, 48, 116-119.

8486 J . Org. Chem., Vol. 66, No. 25, 2001
Pazos and Iglesias
Sch em e 3a
a
(a) H2NNH2‚H2O, Et3N, EtOH, 80-90%. (b) I2, DBN, ether, 70-75%. (c) i. t-BuLi, THF, -78 °C; ii. B(OMe)3, -78 to 0 °C; iii. Pd(PPh3)4,
19, 10% aq TlOH, 25 °C, 3 h, 84%. (d) I2, CH2Cl2, 25 °C. (e) 5 M KOH, EtOH, 70 °C, 91%.
Sch em e 4a
Sch em e 5a
a
(a) TrisNHNH2, MeOH, cat. concentrated HCl (24, ref 27a;
25, refs 27a, 28; 26, 75%). (b) TrisNHNH2, CH3CN, concentrated
HCl, ref 29.
ture. Although trisylhydrazine is an expensive reagent,
it can be prepared from the corresponding sulfonyl
chloride and hydrazine hydrate.26
Trisylhydrazones 24,27a 25,27a,28 and 26, were subjected
to the Shapiro-Suzuki sequence for generation of the
cyclohexenyl boronates and their coupling with tetraenyl
iodide 19 (Scheme 5). After treating the trisylhydrazones
with n-BuLi in THF at -78 °C and warming up to 0 °C
to induce the elimination from the dianion (N2 evolution
was observed), subsequent treatment of the resultant
cyclohexenyllithium with B(Oi-Pr)3 at -78 °C and then
at 0 °C, afforded the corresponding boronic esters.
Sequential addition of Pd(PPh3)4, a solution of tetraenyl
iodide 19 in THF, and a 10% aqueous TlOH solution
afforded, after stirring at 25 °C, workup, and purification,
the desired ethyl retinoate analogues (28-30) in good
yields (Scheme 5). In keeping with the strong preference
for deprotonation at the least substituted R-position
(RCH3 > R2CH2 > R3CH) exhibited by the Shapiro
reaction,27 trisylhydrazone 25 afforded regioselectively
retinoid 29.
a
(a) i. n-BuLi, -78 f 0 °C; ii. B(Oi-Pr)3, -78 f 0 °C; iii. iodide
19, Pd(PPh3)4, 10% aq TlOH, 25 °C (28, 0.5 h, 65%; 29, 1 h, 91%;
30, 1 h, 97%). (b) I2, CH2Cl2, 25 °C.
bases such as s-BuLi in TMEDA),29 and addition to the
imine carbon competes with elimination.30 Therefore,
synthesis of ethyl 9-cis-1-demethylretinoate 33 required
instead the iodine-lithium exchange variant, as de-
scribed in Scheme 3, to access the cyclohexenyl boronate.
Thus, treatment of hydrazone 31 (mixture of diastereo-
isomers) with iodine and DBN provided alkenyl iodide
32, which was treated with t-BuLi in THF at -78 °C,
followed by addition of B(OMe)3, to afford the nonisolated
boronate. The application of the general procedure for
the Suzuki coupling described above provided ethyl 9-cis-
1-demethylretinoate 33 in excellent yield (93%) (Scheme
6).
A second limitation of the Shapiro reaction for trisyl-
hydrazones with different substitution pattern is the
inability to generate the more substituted cycloalkenyl-
lithium intermediate by nitrogen elimination from the
dianion.13 Therefore, for the synthesis of ethyl 9-cis-1,1-
The inefficient generation of a cyclohexenyl boronate
from hydrazone 27 (Scheme 4) confirms that steric
hindrance in hydrazones with tertiary carbons at CR
slows down hydrogen abstraction (even using strong
(26) Cusack, N. J .; Reese, C. B.; Risius, A. C.; Roozpeikar, B.
Tetrahedron 1976, 32, 2157-2162.
(27) (a) Chamberlin, A. R.; Stemke, J . F.; Bond, F. T. J . Org. Chem.
1978, 43, 147-154. (b) For some exceptions, see: Trost, B. M.;
Nanninga, T. N. J . Am. Chem. Soc. 1985, 107, 1293-1299.
(28) Kolonko, K. J .; Shapiro, R. H. J . Org. Chem. 1978, 43, 1404-
1408.
(29) Corey, E. J .; Estreicher, H. Tetrahedron Lett. 1980, 21, 1113-
1116.
(30) Siemeling et al. have described the first example of a Shapiro
reaction on a substrate that contains only tertiary R-carbons in high
yield, probably due to the formation of a conjugated system. Siemeling,
U.; Neumann, B.; Stammler, H.-G. J . Org. Chem. 1997, 62, 3407-
3408.

Synthesis of 9-cis-Retinoic Acid
J . Org. Chem., Vol. 66, No. 25, 2001 8487
Sch em e 6a
products, which were difficult to separate by column
chromatography (SiO2, C18-SiO2). Last, since triflate 34
is not sterically hindered, a Stille coupling14 was alter-
natively contemplated (Scheme 7).11g,h Using Farina’s
optimized conditions [Pd2(dba)3 (2.5 mol %), AsPh3 (20
mol %) in NMP],17 alkenyl triflate 34 was coupled to
tetraenyl stannane 10 at 25 °C in 3 h,11h to obtain the
desired ethyl 9-cis-1,1-bisdemethylretinoate 36 in excel-
lent yield (95%).
To complete the preparation of the desired 9-cis-
retinoic acid analogues, ethyl 9-cis-retinoates (28-30, 33,
and 36) were saponified (5 M KOH) at 70 °C for 30 min,16a
affording the carboxylic acids (3-7) in high yields (85-
95%). Their biological activities, including binding to
RXRR, will be described elsewhere.
In summary, a new straightforward approach to 9-cis-
retinoic acid (2) and its ring-demethylated analogues 3-7
has been developed, which builds the C6-C7 bond of the
polyene skeleton by the C9 (down to C6, for the demethy-
lated retinoids) + C11 strategy using as key step a Suzuki
reaction without isolation of the unstable boronic acids
and tetraenyl iodide 19. For some of those ring-modified
analogues a combined Shapiro-Suzuki reaction repre-
sents the shortest route. Alternative procedures (Suzuki
reaction with an organoborane generated in situ by
iodine-lithium exchange or Stille reaction) have been
used as well, affording the polyenes in high yield and
configurational fidelity.
a
(a) H2NNH2‚H2O, Et3N, EtOH, 85%. (b) I2, DBN, Et2O, 65%.
(c) i. t-BuLi, THF, -78 °C; ii. B(OMe)3, -78 f 0 °C; iii. Pd(PPh3)4,
iodide 19, 10% aq TlOH, 25 °C, 3 h, 93%.
Sch em e 7a
Exp er im en ta l Section
Gen er a l P r oced u r es.11g,h (Abbreviations: DMPU, 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NMP, 1-meth-
yl-2-pyrrolidinone).
a
(a) i. i-Pr2NH, MeMgBr, 0 °C; ii. N-phenyltriflimide, THF, 0
(2Z,4E)-3-Met h yl-5-(t r i-n -b u t ylst a n n yl)p en t a -2,4-d ie-
n a l (15). MnO2 (8.31 g, 0.10 mol) and K2CO3 (13.2 g, 0.10 mol)
were added to a stirred solution of alcohol 1415b (2.06 g, 5.32
mmol) in CH2Cl2 (38 mL). After stirring for 30 min at 25 °C,
the suspension was filtered through Celite, and the filtrate
was evaporated. Purification of the residue by column chro-
matography (SiO2, 90:8:2 hexane/EtOAc/Et3N) afforded 1.88
°C (refs 11 g, 34, 35; 63%). (b) i. (Bu3Sn)2Cu(CN)Li2, -50 f -20
°C, 2 h. ii. AgOAc, 25 °C, 2 h (refs 34b, 36; 91%). (c) Stannane 10,
Pd2(dba)3, AsPh3, NMP, 25 °C, 3 h, 95%.
bisdemethylretinoate 36 recourse was also made to the
iodine-lithium variant (Scheme 7). The regioselective
formation of the thermodynamic magnesium enolate
derived from 2-methylcyclohexanone has been previously
described using diisopropylamidylmagnesium bromide.31
Triflate 34,11g,31,32 obtained by trapping the enolate with
N-phenyltriflimide, was converted into alkenyl stannane
35,32b,33 by treatment with a stannyl cuprate prepared
from CuCN and Bu3SnLi. Unfortunately, all attempts to
effect the tin-lithium exchange met with failure. On the
other hand, conversion of stannane 35 into the corre-
sponding cycloalkenyl iodide34 afforded mixtures of dif-
ficult separation. Likewise, transformation of this stan-
nane into the corresponding vinyl bromide,32b by treatment
with a solution of Br2 in CH2Cl2, led to the desired
compound, admixed with starting material and addition
1
g (92%) of 15 as a yellow oil. FTIR (NaCl) ν 1673 (s) cm-1. H
NMR (400 MHz, C6D6) δ 0.9-1.1 (m, 15H), 1.3-1.4 (m, 6H),
1.5-1.6 (m, 6H), 1.64 (s, 3H), 5.84 (d, J ) 7.5 Hz, 1H), 6.78
2
(dt, J ) 19.2 Hz, J Sn-H ) 64.3 Hz, 1H), 7.69 (dt, J ) 19.2 Hz,
3J Sn-H ) 60.1 Hz, 1H), 10.37 (d, J ) 7.5 Hz, 1H) ppm. 13C NMR
(100 MHz, C6D6) δ 10.0, 14.1, 20.5, 27.8, 29.7, 128.4, 141.3,
141.9, 153.5, 189.0 ppm. HRMS (EI+) calcd for C18H34O120Sn
386.1632, found 386.1639.
Eth yl (2E,4E,6Z,8E)-3,7-Dim eth yl-9-(tr i-n -bu tylstan n yl)-
n on a -2,4,6,8-tetr a en oa te (10). A cold (0 °C) solution of
diethyl 3-(ethoxycarbonyl)-3-methylprop-2-enylphosphonate
(1.80 g, 6.80 mmol) in THF (15.0 mL) was treated with DMPU
(1.62 mL, 13.38 mmol) and n-BuLi (2.8 mL, 2.35 M in hexanes,
6.57 mmol). After stirring the mixture at 0 °C for 20 min, it
was cooled to -115 °C and a solution of aldehyde 15 (1.74 g,
4.53 mmol) in THF (15.0 mL) was slowly added. The reaction
mixture was stirred at -115 °C for 30 min, and then it was
allowed to warm to -40 °C to complete the reaction. A
saturated aqueous NH4Cl solution was added, and the reaction
mixture was extracted with Et2O (3×). The combined organic
layers were washed with water and brine, dried (MgSO4), and
evaporated. Purification of the residue by column chromatog-
raphy (SiO2-C18, 60:40 CH3CN/MeOH) afforded 2.10 g of 10
(31) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1984,
106, 7500-7506.
(32) (a) Crisp, G. T.; Scott, W. J . Synthesis 1985, 335-337. (b) Wulff,
W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.;
Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J . Org.
Chem. 1986, 51, 277-279.
(33) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D.
Tetrahedron Lett. 1988, 29, 4795-4798.
1
(94%) as a yellow oil. FTIR (NaCl) ν 1711 (s) cm-1. H NMR
(34) (a) Seyferth, D.; Weiner, M. A. J . Am. Chem. Soc. 1962, 84,
361-364. (b) Cunico, R. F.; Clayton, F. J . J . Org. Chem. 1976, 41,
1480-1482. (c) Chen, S.-M. L.; Schaub, R. E.; Grudzinskas, C. V. J .
Org. Chem. 1978, 43, 3450-3454. (d) Seyferth, D.; Vick, S. C. J .
Organomet. Chem. 1978, 144, 1-12. (e) Piers, E.; Morton, H. E. J . Org.
Chem. 1979, 44, 3437-3439. (f) Cooke, J r. M. P. J . Org. Chem. 1982,
47, 4963-4968. (g) J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982,
23, 3851-3854.
(400 MHz, CDCl3) δ 0.90 (t, J ) 7.2 Hz, 3H), 0.9-1.1 (m, 15H),
1.2-1.4 (m, 6H), 1.5-1.7 (m, 6H), 1.94 (s, 3H), 2.34 (d, J )
0.7 Hz, 3H), 4.17 (q, J ) 7.2 Hz, 2H), 5.77 (s, 1H), 6.09 (d, J )
11.4 Hz, 1H), 6.22 (d, J ) 15.1 Hz, 1H), 6.47 (dt, J ) 19.1 Hz,
2J Sn-H ) 68.9 Hz, 1H), 7.16 (dd, J ) 15.1, 11.4 Hz, 1H), 7.19
3
(dt, J ) 19.1 Hz, J Sn-H ) 63.0 Hz, 1H) ppm. 13C NMR (100

8488 J . Org. Chem., Vol. 66, No. 25, 2001
Pazos and Iglesias
MHz, CDCl3) δ 9.7, 13.6, 13.7, 14.3, 20.3, 27.3, 29.1, 59.6, 118.9,
128.0, 129.4, 133.6, 134.9, 138.8, 142.1, 152.5, 167.1 ppm.
HRMS (EI+) calcd for C25H44O2118Sn 494.2357, found 494.2361.
2,2,6-Tr im eth ylcycloh exa n on e Hyd r a zon e (17). Gen -
er a l P r oced u r e for th e P r ep a r a tion of Hyd r a zon es. A
solution of ketone 16 (0.50 g, 3.57 mmol) in absolute EtOH
(2.5 mL) was treated with H2NNH2‚H2O (3.1 mL, 0.06 mol)
and Et3N (0.75 mL, 5.39 mmol). The reaction mixture was
stirred at 100 °C until TLC monitoring showed complete
disappearance of the starting material (approx 2-3 days).
After evaporation of the solvent and the excess of reagents,
the crude was extracted with Et2O (3×). The combined organic
layers were dried (Na2SO4) and evaporated. Purification of the
residue by column chromatography (neutral alumina, grade
II, 75:25 hexane/EtOAc) afforded a white solid (mp 67 °C),
identified as 17 (0.48 g, 87%). FTIR (NaCl) ν 3600-3100 (br),
g, 0.030 mmol), followed by iodide 19 [simultaneously gener-
ated by treating stannane 10 (0.15 g, 0.30 mmol) with a
solution of iodine in CH2Cl2] dissolved in THF (1.0 mL), were
then added. After stirring for 10 min, a 10% solution of TlOH
in water was added (2.6 mL, 1.16 mmol), and the final mixture
was stirred at 25 °C for 30 min. It was then diluted with Et2O
and filtered through Celite. The filtrate was washed with a
saturated aqueous NaHCO3 solution (3×), dried (Na2SO4), and
evaporated. The crude residue was purified by column chro-
matography (SiO2, 90:10 hexane/EtOAc) to afford 28 (0.06 g,
65%) as a yellow solid (mp 77.5 °C, hexane/EtOAc). FTIR
1
(NaCl) ν 1710 (s) cm-1. H NMR (400 MHz, CDCl3) δ 1.29 (t,
J ) 7.1 Hz, 3H), 1.6-1.8 (m, 4H), 1.98 (s, 3H), 2.0-2.3 (m,
4H), 2.36 (s, 3H), 4.17 (q, J ) 7.1 Hz, 2H), 5.77 (s, 1H), 5.90
(br s, 1H), 6.05 (d, J ) 11.5 Hz, 1H), 6.21 (d, J ) 15.1 Hz, 1H),
6.37 (d, J ) 15.8 Hz, 1H), 6.73 (d, J ) 15.8 Hz, 1H), 7.21 (dd,
J ) 15.1, 11.5 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ
13.9, 14.3, 21.0, 22.4, 22.5, 24.6, 26.3, 59.6, 118.5, 121.1, 128.4,
129.6, 132.2, 134.5, 134.8, 136.1, 138.2, 152.7, 167.2 ppm.
HRMS (EI+) calcd for C19H26O2 286.1933, found 286.1935.
1637 (w) cm-1 1H NMR (400 MHz, CDCl3): δ 1.12 (s, 3H),
.
1.13 (s, 3H), 1.16 (d, J ) 7.5 Hz, 3H), 1.3-1.9 (m, 6H), 2.8-
3.0 (m, 1H), 4.6-5.1 (br s, 2H) ppm. 13C NMR (100 MHz,
CDCl3) δ 17.2, 17.4, 26.5, 28.9, 29.5, 31.7, 37.6, 40.4, 162.5
ppm. HRMS (EI+) calcd for C9H18N2 154.1470, found 154.1477.
1,3,3-Tr im eth yl-2-iodocycloh ex-1-en e (13). Gen er al P r o-
ced u r e for th e P r ep a r a tion of Alk en yl Iod id es. To a
solution of hydrazone 17 (0.40 g, 2.59 mmol) and excess DBN
(2.88 mL, 23.34 mmol) in Et2O (10 mL) was added dropwise a
solution of iodine (1.36 g, 5.37 mmol) in Et2O (10 mL). The
mixture became turbid, and by the end of the addition a brown
layer had formed. After 15 min of additional stirring, a
saturated aqueous NaHCO3 solution was added. The organic
phase was dried (Na2SO4) and filtered, and the solvent was
removed in vacuo. The resultant dark red oil was dissolved in
benzene (10 mL), and the solution was then refluxed in the
presence of DBN for 2.5 h. After cooling to room temperature,
the mixture was poured into Et2O and washed with a 1 M
aqueous Na2S2O3 solution (3×). The organic layer was dried
(Na2SO4), filtered, and evaporated. The residue was purified
by column chromatography (SiO2, hexane) to afford 0.47 g of
iodide 13 (73%) as a pale yellow oil. 1H NMR (400 MHz, C6D6)
δ 1.20 (s, 6H), 1.3-1.6 (m, 4H), 1.88 (s, 3H), 1.7-1.9 (m, 2H)
ppm. 13C NMR (100 MHz, C6D6) δ 19.7, 31.2, 31.7 (25), 33.7,
(2E,4E,6Z,8E)-9-(Cycloh ex-1-en -1-yl)-3,7-d im eth yln on a -
2,4,6,8-t et r a en oic Acid (3). Gen er a l P r oced u r e for t h e
Hyd r olysis of Ester s. A solution of ester 28 (0.03 g, 0.10
mmol) in EtOH (0.2 mL) was treated with a 5 M aqueous KOH
solution (0.19 mL) and then refluxed for 30 min. The solution
was cooled to 25 °C, acidified with 10% HCl, and then extracted
with a 70:30 Et2O/CH2Cl2 mixture. The combined organic
layers were washed with brine, dried (Na2SO4), and concen-
trated. The residue was purified by chromatography on silica
gel (95:5 CH2Cl2/MeOH) to afford 0.02 g of 3 (85%) as a yellow
solid (mp 162 °C, hexane/EtOAc). FTIR (NaCl) ν 3400-2900
1
(br), 1668 (s) cm-1. H NMR (400 MHz, CDCl3) δ 1.4-1.7 (m,
4H), 2.01 (s, 3H), 2.2-2.4 (m, 4H), 2.39 (s, 3H), 5.83 (s, 1H),
5.94 (br s, 1H), 6.08 (d, J ) 11.7 Hz, 1H), 6.26 (d, J ) 15.3 Hz,
1H), 6.41 (d, J ) 15.8 Hz, 1H), 6.76 (d, J ) 15.8 Hz, 1H), 7.18
(dd, J ) 15.3, 11.7 Hz, 1H) ppm. 13C NMR (100 MHz, CD3-
SOCD3) δ 13.4, 20.6, 21.9, 22.0, 24.0, 25.6, 119.3, 121.3, 128.7,
129.5, 131.7, 134.5, 134.7, 135.9, 137.4, 151.7, 167.7 ppm.
HRMS (EI+) calcd for C17H22O2 258.1620, found 258.1626.
Eth yl (2E,4E,6Z,8E)-9-(6-Meth ylcycloh ex-1-en -1-yl)-3,7-
d im eth yln on a -2,4,6,8-tetr a en oa te (29). According to the
general procedure described above for the one-pot Shapiro-
Suzuki reaction, hydrazone 2527a,28 (0.15 g, 0.38 mmol) was
treated with n-BuLi (0.37 mL, 3.0 M in hexane, 1.14 mmol),
followed by B(Oi-Pr)3 (0.17 mL, 0.75 mmol) and iodide 19
[previously generated from stannane 10 (0.15 g, 0.30 mmol)].
After stirring the mixture for 1 h at 25 °C, purification of the
residue by column chromatography (SiO2, 90:10 hexane/
EtOAc) afforded 29 (0.08 g, 91%) as a yellow oil. (See
Supporting Information for characterization data).
(2E,4E,6Z,8E)-9-(6-Me t h ylcycloh e x-1-e n -1-yl)-3,7-d i-
m eth yln on a -2,4,6,8-tetr a en oic Acid (4). According to the
general procedure described above for the hydrolysis of esters,
29 (0.03 g, 0.10 mmol) in ethanol (0.22 mL) was treated with
a 5 M aqueous KOH solution (0.19 mL) and then refluxed for
30 min. Purification by chromatography (SiO2, 95:5 CH2Cl2/
MeOH) afforded 0.02 g of 4 (95%) as a yellow solid (mp 92 °C,
hexane/EtOAc). (See Supporting Information for characteriza-
tion data).
38.0, 39.7, 117.6, 137.7 ppm. HRMS (EI+) calcd for C9H15
250.0219, found 250.0210.
I
Eth yl (2E,4E,6Z,8E)-3,7-Dim eth yl-9-(2,6,6-tr im eth ylcy-
cloh ex-1-en -1-yl)n on a -2,4,6,8-tetr a en oa te (12).16a-b Gen -
er a l P r oced u r e for th e Su zu k i Rea ction . A cold (-78 °C)
solution of iodide 13 (0.09 g, 0.38 mmol) in THF (2 mL) was
treated with t-BuLi (0.47 mL, 1.70 M in pentane, 0.80 mmol).
After stirring for 1 h, B(OMe)3 (0.08 mL, 0.75 mmol) was
added, and the reaction mixture was stirred at 0 °C for an
additional 1 h. Pd(PPh3)4 (0.035 g, 0.030 mmol) was added,
followed by iodide 19 [simultaneously generated by treatment
of stannane 10 (0.15 g, 0.30 mmol) with a solution of iodine in
CH2Cl2] in THF (0.6 mL), and a 10% aqueous TlOH solution
(2.6 mL, 1.16 mmol). After stirring for 3 h at 25 °C, the reaction
mixture was diluted with Et2O and filtered through Celite.
The organic layer thus obtained was washed with a saturated
aqueous NaHCO3 solution (3×), dried (Na2SO4), and evapo-
rated. Purification of the residue by column chromatography
(SiO2, hexane/EtOAc), afforded 0.08 g of 12 (84%) as a yellow
1
oil. H NMR (400 MHz, CDCl3) δ 1.05 (s, 6H), 1.30 (t, J ) 7.1
2,2-Dim eth ylcycloh exa n on e 2,4,6-Tr iisop r op ylben z-
en esu lfon ylh yd r a zon e (26). Ketone 22 (0.40 g, 3.17 mmol)
was added with vigorous stirring to a solution of finely
powdered 2,4,6-triisopropylbenzenesulfonylhydrazine (0.95 g,
3.17 mmol) in MeOH (3.2 mL). The suspension dissolved upon
addition of concentrated hydrochloric acid (0.03 mL), and the
product started to crystalize. The reaction mixture was kept
at -10 °C overnight. The product was filtered, washed with
cold MeOH, and dried (25 °C, 0.5 mmHg) affording hydrazone
26 (0.97 g, 75%) as white crystals (mp 144 °C, MeOH). FTIR
(NaCl) ν 3600-3100 (br), 1365 (w), 659 (w) cm-1. 1H NMR (400
MHz, CDCl3) δ 1.01 (s, 6H), 1.31 (d, J ) 6.8 Hz, 18H), 1.2-1.6
(m, 6H), 2.0-2.2 (m, 2H), 2.96 (sept, J ) 6.8 Hz, 1H), 4.24
(sept, J ) 6.8 Hz, 2H), 7.21 (s, 2H), 7.32 (s, 1H) ppm. 13C NMR
(62 MHz, CDCl3) δ 21.2, 22.6, 23.5, 24.7, 25.9, 26.8, 29.7, 34.1,
Hz, 3H), 1.4-1.7 (m, 4H), 1.76 (s, 3H), 2.00 (s, 3H), 1.9-2.0
(m, 2H), 2.34 (d, J ) 1.0 Hz, 3H), 4.17 (q, J ) 7.1 Hz, 2H),
5.77 (s, 1H), 6.06 (d, J ) 11.5 Hz, 1H), 6.22 (d, J ) 15.1 Hz,
1H), 6.28 (d, J ) 16.0 Hz, 1H), 6.35 (d, J ) 16.0 Hz, 1H), 7.09
(dd, J ) 15.1, 11.5 Hz, 1H) ppm.
E t h yl (2E,4E,6Z,8E)-(Cycloh ex-1-en -1-yl)-3,7-d im et h -
yln on a -2,4,6,8-tetr a en oa te (28). Gen er a l P r oced u r e for
th e On e-P ot Sh a p ir o-Su zu k i Rea ction . A solution of
n-BuLi in hexane (0.37 mL, 3.07 M, 1.14 mmol) was added to
a cold (-78 °C) suspension of 2427a (0.14 g, 0.38 mmol) in THF
(1.0 mL), and the solution was stirred for 30 min. Nitrogen
evolution was observed when the temperature was taken up
to 0 °C, before cooling to -78 °C for the addition of triisopropyl
borate (0.17 mL, 0.75 mmol). The mixture was stirred for 1 h
at 0 °C and then heated to room temperature. Pd(PPh3)4 (0.035

Synthesis of 9-cis-Retinoic Acid
J . Org. Chem., Vol. 66, No. 25, 2001 8489
39.0, 40.7, 123.4, 124.0, 151.2, 153.0, 164.2 ppm. HRMS (EI+)
calcd for C23H38N2O2S 406.2654, found 406.2652.
general procedure described above for the hydrolysis of esters,
33 (0.04 g, 0.14 mmol) in EtOH (0.31 mL) was treated with a
5 M aqueous KOH solution (0.25 mL) and then refluxed for
20 min. The residue was purified by chromatography on silica
gel (95:5 CH2Cl2/MeOH) to afford 0.03 g of 6 (86%) as a yellow
solid (mp 95 °C, hexane/EtOAc). (See Supporting Information
for characterization data).
Eth yl (2E,4E,6Z,8E)-3,7-Dim eth yl-9-(6,6-d im eth ylcyclo-
h ex-1-en -1-yl)n on a -2,4,6,8-tetr a en oa te (30). According to
the general procedure described above for the one-pot Sha-
piro-Suzuki reaction, hydrazone 26 (0.15 g, 0.38 mmol) was
treated with n-BuLi (0.37 mL, 3.1 M in hexane, 1.14 mmol),
followed by B(Oi-Pr)3 (0.17 mL, 0.75 mmol), and iodide 19
[previously generated from stannane 10 (0.15 g, 0.30 mmol)].
The reaction mixture was stirred for 1 h at 25 °C. Purification
by column chromatography (SiO2, 90:10 hexane/EtOAc) af-
forded 30 (0.09 g, 97%) as a yellow oil. (See Supporting
Information for characterization data).
(2E,4E,6Z,8E)-3,7-Dim eth yl-9-(6,6-d im eth ylcycloh ex-1-
en -1-yl)n on a -2,4,6,8-tetr a en oic Acid (5). According to the
general procedure described above for the hydrolysis of esters,
30 (0.05 g, 0.18 mmol) in EtOH (0.40 mL) was treated with a
5 M aqueous KOH solution (0.32 mL) and then refluxed for
30 min. The residue was purified by chromatography on silica
gel (95:5 CH2Cl2/MeOH) to afford 0.05 g of 5 (92%) as a yellow
solid (mp 135 °C, hexane/EtOAc). (See Supporting Information
for characterization data).
Eth yl (2E,4E,6Z,8E)-3,7-Dim eth yl-9-(2-m eth ylcycloh ex-
1-en -1-yl)n on a -2,4,6,8-tetr a en oa te (36). A solution of Pd2-
(dba)3 (0.010 g, 0.011 mmol) in NMP (3.2 mL) was treated with
AsPh3 (0.03 g, 0.11 mmol). After stirring for 5 min, a solution
of triflate 3411g,31,32 (0.1 g, 0.41 mmol) in NMP (0.6 mL) was
added, followed, after 10 min, by a solution of stannane 10
(0.22 g, 0.45 mmol) in NMP (0.6 mL). The resulting mixture
was stirred at 25 °C for 3 h. Saturated aqueous KF solution
was added, and the mixture was stirred for 30 min and
extracted with Et2O (3×). The combined organic extracts were
washed with H2O and saturated aqueous KF solution, dried
(Na2SO4), and evaporated. The residue was purified by column
chromatography (SiO2, 90:10 hexane/EtOAc) to afford 0.12 g
(95%) of 36 as a yellow oil. (See Supporting Information for
characterization data).
2,6-Dim eth ylcycloh exa n on e Hyd r a zon e (31). According
to the general procedure described above for the preparation
of hydrazones, 31 was prepared from ketone 23 (1.0 g, 7.92
(2E,4E,6Z,8E)-3,7-Dim eth yl-9-(2-m eth ylcycloh ex-1-en -
1-yl)n on a -2,4,6,8-tetr a en oic Acid (7). According to the
general procedure described above for the hydrolysis of esters,
36 (0.04 g, 0.15 mmol) in EtOH (0.34 mL) was treated with a
5 M aqueous KOH solution (0.27 mL) and then refluxed for
30 min. The residue was purified by chromatography on silica
gel (95:5 CH2Cl2/MeOH) to afford 0.04 g of 7 (90%) as a yellow
solid (mp 187 °C, hexane/EtOAc). (See Supporting Information
for characterization data).
1
mmol) as a very thick pale yellow oil (0.95 g, 85%) whose H
NMR spectrum revealed the presence of a mixture of diaste-
reoisomers in a 3:1 ratio. (See Supporting Information for
characterization data).
1,3-Dim eth yl-2-iod ocycloh ex-1-en e (32). According to the
general procedure described above for the preparation of
alkenyl iodides, hydrazone 31 (0.40 g, 2.85 mmol) was con-
verted into iodide 32 (0.44 g, 65%), which was isolated as a
pale yellow oil. (See Supporting Information for characteriza-
tion data).
Eth yl (2E,4E,6Z,8E)-3,7-Dim eth yl-9-(2,6-d im eth ylcyclo-
h ex-1-en -1-yl)n on a -2,4,6,8-tetr a en oa te (33). According to
the general procedure described above for the Suzuki reaction,
iodide 32 (0.18 g, 0.78 mmol) was treated with a solution of
t-BuLi in pentane (0.94 mL, 1.7 M, 1.60 mmol) followed by
B(OMe)3 (0.17 mL, 1.53 mmol) and iodide 19 [in situ generated
from stannane 10 (0.30 g, 0.60 mmol)] for 3 h at 25 °C, to afford
33 (0.17 g, 93%) as a yellow oil. (See Supporting Information
for characterization data).
Ack n ow led gm en t. We thank Spanish Ministry of
Education and Culture (CICYT, Grant SAF980243),
Xunta de Galicia (PGIDT99 PXI30105B), and CIRD-
Galderma for financial support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and copies of 1H and 13C NMR spectra for all new
compounds described in the Experimental Section. This mate-
rialis availablefreeofchargevia theInternet at http://pubs.acs.org.
(2E,4E,6Z,8E)-3,7-Dim eth yl-9-(2,6-d im eth ylcycloh ex-1-
en -1-yl)n on a -2,4,6,8-tetr a en oic Acid (6). According to the
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