Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid

Article abstract of DOI:10.1016/j.tetlet.2008.05.136

(E)-4-((3-Ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid, 6, was synthesized in 87% starting from β-cyclocitral. The target compound 6 was synthesized starting from 1 via a Grignard reaction to form alcohol 2. Compound 2 was converted to Wi

Full text of DOI:10.1016/j.tetlet.2008.05.136

Tetrahedron Letters 49 (2008) 4695–4696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-
enylidene)methyl)benzoic acid
d
Bhaskar C. Das a,b,c, , George W. Kabalka
*
a Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
b Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
c Albert Einstein College Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
d Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN,37996-1600, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
(E)-4-((3-Ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid, 6, was synthesized in 87%
starting from b-cyclocitral. The target compound 6 was synthesized starting from 1 via a Grignard reac-
tion to form alcohol 2. Compound 2 was converted to Wittig salt 3 by treatment with aldehyde 4 in butyl-
lithium and hexane at À78 °C to form ester 5. Ester 5 was saponified and, following acidification, acid 6
was isolated as white solid yield 87%.
Received 6 May 2008
Revised 22 May 2008
Accepted 28 May 2008
Available online 4 June 2008
Published by Elsevier Ltd.
Keywords:
Retinoids
Peptidomimetics
1,4 Diene and Wittig reaction
Our long-term goal is to develop novel diagnostic and therapeu-
tic agents for retinoic acid receptors antagonist, agonist and related
signaling pathways, and to identify new gene targets of these path-
ways. For this purpose, we have prepared a variety of retinoic acid
analogues and evaluated their bio-activity using developing zebra
fish embryos.
two cellular retinoic acid-binding proteins (referred to as CRABP-
I and CRABP-II) are believed to be involved in the presentation of
ATRA to metabolizing CYP enzymes and its channeling to the
RAR, receptors.7,8 One of the strategies for preventing in vivo cata-
bolism of ATRA is to inhibit the P450 enzymes responsible for this
process. This may yield effective agents for the chemoprevention
and/or treatment of cancers and dermatological diseases.9 Major
emphasis has been given to liarozole, the most studied and first
Retinoic Acid Metabolism Blocking Agents (RAMBAs) to undergo
clinical investigation and different small molecules for example
4-azolyl retinoid, benzeneacetic acid derivatives, and 2,6-disubsti-
tuted naphthalenes.10
All-trans-retinoic acid (ATRA), the biologically most active
metabolite of vitamin A, plays a major role in the regulation of gene
expression, in cellular differentiation and proliferation of epithelial
cells.1 Differentiating agents redirect cells toward their normal phe-
notype and therefore may reverse or suppress evolving malignant
lesions or prevent cancer; they represent an attractive target for
medicinal intervention. ATRA is being used in differentiation ther-
apy of cancer, in cancer chemoprevention, and for the treatment
of dermatological diseases, including, acne, psoriasis, and ichthyo-
sis.2 Recently, ATRA has proven useful in cancer chemotherapy.3
One of the most impressive effects of ATRA is on acute promyelo-
cytic leukemia. Treatment of acute promyelocytic leukemia patients
with high doses of ATRA resulted in complete remission.4,5 In spite
of these encouraging results, the effects of prolonged ATRA therapy
on human cancers in the clinic have been disappointing, but treat-
ment of dermatological diseases has been far more promising.
It has been suggested that the therapeutic effects of ATRA are
undermined by its rapid in vivo metabolism and catabolism by
cytochrome P450 enzymes.6 An important consideration is that
Though major emphasis has been given to RAMBAs, we envi-
sioned the synthesis of analogues of ATRA (A) in Scheme 1 which
entails changing the flexible alkene backbone to a more rigid
O
OH
O
OH
(A)
(B)
H
HO
(6)
O
* Corresponding author. Tel.: +1 718 430 2422; fax: +1 718 430 8853.
E-mail address: bdas@aecom.yu.edu (B. C. Das).
Scheme 1.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.136

4696
B. C. Das, G. W. Kabalka / Tetrahedron Letters 49 (2008) 4695–4696
OH
phenyl ring, B could act as RAMBA itself. During our investigation,
we discovered an unusual reaction which produced 6, in Scheme 1.
The proposed synthesis of B involved straightforward reactions
but, unexpectedly, generated 6 rather than B. The structure of 6
was confirmed by the NMR (1H, 13C, NOE) experiments and HRMS.
From 1H NMR d 2.19 (q, 2H) and 13C d 22.3 is the characteristic
peak for methylene peak at 4-position of cyclohexene ring system.
NOE experiment clearly indicates phenyl ring at trans position.
Compound 6 (1H–1H NOes: 6.46 ppm?7.38 ppm-4%, 6.46 ppm?
1.85 ppm-18%, 7.39 ppm?7.90 ppm-7%, 7.39 ppm >6.46 ppm-4%,
7.39 ppm ? 2.55 ppm À1%.
PPh3.HBr
CH3OH
CHO
CH3MgBr
1. n-BuLi, hexane, ether
THF, 2 h, 72%
2. OHC
85%
CO2CH3
rt, 72 h, 78%
+
(1)
PPh3
(3)
(2)
(4)
NaOH (aq)
CH3CH2OH
87%
H
H
O
HO
(5)
O
(6)
O
Scheme 2.
The synthesis of 6 involves the reaction with methyl magne-
sium bromide with b-cyclocitral in THF to give alcohol 2 as a yel-
low oil (Scheme 2).11 The alcohol gave satisfactory spectral data
and was directly converted to 3 by treatment with triphenylphos-
phine hydrobromide in methanol. Recrystallization of 3 from
methanol/ether (1:6) gave a yellow crystalline solid.12 Formation
of the Wittig reagent from 3 in ether was accomplished with n-
butyllithium in hexane at room temperature (dark-red color), then
the Wittig reagent was treated with methyl 4-formylbenzoate 4 in
ether at À78 °C for 10–15 min and then stirred at room tempera-
ture under a nitrogen atmosphere for 30 h. After work up, crude es-
ter 5 was purified by flash column chromatography (hexane/ethyl
acetate: 98/2) to give a brown oil in 85% yield.13 The ester was
saponified to generate a white solid which was filtered, washed
with water, and dried. The product was recrystallized from hot eth-
anol and washed with dry hexane to give acid 6 as white crystals
(87%) yield.14 The structure was confirmed by 1H, 13C NMR and
NOE experiment, HMBC, and HRMS.
Acknowledgments
The author B.C.D. is thankful to AECOM for start up funding
Sean Cahill for NMR experiments. The instrumentation in the AE-
COM Structural NMR Resource is supported by the Albert Einstein
College of Medicine and in part by Grants from the NSF
(DBI9601607 and DBI0331934), the NIH (RR017998) and the HHMI
Research Resources for Biomedical Sciences.
Supplementary data
Supplementary data (1H, 13C NMR, NOE and HRMS) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.05.136.
References and notes
Although a detailed study has not yet been completed, the for-
mation of 6 could arise as outlined in the following scheme.
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Bakker, J. E.; Siegenthaler, G.; Van der Kerkhof, P. C.; Schalkwijk, J. Br. J.
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OH
Br
PPh3.HBr
CH3OH
+
(2)
PPh3
(3)
:
PH3
_
:
1. n-BuLi, hexane, ether
H+ shift
4. Degos, L.; Chomienne, C.; Daniel, M. T.; Berger, R.; Dombert, H.; Fenaux, P.;
Castaigne, S. Lancet 1990, 336, 1440–1441.
_
[most likely
5. Warrell, R. P.; Frankel, S. R.; Miller, W. H.; Scheinberg, D. A.; Itri, L. M.;
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Gordon, M. S.; Dmitrovsky, E. N. Engl. J. Med. 1991, 324, 1385–1393.
6. Hong, W. K.; Itri, L. In The Retinoids: Biology, Chemistry, and Medicine, 2nd ed.;
Sporn, M. B., Roberts, A. B., Goodman, D. S., Eds.; Raven: New York, 1994; pp
923–930.
+
PPh3
intermolecular]
PPh3
+
1. n-BuLi, hexane, ether
NaOH (aq)
7. Trump, D. L.; Smith, D.; Stiff, D.; Adedoyin, A.; Bahnson, R.; Day, R.; Branch, R.
Proc. Am. Soc. Clin. Oncol. 1994, 751, 241.
CH3CH2OH
2. OHC
CO2CH3
O
_
H
(4)
H
8. (a) Mundi, J.; Frankel, S. R.; Miller, W. H., Jr.; Jakubowski, A.; Scheinberg, D. A.;
Young, C. W.; Dmitrovsky, E.; Warrell, R. P., Jr. Blood 1992, 79, 299–303; (b)
Mundi, J.; Frankel, S. R.; Miller, W. H., Jr.; Huselton, C.; Degrazia, F.; Garland, W.
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+
PPh3
HO
(5)
O
(6)
O
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Compound 2 when treated with triphenyl phosphine hydrogen
bromide in methanol, forms the expected allylic bromide. Nucleo-
philic attack of the triphenylphosphine at the b-carbon of the
allylic bromide results in the formation of 3. Addition of butyllith-
ium results in deprotonation at the carbon adjacent to the phos-
phonium ion. An intermolecular, proton shift then generates the
ylide that reacts in a Wittig reaction to generate the observed prod-
uct, 5. Saponification and acidification then generates 6.
In summary, we report here the synthesis of a novel analogue of
ATRA generated by replacing the acyclic alkene backbone with a
phenyl ring. The biological activity of 6 and its derivatives is cur-
rently underway and will submitted for publication in the near
future. The formation of 6 involved an unusual triphenylphospine
substitution reaction which may comprise a new method for con-
verting allylic tertiary alcohols to dienes. The generality of the new
reaction is currently being investigated.
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Gonza’ lez, R. J. Org. Chem. 2003, 68, 3585–3592.
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14.
A detailed experimental procedure follows: Compound (6)—ester 5 (1.08 g,
3.61 mmol) was dissolved in ethanol (17 mL), while maintaining at a N2
atmosphere. An aqueous solution of NaOH (0.83 g, 21 mmol in 36 mL H2O) was
added. The reaction mixture was heated at reflux under N2 for 5 h during
which, the mixture became a clear yellow solution. After cooling to near room
temperature, the solution was acidified with concentrated aqueous HCl. A
white solid formed and was filtered, washed with water. The solid was dried
and recrystallized from hot ethanol. After washing with dry hexane, 6 was
obtained as white crystals (0.89 g, 87%), mp 187 °C. 1H NMR (300 MHz, DMSO-
d6): d 13.0–12.6 (br s, 1H), 7.90–7.82 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8 Hz, 2H),
6.47 (s, 1H), 2.55 (m, 2H), 2.19 (q, 2H), 1.86 (s, 3H), 1.44 (m, 2H), 1.05 (s, 6H)
and 1.03 (t, J = 8 Hz, 3H) 13C NMR (75 MHz, DMSO-d6): d 148.1, 142.8, 141.2,
129.03, 127.8, 126.6, 120.5, 67.1, 38.1, 35.4, 27.3, 23.7, 22.3 and 14.6. HR FT-ICR
MS: calcd for C19H24O2 ([M+H]+) 285.1848; found: 285.1856.