Stereoselective synthesis of tetrazole CB92834, a potent retinoid compound

Article abstract of DOI:10.1016/j.tet.2005.03.023

An improved, convergent synthesis of CB92834 is relying on a Suzuki cross-coupling reaction and easily allows multigram-scale preparation of the compound. The approach features three highly stereoselective steps.

Full text of DOI:10.1016/j.tet.2005.03.023

Tetrahedron 61 (2005) 4755–4759
Stereoselective synthesis of tetrazole CB92834, a potent
retinoid compound
*
Goulnara Garipova, Arnaud Gautier and Serge R. Piettre
´ ´ ´ ´ `
Laboratoire des Fonctions Azotees et Oxygenees Complexes, UMR CNRS 6014, IRCOF-Universite de Rouen, Rue Tesnieres,
F-76821 Mont Saint Aignan, France
Received 25 January 2005; revised 4 March 2005; accepted 7 March 2005
Available online 31 March 2005
Abstract—An improved, convergent synthesis of CB92834 is relying on a Suzuki cross-coupling reaction and easily allows multigram-scale
preparation of the compound. The approach features three highly stereoselective steps.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
only is it linear, but it also relies on a Wittig reaction
between the phosphorus ylid generated from phosphonium
salt 5 (prepared from toluene (2) in three steps) and
p-cyanoacetophenone (6) to create the carbon–carbon
double bond featuring the requisite Z configuration
(Scheme 1). The reaction is reported as being poorly
stereoselective, delivering a 7:3 mixture of Z and E isomers
(7 and 8, respectively). In addition, it suffers from a tedious
separation procedure of the two isomers, requiring three
sequential chromatography on silica to isolate the desired
one 7 in only 35% yield. Attemps to either improve the
stereoselectivity of this step or isomerize the E isomer into
the Z, all failed in our hands.7 We describe below a much
improved preparation of 9 which allows easy, multi-gram
scale synthesis of the compound.
The increasing incidence of cancer in the world has induced
massive efforts aiming at the development of the most
efficient treatments of the disease.1 Among the various
approaches, chemoprevention is the use of non-cytotoxic
therapeutic intervention at the early stages of carcinogenesis
against the development and progression of mutant clones to
invasive cancer. The chemopreventive potential of retinoids
has been the focus of much attention over the last decade.2
Retinoids are defined as molecules related to all-trans-
retinoic acid, and for which biological activities are
mediated by two types of receptors, retinoic acid receptors
(RARs) and retinoid X receptors (RXRs).3 With respect to
the various isotypes of these receptors, the retinoids-induced
effects include modifications of (i) cell proliferation, (ii)
apoptosis (cell death) and (iii) reversal of premalignancy by
inducing differentiation processes. Retinoids have been
shown to be active on breast, lung, cervical and head and
neck cancers, as well as on neuroblastoma and acute
promyelocytic leukemia. Although much important data has
been obtained, the exact signaling pathways required for
retinoids to exert their biological effects remain elusive.4
The design of a more efficient synthesis of the target
compound required the stereocontrolled production of the
vinyl C–C double bond with the requisite Z stereochemistry.
We chose to exploit the well-documented stereoselectivity
of a Suzuki cross-coupling reaction between boronate 10
(subunit A) and Z vinyl bromide 11 (subunit B)
(Scheme 2).8
Preparation of subunit A was accomplished through the
three step sequence depicted in Scheme 3. Thus, bromide 12
was produced by a double Friedel–Crafts alkylation of
bromobenzene and the resultant aryl bromide was trans-
formed into boronate 10 by the method of Miyaura.9,10 The
use of Pd(dppf)Cl2 proved to be particularly efficient,
allowing a low loading of catalyst (1 mol%) and the
isolation of 10 in good yield by simple distillation.
Recently, a class of 1,2-bisaryl alkenes featuring a Z
configuration has been reported as displaying promising
activities on RARs and RXRs.5 The foremost representative
of this class of compound is tetrazole 9.6 However, the
published preparation of 9 suffers from several drawbacks
which impede its use on multigram-scale synthesis. Not
Keywords: Z-alkene synthesis; Tetrazole; Retinoid; Suzuki cross-coupling
reaction.
Quite obvious was the fact that the success of the new
approach heavily depended on our ability to
*
Corresponding author. Tel.: C33 235 52 2970; fax: C33 235 52 2971;
e-mail: serge.piettre@univ-rouen.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.023

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G. Garipova et al. / Tetrahedron 61 (2005) 4755–4759
Scheme 1. Published synthesis of tetrazole 9. Reagents and conditions: (a) AlCl3, 110 8C; (b) N-bromosuccinimide, CH2Cl2; (c) P(C6H5)3; (d) n-BuLi,
4-cyanoacetophenone (6); (e) three sequential chromatography separations; (f) Me3SiN3, (n-Bu3Sn)2O.
from methanol allowed the isolation of the pure E isomer 13
in virtually quantitative yield.11 A sequence of bromination/
decarboxylative debromination proved to be particularly
gratifying, delivering exclusively the Z vinyl bromide 11 in
88% yield, the result of an anti elimination of bromide.12,13
The whole sequence of reactions (four steps) required a
single purification by distillation and compound 11
could easily be produced on multi-gram scale without
experiencing a drop in yields.
Coupling of subunits A and B (boronate 10 and vinyl
Scheme 2. Stereoselective approach to 7
bromide 11) could again be achieved on multi-gram scale
and was found to be completely stereoselective: product 7
was the sole isomer detected in the crude sample
(Scheme 5).14 Purification of this material reproducibly
afforded the desired compound 7 in 71–74% isolated yield.
Production of the tetrazole cycle present in the final product
was then carried out on multi-gram scale according to
literature procedure.15 Treating (7) at 110 8C for 12 h with
trimethylsilyl azide in the presence of a catalytic amount of
bis-(tri-n-butyltin)oxide furnished target molecule 9 in 80%
isolated yield.
stereoselectively generate vinyl bromide 11, with the
requisite Z stereochemistry. Acid 13 was stereoselectively
produced by a Wadsworth–Emmons reaction between
ketone 6 and triethyl phosphonoacetate in dry ethanol
followed by saponification and protonation of the resultant
product (Scheme 4). The Z/E isomer ratio was found to
strongly depend on the solvent. Thus, carrying out the
Wadsworth–Emmons reaction in diethyl ether or tetra-
hydrofuran (THF) led to a 3:7 mixture in favor of the E
isomer. Conducting the reaction in ethanol, however, led to
an increase of the selectivity to 98:2. Hydrolysis of the ester
group led to the desired acid, and a simple crystallisation
Thus, this new, convergent approach allows the preparation
of 9 with a global yield of 30%; three of the five steps of the
Scheme 3. Synthesis of subunit A. Reagents and conditions: (a) AlCl3, bromobenzene; (b) bis-(pinacolato)diboron, KOAc, Pd(dppf)Cl2 (1 mol%).

G. Garipova et al. / Tetrahedron 61 (2005) 4755–4759
4757
Scheme 4. Stereocontrolled synthesis of subunit B. Reagents and conditions: (a) dry ethanol, sodium, triethylphosphonoacetate; (b) KOH, methanol; (c) Br2,
CHCl3; (d) dry acetone, K2CO3.
Scheme 5. Coupling of subunits A and B. Reagents and conditions: (a) NaHCO3, Pd(dppf)Cl2; (b) TMSN3, [n-Bu)3Sn]2O (10 mol%).
sequence (i. e., 6/13, 13/11, 10C11/7) are highly
stereoselective, providing the desired isomer in excess of
98% in each case. The synthesis is applicable to large-scale
production of 9 and is potentially useful for the preparation
of analogues structurally related to the parent compound.
drying over MgSO4 and evaporation yield 30 g of the
desired ethyl ester as a 98:2 mixture of E/Z isomers. This
crude material is then hydrolyzed by stirring overnight at
room temperature in a solution of potassium hydroxide
(16 g) in methanol (200 mL). Addition of concentrated HCl
at 0 8C until pHZ4 results in the precipitation of a white
solid. Filtration, sequential washing of the solid with water
and methanol, and drying in vacuum yield 25 g of pure (E)
acid 13 (96% over two steps). Mp (methanol)Z192 8C. 1H
NMR (DMSO-d6) d 7.64 (d, JZ8.2 Hz, 2H), 7.53 (d, JZ
8.2 Hz, 2H), 6.02 (s, 1H), 2.31 (s, 3H). 13C NMR (DMSO-
d6) d 167.8, 152.2, 145.9, 132.5, 127.2, 119.7, 118.8, 111.3,
17.1. IR (neat) n 3448, 2258, 1654, 1026 cmK1. Calcd for
C10H8BrN: C, 71.03; H, 4.26. Found: C, 71.72; H, 5.02.
2. Experimental
2.1. General
1
Unless otherwise stated, H NMR, 13C NMR spectra were
recorded in deuterated chloroform on a Brucker AM200
spectrometer operating at 200 and 50 MHz, respectively.
Chemical shifts are expressed in parts per million (ppm)
relative to (CH3)4Si (1H) and CDCl3, (13C). IR spectra were
recorded on a FT-IR spectrometer. Combustion data were
obtained from the analytical department of the University of
Rouen. Commercially available chemicals were used with-
out further purification.
2.1.2. (Z) 1-Bromo-2-(4-cyanophenyl)propene (11). To a
suspension of acid 13 (25 g, 134 mmol) in chloroform
(300 mL) at 0 8C is added bromine (23.5 g, 146 mmol) and
the resultant mixture is stirred for 12 h. The reaction can be
monitored by 1H NMR spectrometry (d 7.7 (m, 4H), 5.0 (s,
1H), 2.52 (s, 3H)). The clear orange solution is then
evaporated and the residue is dissolved in dry acetone
(250 mL); NaHCO3 (15 g) is added and the mixture is
refluxed for 16 h. Filtration and evaporation under reduced
pressure deliver a crude, oily residue which is partitioned
between water and ethyl acetate. The water layer is
extracted with additional AcOEt and the combined organic
layers are dried over magnesium sulfate. Evaporation under
reduced pressure and distillation (154 8C/0.5 mbar) give
2.1.1. (E) 3-(4-Cyanophenyl)-but-2-enoic acid (13).
Sodium (3.5 g) is added in small portion to dry ethanol
(250 mL). When reaction of the metal is complete, the
solution is cooled down to 0 8C and neat triethyl-
phosphonoacetate (30 g, 137 mmol) is added. After
15 min of stirring at the same temperature, the solution is
warmed up to room temperature and a solution of
4-cyanoacetophenone (6) (20 g, 138 mmol) in dry ethanol
(25 mL) is added dropwise. The resultant red solution is
stirred for 30 min, after which period of time the solvent is
evaporated. Extraction with 10% aqueous NaHCO3/AcOEt,
1
16.5 g of product 11 as a colorless liquid (88% yield). H
NMR (CDCl3) d 7.60 (d, JZ8.0 Hz, 2H), 7.38 (d, JZ
8.0 Hz, 2H), 6.27 (s, 2H), 2.1 (s, 3H). 13C NMR (CDCl3) d

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G. Garipova et al. / Tetrahedron 61 (2005) 4755–4759
144.8, 140.0, 132.0, 128.6, 118.6, 111.2, 103.5, 24.4. IR
(neat) n 3072, 2914, 2850, 2228, 1604, 1500, 842 cmK1
2228, 1216, 756 cmK1. Calcd for C24H27N: C, 87.49; H,
8.26; N, 4.25. Found: C, 87.51; H, 8.38; N, 4.23.
.
Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31. Found: C,
54.12; H, 3.67; N, 6.57.
2.1.6. 5-{4-[1-Methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-1H-tetra-
zole 9. Nitrile 7 (3 g, 9.12 mmol), trimethylsilyl azide
(3.15 g, 27.4 mmol) and bis-(tri-n-butyltin)oxide (540 mg,
0.91 mmol (10 mol%)) are added to toluene (10 mL). The
reaction flask is flushed with nitrogen and the mixture is
heated at 110 8C for 12 h. The mixture is then cooled down,
the volatiles are removed under reduced pressure and the
residue is filtered through silica which is washed with a 98:2
mixture of heptane/AcOEt. The solvents are evaporated and
the resultant white solid is recrystallized from heptane to
deliver 2.7 g (80%) of 9. MpZ192–193 8C (lit.5: 191–
193 8C). 1H NMR (CDCl3) d 8.04 (d, JZ8.4 Hz, 2H), 7.38
(d, JZ8.4 Hz, 2H), 7.03 (d, JZ8.0 Hz, 2H), 6.83 (s, 1H),
6.72 (d, JZ8.0 Hz, 2H), 6.48 (s, 1H), 2.19 (s, 3H), 1.53 (s,
4H), 1.16 (s, 6H), 0.92 (s, 6H). 13C NMR (CDCl3) d 156.6,
147.2, 144.7, 143.7, 136.4, 134.2, 130.0, 128.6, 128.3,
127.9, 126.6, 126.5, 121.9, 35.4, 34.4, 34.2, 32.1, 31.9, 27.2.
IR (neat) (n 3420, 2962, 2856, 1614, 1490, 1456, 1362, 908,
732 cmK1. Calcd for C24H28N4: C, 77.32%; H, 7.53%. Fd:
C, 77.61%; H, 7.63%.
2.1.3. 1,2,3,4-Tetrahydro-1,1,4,4-tetramethyl-6-bromo-
naphthalene (12). To dry CH2Cl2 (20 mL) at 0 8C are
sequentially added aluminium trichloride (5.6 g, 42 mmol),
neat 2,5-dicloro-2,5-dimethylhexane16 (20 g, 109 mmol)
and a solution of bromobenzene (17.2 g, 109.3 mmol) in
CH2Cl2 (20 mL). The mixture is warmed up to room
temperature and stirred overnight. It is then slowly poured
onto crushed ice (100 g). Extraction with AcOEt (200 mL),
decantation, washing of the organic layer with 10% aqueous
NaHCO3 (100 mL), drying of the organic layer over
magnesium sulfate and evaporation of the volatiles left an
oily residue which was subjected to distillation (150 8C/
1
0.5 mbar) to furnish 18.9 g of 12 (70% yield). H NMR
(CDCl3) d 7.40 (s, 1H), 7.22 (d, JZ8.8 Hz, 2H), 7.16 (d, JZ
8.8 Hz, 2H), 1.65 (s, 4H), 1.25 (s, 12H). 13C NMR (CDCl3)
d 147.4, 143.8, 141.7, 129.6, 129.0, 128.6, 35.1, 34.2, 32.0.
IR (neat) n 2960, 1458, 1364, 908, 816, 734 cmK1. Calcd for
C14H19Br: C, 63.20; H, 7.10. Found: C, 63.42; H, 6.81.
2.1.4. 1,2,3,4-Tetrahydro-1,1,4,4-tetramethyl-6-pinaco-
latoboronaphthalene (10). Compound 12 (6.3 g,
23.6 mmol), bis-(pinacolato)diboron (5.0 g, 19.7 mmol),
Pd(dppf)Cl2 (140 mg, 0.19 mmol (1 mol%)) and potassium
acetate (5.2 g, 59.1 mmol) are sequentially added to
degassed dimethyl sulfoxide (DMSO) (40 mL) under inert
atmosphere. The reaction is carried out at 80 8C for 20 h.
After cooling, the mixture is poured into water and extracted
with AcOEt. The organic layer is evaporated and the residue
is dissolved in a 1:1 mixture of heptane/AcOEt (15 mL) and
filtered over a plug of silica gel. Washing with additional
heptane/AcOEt (1:1) (10 mL) and evaporation of the
volatiles delivers the crude product (10 g). Distillation
(130 8C/0.5 mbar) yields 5.5 g (74%) of pure product 10. 1H
NMR (CDCl3) d 7.75 (s, 1H), 7.55 (d, JZ8.0 Hz, 1H), 7.28
(d, JZ8.0 Hz, 2H), 1.66 (s, 4H), 1.3 (s, 12H), 1.26 (s, 12H).
Acknowledgements
Support from Anvar is gratefully acknowledged. Dr. A.-R.
Schoofs is thanked for his interest in the program.
References and notes
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.
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2.1.5. (Z) 4-[1-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-
naphthalenyl)-2-propenyl]benzonitrile (7). Bromide 11
(3.7 g, 16.9 mmol), boronate 10 (5.3 g, 16.9 mmol),
Pd(dppf)Cl2 (124 mg, 0.17 mmol (1 mol%)) and NaHCO3
(4.3 g, 50.3 mmol) are sequentially placed in a flask
containing a degassed mixture of 1,4-dioxane (60 mL) and
water (25 mL) under nitrogen. The reaction is stirred at
80 8C for 20 h. After cooling, the mixture is poured into
water and extracted with AcOEt. Evaporation of the
volatiles, filtration of the residue through silica and elution
with heptane/AcOEt (2:1) give 4.0 g (72%) of product 7.
MpZ121–123 8C (lit.5: 95–97 8C).17 1H NMR (CDCl3) d
7.58 (d, JZ8.4 Hz, 2H), 7.32 (d, JZ8.4 Hz, 2H), 7.12 (d,
JZ8.0 Hz, 1H), 6.79 (s, 1H), 6.75 (d, JZ87.0 Hz, 1H), 6.54
(s, 1H), 2.20 (s, 3H), 1.61 (s, 4H), 1.23 (s, 6H), 1.00 (s, 6H).
13C NMR (CDCl3) d 148.3, 144.7, 144.0, 135.9, 134.0,
132.8, 129.7, 129.2, 127.9, 126.8, 126.7, 119.4, 110.8, 35.4,
35.4, 34.5, 34.3, 32.2, 32.0, 26.9. IR (neat) n 2975, 2962,
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6. Designated by the number CB92834 in Ref. 5.
7. Attempts to increase the Z/E ratio by using other bases were
met with little success: thus, for instance, NaHMDS, KHMDS,
LiHMDS in THF gave 8:2, 1.5:1 and 1:1 ratios of 7 and 8,

G. Garipova et al. / Tetrahedron 61 (2005) 4755–4759
4759
respectively. Attempts to isomerize the E double bond to its Z
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two isomers.
13. The exclusive transformation of 13 into the Z isomer 11 is
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the methyl 13C and the cis-olefinic hydrogen.
14. The literature reports on the 1H NMR spectrometry data of the
corresponding E stereoisomer. See: Dawson, M. I.; Hobbs,
P. D.; Derdzinski, K. A.; Chao, W.-R.; Frenking, G.; Loew,
G. A.; Jetten, A. M.; Napoli, J. L.; Williams, J. B.; Sani, B. P.;
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17. The melting point was determined on an analytically pure
sample. We do not explain the discrepancy with the literature
data.