New synthetic approach to atypical retinoids: application of a versatile annulation procedure

Article abstract of DOI:10.1016/j.tet.2006.12.038

A new approach to an atypical retinoid is presented. The C₁₅ skeleton was built up by exploiting a step-by-step sequence: the C₉ fragment of an intermediate was homologated by reaction with a C₄ phosphorane, and then submitted to a benzannulation reaction. The last two carbon atoms were inserted by a Wittig reaction with the C₂ phosphorane of ethyl bromoacetate. Manipulation of functional groups was then performed.

Full text of DOI:10.1016/j.tet.2006.12.038

Tetrahedron 63 (2007) 2351–2356
New synthetic approach to atypical retinoids: application
of a versatile annulation procedure
a
b
a
Elisabetta Brenna,a, Claudio Fuganti, Giovanni Fronza, Francesco G. Gatti,
*
Federico Salaa and Stefano Serrab,
*
aDipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Politecnico di Milano,
Via Mancinelli 7, I-20131 Milano, Italy
bCNR—Istituto di Chimica del Riconoscimento Molecolare, Politecnico di Milano, Via Mancinelli 7, I-20131 Milano, Italy
Received 7 September 2006; revised 27 November 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—A new approach to an atypical retinoid is presented. The C15 skeleton was built up by exploiting a step-by-step sequence: the C9
fragment of an intermediate was homologated by reaction with a C4 phosphorane, and then submitted to a benzannulation reaction. The last
two carbon atoms were inserted by a Wittig reaction with the C2 phosphorane of ethyl bromoacetate. Manipulation of functional groups was
then performed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The so-called atypical retinoids are a class of compounds
having a retinoid like structure: they activate certain retinoid-
acid receptors as well as exerting a growth regulatory or
apoptogenic activity that is not receptor mediated.1 The main
compounds of this class (Scheme 1) are 4-hydroxyphenyl-
retinamide (4-HPR) (1), and the adamantyl substituted deriv-
atives AHPN (2), adapalene (3), AHPC (4) and 3A-AHPC
(5). Their chemopreventive and chemotherapeutic potentials
are being intensively investigated, and they are considered to
be highly promising as less toxic drugs in cancer therapy and
prevention.2 The development of new efficient synthetic
strategies to this type of substrates would be of great help
in their investigation and in the elucidation of their precise
mechanism of action on cell proliferation and apoptosis.
The current synthetic approach to the biaryl derivatives 2–5
is based on the Suzuki–Miyaura palladium-catalysed
cross-coupling of organoboron compounds,3 on the nickel-
catalysed Negishi reaction of zincate derivatives,4 or on the
Grignard coupling mediated by PdCl2(PPh3)2 complexes.5
Metal catalysis is employed to obtain the C–C single bond
between the two aromatic moieties.
Scheme 1.
benzoic acid derivatives of type I, starting from unsaturated
aldehydes II.6 The key step is the cyclisation of acid III
promoted either by ethyl chloroformate or by trifluoroacetic
anhydride in THF solution in the presence of triethylamine.
We have successfully employed this procedure for the
synthesis of biphenyl systems, such as the binol analogue 6.7
In the past, we developed an efficient benzoannulation
procedure (Scheme 2) to prepare 4-substituted-3-hydroxy-
We report herein the application of this synthetic path for
the preparation of the atypical retinoid 5,8 to showcase the
efficiency of our annulation procedure for the preparation of
this class of useful cancer drugs.
Keywords: Atypical retinoids; Annulation; Benzene ring; Cancer therapy.
* Corresponding authors. Tel.: +39 02 23993077; fax: +39 02 23993080
(E.B.); tel.: +39 02 23993073; fax: +39 02 23993080 (S.S.); e-mail
addresses: elisabetta.brenna@polimi.it; stefano.serra@polimi.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.038

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E. Brenna et al. / Tetrahedron 63 (2007) 2351–2356
Scheme 2.
2. Results and discussion
4-Hydroxy-3-adamantylbenzaldehyde 9 was devised as the
starting material (Scheme 4) and was prepared by Friedel–
Crafts alkylation of 4-hydroxybenzaldehyde with adamanta-
nol in CH2Cl2, in the presence of sulfuric acid. The alcohol
was protected to give the benzyl derivative 10, which was
submitted to a Wittig reaction to afford the unsaturated
ester 11. The ester group was reduced with Red-AlÒ
at ꢀ20 ꢁC to afford alcohol 12 that was oxidised with
MnO2 in CH2Cl2. The resulting unsaturated aldehyde 13
Compound 5 satisfies the structural requirement for the
application of our procedure since its potential precursor 7
is a 4-substituted-3-hydroxy-benzoic acid (Scheme 3).
Alkylation of the phenolic group and conversion of the
methyl ester moiety into the cinnamic acid group complete
the sequence to give the target compound. The preparation
of acid 8 was thus required.
Scheme 3.
Scheme 4. Reagents and conditions: (i) NaH, DMF, PhCH2Cl; (ii) Ph3P]CHCOOEt, CHCl3, reflux; (iii) Red-AlÒ, toluene, ꢀ20 ꢁC; (iv) MnO2, CH2Cl2, reflux;
(v) phosphorane 14, toluene, reflux and (vi) (CF3CO)2O, Et3N, THF.

E. Brenna et al. / Tetrahedron 63 (2007) 2351–2356
2353
Scheme 5. Reagents and conditions: (i) K2CO3, acetone, phthalimido derivative 16; (ii) H2, Pd/C; (iii) KOH, MeOH, then Ac2O in pyridine; (iv) ClCOOEt,
Et3N; then NaBH4; (v) MnO2, CH2Cl2; (vi) Ph3P]CHCOOEt, CH2Cl2, reflux; (vii) NaOH, H2O, EtOH, reflux: Schotten–Baumann.
was treated with phosphorane 149 to afford derivative 8 to be
used for the benzannulation reaction. Reaction with trifluoro-
acetic acid anhydride and triethylamine gave the key biaryl
intermediate 7.
of a six carbon atom moiety with a nine carbon atom unit.
Manipulation of functional groups was performed before
coupling, and the employment of metal catalysis required
careful purification of the product, to reduce the metal impu-
rity content in the final compound.
The next sequence (Scheme 5) concerned functionalisation
of the phenol with the 3-acetamidopropyl moiety and the
conversion of the ethyl ester into the cinnamic acid frag-
ment. The first goal was achieved by a classical Gabriel syn-
thesis: the suitable alkyl phthalimide 15 was prepared by
treatment of compound 7 with potassium carbonate and de-
rivative 1610 in acetone solution. After debenzylation, com-
pound 17 was obtained, and then submitted to saponification
and acetylation, to afford derivative 18.
In contrast, we built up the C15 skeleton by exploiting a step-
by-step sequence: the C9 fragment of intermediate 13 was
homologated by reaction with the C4 phosphorane 14, and
then cyclised. The last two carbon atoms were inserted by
a Wittig reaction with the C2 phosphorane of ethyl bromo-
acetate. Manipulation of functional groups was then per-
formed after annulation. This cyclisation procedure, based
on the key intermediate 8, does not suffer from much inter-
ference due to the presence of other functional groups, and
can be applied to obtain a large number of biaryl compounds
structurally related to 5, to be eventually investigated for
cancer therapy.
Interestingly enough, when compound 18 was treated with
ethyl chloroformate and then reduced with NaBH4, we
also observed the reduction of one of the carbonyl group
of the phthalimido moiety, and compound 19 was obtained.
Nonetheless, MnO2 oxidation restored this carbonyl func-
tion and oxidised the primary alcohol to aldehyde 20. Wittig
homologation, followed by saponification, and Schotten–
Baumann acetylation of the amino group gave the final
compound 5.
4. Experimental
4.1. General
GC–MS analyses were performed on a HP 6890 gas-
chromatograph equipped with a 5973 mass-detector, using
a HP-5MS column (30 mꢂ0.25 mmꢂ0.25 mm). The follow-
ing temperature program was employed: 60 ꢁC (1 min)/
6 ꢁC/min/150 ꢁC (1 min)/12 ꢁC/min/280 ꢁC (5 min). 1H
and 13C NMR spectra were recorded on a Bruker AC-250
spectrometer (250 MHz and 62.5 MHz, respectively), in
CDCl3 solution at rt unless otherwise stated, using TMS as
3. Conclusions
The advantage of the method described is the use of a benz-
annulation reaction instead of a metal catalysed coupling.
The 15 carbon atom skeleton of compound 5 (Scheme 1)
was obtained in the literature7 by a modified Suzuki coupling

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E. Brenna et al. / Tetrahedron 63 (2007) 2351–2356
an internal standard; J values are given in Hertz. All the
chromatographic separations were carried out on silica gel
columns. Microanalyses were determined on a Analyzer
1106 Carlo Erba.
4.1.4. (E)-3-(3-Adamantyl-4-benzyloxy-phenyl)prop-2-
en-1-ol (12). To a solution of 11 (37.0 g, 0.088 mol) in
toluene (400 mL) Red-AlÒ (3.5 M in toluene, 27.6 mL,
0.097 mol) was added dropwise at ꢀ20 ꢁC. After 1 h, the
reaction mixture was poured into ice, treated with H2SO4
(2 N) and extracted with ethyl acetate. The organic phase
was dried (Na2SO4), and concentrated under reduced pres-
sure. The residue was chromatographed (hexane/ethyl ace-
4.1.1. 3-Adamantyl-4-hydroxybenzaldehyde (9). A solu-
tion of 4-hydroxybenzaldehyde (24.4 g, 0.20 mol), 1-ada-
mantanol (33.4 g, 0.22 mol) and concentrated sulfuric acid
(10 mL) in CH2Cl2 (350 mL) was stirred at rt for 24 h.
The reaction mixture was poured into ice, neutralised with
NaHCO3, and extracted with CH2Cl2. The organic phase
was dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(hexane/ethyl acetate, 7/3) to afford 9 (38.4 g, 75%) as a
1
tate, 7/3), to afford 12 (22.4 g, 68%) as a liquid: H NMR
(250 MHz, CDCl3): d 7.55–7.10 (m, 7H, ArH), 6.91 (d,
J¼8.3, 1H, H–C(5)), 6.57 (d, J¼16.4, 1H, Ar–CH]), 6.27
(dt, J¼16.4, 5.9, 1H, C]CH), 5.13 (s, 2H, CH2Ph), 4.31
(d, J¼5.9, 2H, CH2OH), 2.21–2.15 (m, 6H, adamantane),
2.09–2.03 (m, 3H, adamantane), 1.78–1.72 (m, 6H, adaman-
tane) ppm. 13C NMR (CDCl3): d 157.7, 138.7, 137.3, 131.7,
129.2, 128.5, 127.7, 127.3, 112.8, 70.3, 64.0, 40.4, 37.1,
29.2 ppm. Anal. Calcd for C26H30O2: C, 83.38; H, 8.07.
Found: C, 83.21; H, 8.16.
1
reddish solid: mp 125 ꢁC; H NMR (250 MHz, CDCl3):
d 9.87 (s, 1H, CHO), 7.79 (d, J¼1.7, 1H, H–C(2)), 7.64
(dd, J¼1.7, 8.3, 1H, H–C(6)), 6.77 (d, J¼8.3, 1H, H–
C(5)), 2.18–2.09 (m, 9H, adamantane), 1.84–1.78 (m, 6H,
adamantane) ppm. 13C NMR (CDCl3): d 191.6, 160.6,
137.2, 129.9, 129.7, 128.2, 117.3, 70.6, 40.3, 37.0, 36.9,
28.9 ppm; GC/MS: tR¼27.18 min, m/z (%)¼256 (100)
[M+], 199 (25), 171 (20). Anal. Calcd for C17H20O2: C,
79.65; H, 7.86. Found: C, 79.48; H, 7.97.
4.1.5. (E)-3-(3-Adamantanyl-4-benzyloxy-phenyl)acryl-
aldehyde (13). A mixture of MnO2 (1.5 equiv) and unsatu-
rated alcohol 12 (22.0 g, 0.059 mol) in CH2Cl2 (300 mL)
was refluxed for 30 min. The reaction mixture was filtered
and concentrated under reduced pressure. After column
chromatography (hexane/ethyl acetate, 9/1) aldehyde 13
was obtained (16.2 g, 74%) as a white solid: mp 138 ꢁC;
1H NMR (250 MHz, CDCl3): d 9.64 (d, J¼7.5, 1H, CHO),
7.55–7.30 (m, 8H, ArH+CH]), 6.96 (d, J¼8.3, 1H, H–
C(5) of the tri-substituted benzene ring), 6.62 (dd, J¼15.7,
7.5, 1H, CH]CHO), 5.16 (s, 2H, CH2Ph), 2.17–2.11
(m, 6H, adamantane), 2.08–2.02 (m, 3H, adamantane),
1.78–1.72 (m, 6H, adamantane) ppm. 13C NMR (CDCl3):
d 28.9, 36.9, 37.2, 40.4, 70.4, 112.9, 126.3, 126.6, 127.3,
127.5, 127.8, 128.0, 128.6, 136.5, 139.3, 152.0, 153.4,
193.6 ppm. Anal. Calcd for C26H28O2: C, 83.83; H, 7.58.
Found: C, 83.75; H, 7.41.
4.1.2. 3-Adamantyl-4-benzyloxybenzaldehyde (10). A
solution of 9 (38.0 g, 0.148 mol) in DMF (50 mL) was added
dropwise into a suspension of NaH (60% in mineral oil,
0.163 mol) in DMF (200 mL). After 30 min, benzyl chloride
(20.5 g, 0.163 mol) was added. The reaction mixture was
stirred at rt for 1 h, then poured into ice, neutralised and
extracted with ethyl acetate. The organic phase was dried
(Na2SO4), and concentrated under reduced pressure. The res-
idue was chromatographed (hexane/ethyl acetate, 95/5), to
afford 10 (48.6 g, 95%) as a yellow solid: mp 99 ꢁC;
1H NMR (250 MHz, CDCl3): d 9.89 (s, 1H, CHO),
7.82 (d, J¼1.7, 1H, H–C(2)), 7.70 (dd, J¼1.7, 8.3, 1H,
H–C(6)), 7.55–7.30 (m, 5H, Ph), 7.04 (d, J¼8.3, 1H,
H–C(5)), 5.21 (s, 2H, CH2Ph), 2.18–2.12 (m, 6H, adaman-
tane), 2.09–2.05 (m, 3H, adamantane), 1.76–1.70 (m, 6H,
adamantane) ppm. 13C NMR (CDCl3): d 191.3, 162.9,
139.3, 136.2, 130.1, 129.8, 128.6, 128.7, 128.1, 127.4,
112.4, 40.3, 37.3, 37.0, 28.9 ppm; GC/MS: tR¼31.95 min,
m/z (%)¼346 (16) [M+], 255 (24), 91 (100). Anal. Calcd
for C24H26O2: C, 83.20; H, 7.56. Found: C, 83.09; H, 7.69.
4.1.6. (3E,5E)-6-(3-Adamantyl-4-benzyloxy-phenyl)-3-
(ethoxycarbonyl)hexa-3,5-dienoic acid (8). A solution of
aldehyde 13 (16.0 g, 0.043 mol) and phosphorane 14
(19.1 g, 0.047 mol) in toluene (500 mL) was refluxed for
2 h. The reaction mixture was concentrated under reduced
pressure and chromatographed (hexane/ethyl acetate, 1/1)
to afford compound 8 (16.5 g, 77%) as a white solid: mp
1
77 ꢁC; H NMR (250 MHz, CDCl3): d 7.52 (d, J¼11.3,
4.1.3. (E)-Ethyl 3-(3-adamantyl-4-benzyloxy-phenyl)-
acrylate (11). A solution of 10 (48.0 g, 0.138 mol) in toluene
(350 mL) in the presence of Ph3P]CHCOOEt (52.9 g,
0.152 mol) was refluxed for 3 h. After the usual work-up, the
residue was purified by column chromatography (hexane/
ethyl acetate, 9/1), to afford 11 (37.3 g, 65%) as a viscous
liquid: 1H NMR (250 MHz, CDCl3): d 7.65 (d, J¼17,
1H, Ar–CH]), 7.45–7.30 (m, 7H, ArH), 6.92 (d, J¼8.3,
1H, H–C(5)), 6.31 (d, J¼17, 1H, C]CHCOOR), 5.15
(s, 2H, CH2Ph), 4.25 (q, J¼7.1, 2H, COOCH2), 2.17–2.11
(m, 6H, adamantane), 2.08–2.02 (m, 3H, adamantane),
1.75–1.69 (m, 6H, adamantane), 1.33 (t, J¼7.1, 3H,
COOCH2CH3) ppm. 13C NMR (CDCl3): d 167.1, 159.2,
143.9, 137.9, 136.3, 130.2, 128.6, 128.3, 128.0, 127.3,
127.2, 115.2, 114.5, 70.1, 60.3, 40.3, 37.3, 37.0, 28.9, 14.4;
GC/MS: tR¼40.56 min, m/z (%)¼416 (42) [M+], 324 (32),
91 (100). Anal. Calcd for C28H32O3: C, 80.73; H, 7.74.
Found: C, 80.62; H, 7.83.
1H, H–C(4)), 7.50–7.15 (m, 7H, ArH), 6.94 (d, J¼15.4,
1H, H–C(6)), 6.91 (d, J¼8.3, 1H, H–C(5)), 6.84 (dd,
J¼15.4, 11.3, 1H, H–C(5)), 5.13 (s, 2H, CH2Ph), 4.25 (q,
J¼7.2, 2H, COOCH2), 3.57 (s, 2H, CH2COO), 2.17–2.11
(m, 6H, adamantane), 2.07–2.01 (m, 3H, adamantane),
1.77–1.69 (m, 6H, adamantane), 1.31 (t, J¼7.2, 3H,
COOCH2CH3) ppm. 13C NMR (CDCl3): d 14.2, 29.0,
32.7, 37.0, 37.2, 40.4, 61.0, 70.3, 112.8, 120.3, 121.7,
126.2, 126.4, 127.2, 127.8, 128.5, 128.7, 136.9, 139.0,
142.4, 142.1, 158.9, 167.7, 175.8 ppm. Anal. Calcd for
C32H36O5: C, 76.77; H, 7.25. Found: C, 76.58; H, 7.39.
4.1.7. Ethyl 50-(adamantanyl)-40-(benzyloxy)-2-hydroxy-
biphenyl-4-carboxylate (7). A solution of 8 (16.0 g,
0.032 mol) and Et3N (9.69 g, 0.096 mol) in THF (200 mL)
was treated with (CF3CO)2O (15.4 g, 0.064 mol) at 0 ꢁC. The
reaction mixture was stirred at rt for 30 min, poured into ice,
neutralised and extracted with diethyl ether. The organic

E. Brenna et al. / Tetrahedron 63 (2007) 2351–2356
2355
phase was dried (Na2SO4) and concentrated under reduced
pressure. Column chromatography (hexane/ethyl acetate,
7/3) gave compound 7 (10.9 g, 71%) as a viscous liquid:
1H NMR (250 MHz, CDCl3): d 7.70–7.20 (m, 10H, ArH),
7.05 (d, J¼8.3, 1H, H–C(5) of the adamantyl substituted
benzene ring), 5.5 (br s, 1H, OH), 5.19 (s, 2H, CH2Ph),
4.40 (q, J¼7.2, 2H, COOCH2), 2.22–2.16 (m, 6H, adaman-
tane), 2.07–2.01 (m, 3H, adamantane), 1.78–1.71 (m, 6H,
adamantane), 1.38 (t, J¼7.2, 3H, COOCH2CH3) ppm. 13C
NMR (CDCl3): d 14.3, 29.0, 37.0, 37.3, 40.5, 60.9, 70.3,
113.2, 116.8, 121.7, 127.2, 127.3, 127.6, 127.8, 128.5,
130.1, 130.6, 133.0, 137.0, 139.6, 146.8, 152.7, 157.9,
165.8 ppm. Anal. Calcd for C32H34O4: C, 79.64; H, 7.10.
Found: C, 79.76; H, 7.21.
KOH (0.780 g, 0.014 mol) in methanol (200 mL). After
the usual work-up, the residue was acetylated by reaction
with Ac2O (25 mL) in pyridine (50 mL), to give compound
1
18 (4.83 g, 89%) as a viscous liquid: H NMR (250 MHz,
CDCl3): d 7.85–7.74 (m, 3H, ArH), 7.72–7.64 (m, 3H,
ArH), 7.53 (d, J¼2.0, 1H, ArH), 7.44 (dd, J¼8.6, 2.4, 1H,
ArH), 7.40 (d, J¼8.0, 1H, ArH), 7.03 (d, J¼8.3, 1H,
H–C(5) of the adamantyl substituted benzene ring), 4.11
(t, J¼6.1, 2H, CH2O), 3.82 (t, J¼6.5, 2H, CH2N), 2.37 (s,
3H, OAc), 2.19–2.13 (m, 2H, CH2), 2.12–2.06 (m, 9H,
adamantane), 1.80–1.74 (m, 3H, adamantane) ppm. Anal.
Calcd for C36H35NO7: C, 72.83; H, 5.94; N, 2.36. Found:
C, 72.71; H, 5.79; N, 2.21.
4.1.11. 3-(Adamantyl)-20-(3-(1-hydroxy-3-oxoisoindolin-
2-yl)propoxy)-40-(hydroxymethyl)biphenyl-4-yl acetate
(19). To a solution of 18 (4.50 g, 7.59 mmol) in Et3N
(100 mL), ClCOOEt (0.901 g, 8.34 mmol) was added drop-
wise at 0 ꢁC. After the usual work-up the residue was dis-
solved in CH2Cl2/MeOH 2/1 (150 mL) and treated with
NaBH4 (0.316 g, 8.34 mmol). After the usual work-up com-
pound 19 (3.17 g, 72%) was recovered by column chromato-
graphy (hexane/ethyl acetate, 4/6) as a viscous liquid:
1H NMR (250 MHz, CDCl3): d 7.69–7.65 (m, 1H, ArH),
7.55–7.25 (m, 6H, ArH), 6.99–6.95 (m, 3H, ArH), 5.54 (br
s, 1H, NCH–OH), 4.66 (s, 2H, CH2OH), 4.13–3.97 (m,
2H, CH2O), 3.56–3.50 (m, 2H, CH2N), 2.36 (s, 3H, OAc),
2.11–1.97 (m, 11H, 9H, adamantane+CH2), 1.80–1.75 (m,
3H, adamantane) ppm. 13C NMR (CDCl3): d 21.7, 28.2,
29.0, 37.0, 37.4, 41.4, 65.1, 66.5, 82.4, 111.9, 119.5,
123.1, 123.2, 123.5, 127.9, 128.7, 129.5, 130.3, 130.7,
131.8, 131.9, 136.0, 140.6, 141.9, 144.2, 148.2, 155.9,
167.6, 170.0 ppm. Anal. Calcd for C36H39NO6: C, 74.33;
H, 6.76; N, 2.41. Found: C, 74.49; H, 6.85; N, 2.38.
4.1.8. Ethyl 50-(adamantanyl)-40-(benzyloxy)-2-(3-(1,3-
dioxoisoindolin-2-yl)propoxy)biphenyl-4-carboxylate
(15). A mixture of 7 (10.0 g, 0.021 mol), K2CO3 (3.18 g,
0.023 mol) and phthalimido derivative 1610 (5.60 g,
0.021 mol) in acetone (300 mL) was refluxed for 4 h. The
reaction mixture was poured into ice, and extracted with
ethyl acetate. The organic phase was dried (Na2SO4) and
concentrated under reduced pressure. Column chromato-
graphy (hexane/ethyl acetate, 1/1) gave compound 15
(9.55 g, 68%) as a white solid: mp 165 ꢁC; 1H NMR
(250 MHz, CDCl3): d 7.85–7.20 (m, 14H, ArH), 6.98 (d,
J¼8.3, 1H, H–C(5) of the adamantyl substituted benzene
ring), 5.16 (s, 2H, CH2Ph), 4.39 (q, J¼7.2, 2H, COOCH2),
4.09 (t, J¼6.2, 2H, CH2O), 3.83 (t, J¼6.6, 2H, CH2N),
2.22–2.16 (m, 6H, adamantane), 2.19–2.13 (m, 2H, CH2),
2.07–2.00 (m, 3H, adamantane), 1.75–1.69 (m, 6H, adaman-
tane), 1.40 (t, J¼7.2, 3H, OCH2CH3) ppm. 13C NMR
(CDCl3): d 14.2, 28.5, 29.0, 35.3, 37.0, 37.1, 40.5, 60.8,
66.2, 70.1, 112.1, 113.3, 122.4, 123.0, 127.2, 127.5, 127.9,
128.0, 128.3, 129.5, 129.7, 130.3, 132.0, 133.7, 135.8,
137.3, 137.8, 155.4, 157.3, 166.3, 168.0 ppm. Anal. Calcd
for C43H43NO6: C, 77.11; H, 6.47; N, 2.09. Found: C,
77.01; H, 6.60; N, 2.19.
4.1.12. 3-(Adamantanyl)-20-(3-(1,3-dioxoisoindolin-2-yl)-
propoxy)-40-formylbiphenyl-4-yl acetate (20). A mixture
of MnO2 (1.5 equiv) and compound 19 (3.00 g, 5.1 mmol)
in CH2Cl2 (1000 mL) was refluxed for 3 h. The reaction
mixture was filtered and concentrated under reduced pres-
sure. After column chromatography (hexane/ethyl acetate,
1/1) compound 20 was obtained (2.23 g, 75%) as a viscous
4.1.9. Ethyl 50-(adamantanyl)-2-(3-(1,3-dioxoisoindolin-
2-yl)propoxy)-40-hydroxybiphenyl-4-carboxylate (17).
Compound 15 (9.50 g, 0.014 mol) was hydrogenated in the
presence of Pd/C (0.500 g) in ethanol solution (200 mL).
The reaction mixture was filtered and concentrated under
reduced pressure to give compound 17 (5.60 g, 69%) as a
1
liquid: H NMR (250 MHz, CDCl3): d 9.97 (s, 1H, CHO),
7.81–7.65 (m, 2H, ArH), 7.72–7.65 (m, 2H, ArH), 7.5–
7.40 (m, 5H, ArH), 7.03 (d, J¼8.3, 1H, H–C(5) of the
adamantyl substituted benzene ring), 4.11 (t, J¼6.2, 2H,
CH2O), 3.82 (t, J¼6.7, 2H, CH2N), 2.37 (s, 3H, OAc),
2.19–2.13 (m, 2H, CH2), 2.11–2.05 (m, 9H, adamantane),
1.80–1.75 (m, 3H, adamantane) ppm. 13C NMR (CDCl3):
d 21.6, 28.4, 28.9, 29.5, 35.1, 36.9, 41.1, 66.1, 111.1,
123.1, 123.8, 124.1, 127.7, 128.5, 131.3, 131.9, 133.8,
134.5, 136.6, 137.1, 140.4, 148.9, 156.1, 168.1, 169.2,
191 ppm. Anal. Calcd for C36H35NO6: C, 74.85; H, 6.11;
N, 2.42. Found: C, 74.72; H, 6.01; N, 2.38.
1
viscous liquid: H NMR (250 MHz, CDCl3): d 7.84–7.79
(m, 2H, ArH), 7.72–7.67 (m, 3H, ArH), 7.59 (d, J¼1.7,
1H, ArH), 7.39 (d, J¼2.2, 1H, ArH), 7.39–7.32 (m, 2H,
ArH), 6.68 (d, J¼8.3, 1H, H–C(5) of the adamantyl
substituted benzene ring), 4.39 (q, J¼7.0, 2H, COOCH2),
4.09 (t, J¼6.1, 2H, CH2O), 3.83 (t, J¼7.0, 2H, CH2N),
2.20–2.13 (m, 8H, 6H, adamantane+CH2), 2.12–2.05 (m,
3H, adamantane), 1.82–1.75 (m, 6H, adamantane), 1.40 (t,
J¼7.0, 3H, OCH2CH3) ppm. 13C NMR (CDCl3): d 14.2,
28.4, 29.0, 35.3, 36.7, 37.0, 40.4, 60.9, 66.1, 113.2, 116.3,
127.8, 128.0, 128.9, 129.4, 130.3, 131.8, 133.8, 135.8,
136.1, 154.7, 155.3, 166.6, 168.3 ppm. Anal. Calcd for
C36H37NO6: C, 74.59; H, 6.43; N, 2.42. Found: C, 74.43;
H, 6.32; N, 2.59.
4.1.13. (E)-Ethyl 3-(40-acetoxy-50-(adamantyl)-2-(3-(1,3-
dioxoisoindolin-2-yl)propoxy)biphenyl-4-yl)acrylate
(21). A solution of 20 (2.1 g, 3.63 mmol) in toluene (70 mL)
in the presence of Ph3P]CHCOOEt (1.39 g, 3.99 mmol)
was refluxed for 3 h. After the usual work-up, the residue was
purified by column chromatography (hexane/ethyl acetate,
9/1), to afford compound 21 (1.50 g, 64%) as aviscous liquid:
1H NMR (250 MHz, CDCl3): d 7.83–7.78 (m, 2H, ArH),
4.1.10. 40-Acetoxy-50-(adamantyl)-2-(3-(1,3-dioxoiso-
indolin-2-yl)propoxy)biphenyl-4-carboxylic acid (18).
Derivative 17 (5.30 g, 9.15 mmol) was hydrolysed with

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E. Brenna et al. / Tetrahedron 63 (2007) 2351–2356
7.73–7.63 (m, 3H, ArH+CH]), 7.52–7.48 (m, 1H, ArH),
7.40 (dd, J¼2.1, 8.4, 1H, ArH), 7.35–7.29 (m, 1H, ArH),
7.19 (dd, J¼1.4, 8.0, 1H, ArH), 7.09 (d, J¼1.4, 1H,
ArH), 7.00 (d, J¼8.3, 1H, H–C(5) of the adamantyl sub-
stituted benzene ring), 6.44 (d, J¼15.8, 1H, CH]COO),
4.28 (q, J¼7.1, 2H, COOCH2), 4.04 (t, J¼6.2, 2H, CH2O),
3.82 (t, J¼6.7, 2H, CH2N), 2.36 (s, 3H, OAc), 2.18–2.12 (m,
2H, CH2), 2.10–2.05 (m, 9H, adamantane), 1.80–1.75 (m,
3H, adamantane), 1.35 (t, J¼7.1, 3H, COOCH2CH3) ppm.
13C NMR (CDCl3): d 14.3, 21.6, 28.4, 28.8, 35.1, 36.8, 41.1,
60.4, 66.1, 111.1, 118.4, 123.1, 123.7, 124.1, 127.7, 128.4,
131.3, 131.9, 133.9, 134.5, 136.6, 137.0, 140.0, 144.5,
148.9, 156.1, 168.8, 168.1, 169.2 ppm. Anal. Calcd for
C30H35NO5: C, 73.60; H, 7.21; N, 2.86. Found: C, 73.48;
H, 7.38; N, 2.71.
adamantane), 1.84–1.78 (m, 2H, CH2), 1.77 (s, 3H,
COCH3), 1.75–1.71 (m, 6H, adamantane) ppm. 13C NMR
(DMSO-2H6): d 22.7, 29.1, 28.7, 35.9, 36.9, 40.2, 65.9,
111.9, 116.3, 118.7, 121.6, 127.7, 127.8, 128.2, 130.4,
132.9, 134.0, 135.2, 144.4, 155.6, 155.8, 168.0, 170.0.
References and notes
1. Altucci, L.; Gronemeyer, H. Nat. Rev. Cancer 2001, 1, 181–
193.
2. Holmes, W. F.; Dawson, M. I.; Soprano, R. D.; Soprano, K. J.
J. Cell Physiol. 2000, 185, 61–67; Sun, S. Y.; Yue, P.; Ghong,
W. K.; Lotan, R. Cancer Res. 2000, 60, 6537–6543; Dawson,
M. I.; Hobbs, P. D.; Peterson, V. J.; Leid, M.; Lange, C. W.;
Feng, K.; Chen, G.; Gu, J.; Li, H.; Kumar Kolluri, S.; Zhang,
X.; Zhang, Y.; Fontana, J. A. Cancer Res. 2001, 61, 4723–4730.
3. Miyaura, A.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
4. (a) Charpentier, B.; Bernardon, J. M.; Eustache, J.; Millois, C.;
Martin, B.; Michel, S.; Shroot, B. J. Med. Chem. 1995, 38,
4993–5006; (b) Shroot, B.; Eustache, J.; Bernardon, J. M.
U.S. Patent 4,717,720, 1988; (c) Shroot, B.; Eustache, J.;
Bernardon, J. M. EP 199636 B1, 1989.
5. Liu, Z.; Xiang, J. Org. Process Res. Dev. 2006, 10, 285–288.
6. Brenna, E.; Fuganti, C.; Perozzo, V.; Serra, S. Tetrahedron
1997, 53, 15029–15040.
7. Brenna, E.; Scaramelli, L.; Serra, S. Synlett 2000, 357–358.
8. Dawson, M. I.; Harris, D. L.; Liu, G.; Hobbs, P. D.; Lange,
C. W.; Jong, L.; Bruey-Sedano, N.; James, S. Y.; Zhang, X.;
Peterson, V. J.; Leid, M.; Farhana, L. A.; Rishi, K.; Fontana,
J. A. J. Med. Chem. 2004, 47, 3518–3536.
4.1.14. (E)-3-(2-(3-Acetamidopropoxy)-50-(adamantyl)-
40-hydroxybiphenyl-4-yl)acrylic acid (5).8 A solution of
21 (1.40 g, 1.65 mmol) and KOH (0.399 g, 7.13 mmol) in
methanol (30 mL) was refluxed for 4 h. The reaction mixture
was poured into water, treated with HCl 10% and extracted
with ethyl acetate. The solution was dried (Na2SO4) and con-
centrated under reduced pressure, to give a residue, which
was dissolved in alkaline water and treated with acetic anhy-
dride (0.168 g, 1.65 mmol). After the usual work-up com-
pound 5 was recovered (0.371 g, 46%) after purification by
column chromatography (hexane/ethyl acetate, 1/1) as
a white solid: mp 197 ꢁC; 1H NMR8 (DMSO-2H6): d 12.45
(br s, 1H, COOH), 9.35 (s, 1H, OH), 7.80 (t, J¼5.3, 1H,
NH), 7.59 (d, J¼16.0, 1H, ArCH]C), 7.35 (s, 1H, ArH),
7.30–7.25 (m, 3H, ArH), 7.20 (dd, J¼8.4 and 2.5, 1H,
ArH), 6.80 (d, J¼8.4, 1H, H–C(5) of the adamantyl sub-
stituted benzene ring), 6.56 (d, J¼16.0, 1H, C]CHCO2),
4.05 (t, J¼6.5, 2H, CH2O), 3.17 (q, J¼5.7, 2H, CH2N),
2.13–2.07 (m, 6H, adamantane), 2.05–2.00 (m, 3H,
€
9. Roder, E.; Krauss, H. Liebigs Ann. Chem. 1992, 177–181.
10. Kuang, Y.; Huang, J.; Chen, F. Synth. Commun. 2006, 36,
1515–1519.