High-yielding TfOH-catalyzed condensation of phenols with aromatic aldehydes at high pressure. A model synthesis of the benzylidene biphenol key skeleton of blepharismins

Article abstract of DOI:10.1016/S0040-4039(01)00208-8

An approach to the benzylidene biphenol key component of blepharismins, photoreceptor pigments isolated from Blepharisma japonicum, is reported. This method relies on an efficient TfOH-catalyzed condensation of phenols with aromatic aldehydes in EtOH as a solvent at 3 kbar pressure.

Full text of DOI:10.1016/S0040-4039(01)00208-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2493–2496
High-yielding TfOH-catalyzed condensation of phenols with
aromatic aldehydes at high pressure. A model synthesis of the
†
benzylidene biphenol key skeleton of blepharismins
a
a
b
c
a,
Takeshi Ohishi, Tomoyuki Kojima, Tatsuomi Matsuoka, Motoo Shiro and Hiyoshizo Kotsuki *
a
Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
b
Department of Biology, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
c
Rigaku Corporation, Matsubara-cho, Akishima, Tokyo 196, Japan
Received 4 December 2000; revised 24 January 2001; accepted 2 February 2001
Abstract—An approach to the benzylidene biphenol key component of blepharismins, photoreceptor pigments isolated from
Blepharisma japonicum, is reported. This method relies on an efficient TfOH-catalyzed condensation of phenols with aromatic
aldehydes in EtOH as a solvent at 3 kbar pressure. © 2001 Elsevier Science Ltd. All rights reserved.
Blepharismins 1–5 (1–5), which have recently been iso-
lated from the protozoan Blepharisma japonicum, are
pink-colored pigments that represent a new structural
ponents: a perylenequinone structure, an anthraquinone
segment, and a benzylidene biphenol moiety. The latter
of these gives blepharismins the ability to generate
considerable intramolecular distortion, and is a chal-
lenging issue for synthetic chemists. The most explicit
answer to this problem must be the condensation of
phenols with benzaldehydes. Although several methods
to achieve this type of transformation have been
reported in the literature, most are unsatisfactory with
respect to their generality, selectivity, productivity and
2
class of natural products. Not only do blepharismins
act as photosensors responsible for the photobehavior
of that unicellular organism, they also exhibit a variety3
of biological activities including anti-retroviral activity.
Over the past few years we have been very interested in
discovering their mode of action at a molecular level.
However, the limited quantities of blepharismins avail-
able from natural sources prompted us to try to synthe-
6
efficiency. We expected that the application of a high-
4
size these molecules.
pressure technique would provide a new general alter-
native to more classical methods, since it is well known
that organic reactions with a large molecular contrac-
Structurally, blepharismins can be classified into natu-
rally occurring polycyclic quinones, like hypericin and
7
tion are highly favorable under high pressure. We
5
stentorin, and can be divided into three discrete com-
describe here the realization of this expectation.
*
Corresponding author. Tel.: +81-88-844-8298; fax: +81-88-844-8359; e-mail: kotsuki@cc.kochi-u.ac.jp
High-Pressure Organic Chemistry. Part 24. For Part 23, see: Ref. 1.
†
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00208-8

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T. Ohishi et al. / Tetrahedron Letters 42 (2001) 2493–2496
To establish the optimum conditions, the reaction
In conclusion, we have developed a simple and efficient
synthetic method for the high-pressure-promoted con-
densation of phenols with aromatic aldehydes using
TfOH as a strong acid catalyst. Furthermore, the suc-
cessful construction of 24, a key skeleton of blepharis-
mins, demonstrates the potential utility of this
technique to derive blepharismins themselves. Further
studies along these lines are now in progress.
between 4-t-butylphenol (6) and p-anisaldehyde (7) was
8
examined under a variety of conditions (Table 1). Of
several acids tested, the best results were obtained using
a catalytic amount of trifluoromethanesulfonic acid
9
(
TfOH) as a very strong acid, and at 3 kbar pressure
the reaction was dramatically accelerated to give the
adduct 8 in 87% yield (run 4). However, no significant
increase in the product yield was observed at higher
pressures (runs 5 and 6).
Typical experimental procedure for the preparation of
8
: A mixture of 4-t-butylphenol (3b; 750 mg, 5.0
mmol), p-anisaldehyde (7, 136 mg, 1 mmol), and TfOH
25 mg, 0.16 mmol) in EtOH (1.5 ml) was placed in a
The general feasibility of this method is shown in
1
0–14
Scheme 1.
Thus, several reactions with a series of
(
phenols and aldehydes gave the desired adducts 9–18 in
good yields. For the less-reactive substrates such as
Teflon reaction vessel at 3 kbar and 60°C for 24 h.
After evaporation of the solvent, the crude product was
purified by preparative TLC (hexane/AcOEt=2:1) to
give 8 (362 mg, 87%) as a colorless solid: mp 125.5–
1
1
s), 3.81 (3H, s), 4.89 (2H, br s), 5.82 (1H, s), 6.76 (2H,
d, J=8.5 Hz), 6.86 (2H, d, J=8.6 Hz), 6.96 (2H, d,
J=2.4 Hz), 7.09 (2H, d, J=8.6 Hz), 7.15 (2H, dd,
2
,4-dimethylphenol, p-chlorobenzaldehyde and p-
nitrobenzaldehyde, rather drastic conditions were nec-
essary to prepare sufficient amounts of the products 10,
27.0°C (from hexane–CH Cl ); FTIR (KBr) 3352,
2 2
1 1
1
4 and 15. We also examined the reaction using
−
510 cm ; H NMR (400 MHz, CDCl ) l 1.18 (18H,
3
propanal as an aliphatic aldehyde, and in this case a
fairly low yield of the adduct 19 (10%) was observed,
15
accompanied by a xanthene-type compound 20 (31%).
Terephthaldicarboxaldehyde also reacted smoothly
with 6.0 equiv. of 2-naphthol to produce tetranaphthol
13
J=8.5, 2.4 Hz); C NMR (100 MHz, CDCl ) l 31.4
3
(×6), 34.1 (×2), 44.3, 55.2, 114.0 (×2), 115.7 (×2), 124.7
(×2), 127.2 (×2), 128.3 (×2), 130.2 (×2), 133.4, 143.7
(×2), 151.2 (×2), 158.4.
18 in 85% yield.
With these results in hand, we were able to construct a
key skeleton of blepharismins (Scheme 2). Thus, treat-
ment of naphthol 21 with 7 according to the standard
procedure produced the adduct 22 in 83% yield. Methy-
lation of the two phenol groups followed by debenzyla-
tion under catalytic hydrogenation conditions gave
bisnaphthol 23 in 85% yield. Intramolecular oxidative
biaryl coupling of this sample took place by Koga’s
Acknowledgements
This work was supported in part by a Scientific
Research Grant from the Ministry of Education, Sci-
ence, Sports and Culture of Japan (No. 10480151), and
a Grant-in-Aid for Special Scientific Research from
Kochi University. We are grateful to Professor Y.
Fukuyama of Tokushima Bunri University for MS/
HRMS measurements. We also thank Central Glass
Co. Ltd., for generously supplying TfOH.
1
6
copper-catalyzed reaction to furnish the benzylidene
biphenol derivative 24, which is a key component of
blepharismins, in 73% yield. Interestingly, the spectral
data show that 24 exists mostly as a cyclized hemiacetal
form of 25, implying the spatial proximity of two
1
7
phenol functions.
Table 1. Acid-catalyzed condensation of 6 with 7 under various conditions
a
Run
Catalyst (0.1 equiv.)
Pressure (kbar)
Yield of 8 (%)
1
2
3
4
5
6
CH COOH
Conc. HCl
TfOH
TfOH
TfOH
0.001
0.001
0.001
3
5
7
No reaction
29
46
87
87
86
3
b
TfOH
a
Isolated yield.
b
3
equiv. of 6 was used.

T. Ohishi et al. / Tetrahedron Letters 42 (2001) 2493–2496
2495
Scheme 1.
Scheme 2.

2
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T. Ohishi et al. / Tetrahedron Letters 42 (2001) 2493–2496
tion of aromatic aldehydes, see: (a) Ito, S.; Kikuchi, S.;
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30
24
5
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.
.