Chromophoric binaphthyl derivatives

Article abstract of DOI:10.1021/ol051139n

(Chemical Equation Presented) A short synthetic route is outlined, starting from bromo-BN derivatives, via halogen lithium exchange, subsequent Michael reaction with dimethylaminoacrolein, hydrolysis to the corresponding aldehyde, and final condensation with a benzothiazolium unit to produce a BN-pentamethinium system, which absorbs in the visible range around 450 nm. Enantiopure ligands show a decent Cotton effect in the CD spectrum. Preliminary data show potential of these compounds in the area of supramolecular chemistry (enantioselective recognition) and also for medicinal application (induction of apoptosis).

Full text of DOI:10.1021/ol051139n

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
661-3664
Chromophoric Binaphthyl Derivatives
†
†
†
‡
§
3
Tom a´ sˇ B rˇ ´ı za, Zden eˇ k Kej ´ı k, Petr Va sˇ ek, Jarmila Kr a´ lov a´ , Pavel Mart a´ sek,
§
,†
Ivana C ´ı sa rˇ ov a´ , and Vladim ´ı r Kr a´ l*
Department of Analytical Chemistry Technick a´ 5, Institute of Chemical Technology,
CZ-166 28, Prague 6, Czech Republic, and Institute of Molecular Genetics,
Academy of Sciences, Fleming’s Square 2, CZ-166 10, Prague 6, Czech Republic, and
First Faculty of Medicine, Charles UniVersity in Prague, Kate rˇ insk a´ 32,
CZ-121 08 Prague 2, Czech Republic
Vladimir.kral@Vscht.cz
Received May 16, 2005
ABSTRACT
A short synthetic route is outlined, starting from bromo-BN derivatives, via halogen lithium exchange, subsequent Michael reaction with
dimethylaminoacrolein, hydrolysis to the corresponding aldehyde, and final condensation with a benzothiazolium unit to produce a BN
−
pentamethinium system, which absorbs in the visible range around 450 nm. Enantiopure ligands show a decent Cotton effect in the CD
spectrum. Preliminary data show potential of these compounds in the area of supramolecular chemistry (enantioselective recognition) and
also for medicinal application (induction of apoptosis).
Binaphthyl derivatives have been used in the construction
of a variety of receptors, including chiral sensing systems
for biologically important analytes. Examples include recep-
tors for amino acids,1-3 saccharides,4-6 carboxylates. In
addition, they have been used as building blocks in syntheses
progress, there is a significant drawback inherent in this class
of receptors. They cannot be applied in the chromophoric
detection of a binding event.
7,8
This limitation may be overcome via the appendage of a
chromophoric unit to the binaphthyl skeleton. There are only
a few examples of chromophoric binaphthyl derivatives
known to date. To the best of our knowledge, there is only
one example where azobenzene photochromism is combined
9
of chiral dendrimers and linear polymers. Despite this
†
Institute of Chemical Technology.
Academy of Sciences.
Charles University in Prague.
‡
§
10
with the chirality of a 2,2′-dihydroxy-1,1′-binaphthyl unit.
(1) Hernandez, J. V.; Oliva, A. I.; Simon, L.; Muniz, F. M.; Grande,
We described recently reported binaphthyl-decorated por-
phyrin macrocycles, where cooperativity of Binap OH groups
on the macrocyclic scaffold led to selective binding of
M.; Moran, J. R. Tetrahedron Lett. 2004, 45, 4831-4833.
2) Tsubaki, K.; Tanaka, H.; Morikawa, H.; Fuji, K. Tetrahedron 2003,
9, 3195-3199.
3) Asakawa, M.; Brown, C. L.; Pasini, D.; Stoddart, J. F.; Wyatt, P. G.
(
5
(
1
1-13
J. Org. Chem. 1996, 61, 7234-7235.
oligosaccharides in protic media.
(
4) Rusin, O.; Kr a´ l, V. Eur. J. Chem. 2002, 8, 655-663.
(
5) Droz, A. S.; Neidlen, U.; Anderson, S.; Seiler, P.; Diederich, F. HelV.
Chim. Acta 2001, 84, 2243-2289.
(9) Pu, L. Macromol. Rapid Commun. 2000, 21, 795-809.
(10) van Delden, R. A.; Mecca, T.; Rosini, C.; Feringa, B. L. Chem.
Eur. J. 2004, 10, 61-70.
(11) Rusin, O.; Lang, K.; Kral, V. Chem. Eur. J. 2002, 8, 655-663.
(12) Rusin, O.; Kral, V. Sens. Actuators, B: Chem. 2001, 1-3, 331-335.
(13) Rusin, O.; Kral, V. Chem. Commun. 1999, 23, 2367-2368.
(
(
6) Rusin, O.; Kr a´ l, V. Tetrahedron Lett. 2001, 42, 4235-4238.
7) Sebo, L.; Schweizer, B.; Diederich, F. HelV. Chim. Acta 2000, 83,
8
0-92.
(8) Stibor, I.; Holakovsk y´ , R.; Mustafina, A. R.; Lhot a´ k, P. Collect.
Czech. Chem. Commun. 2004, 69, 365-383.
1
0.1021/ol051139n CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/20/2005

Scheme 1. Synthesis of Polymethinium Binaphthyl
Chromophores 7 and 8a
a
Reagents and conditions: (a) (MeO)
1) BuLi, THF, -78 °C, 10 min; (2) dimethylaminoacrolein, -78
C to rt, 60 min; (3) HBF in THF, -78 °C to rt. (c) THF/H
3:2), 50 °C, 2 h. (d) (1) NaH 0 °C, 15 min; (2) BuLi, THF, -78
C, 10 min; (3) dimethylaminoacrolein, -78 °C to rt, 60 min; (4)
HBF in THF, -78 °C to rt; (5) THF/H O (3:2), 50 °C, 2 h. (e)
-Methyl-3-propyl benzothiazolium iodide, n-BuOH/benzene (7:
), MgSO , reflux 5 h.
2 2 2 3 3
SO , K CO , CH CN. (b)
(
°
(
°
4
2
O
4
2
2
3
4
Figure 1. Single-crystal X-ray structure of dialdehyde 6.
To pursue our strategy to develop novel, inherently
chromophoric 1,1′-binaphthyl systems, we selected a poly-
methinium salt as the chromophore. Polymethinium salts are
very interesting, stable, conjugated systems with verstaile
properties, allowing their use in nonlinear optical and
medicinal applications.14 They have been employed, for
example, as antitumor agents. Therefore, an important goal
of this work is to synthesize chromophoric binaphthol-
polymethine systems for use as novel photosensitizers, as
potential antitumor agents for photodynamic therapy. Since
the structure of this type of chromophore is very different
from classical porphyrin and porphyrinoid derivatives, we
envision novel properties to emanate from such compounds.
Initially, we decided to develop synthetic methods for the
preparation of polymethinium binaphthyl chromophores from
racemic compounds. Consequently, the method will be used
for the preparation of enantiomerically pure chromophores
from (R)-binaphthols.
N,N-dimethylaminoacroleine (DMAA). Binaphthyl deriva-
tives 1 and 2, after transmetalation with BuLi at -78 °C,
were transformed to the corresponding lithium salts. In the
case of binaphthyl 1, we used 4 equiv of BuLi due to the
two -OH groups. The lithium salts were treated with DMAA
over a temperature range from -78 to 20 °C. The reaction
was quenched with an ethereal solution of tetrafluoroboric
acid to furnish the binaphthyl trimethinium salts 3 and 4.
These salts are sensitive to air and solvent moisture.
Therefore, they were used without further purification.
Trimethinium salts 3 and 4 do not fulfill the requirement
for photosensitizers, since their maxima in the UV-vis
region are at 220 nm. Therefore, we extended the conjugation
of the trimethinium chromophore to pentamethinium, ac-
cording to the strategy summarized in (Scheme 1). The
trimethinium salts 3 and 4 were converted to corresponding
15
aldehydes 5 and 6 (Figure 1) via hydrolysis in a THF-H
2
O
As starting substrates for development of the synthetic
protocol, we chose racemic 1,1′-binaphthyl-2,2′-diol 1 and
racemic dimethoxyderivate 2, prepared from commercial
medium at 50 °C.
Aldehydes 5 and 6 were used as building blocks toward
the synthesis of desired polymethinium binaphthyl salts 7
and 8. We used a general method for transforming poly-
1
6
dibromobinaphthol 1, according to a published procedure,
in 80% yield.
1
7
methine aldehydes to polymethinium salts. We reacted
-methyl-3-propyl-benzothiazolium iodide with 5 or 618 in
a mixture of n-BuOH/PhH (7:3) in the presence of anhydrous
MgSO
. This afforded the desired binaphthyl salts 7 and 8.19
The key synthetic step involves selection of a proper agent
for the introduction of polymethinium chains. We employed
2
4
(
14) Mishra, A.; Behera, K. R.; Behera, K. P.; Mishra, K. P.; Behera, B.
G.; Chem. ReV. 2000, 100, 1973-2011.
15) Kawakami, M.; Koya, K.; Ukai, T.; Tatsuta, N.; Ikegawa, A.;
Ogawa, K.; Shishidi, T.; Chen, L. B. J. Med. Chem. 1998, 41, 130-142.
16) Cuntze, J.; Owens, L.; Alc a´ zar, V.; Seiler, P.; Diederich, F. HelV.
Chim. Acta 1995, 78, 367-390.
In the second-generation synthesis, involving optically pure
materials, we decided to prepare the chromophore from (R)-
(
(
(17) Narayanan, N.; Patonay, G. J. Org. Chem. 1995, 60, 2391-2395.
Org. Lett., Vol. 7, No. 17, 2005
3662

Figure 3. ECD spectrum of receptor 7a in DMSO.
Figure 2. UV-vis spectra of receptor 8 in various solvents.
zothiazolium unit was accomplished under the same condi-
tions as described above, resulting in the desired (R)-
polymethinium binaphthyl chromophore 7a (Scheme 1).
UV-vis spectra of binaphthyl derivative 8 were measured
in buffer-RB-7.28 pH, methanol, and dimethyl sulfoxide
6
,6′-dibromo-1,1′-binaphthyl-2,2′-diol 1a. We have slightly
modified the aforementioned method. First, 1a was trans-
formed to the sodium salt with NaH followed by lithiation.
After addition of DMAA, the reaction was quenched with
tetrafluoroboric acid. The salt was not isolated, and a solution
(Figure 2).
For chiral binaphthyl derivate 7a, the ECD spectra were
measured in dimethyl sulfoxide (Figure 3).
2
of THF and H O (3:2) was added. After the mixture was
Initial studies of enantioselective complexation involved
selected amino acids in buffered media (pH 7.2). Phe (c )
heated at 50 °C, the corresponding bisaldehyde 5a was
obtained. The final step involving connection of the ben-
-
4
1
.16 × 10 ) was used in 11.6 equiv for 1 equiv of binaph-
-5
(18) Compound 6: Description of Synthesis. A flask equipped with a
thyl 7a (c ) 1.00 × 10 ). The complexation of D- and
L-phenylalanine by receptor 7a was carried out at pH 7.2
(Figure 4).
magnetic stirbar and a septum was charged with polymethinium salt 4 (90
mg, 0.14 mmol), H2O (2 mL), and THF (3 mL). The reaction mixture was
heated in an oil bath to 55 °C for 2 h. After the reaction mixture was cooled
to laboratory temperature, H2O (5 mL) was added. The reaction mixture
was extracted with CH2Cl2 (2 × 5 mL). The organic portion was dried
with anhydrous MgSO4. Solvents were removed in vacuo. After column
chromatography on silica (3 × 27 cm, eluent ) Et2O), product bis-aldehyde
1
6
(53 mg, 91%) was obtained. H NMR (300 MHz, CDCl3, 20 °C, TMS):
3
3
δ ) 9.76 (d, J (H,H) ) 7.7 Hz, 2H), 8.05 (d, J (H,H) ) 9.6 Hz, 2H),
3
3
8
(
.03 (d, J (H,H) ) 2.47 Hz, 2H), 7.60 (d, J (H,H) ) 15.7 Hz, 2H), 7.50
3 4 3
d, J (H,H) ) 9.1 Hz, 2H), 7.42 (dd, J (H,H) ) 1.9 Hz, J (H,H) ) 9.1
3
3
3
Hz, 2H), 7.10 (d, J (H,H) ) 9.1 Hz, 2H), 6.72 (dd, J (H,H) ) 7.7 Hz, J
1
3
(
H,H) ) 15.7 Hz, 2H), 3.81 (s, 6H). C NMR (100.6 MHz, CDCl3, 20 °C,
TMS): δ ) 193.7, 156.6, 153.0, 135.2, 131.2, 130.8, 129.4, 128.7, 127.8,
26.0, 124.2, 119.0, 114.4, 56.6. IR (CDCl3) ν ) 3024, 1674, 1618 (Cd
O). LRMS: calcd for C28H22O4 (MH), 422.5; found, 422.7.
19) Compound 8: Description of Synthesis. A flask equipped with a
1
(
magnetic stirbar and an azeotropic head with a reflux condenser was charged
with dialdehyde 6 (88 mg, 0.21 mmol), 2-methyl-3-propyl-benzothiazolium
iodide (133 mg, 0.42 mmol), dry PhH (4.5 mL), and dry butan-1-ol (10.5
mL). Dry MgSO4 (1 g) was added to the azeotropic head. The mixture was
heated at reflux for 6 h and 25 min. After this time, starting bis-aldehyde
was consumed (monitored by TLC). The reaction mixture was evaporated
to dryness, and CH2Cl2 (5 mL) was added. The solid was material was
filtered. The solution after filtration was shaken with Et2O (2 mL), and the
solid was filtered off and washed with MeOH (2 mL). Both solid fractions
were mixed and dried in vacuo. The salt 8 was obtained as a black-red
Figure 4. UV-vis spectrum of 7a: interaction with D- and
L-phenylalanine pH 7.2, 67 mM phosphate buffer.
1
solid (72 mg, 34%). H NMR (300 MHz, DMSO-d6, 20 °C, TMS): δ )
3
3
8
8
2
.42 (d, J (H,H) ) 8.0 Hz, 2H), 8.30 (d, J (H,H) ) 8.3 Hz, 2H), 8.24-
3
3
.08 (m, 6H), 7.86 (t, J (H,H) ) 7.4 Hz, 2H), 7.76 (t, J (H,H) ) 7.7 Hz,
3
3
H), 7.72-7.58 (m, 8H), 7.46 (dd, J (H,H) ) 14.9 Hz, J (H,H) ) 15.1
3
3
Hz, 2H), 7.00 (d, J (H,H) ) 8.8 Hz, 2H), 4.72 (t, J (H,H) ) 7.2 Hz, 4H),
We have developed the synthesis of chromophores 7, 7a,
and 8, trimethinium and pentamethinium binaphthyl systems,
in rameric 7, 8, and enantioselective 7a form as well.
Although the major focus of the present work is on synthetic
methodology, we would like to present also potential for
3
3
3
6
1
1
1
.77 (s, 6H), 1.86 (q, J (H,H) ) 7.2 Hz, 4H), 1.00 (t, J (H,H) ) 7.2 Hz,
13
H). C NMR (100.6 MHz, DMSO-d6, 20 °C, TMS): δ ) 171.0, 156.2,
50.0, 145.7, 141.3, 134.2, 130.9, 130.8, 130.6, 129.5, 128.6, 128.3, 128.1,
26.8, 125.3, 124.4, 124.1, 118.2, 116.7, 115.8, 114.9, 56.2, 49.9, 22.1,
0.7. UV/vis (MeOH): λmax (ꢀ) ) 468 (29779), 331 (13830), 220 (53195).
LRMS: for C50H46N2O2S2. 2I (MH-2I): calcd, 771.1; found, 771.6.
Org. Lett., Vol. 7, No. 17, 2005
3663

application of this class of compounds, namely, in two
areas: First, even reported systems showed enantioselective
complexation of selected amino acids under physiological
conditions (See Supporting Information). The synthesis of
more advanced receptors and enantioselective complexation
is currently being explored in our laboratory. The vision for
the second potential application came from recently reported
interesting behavior of polymethine salts, which can function
as inducers of apoptosis.20
Acknowledgment. Authors gratefully acknowledge fi-
nancial support of the Ministry of Education of the Czech
Republic (MSM 223400008). This work was also supported
by GACR Nos. 203/02/0933, 309/02/1193, 203/02/0420, and
3
01/04/1315.
Supporting Information Available: Experimental details
for various compounds mentioned herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
20) Shazib, P.; Seyed, M. A.; Jayshreekumari L. H.; Clement, M.-V.;
Loh, K. W. Blood 1999, 93, 4096-4108.
OL051139N
3664
Org. Lett., Vol. 7, No. 17, 2005