Synthesis and characterization of novel bifunctional hemithioindigo chromophores.

Article abstract of DOI:10.1021/ol027102+

[structure: see text] General methods for the synthesis of novel bifunctional hemithioindigo (HT) compounds, e.g., omega-amino acid derivatives, are presented. The photochromic properties of the photoswitches have been characterized by UV-vis and (1)H NMR

Full text of DOI:10.1021/ol027102+

ORGANIC
LETTERS
2003
Vol. 5, No. 2
141-144
Synthesis and Characterization of Novel
Bifunctional Hemithioindigo
Chromophores
Wencke Steinle and Karola Ru1ck-Braun*
Technische UniVersita¨t Berlin, Institut fu¨r Chemie, Strasse des 17. Juni 135,
D-10623 Berlin, Germany
krueck@chem.tu-berlin.de
Received October 14, 2002
ABSTRACT
General methods for the synthesis of novel bifunctional hemithioindigo (HT) compounds, e.g., ω-amino acid derivatives, are presented. The
photochromic properties of the photoswitches have been characterized by UV−vis and 1H NMR spectroscopy.
Photochromic compounds are becoming increasingly popular
for a series of biological applications based on the reversible
photocontrol of the structure and function of biomolecules.1
Several approaches to photomodulating biological functions
such as biocatalysis,2,3 ion transport,4,5 cell adhesion,6 protein
folding,7 or membrane properties8 have been employed. Most
of these studies involved the chemical modification of
nucleotides, peptides, proteins, and lipids using azobenzenes
as reversible photoswitchable chromophores.2-7 In the past,
one major strategy for proteins was random-chemical
substitution of the chromophore to multiple undefined sites
of the biomolecule.1 Nowadays, rational concepts focus on
site-specific incorporation based on the design to photo-
operate not only steric or ion-dipole interactions but also
conformational transitions of structural elements of proteins
and peptides as, for example, â-turns and helices.7,9,10 In this
context, novel chromophores with useful optical properties
are gaining attention for tailor-made designs. Photochromic
hemithioindigos are considered to be an interesting class of
chromophore because of the frequent reversibility of the
light-induced isomerizations or the thermal stability of the
photochromic states among other beneficial properties.8,11-13
For example, Fyles reported on novel photoswitchable lipids
(1) Willner, I.; Rubin, I. Angew. Chem., Int. Ed. Engl. 1996, 35, 367-
385.
(2) (a) Yamazawa, A.; Liang, X.; Asanuma, H.; Komiyama, M. Angew.
Chem., Int. Ed. 2000, 39, 2356-2357. (b) Asanuma, H.; Liang, X.; Yoshida,
T.; Yamazawa, A.; Komiyama, M. Angew. Chem., Int. Ed. 2000, 39, 1316-
1318.
(3) James, D. A.; Burns, D. C.; Woolley, G. A. Protein Eng. 2001, 14,
983-991.
(4) Osman, P.; Martin, S.; Milojevic, D.; Tansey, C.; Separovic, F.
Langmuir 1998, 14, 4238-4242.
(5) (a) Borisenko, V.; Burns, D. C.; Zhang, Z.; Woolley, G. A. J. Am.
Chem. Soc. 2000, 122, 6364-6370. (b) Lien, L.; Dominic, C. J. J.; Zhang,
Z.; Wooley, G. A. J. Am. Chem. Soc. 1996, 118, 12222-12223.
(6) Haiqian, Z.; Hiroaki, S.; Ning, G.; Hiroshi, S.; Masahiko, S. J.
Southeast UniV. 2001, 17, 22-26.
(7) (a) Cattani-Scholz, A.; Renner, C.; Cabrele, C.; Behrendt, R.;
Oesterhelt, D.; Moroder, L. Angew. Chem., Int. Ed. 2002, 41, 289-292.
(b) Behrendt, R.; Renner, C.; Schenk, M.; Wang, F.; Wachtveitl, J.;
Oesterhelt, D.; Moroder, L. Angew. Chem., Int. Ed. 1999, 38, 2771-2774.
(c) Renner, C.; Cramer, J.; Behrendt, R.; Moroder, L. Biopolymers 2000,
54, 501-514. (d) Renner, C.; Behrendt, R.; Spo¨rlein, S.; Wachtveitl, J.;
Moroder, L. Biopolymers 2000, 54, 489-500. (e) Renner, C.; Behrendt,
R.; Heim, N.; Moroder, L. Biopolymers 2002, 63, 382-393. (f) Spo¨rlein,
S.; Carstens, H.; Satzger, H.; Renner, C.; Behrendt, R.; Moroder, L.; Tavan,
P.; Zinth, W.; Wachtveitl, J. PNAS 2002, 99, 7998-8002. (g) Behrendt,
R.; Schenk, M.; Musiol, H.-J.; Moroder, L. J. Peptide Sci. 1999, 5, 519-
529.
(8) Eggers, K.; Fyles, T. M.; Montoya-Pelaez, P. J. J. Org. Chem. 2001,
66, 2966-2977.
(9) Ulysee, L.; Cubillos, J.; Chmielewski, J. J. Am. Chem. Soc. 1995,
117, 8466-8467.
(10) (a) Kumita, J. R.; Smart, O. S.; Woolley, G. A. PNAS 2000, 97,
3803-3808. (b) Flint, D. G.; Kumita, J. R.; Smart, O. S.; Woolley, G. A.
Chem. Biol. 2002, 9, 391-397.
10.1021/ol027102+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/18/2002

containing a hemithioindigo chromophore as part of the fatty
acid for the reversible control of membrane processes.8 Other
hemithioindigo derivatives suitable for incorporation into
biomolecules have, to our knowledge, never been explored.
In this report we describe our approach to novel bifunc-
tional hemithioindigo chromophores such as dicarboxylic
acid esters and ω-amino acid-derivatives for incorporation
into peptides and proteins. We initiated our studies starting
from the literature-known thioindoxyl carboxylic acid chlo-
ride14 1 (Table 1) by examining the use of MeOH and
rable mixture of 3c and 3a in 64% yield in a ratio of 37:63
as determined by 1H NMR. Formation of 3a can be explained
by tert-butyl ester cleavage and transesterification in the
presence of hydrogen chloride during esterification of the
carboxylic acid chloride. With triethylamine as an additive
instead of pyridine, decomposition of thioindoxyl 1 took
place in the presence of aldehyde 2c and methanol. Increasing
the amount of piperidine (2.3 equiv) in the absence of
pyridine afforded amide 4 (Scheme 1) in 54% yield
(recrystallized from MeOH).
Scheme 1
Table 1. Synthesis of Hemithioindigo-Based Dicarboxylic
Acid Esters 3
entry
aldehyde
3
R1
yielda (%)
1b
2a
2b
2c
3a
3b
3c
OCH2CO2Me
CO2Me
OCH2CO2 Bu
50
50
52
2b
t
3b,c
a Isolated yields. b All reactions were carried out with 0.05-0.15 mL of
piperidine as a catalyst. c Reaction was performed in the presence of 1.1
equiv of pyridine as an additive.
We then prepared hemithioindigo ω-amino acid derivative
6 starting from 1, aldehyde 5, and methanol by applying
exactly the same conditions as for 3c. But surprisingly the
reactions produced inconsistent results regarding yield and
purity (entry 1, Table 2). Thus, the reaction conditions were
benzaldehydes 2a-c for the construction of compounds 3a,b
as well as the selectively protected dicarboxylic acid ester
3c via simultaneous esterification in the 7-position and base-
catalyzed aldol condensation in the 2-position. Various
reaction conditions were examined, and a brief summary of
the results obtained is presented in Table 1. The reactions
of the thioindoxyl 1 with benzaldehydes 2a-c in the presence
of methanol were generally carried out with piperidine as a
catalyst.11 Hemithioindigos 3a and 3b were isolated in 50%
yield after crystallization from 1:1 toluene/MeOH as yellow
and orange powders, respectively, free from impurities and
decomposition products. Chromatography on silica gel led
to decomposition.
Table 2. Synthesis of the ω-Amino Acid Derivative 6
By far, the cleanest reaction yielding 3c was obtained in
the presence of 1.1 equiv of pyridine (52%, recrystallized
from ether/pentane). Otherwise, the formation of substantial
amounts of byproduct 3a was found, furnishing an insepa-
MeOH
1
5
pyridine conversion of 5 yield
entry (equiv) (equiv) (equiv) (equiv)
(%)
(%)a
1
2
3
5
5
7.5
1.0
1.0b
1.5b
1.1
1.0
1.0
1.1
13
19.5
61
81
98
79
98
98
(11) (a) Yamaguchi, T.; Seki, T.; Tamaki, T.; Ichimura, K. Bull. Chem.
Soc. Jpn. 1992, 65, 649-656. (b) Seki, T.; Tamaki, T.; Yamaguchi, T.;
Ichimura, K. Bull. Chem. Soc. Jpn. 1992, 65, 657-663. (c) Ichimura, K.;
Seki, T.; Tamaki, T.; Yamaguchi, T. Chem. Lett. 1990, 1645-1646.
(12) Rea´monn, L. S. S.; O’Sullivan, W. I. J. Chem. Soc., Perkin Trans.
1 1977, 1009-1012.
a Yield of isolated crude material 6. b Reaction was carried out in the
presence of 4 Å MS.
(13) (a) Mostoskavskii, M. A.; Izmail’skii, V. A. J. Gen. Chem. USSR
1961, 17, 21-31. (b) Mostoskavskii, M. A.; Izmail’skii, V. A. J. Gen. Chem.
USSR 1963, 33, 727-731. (c) Mostoskavskii, M. A.; Izmail’skii, V. A. J.
Gen. Chem. USSR 1965, 35, 519-523.
optimized with a sequential reaction protocol of esterification
of thioindoxyl carboxylic acid chloride 1 prior to the
(14) Irie, M.; Kato, M. J. Am. Chem. Soc. 1985, 107, 1024-1028.
142
Org. Lett., Vol. 5, No. 2, 2003

piperidine-catalyzed aldol condensation in degassed solution.
Turnover and yield of ω-amino acid derivative 6 were
improved up to 98% by increasing the number of equivalents
of MeOH and pyridine (entries 2 and 3, Table 2) in the
presence of 4 Å molecular sieves. The material contained
only tiny amounts of byproduct, presumably due to the
oxidation of excess thioindoxyl precursor and esterification
intermediate. However, deprotection strategies were inves-
tigated with the functionalized hemithioindigos 3a-c and 4
before further optimizations of the reaction protocols.
Scheme 3
Deprotection of hemithioindigo tert-butyl esters with 1:1
TFA/DCM and 90:2:2 TFA/TIPS/H2O produced no isolable
compounds.15,16 The decomposition is explained as a con-
sequence of carbocation attack on sulfur and/or hydride attack
on the R,â-unsaturated carbonyl moiety. Alternatively, reac-
tions employing reagent K (TFA/water/thioanisole/phenol/
ethanedithiole) at room temperature were very promising and
gave, for example, compound 7 in 80% yield (Scheme 1).
However, for deprotection of the N-Boc-protected hemi-
thioindigo compound 6, treatment with HCl in dioxane
proved to be superior, yielding the salt 8 quantitatively.
3 h. Compound 10 was purified by chromatography on
Florisil and isolated in 80% yield.
First attempts to apply N-Boc-protected ω-amino acid 10
in peptide synthesis proved to be successful. Treatment of
10 with (S)-H-Lys(Cbz)-OMexHCl in the presence of HOBt,
EDC, and DIEA in DMF furnished dipeptide 11 in 88%
isolated yield (Scheme 4).7g
Scheme 4
All attempts to selectively deprotect hemithioindigo methyl
esters proved to be a challenge. Experiments under basic
conditions (LiOH/THF, KOtBu/Et2O/H2O, NaOH/MeOH,
Ba(OH)2/MeOH, NaOH/DMF/H2O) failed.15,16 Decomposi-
tion of the hemithioindigo core unit was observed, presum-
ably via retro-aldol reaction because of the presence of the
1
aldehyde precursors determined by H NMR spectroscopy
of the crude reaction products. Similarly, exposure of 3a to
Me3SiCl/NaI in MeCN or NaCN/LiI in DMF at elevated
temperatures led to decomposition.15-17 Fortunately, the
application of PhSH and K2CO3 in NMP at 190 °C gave
product 9 in 89% yield (Scheme 2).18
After demonstrating the feasibility of the synthesis of
bifunctional hemithioindigo compounds, we evaluated their
photochromic properties in organic solvents. The UV-vis
spectra of 3a,b, 9, and 10 in DCM or MeOH in the dark
adapted state showed a typical maximum at about 438-444
nm, as expected for the (Z)-isomers according to previous
work ((5 nm).8,11,13 Irradiation at 406 nm causes the
appearance of a broad maximum of the (E)-isomers at about
447-461 nm in either DCM or MeOH (Table 3). Presum-
ably, the data collected in Table 3 refer to general observa-
tions related to (a) differences in the substitution pattern in
the 4′-position at the phenyl residue and (b) differences in
the polarity of the solvents as well as (c) in the functional
group polarity.8,11-13
Scheme 2
In all cases, photoisomerization is readily observed at 406
nm (Z-to-E isomerization) and at 480 nm (E-to-Z isomer-
ization) showing isosbestic points and reversibility during
irradiation for several days. The quantitative analysis of the
isomer ratios in the photostationary states (pss) at 406 and
However, this deprotection procedure requires careful
purification of the starting material. Therefore, the direct
synthesis of N-Boc-protected ω-amino acid 10 was inves-
tigated next (Scheme 3). In a final series of experiments,
reaction of 1 (1.5 equiv) with benzaldehyde 5 (1 equiv) in
7:3 NaOH(1%)/tBuOH performed very well. Heating at
reflux led to complete consumption of the aldehyde within
1
480 nm was determined by H NMR spectroscopy, since,
e.g., the vinyl protons of both isomers give diagnostic signals
1
in the H NMR spectra (Table 3). In the dark adapted state
for compound 3a (CD2Cl2) and 10 (CD3OD), the (Z)-isomer
is observed exclusively, whereas for compound 9 (CD3OD),
the Z:E ratio is 93:7. The thermal E-to-Z isomerization
proceeds rather slowly with a half-life of 138 h for 3a in
CD2Cl2 and of 20 and 22 h for 9 and 10, respectively, in
CD3OD at 25 °C. For the 7-alkoxy carbonyl-substituted
hemithioindigos evaluated in this study, more enriched
(15) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag: Stuttgart,
1994.
(16) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; Wiley & Sons: New York, 1999.
(17) Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K. J. Org. Chem.
1983, 48, 3667-3671.
(18) Sharma, L.; Nayak, M. K.; Chakraborti, A. K. Tetrahedron 1999,
55, 9595-9600.
Org. Lett., Vol. 5, No. 2, 2003
143

Table 3. Photochromic Properties of Hemithioindigo Compounds at Room Temperature
λmax (nm)
ꢀ (dm3 M-1 cm-1
(Z)-isomer
)
Ed
isosbestic points
CE (%)
t1/2 (h)
CZa,c (%)
95e
a,b
compound
solvent
Z
3a
3a
3b
9
10
10
CH2Cl2
CH3OH
CH2Cl2
CH3OH
CH2Cl2
CH3OH
440
438
438
444
438
442
450
457
447
461
450
450
13830
7453
10846
8667
6290
6155
376,455
379,456
365,454
481,461
366,449
365,457
84e
138e
90e
80f
20.5f
22f
81f
81f
82f
1
a Ratios were determined by H NMR spectroscopy. b Conversion to the (E)-isomer determined in the pss (λ ) 406 nm). c Conversion to the (Z)-isomer
determined in the pss (λ ) 480 nm). d Determined in the pss upon illumination with 406 nm. e CD2Cl2, 25 °C. f CD3OD, 25 °C.
samples in both isomeric states and improved thermal
stabilities were determined under illumination in comparison
to 4-, 5-, and 6-alkyl-substituted hemithioindigos reported
previously.8,11
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungsbereich
498). For the donation of equipment, we thank Aventis
Pharma, Germany. We also thank A. G. Woolley, University
of Toronto, Canada, for useful discussions.
In conclusion, we have synthesized and characterized novel
photochromic hemithioindigo-based dicarboxylic acid esters
and ω-amino acid derivatives. These chromophores exhibit
useful optical properties for the photocontrol of the structure
and function of biomolecules. We are currently evaluating
the application of 10 in solid-phase peptide synthesis of
photoswitchable peptides.
Supporting Information Available: Full experimental
procedures and characterization data for 3a-c, 4, and 6-11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL027102+
144
Org. Lett., Vol. 5, No. 2, 2003