Synthesis of rigid photoswitchable hemithioindigo ω-amino acids

Article abstract of DOI:10.1016/j.tetlet.2007.10.110

The synthesis of novel N-Boc- and N-Fmoc protected hemithioindigo-based ω-amino acids is described. An approach to modulate the thermal stability of a hemithioindigo subunit is presented. Placing the amino-group in the stilbene part from the para- to meta

Full text of DOI:10.1016/j.tetlet.2007.10.110

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Tetrahedron Letters 48 (2007) 9044–9047
Synthesis of rigid photoswitchable hemithioindigo x-amino acids
Torsten Schadendorf, Christian Hoppmann and Karola Ruck-Braun*
¨
Technische Universita¨t Berlin, Institut fu¨r Chemie, Strasse des 17, Juni 135, D-10623 Berlin, Germany
Received 22 August 2007; revised 8 October 2007; accepted 15 October 2007
Available online 25 October 2007
Abstract—The synthesis of novel N-Boc- and N-Fmoc protected hemithioindigo-based x-amino acids is described. An approach to
modulate the thermal stability of a hemithioindigo subunit is presented. Placing the amino-group in the stilbene part from the para-
to meta-position leads to an increase of the half-life of the thermally labile E-form from 19 h to 47 h.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The analysis and modulation of the conformation and
function of biomolecules (e.g., ion transport,1 protein
folding,2 cell signaling3 and cell adhesion4,5) with photo-
chromic switches is an area of increasing interest.6
Among the photoisomerizable subunits for the photo-
modulation of secondary structure elements in peptides
and proteins photosensitive x-amino acids are highly
promising candidates. Hemithioindigos possess favour-
able properties for use in biological systems.1,3,7–10
Isomerization (Z!E; E!Z) of hemithioindigos (HTI)
occurs on a picosecond timescale, and contrary to most
other photoswitches only in the visible range.7 Both
photoisomers are planar and unstrained.1 UV/visible
absorption data and thermal stability depend on the nat-
ure and the position of substituents, as well as medium
effects (e.g., concentration, solvent, pH value).11
x-amino acids with the amino group attached directly
to the stilbene part of the hemithioindigo (Scheme 1).
Amino acids have been prepared bearing the amino
group in para- and in meta-position, respectively, to
evaluate the impact of this change in substitution pat-
tern on the thermal E-to-Z-isomerization. A beneficial
meta-substitution effect has been studied in several
works on thermal cis-to-trans isomerization of azobenz-
enes,18,19 leading to a pronounced increase in thermal
stability.9,20 Synthetic routes to Fmoc- and Boc-pro-
tected derivatives for SPPS21 are shown in Scheme 2.
We, herein, report on acidic conditions for the conden-
sation of appropriate Fmoc-protected aldehyde precur-
sors with the thioindoxyl 1,22 followed by hydrolysis
of the carboxylic acid chloride furnishing the Fmoc-
protected x-amino acids 2a,b. For the synthesis of the
Boc-protected building blocks the methods previously
reported by us were applied.7,8
Hemithioindigos are also attractive photoregulators for
the fast initiation of processes of peptides and protein
folding and their investigation.3,12 In addition, hemithi-
oindigos are interesting as active ingredients for medici-
nal applications, for example, as human sphingosine
kinase inhibitors,13 antitumor drugs,14,15 antimalarial
HDP inhibitors16 and photoswitchable lipoxygenase
inhibitors.17 To effectively use the hemithioindigo scaf-
fold in the design of photoswitchable x-amino acids,
the rigidity of both photochromic isomers and the sub-
stantial end-to-end distance change during isomeriz-
ation should not be compromised by a flexible tether.
Consequently, we focused on the development of novel
The aldehydes23 4a and 4b were prepared from the par-
ent amino-substituted benzyl alcohols by Fmoc-protec-
tion24 and subsequent oxidation with manganese
oxide23 in DCM using standard procedures (Scheme 3).
CO2H
NHPG
S
CO2H
λ1
S
λ2, Δ
O
Keywords: Hemithioindigo; Amino acids; Cis/trans-isomerization;
Photoswitch.
Z-form
E-form
NHPG
O
*
Corresponding author. Tel.: +49 30 314 26319; fax: +49 30 314
79651; e-mail: krueck@chem.tu-berlin.de
Scheme 1. Structures of hemithioindigo isomers (Z/E).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.110

T. Schadendorf et al. / Tetrahedron Letters 48 (2007) 9044–9047
9045
NHPG
acidic conditions
PG = Fmoc
COCl
CO2H
NHPG
O
S
S
+
Fmoc: 2a (meta)
2b (para)
Boc: 10 (meta)
11 (para)
basic conditions
PG = Boc
O
O
1
Scheme 2. Hemithioindigo x-amino acids: meta- and para-substitution pattern.
Fmoc-Cl, 1N NaOH,
NH2
NHFmoc
NHFmoc
MnO2, DCM
THF
O
HO
HO
a) meta: 92%
b) para: 87%
a) meta: 75%
b) para: 87%
3a (meta)
3a (para)
4a (meta)
4b (para)
Scheme 3. Synthesis of aldehydes 4a,b.
O
Cl
NHFmoc
4M HCl/dioxane, r.t.;
then THF/water, Δ
NHFmoc
CO2H
O
S
S
+
a) meta: 44%
b) para: 34%
2a (meta)
2b (para)
O
4
O
1
Scheme 4. Synthesis of the N-Fmoc-protected hemithioindigo based x-amino acids 2a,b.
pTsOHcat.
acetone/H2O
Boc2O, NaOH,
O
O
O
O
dioxane
quant.
92%
O
O
NHBoc
NHBoc
NH2
5
6
7
Boc2O, 1N NaOH
dioxane
HO
HO
MnO2, DCM
NH2
NBoc
NBoc
94 %
94%
8
9
Scheme 5. Synthesis of aldehydes 7 and 9.
The aldehydes were condensed with thioindoxyl 1 using
4 M HCl in dioxane, followed by treatment with THF/
water (3:1) under reflux to hydrolyze the acid chloride.
The purities of the crude products were estimated by
1H NMR spectroscopy as 60–70% (2a) and 50–60%
(2b), respectively. Compound 2a was purified by recrys-
tallization from ethyl acetate/THF (5:1, twice) to furnish
6.6 g (44%) of a yellow-brown solid, whereas 2.2 g (34%)
of 2b were obtained after flash chromatography on silica
(DCM/MeOH) (Scheme 4). Purification is hampered by
thioindigo side-products of low solubility stemming
from the thioindoxyl acid chloride.
Scheme 5 in two steps. Boc-protection of the commer-
cially available dioxolane 5 and subsequent removal
of the acetal protecting group furnished aldehyde 7.
Aldehyde 9 was obtained from 4-aminobenzylalcohol
by Boc-protection and subsequent oxidation.25,26
CO2H
1
NHBoc
KOH / 2-propanol
reflux, 4 h
S
10
O
24%
NHBoc
O
7
The Fmoc-protected x-amino acids 2a,b showed insuffi-
cient solubility in methanol-d4 for UV/visible as well as
1H NMR studies to determinate the ratio of isomers in
the pss. However, for these measurements the Boc-
protected building blocks 10 and 11 are well suited.
NHBoc
1
CO2H
t
NaOH / BuOH
reflux, 1 h
S
NHBoc
O
11
35%
9
O
The aldehydes 7 and 9 for the synthesis of the
compounds 10 and 11 were prepared according to
Scheme 6. Synthesis of the Boc-protected x-amino acids 10 and 11.

9046
T. Schadendorf et al. / Tetrahedron Letters 48 (2007) 9044–9047
Table 1. Photochromic properties of the Boc-protected hemithioindigo x-amino acids 10 and 11.
eZ (dm3 Mꢀ1 cmꢀ1
)
Isosb. points (nm)
kmax [pss]a (nm)
Z:E [pss]a
t1/2 (h)
b
Substance
kmax [Z] (nm)
10c
11d
433
446
1.3 · 104
360.4, 451.8
390.8, 468.6
447
469
19:81
22:78
47.2
19.3
2.6 · 104
a 415 nm.
b Determination of t1/2 at (303 2) K.
c 6.0 · 10ꢀ5 M (MeOH).
d 3.9 · 10ꢀ5 M (MeOH).
Condensation of these aldehydes with thioindoxyl 1 and
subsequent hydrolysis was achieved under basic condi-
tions in a one-pot procedure. In the condensation of
aldehyde 7 aqueous KOH (2 wt %)/2-propanol (3:1)
was applied. Purification by flash chromatography
(Florisil; ethyl acetate/acetic acid) followed by recrystal-
lization (methanol) furnished the meta-substituted
x-amino acid 10 in 24% yield with high purity in non-
optimized yield. Reaction of aldehyde 9 in aqueous
NaOH (1 wt %)/tert-butanol (6:1) gave the para-substi-
tuted analogue 11 in 35% yield after flash chromato-
graphy (Florisil). The synthesis and purification of all
compounds were not optimized (Scheme 6).
more pronounced push–pull effect of the unprotected
para-substituted x-amino acid derived from 11, depro-
tection was carried out with 4 M HCl in dioxane to
furnish the hydrochloride 12 (Scheme 7). As expected,
the UV/visible absorption spectrum of 12 in the pss
could only be recorded by femtosecond spectroscopy,
due to the very fast thermal E-to-Z-isomerization.28
In summary, the syntheses of Fmoc- and Boc-protected
building blocks of two novel hemithioindigo-based
x-amino acids are reported. By changing the substitu-
tion pattern from para- to meta-substitution in the
stilbene part the half-life could be increased by a factor
2.4. The half-lives of 10 and 11, and the ratios of isomers
in the photostationary states at 415 nm (E:Z ratio
ꢁ80:20) and 514 nm (Z:E ratio >95:5) make these novel
x-amino acids attractive candidates as photochromic
switches for biological investigations.
The photochromic properties of the Boc-protected
x-amino acids 10 and 11 are summarized in Table 1.
The absorption maximum of Z-11 is shifted to 446 nm
in comparison to Z-10 (433 nm). This distinct difference
in the absorption maximum and the doubling of the
extinction coefficient of 11 relative to 10 is addressed
to the push–pull substitution pattern in compound 11.
The E-to-Z ratios at 415 nm were determined in
Acknowledgements
1
MeOH-d4 by H NMR spectroscopy in the photosta-
This work was supported by the Volkswagen Founda-
tion and the Fonds der Chemischen Inudstrie.
tionary state (pss) as 81:19 for the meta-substituted com-
pound 11, and as 78:22 for the para-substituted
hemithioindigo 10. Irradiation at 514 nm gave nearly
the pure thermally stable Z-isomers for both
compounds.
Supplementary data
The synthesis and complete characterisation (1H NMR,
Determination of the half-lives of 10 and 11 were carried
out in degassed methanol (HPLC-grade) by recording
the absorbance change during thermal E-to-Z isomeri-
zation. Assuming that the thermal E-to-Z isomerization
of hemithioindigos in solution follows a first order
kinetic, the rate constant k can be determined according
to Eq. 1.19,27
1
13C NMR, mp, Rf, MS, HR-MS, IR, copies of H and
13C); UV/visible absorption spectra and graphical deter-
mination of the half-life time of 10 and 11 (according to
Scheme 1) are provided as Supplementary data. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2007.10.110.
Az ꢀ Apss
kt ¼ ln
ð1Þ
Az ꢀ At
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