An unexpected triethylsilane-triggered rearrangement of thioaurones to thioflavonols under SPPS conditions

Article abstract of DOI:10.1016/j.tetlet.2008.07.054

Thioaurones are converted to a mixture of thiaindenes and thioflavonols when exposed to reaction conditions employed in SPPS, that is, treatment with trifluoroacetic acid in the presence of triethylsilane.

Full text of DOI:10.1016/j.tetlet.2008.07.054

Tetrahedron Letters 49 (2008) 6033–6035
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected triethylsilane-triggered rearrangement of thioaurones
to thioflavonols under SPPS conditions
Miranda Varedian a, Vratislav Langer b, Jonas Bergquist c, Adolf Gogoll a,
*
a Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala, Sweden
b Environmental Inorganic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, S-412 96 Gothenburg, Sweden
c Department of Physical and Analytical Chemistry, Uppsala University, Box 599, S-751 24 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Thioaurones are converted to a mixture of thiaindenes and thioflavonols when exposed to reaction
conditions employed in SPPS, that is, treatment with trifluoroacetic acid in the presence of triethylsilane.
Ó 2008 Published by Elsevier Ltd.
Received 5 May 2008
Revised 26 June 2008
Accepted 8 July 2008
Available online 12 July 2008
Keywords:
Peptidomimetics
Chromophores
Rearrangement
Reduction
Silanes
Hemithioindigo
Thioaurone
1. Introduction
tude of decomposition products during peptide synthesis, unlike
the chemically stable stilbene analogues. Although there has been
Flavonoids constitute an important group of natural products
with a variety of physiological properties.1 Among these, the auro-
nes constitute a particular subgroup, where the usual C ring is
some speculation about the chemical reason for this instability,6d
there is no evidence so far for the reactions involved. One obvious
possibility is nucleophilic or electrophilic attack on the double
bond or the sulfur atom, respectively.
replaced by
a five-membered heterocyclic ring. Their thio-
analogues, the thioaurones (hemithioindigos), have a long history
as dyes,2 and only recently has their potential use as cytotoxic
agents3 and components for the cosmetics industry4 been
addressed. Thioaurones have also attracted some interest as photo-
isomerizable chromophores.5–7 However, their chemical behavior
is less well studied.2,6d For any use in practical applications,
knowledge about chemical stability under various reaction
conditions is of great importance. In this Letter, we report on
new findings related to the chemical instability of thioaurone
derivatives under conditions encountered during solid-phase
peptide synthesis (SPPS).
In an extension to our previous work on photoswitchable pep-
tidomimetics incorporating a stilbene moiety,8 we found it inter-
esting to investigate whether the conformationally more rigid
thioaurone chromophore might be a useful complement. However,
initial attempts to utilize the previously reported thioaurone ami-
no acid mimetics6 resulted frequently in degradation into a multi-
Interconversions between various types of flavonoids are bio-
chemical processes,1 and these have also been used in the synthe-
sis of both flavonoids and their thio-analogues. Ring expansions of
aurones to flavones,9 or ring contractions of thioflavones to thio-
aurones10 have been reported, transformations which often
involve redox reactions.
2. Results and discussion
During our own attempts to incorporate thioaurones into the
backbone of linear peptidomimetics, decomposition occurred dur-
ing cleavage from the SPPS matrix. This was apparent following
workup as indicated by a fading of the typical yellow color of the
thioaurone, suggesting a reaction involving the chromophore.
In order to clarify these reactions, we synthesized model com-
pound 1a,6a which was exposed to SPPS conditions, that is, treat-
ment with TFA/DCM (85:15) and 0.4% triethylsilane (TES). The
main components of the resulting product mixture were a reduc-
tion product, that is, the thiaindene derivative 2a, and a rearranged
compound, the thioflavonol 3a. The corresponding products were
* Corresponding author. Tel.: +46 18 4713822; fax: +46 18 4713818.
E-mail address: Adolf.Gogoll@biorg.uu.se (A. Gogoll).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.07.054

6034
M. Varedian et al. / Tetrahedron Letters 49 (2008) 6033–6035
the product composition was determined by 1H NMR spectroscopy.
The main components were isolated chromatographically and
characterized by NMR and IR spectroscopy (see Supplementary
data for details).
R
CF3CO2H
Et3SiH
X
S
H
2-Benzylbenzo[b]thiophene-7-carboxylic acid (2a): Faintly yellow
needles (46 mg, 0.17 mmol, 48%). mp = 168–170 °C. 1H NMR
(500 MHz, CDCl3 solution, 25 °C), d = 8.12 (dd, J = 7.6, 1.2 Hz, 1H,
H-6), 7.90 (dd, J = 7.6, 1.2 Hz, 1H, H-4), 7.42 (dd, J = 7.6, 7.6 Hz,
1H, H-5), 7.33 (m, 3H, o + p-Ph), 7.26 (m, 2H, m-Ph), 7.08 (t,
J = 1.1 Hz, 1H, H-3), 4.27 (d, J = 1.1 Hz, 2H, CH2). 13C NMR
(125.7 MHz, CDCl3 solution, 25 °C), d = 170.3 (COO), 147.8 (C-2),
141.4 (C-7/C-3a), 140.6 (C-7a), 139.1 (ipso-Ph), 128.8 (2C, o-Ph),
128.6 (2C, m-Ph), 128.1 (C-4), 127.0 (C-6), 126.4 (p-Ph), 123.9 (C-
5), 122.6 (C-7/C-3a), 120.8 (C-3), 36.6 (CH2). IR (neat): 3023,
2825, 2538, 1682, 1547, 1426, 1278, 1157, 891, 835, 745,
692 cmꢀ1. MS (EI, 70 eV): m/z (%) = 268 (100, M+), 223 (31%,
[MꢀCOOH]+), 191 (22%, [MꢀPh]+).
O
1a-c
R
X
R
S
X
S
+
OH
O
3a-c
2a-c
a, R = COOH, X = H; b, R = COOH, X =
p
-CH2NHBoc;
3-Hydroxy-4-oxo-2-phenyl-4H-1-benzothiopyran-8-carboxylic
acid (3a): A crystalline material was obtained by recrystalliza-
tion from N,N-dimethylformamide solution, colorless crystals,
mp = 248–250 °C. 1H NMR (500 MHz, DMSO-d6 solution,
25 °C), d = 13.83 (br s, 1H, COOH), 9.49 (s, 1H, OH), 8.77 (dd,
J = 8.1, 1.7 Hz, 1H, H-5), 8.47 (dd, J = 7.5, 1.6 Hz, 1H, H-7), 7.74
(dd, J = 8.1, 7.5 Hz, 1H, H-6), 7.69 (m, 2H, o-Ph), 7.54 (m, 2H,
m-Ph), 7.49 (m, 1H, p-Ph). 13C NMR (125.7 MHz, DMSO-d6 solu-
tion, 25 °C), d = 175.0 (C-4), 167.6 (C-9), 144.3 (C-3), 139.3
(C-8a), 135.7 (C-7), 134.8 (ipso-Ph), 134.2 (C-5), 131.6 (C-8),
130.04 (2C, o-Ph), 130.0 (p-Ph), 129.3 (2C, m-Ph), 127.8 (C-2),
127.2 (C-4a), 127.0 (C-6). MS (ESI, 30 eV): m/z (%) = 298.9
(100, [M+H]+).
c, R = CO-Ala, X =
p
-CH2NH-Val-OAc
Scheme 1.
Compound 3aÅDMF (C19H17NO5S), Mr = 371.40, crystal dimen-
sions 0.62 ꢁ 0.52 ꢁ 0.28 mm3, monoclinic, space group P21/c,
a = 10.9536 (5) Å, b = 11.1121 (5) Å, c = 14.6582 (7) Å, b = 100.656
(1)°, V = 1753.39 (14) Å3, Z = 4,
q
calcd = 1.407 g/cm3, absorption
Figure 1. Arrangement of hydrogen-bonded thioflavonol and associated DMF
molecules in the crystal lattice of 3aÅDMF. ORTEP plot13 showing displacement
ellipsoids at the 50% probability level.
coefficient 0.215 mmꢀ1
,
h = 2.31–32.96°. F(000) = 776, T = 153
(2) K, R1 = 0.0319, wR2 = 0.0913. Independent reflections = 6278
[R(int) = 0.0218], restraints = 0, parameters = 256. Crystallographic
data of 3aÅDMF have been deposited with the Cambridge Crystallo-
graphic Data Centre as Supplementary Publication No. CCDC
686651.
obtained from the Boc-protected thioaurone amino acid 1b6a and
from the linear tripeptide 1c6a (Scheme 1). Notably, products from
retro-aldol condensation, or nucleophilic or electrophilic addition,
which were suggested previously as possible decomposition path-
ways, were observed only in trace amounts.
Acknowledgment
In the reaction mixtures, the thioflavonols 3a–c accounted for
between 11% and 38% of the material, and the thiaindenes 2a–c
for between 8% and 88%. The remaining material represented a
mixture of polymers and by-products, which were not character-
ized further. An interesting observation was that thioaurone 1a
was stable in a solution of 50% TFA in DCM for three days, but
decomposed immediately upon addition of a few drops of TES.
The formation of thiaindenes 2 is likely to follow a previously
reported mechanism via formation of an alcohol, which is then
dehydrated under the acidic conditions.11 The thioflavonols 3a–c
are formally obtained by disproportionation of the starting mate-
rial under reductive conditions, followed by rearrangement.
Thioflavonol 3a co-crystallizes with hydrogen-bonded solvent
molecules from a solution in N,N-dimethylformamide (DMF). In
the crystal, molecules are arranged as hydrogen-bonded dimers,
similar to previously reported 3-hydroxyflavone derivatives, for
example, 20-methyl-3-hydroxyflavone.12 Molecules of 3a are
arranged in pairs, hydrogen-bonded via the C@O and C@C–OH
groups of thioflavonol ring C (Fig. 1).
The Swedish Research Council is gratefully acknowledged for
financial support.
Supplementary data
Synthetic details, experimental data for compounds 1–3 and
details of the X-ray crystallographic structure analysis for 3a.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.054.
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