Disila-analogues of the synthetic retinoids EC23 and TTNN: Synthesis, structure and biological evaluation

Article abstract of DOI:10.1039/c2ob25989c

Silicon chemistry offers the potential to tune the effects of biologically active organic molecules. Subtle changes in the molecular backbone caused by the exchange of a carbon atom for a silicon atom (sila-substitution) can significantly alter the biological properties. In this study, the biological effects of a two-fold sila-substitution in the synthetic retinoids EC23 (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid (4a)) and TTNN (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2- naphthoic acid (7a)) as well as their corresponding analogues with an indane instead of a 1,2,3,4-tetrahydronaphthalene skeleton (compounds 5a and 8a) were investigated. Two-fold C/Si exchange in 4a, 5a, 7a and 8a leads to the silicon-analogues disila-EC23 (4b), 5b, disila-TTNN (7b) and 8b, which contain a 1,2,3,4-tetrahydro-1,4-disilanaphthalene (4b, 7b) or 1,3-disilaindane skeleton (5b, 8b). Exchange of the SiCH₂Si moiety of 5b for an SiOSi fragment leads to the disiloxane 6 (2-oxa-1,3-disilaindane skeleton). The EC23 derivative 5a, the TTNN derivative 8a and the silicon-containing analogues 4b, 5b, 6, 7b and 8b were synthesised, and the biological properties of the C/Si pairs 4a/4b, 5a/5b, 7a/7b and 8a/8b and compound 6 were evaluated in vivo using RAR isotype-selective reporter cells. EC23 (4a) and its derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR agonists, which are even more potent than the powerful reference compound TTNPB. Disila-substitution of EC23 (4a) and 5a leads to a moderate decrease in RARα activation, whereas the RARβ,γ activation is almost not affected. In contrast, two-fold C/Si exchange in the weak retinoid agonist TTNN (7a) and 8a resulted in considerably different effects: a significant increase (7a → 7b) and almost no change (8a → 8b) in transcription activation potential for all three RAR isotypes. Disila-TTNN (7b) can be regarded as a powerful RARβ,γ-selective retinoid.

Full text of DOI:10.1039/c2ob25989c

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PAPER
Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis,
structure and biological evaluation†
Josef B. G. Gluyas,a Christian Burschka,a Steffen Dörrich,a Judith Vallet,b Hinrich Gronemeyerb and
Reinhold Tacke*a
Received 23rd March 2012, Accepted 21st June 2012
DOI: 10.1039/c2ob25989c
Silicon chemistry offers the potential to tune the effects of biologically active organic molecules. Subtle
changes in the molecular backbone caused by the exchange of a carbon atom for a silicon atom (sila-
substitution) can significantly alter the biological properties. In this study, the biological effects of a two-
fold sila-substitution in the synthetic retinoids EC23 (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-ylethynyl)benzoic acid (4a)) and TTNN (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-
naphthoic acid (7a)) as well as their corresponding analogues with an indane instead of a 1,2,3,4-
tetrahydronaphthalene skeleton (compounds 5a and 8a) were investigated. Two-fold C/Si exchange in 4a,
5a, 7a and 8a leads to the silicon-analogues disila-EC23 (4b), 5b, disila-TTNN (7b) and 8b, which
contain a 1,2,3,4-tetrahydro-1,4-disilanaphthalene (4b, 7b) or 1,3-disilaindane skeleton (5b, 8b).
Exchange of the SiCH2Si moiety of 5b for an SiOSi fragment leads to the disiloxane 6 (2-oxa-1,3-
disilaindane skeleton). The EC23 derivative 5a, the TTNN derivative 8a and the silicon-containing
analogues 4b, 5b, 6, 7b and 8b were synthesised, and the biological properties of the C/Si pairs 4a/4b,
5a/5b, 7a/7b and 8a/8b and compound 6 were evaluated in vivo using RAR isotype-selective reporter
cells. EC23 (4a) and its derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR agonists, which
are even more potent than the powerful reference compound TTNPB. Disila-substitution of EC23 (4a)
and 5a leads to a moderate decrease in RARα activation, whereas the RARβ,γ activation is almost not
affected. In contrast, two-fold C/Si exchange in the weak retinoid agonist TTNN (7a) and 8a resulted in
considerably different effects: a significant increase (7a → 7b) and almost no change (8a → 8b) in
transcription activation potential for all three RAR isotypes. Disila-TTNN (7b) can be regarded as a
powerful RARβ,γ-selective retinoid.
along with a few synthetic analogues (e.g. bexarotene) are cur-
Introduction
rently in clinical use for the treatment of proliferative skin dis-
eases and/or cancer.2
Retinoids are a group of compounds that are metabolites or syn-
thetic analogues of vitamin A (retinol). The term ‘retinoid’ was
coined by M. Sporn in the mid-1970s when he reported the first
systematic study of a set of vitamin A analogues.1 The naturally
occurring retinoids all-trans retinoic acid (1, ATRA), 9-cis reti-
noic acid (2, 9cRA) and 13-cis retinoic acid (3, 13cRA) (Fig. 1)
Generally, retinoids consist of a bulky hydrophobic group con-
nected to a polar group (usually a carboxylic acid) by a hydro-
phobic linker.3 The synthetic retinoids EC23 (4a),4 a close
mimic of ATRA (1), and TTNN5 (7a) display these typical struc-
tural features, with the 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-
naphthalene skeleton as the bulky hydrophobic group (Fig. 2
and 3). We have previously demonstrated that the carbon/silicon
switch strategy (C/Si exchange, sila-substitution) is a powerful
tool when applied to retinoids based on 1,2,3,4-tetrahydro-
naphthalene or indane skeletons. Sila-substitution has resulted in
an up to ten-fold increase in activity and, in some cases, to
changes of the retinoid receptor subtype selectivity.6 In continu-
ation of these studies, we have now succeeded in synthesising
disila-EC23 (4b), disila-TTNN (7b) and the structurally related
compounds 5a, 5b, 6, 8a and 8b (Fig. 2 and 3). We report here
on the syntheses of 4b, 5a, 5b, 6, 7b, 8a and 8b along with the
aUniversität Würzburg, Institut für Anorganische Chemie, Am Hubland
D-97074 Würzburg, Germany. E-mail: r.tacke@uni-wuerzburg.de;
Fax: +49-931-31-84609; Tel: +49-931-31-85250
bDepartment of Cancer Biology, Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC) CNRS/INSERM/ULP, BP 10142,
F-67404 Illkirch Cedex, C.U. de Strasbourg, France
†Electronic supplementary information (ESI) available: Crystallographic
1
data for compounds 5a, 5b, 8b, 15, 17, 28, 29, 33 and 34 and H, 13C,
15N and 29Si NMR spectra of all new compounds synthesised. CCDC
837993, 837994, 872960, 837995, 837996, 837997, 837998, 837999
and 838000. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25989c
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Fig. 1 Structures of the naturally occurring retinoids all-trans retinoic
acid (1, ATRA), 9-cis retinoic acid (2, 9cRA) and 13-cis retinoic acid
(3, 13cRA).
Fig. 3 Structures of the synthetic retinoid TTNN (7a) and the novel
analogues disila-TTNN (7b), 8a and 8b.
Results and discussion
Retinoid syntheses8
The retinoids 4b, 5a, 5b and 6 were synthesised according to
Schemes 1 and 2. A palladium-catalysed Sonogashira cross
coupling9 of an appropriate aryl iodide (9–12) with methyl
4-ethynylbenzoate (13) gave the protected intermediates 14–17
(yields: 14, 82%; 15, 95%; 16, 97%; 17, 96%). The methyl
esters of 14–16 were then deprotected using potassium hydrox-
ide in methanol–water, followed by acidification with hydro-
chloric acid, to afford the target compounds (yields: 4b, 76%;
5a, 90%; 5b, 95%). Unfortunately, these conditions proved to be
incompatible with the siloxane backbone of compound 17 and
we were unable to obtain a pure sample of 6 using this method-
ology. Omission of the methyl ester protecting group allowed the
direct synthesis of compound 6 in 67% yield by cross coupling
of 4-ethynylbenzoic acid (18) with the aryl iodide 12
(Scheme 2).
The retinoids 7b, 8a and 8b were synthesised according to
Scheme 3. A palladium-catalysed Suzuki–Miyaura cross coup-
ling10 of an appropriate aryl iodide (9–11) with the boronic ester
19, using (1,1′-bis(diphenylphosphino)ferrocene)palladium(II)
dichloride {[Pd(dppf)Cl2]} as the catalyst, gave the protected
intermediates 20–22 (yields: 20, 47%; 21, 62%; 22, 43%). The
methyl esters 20–22 were then deprotected using potassium
hydroxide in methanol–water, followed by acidification with
hydrochloric acid, to afford the target compounds (yields: 7b,
67%; 8a, 72%; 8b, 96%).
Fig. 2 Structures of the synthetic retinoid EC23 (4a) and the novel
analogues disila-EC23 (4b), 5a, 5b and 6.
biological evaluation of 4a, 4b, 5a, 5b, 6, 7a, 7b, 8a and 8b.
These investigations were performed with special emphasis on
the comparison of (i) the C/Si analogues 4a/4b, 5a/5b, 7a/7b
and 8a/8b (effect of two-fold sila-substitution) and (ii) the CH2/
O analogues 5b/6 (effect of replacement of the SiCH2Si frag-
ment with the more polar SiOSi moiety). This study is part of
our ongoing investigations into sila-substituted drugs.6,7
Aryl iodide syntheses
The synthetic challenge in this project was the preparation of the
silicon-containing aryl iodides 9, 11 and 12. As aryl iodides are
increasingly important synthetic intermediates, highlighted by
the recent award of the Nobel Prize in Chemistry for palladium-
catalysed cross-coupling reactions in which aryl iodides are
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Scheme 2 Synthesis of compounds 6 and 17 via Sonogashira cross
coupling.
desired halogenoarenes in a [2 + 2 + 2] cyclisation are very
oxygen-sensitive and tend to decompose, burn or even explode
when exposed to the air.14 A safe in situ preparation of
iodoethyne for use in a [2 + 3] cyclisation has been reported.15
However, we doubted that this procedure would be compatible
with the temperatures and reagent concentrations sometimes
achieved or required in the exothermic [2 + 2 + 2] trimerisation
reaction. So we considered the potential starting materials that
would allow the synthesis of the target aryl iodides 9, 11 and 12.
Two possible routes were proposed (Scheme 4).
Initially method A (Scheme 4) seemed the most attractive,
using trimethylsilylethyne (26) in a cobalt(II)-catalysed [2 + 2 + 2]
cycloaddition with the dialkynes 23–25 to produce the trimethyl-
silyl-substituted compounds 27–29. The intention here was to
utilise iodine monochloride to perform a selective electrophilic
aromatic substitution, by analogy with the work of Vollhardt,16
to produce the desired aryl iodides in a two-step synthesis
(Scheme 5).
Compounds 27 and 28 were synthesised by a [2 + 2 + 2]
cycloaddition catalysed by cobalt(II) bromide and zinc in aceto-
nitrile,17 whereas a system comprising cobalt(II) iodide and zinc
in acetonitrile11 was used in the synthesis of 29 (yields: 27,
34%; 28, 9%; 29, 63%). These reactions provided an interesting
comparison of the two catalytic systems: cobalt(II) iodide proved
to be much more effective than cobalt(II) bromide in the syn-
thesis of compound 29, as the reaction was comparatively selec-
tive for the desired product, with little trimerisation of 26
observed. However, in the case of 27 and 28, the selectivity of
the reaction was not noticeably altered by the use of cobalt(II)
bromide in place of cobalt(II) iodide, although the use of cobalt(II)
bromide resulted in a very slight increase in isolated yield.
An additional benefit of the cobalt(II) bromide system is the stab-
ility of the catalyst solution. Cobalt(II) iodide in acetonitrile
Scheme 1 Synthesis of compounds 4b, 5a and 5b via Sonogashira
cross coupling.
usually the preferred electrophilic coupling partner, there are a
wide variety of methods available for their synthesis. However,
the production of the desired silicon-containing bicyclic aryl
iodides 9, 11 and 12 was constrained by the necessity of utilising
a [2 + 2 + 2] alkyne trimerisation as the key step in the construc-
tion of the bicyclic ring system. This constraint arises from the
required starting materials. Silicon-containing dialkynes, such as
23–25, have been extensively used as reagents in cyclotrimerisa-
tion reactions by our group.6,11,12 On the other hand, not all
monoalkynes are good partners for the [2 + 2 + 2] cycloaddition
reaction. Thus, it is not always possible to build the required
functionality into the monoalkyne precursor. For example, while
halogenoalkynes have been reported and used successfully in
cyclotrimerisation reactions,13 these syntheses utilise a disubsti-
tuted alkyne. The parent compounds of the formula HCuCX
(X = Cl, Br, I) that would be required to directly produce the
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tetrachloromethane at 0 °C allowed the preparation of aryl iodide
12 in 34% yield. The difference in the reactivity towards “I+”
observed for 29 compared with that of compounds 27 and 28 is
likely to be due to the presence of the electron-withdrawing
oxygen atom in the bicyclic ring system. The change in elec-
tronic character of the backbone caused by exchange of an
SiCH2Si or Si(CH2)2Si moiety for an SiOSi fragment seems to
cause the ring silicon atoms to be less susceptible to electrophilic
substitution.
As an alternative methodology for the synthesis of the aryl
iodides was necessary, we turned towards more traditional iodi-
nation chemistry (method B, Scheme 4). A Sandmeyer19 iodina-
tion of the amines 30–32 would allow the synthesis of the target
aryl iodides. Compound 30 has been previously synthesised by
our group,6d though the six-step synthesis with 12% overall
yield (relative to 23) was less than ideal. However, recent
studies17 suggested that it would be possible to produce the
carboxylic acids 33–35 by a [2 + 2 + 2] cycloaddition of the
commercially available monoalkyne 36 with the dialkynes
23–25, followed by an in situ deprotection and subsequent oxi-
dation. A modified one-pot20 Curtius rearrangement21 would
then allow the direct synthesis of the amines 30–32 (Scheme 4).
The aryl iodides 9 and 11 were produced according to
Scheme 6 in a three-step synthesis. A [2 + 2 + 2] cycloaddition
of 3,3-diethoxypropyne (36) and an appropriate dialkyne (23,
24) with a catalytic system comprising cobalt(II) bromide and
zinc in acetonitrile,17 acidification of the reaction mixture with
hydrochloric acid and a Jones oxidation22 of the crude aldehyde
intermediate with potassium dichromate yielded the carboxylic
acids 33 and 34 (yields: 33, 19%; 34, 37%). Treatment of 33 and
34 with diphenoxyphosphoryl azide (DPPA)20,23 and triethyl-
amine in toluene, followed by addition of sodium trimethylsila-
nolate solution,24 afforded the amines 30 and 31 (yields: 30,
46%; 31, 63%). Compounds 30 and 31 were then reacted with
isoamylnitrite in diiodomethane,25 in a modified Sandmeyer19
reaction, to give the aryl iodides 9 and 11 (yields: 9, 33%; 11,
30%). As the aryl iodide 12 was available using the previously
discussed electrophilic aromatic substitution route, we did not
pursue its synthesis via the Sandmeyer iodination method.
The carbon compound 5-iodo-1,1,3,3-tetramethylindane (10)
could be synthesised by conventional aromatic iodination.26
Treatment of 1,1,3,3-tetramethylindane (37) with orthoperiodic
acid, iodine, sulphuric acid, glacial acetic acid and water afforded
10 in 64% yield (Scheme 7).
Scheme 3 Synthesis of the retinoids 7b, 8a and 8b via Suzuki–
Miyaura cross coupling.
decays to produce elemental iodine, whereas the corresponding
bromide does not decompose.18 This stability allows the pre-
paration of stock catalyst solutions of cobalt(II) bromide that can
be stored and used more conveniently. The very low yield of 28
is due to the difficulty of separating the product from the side
product tris(trimethylsilyl)benzene formed by the trimerisation
of 26. Fortuitously, it was possible to separate compound 27
from this by-product by crystallisation from absolute ethanol,
resulting in a higher yield. Unfortunately, as can be seen from
Scheme 5, a selective substitution of the trimethylsilyl group of
compound 27 or 28 with an iodine atom was not possible. Treat-
ment of these compounds with iodine monochloride resulted in a
complex mixture, the major component of which could be ident-
ified as triiodobenzene by GC-MS analysis. In contrast, reaction
of compound 29 with a slight excess of iodine monochloride in
The set of novel compounds reported herein were character-
1
ised by H, 13C, 15N and 29Si NMR spectroscopy, mass spec-
trometry, and elemental analyses or high-resolution mass
spectrometry.8 In addition, compounds 5a, 5b, 8b, 15, 17, 28,
29, 33 and 34 were structurally characterised by single-crystal
X-ray diffraction.
Crystal structure analyses
Compounds 5a, 5b, 8b, 15, 17, 28, 29, 33 and 34 were structu-
rally characterised by single-crystal X-ray diffraction. The mol-
ecular structures of 5a, 8b, 17 and 33 are shown in Fig. 4–7.
Selected bond lengths, bond angles and torsion angles are com-
piled in the respective figure legends. These data give some
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Scheme 4 Proposed routes to the silicon-containing aryl iodides 9, 11 and 12.
Scheme 6 Synthesis of the silicon-containing aryl iodides 9 and 11 via
a Sandmeyer iodination of the corresponding aryl amines.
Scheme 5 Attempted synthesis of the silicon-containing aryl iodides
9, 11 and 12 via selective electrophilic aromatic substitution.
Scheme 7 Synthesis of compound 10.
For full details of the crystal structure analyses for all com-
pounds studied, see the ESI.†
information about the structural features of the four differ-
ent bicyclic ring systems synthesised in this study, the indane
(5a), 1,3-disilaindane (8b), 2-oxa-1,3-disilaindane (17) and
1,2,3,4-tetrahydro-1,4-disilanaphthalene (33) skeletons. The ring
systems of compounds 5b, 15, 28, 29 and 34 do not differ sig-
nificantly from the corresponding systems observed for 5a, 8b,
17 and 33. Thus, these structures will not be discussed further.
Biological studies
In order to compare the in vivo transcription activation capacities
of EC23 (4a) and TTNN (7a) and their derivatives disila-EC23
(4b), 5a, 5b, 6, disila-TTNN (7b), 8a and 8b, we used a cellular
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Fig. 4 Molecular structure of 5a in the crystal. Selected bond lengths
[Å], bond angles [°] and torsion angles [°]: C1–C2 1.560(3), C2–C3
1.545(3), C1–C5 1.522(2), C3–C4 1.521(2), C4–C5 1.388(2); C1–C2–
C3 107.85(16), C1–C5–C4 111.48(15), C3–C4–C5 111.69(14), C2–C1–
C5 101.66(14), C2–C3–C4 101.42(15); C4–C5–C1–C2 10.9(2), C5–
C1–C2–C3 −21.9(2), C1–C2–C3–C4 24.2(2), C2–C3–C4–C5
−17.78(19), C3–C4–C5–C1 4.40(19).
Fig. 6 Molecular structure of one of the three crystallographically
independent molecules of 17 in the crystal. Selected bond lengths [Å],
bond angles [°] and torsion angles [°]: Si1–O1 1.656(2), Si2–O1 1.653(3),
Si1–C2 1.878(3), Si2–C1 1.887(3), C1–C2 1.421(4); Si1–O1–Si2
118.36(15), Si1–C2–C1 112.6(2), Si2–C1–C2 111.7(2), O1–Si1–C2
98.48(14), O1–Si2–C1 98.66(13); C1–C2–Si1–O1 1.2(3), C2–Si1–O1–
Si2 −3.7(2), Si1–O1–Si2–C1 4.4(2), O1–Si2–C1–C2 −3.3(3), Si2–C1–
C2–Si1 1.3(3).
Fig. 7 Molecular structure of 33 in the crystal. Selected bond lengths
[Å], bond angles [°] and torsion angles [°]: Si1–C1 1.8731(17), Si1–C4
1.8937(15), Si2–C2 1.8754(17), Si2–C3 1.8880(15), C1–C2 1.546(2),
C3–C4 1.415(2); Si1–C1–C2 112.23(11), Si1–C4–C3 123.13(11), Si2–
C2–C1 111.82(11), Si2–C3–C4 123.93(11), C1–Si1–C4 108.67(7), C2–
Si2–C3 108.49(7); Si1–C1–C2–Si2 −65.99(15), Si1–C4–C3–Si2
5.09(19), C1–Si1–C4–C3 −16.84(15), C1–C2–Si2–C3 49.13(14),
C2–C1–Si1–C4 48.72(13), C2–Si2–C3–C4 −17.55(15).
Fig. 5 Molecular structure of 8b in the crystal. Selected bond lengths
[Å], bond angles [°] and torsion angles [°]: Si1–C1 1.880(2), Si2–C1
1.880(3), Si1–C3 1.891(2), Si2–C2 1.891(2), C2–C3 1.412(3); Si1–C1–
Si2 107.20(11), Si1–C3–C2 114.93(14), Si2–C2–C3 115.44(15), C1–
Si1–C3 100.95(10), C1–Si2–C2 100.51(10); C2–C3–Si1–C1 1.09(19),
C3–Si1–C1–Si2 −6.91(17), Si1–C1–Si2–C2 9.25(17), C1–Si2–C2–C3
−9.5(2), Si2–C2–C3–Si1 5.5(2).
apparent. Secondly, replacement of the CCH2CH2C moiety of
EC23 with a CCH2C fragment (4a → 5a) results in only a mo-
derate decrease in transactivation potential, which is most pro-
nounced for RARα. Thirdly, similarly to the disila-substitution
of EC23 (4a → 4b), two-fold C/Si exchange in 5a (→ 5b)
results in a minor loss of RARα activity, with almost no change
in RARβ,γ activation. Introduction of the more polar SiOSi frag-
ment in place of the SiCH2Si moiety of 5b (→ 6) leads to a
decrease in RARα,β,γ activation at low concentrations, whereas
at higher concentrations similar transcription activation capacities
of 5b and 6 were observed. In conclusion, EC23 (4a) and its
derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR
agonists, which are even more potent than the powerful reference
compound TTNPB. Similarly to the disila-substitution of several
structurally related retinoids (such as bexarotene, TTNPB,
SR11237, AM80 (tamibarotene) and AM580),6 only moderate
reporter system that has been described previously.6d,27 Briefly,
two chimeric constructs, comprising a chimeric receptor com-
posed of the RAR ligand-binding domain (GAL4-RARα,β,γ)
and a luciferase-based reporter gene (‘17mer-G-Luc’) driven by
the GAL4 response element (‘17mer’) in front of the minimal
β-globin (‘G’) promoter, have been stably introduced into HeLa
cells. For comparison, we used the powerful synthetic pan-RAR
agonist TTNPB. Dose–response curves were established with the
three reporter cell lines for the different test compounds using
luciferase activity as read-out (Fig. 8 and 9).
The dose–response profiles of the test compounds given in
Fig. 8 revealed some important differences. Firstly, the two-fold
sila-substitution of EC23 (4a → 4b) results in a minor loss of
RARα activity, whereas in the case of the two other RAR iso-
types no significant differences in the activities of 4a and 4b are
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Fig. 9 Dose–response curves of the indicated ligands (TTNPB, 7a, 7b,
8a, 8b) with RARα (upper), RARβ (middle) and RARγ (lower) reporter
cells. Cells were exposed to the various ligands and the transcription
activation through the RAR isotypes was monitored as induced lucifer-
ase activity. The data are derived from at least three independent exper-
iments, with duplicates in each of the experiments; the standard
deviations (S.E.M.) are indicated.
Fig. 8 Dose–response curves of the indicated ligands (TTNPB, 4a, 4b,
5a, 5b, 6) with RARα (upper), RARβ (middle) and RARγ (lower) repor-
ter cells. Cells were exposed to the various ligands and the transcription
activation through the RAR isotypes was monitored as induced lucifer-
ase activity. The data are derived from at least three independent exper-
iments, with duplicates in each of the experiments; the standard
deviations (S.E.M.) are indicated.
tetrahydronaphthalene backbone of TTNN (7a) and the indane
and 1,3-disilaindane skeletons of 8a and 8b, respectively, are
unfavourable for RAR binding and/or co-activator interaction;
this effect is apparently relieved by disila-substitution of TTNN
(7a → 7b). This generates a retinoid that, while somewhat less
active than TTNPB, has considerable RARβ,γ activity above
10 nM; significant RARα activation requires approximately a
ten-fold higher concentration of 7b. The C/Si analogues 8a
(indane skeleton) and 8b (1,3-disilaindane skeleton) display very
similar activities. Like the parent compound 7a neither 8a nor
8b shows significant RARα activity; both display RARβ,γ selec-
tivity but require an approximately 10-fold higher ligand
biological effects have been observed for this series of
compounds.
The most important message that can be extracted from the
comparison of the dose–response profiles given in Fig. 9 is that
disila-substitution of the weak retinoid agonist TTNN (7a → 7b)
results in a significant gain in transcription activation potential
for all three RAR isotypes (increase in potency by factors of ca.
3 (RARβ) or 10 (RARγ)). However, replacement of the
CCH2CH2C moiety of TTNN with a CCH2C fragment (7a →
8a) significantly decreases the activity, and two-fold C/Si
exchange in 8a (→8b) does not lead to a gain in activity.
Together these results suggest that the lipophilic 1,2,3,4-
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concentration than TTNN (7a). In summary, two-fold sila-substi-
tution of 7a (1,2,3,4-tetrahydronaphthalene skeleton) and 8a
(indane skeleton) leads to considerably different effects: a sig-
nificant increase (7a → 7b) and almost no change (8a → 8b) in
transcription activation potential for all three RAR isotypes.
Disila-TTNN (7b) can be regarded as a powerful RARβ,γ-selec-
tive retinoid.
Further investigations, including the structural characterisation
of the receptor–ligand binding interactions, are necessary to fully
interpret the structure–activity relationships observed in this
study. The subtle structural alterations (C/Si and SiCH2Si/SiOSi
exchange) in the retinoids discussed herein, and those investi-
gated in earlier studies,6 can result in measurable biological
effects (both decrease and increase in activity) emphasising that
silicon chemistry can be used as a powerful tool for drug design
and development.
ESI-HRMS spectra were recorded on a Bruker MicrOTOF
instrument using solutions in trichloromethane–acetonitrile (1 : 1
(v/v)) and EI-HRMS spectra were recorded on a Finnigan
MAT90 instrument. Elemental analyses were carried out using a
VarioMicro apparatus (Elementar Analysensysteme GmbH) or a
EURO EA Elemental Analyzer (EuroVector).
4-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)-
benzoic acid (4a, EC23). This compound was generously
donated by Reinnervate Ltd (for synthesis see ref. 4b).
4-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-1,4-disilanaphthalen-
6-ylethynyl)benzoic acid (4b, disila-EC23). A mixture of 14
(144 mg, 380 μmol), potassium hydroxide (213 mg, 3.80 mmol)
and methanol–water (3 : 1 (v/v), 8 mL) was heated under reflux
for 6 h. Hydrochloric acid (4 M, 10 mL) was then added to the
reaction mixture, followed by ethyl acetate (60 mL). Separation
of the organic layer, drying over sodium sulphate, filtration and
concentration under reduced pressure gave a white powder,
which was crystallised from acetonitrile (cooling of a boiling
solution to 20 °C) to afford 4b in 76% yield (105 mg, 288 μmol)
as a colourless crystalline solid. 1H NMR (500.1 MHz, CD2Cl2):
δ = 0.24 (s, 6 H, Si(CH3)2), 0.26 (s, 6 H, Si(CH3)2), 1.04 (s,
Experimental
Syntheses: general remarks8
All reactions were carried out under dry argon, unless otherwise
stated. Reaction workup was carried out in air with no specific
precautions against oxygen or moisture. Acetonitrile, triethyl-
amine, N,N-dimethylformamide and toluene were dried and dis-
tilled according to standard procedures and stored under dry
nitrogen. All of the other solvents were distilled prior to use or
purchased with analytical purity. Column chromatography was
carried out using silica gel (40–63 μm; Merck). Silica gel masses
for chromatography were determined according to ref. 28.
Reversed phase medium pressure chromatography (RP-MPLC)
was performed as follows: pressure, 16 bar; column, 50 ×
2.5 cm; RP-18 silica gel, YMC ODS-A, 15 μm; detector, Knauer
Variable Wavelength Monitor. Bulb-to-bulb distillations were
accomplished using a Büchi GKR-50 or a Büchi B-580 Glass
Oven apparatus. Melting points were determined with a Büchi
Melting Point B-540 apparatus using samples in open glass
capillaries or by differential scanning calorimetry using a Mettler
Toledo DSC 823 apparatus. 1H, 13C, 15N and 29Si NMR
spectra29 were recorded at 23 °C on a Bruker Avance 500
(1H, 500.1 MHz; 13C, 125.8 MHz; 29Si, 99.4 MHz), a Bruker
Avance 400 (1H, 400.1 MHz; 13C, 100.6 MHz; 15N, 40.6 MHz;
29Si, 79.5 MHz) or a Bruker DRX-300 NMR spectrometer (1H,
300.1 MHz; 13C, 75.5 MHz; 15N, 30.4 MHz; 29Si, 59.6 MHz)
using CDCl3, CD2Cl2 or [d6]DMSO as the solvent. Chemical
shifts (ppm) were determined relative to internal CHCl3 (1H, δ =
7.24 ppm; CDCl3), internal CHDCl2 (1H, δ = 5.32 ppm;
CD2Cl2), internal [d5]DMSO (1H, δ = 2.49 ppm; [d6]DMSO),
internal CDCl3 (13C, δ = 77.0 ppm; CDCl3), internal CD2Cl2
(13C, δ = 53.8 ppm; CD2Cl2), internal [d6]DMSO (13C, δ =
39.5 ppm; [d6]DMSO), external H2NC(O)H (90% in [d6]-
DMSO) (15N, δ = −268.0 ppm; [d6]DMSO) or external TMS
(29Si, δ = 0 ppm; CDCl3, CD2Cl2 [d6]DMSO). Assignment of
the 1H and 13C NMR data was supported by 1H,1H gradient
selected COSY along with gradient selected 13C,1H HMQC and
HMBC experiments. All 15N NMR spectra were obtained using
inverse correlation 15N,1H HMQC or HMBC experiments.
EI-MS spectra were recorded on either a Thermo Trio 1000 or a
Varian 320-MS SQ mass spectrometer operating at 70 eV.
3
4
4 H, SiCH2C), 7.50 (dd, 1 H, J = 7.5 Hz, J = 1.5 Hz, H–7,
THN), 7.52 (dd, 1 H, 3J = 7.5 Hz, 5J = 1.0 Hz, H-8, THN), 7.66
(m, 2 H, H-3/H-5, Benz), 7.68 (m, 1 H, H-5, THN), 8.10 ppm
(m, 2 H, H-2/H-6, Benz), COOH not observed. 13C NMR
(125.8 MHz, CD2Cl2): δ = −1.64 (Si(CH3)2), −1.59 (Si(CH3)2),
7.59 (SiCH2C), 7.62 (SiCH2C), 89.1 (THN–CuC), 93.6 (THN–
CuC), 122.4 (C-6, THN), 128.8 (C-1, Benz), 129.3 (C-4,
Benz), 130.5 (C-2/C-6, Benz), 131.0 (C-7, THN), 132.0 (C-3/
C-5, Benz), 133.7 (C-8, THN), 136.6 (C-5, THN), 146.7 (C-4a
or C-8a, THN), 147.6 (C-4a or C-8a, THN), 170.7 ppm
(COOH). 29Si NMR (99.4 MHz, CD2Cl2): δ = −6.6, −6.5 ppm.
EI-MS: m/z (%) 364 (30) [M+], 349 (29) [M+ − CH3], 73 (100).
ESI-HRMS: m/z 363.12398 (found); calcd for C21H23O2Si2
[M − H]−: 363.12421.
4-(1,1,3,3-Tetramethylindan-5-ylethynyl)benzoic acid (5a). A
mixture of 15 (264 mg, 794 μmol), potassium hydroxide
(446 mg, 7.95 mmol) and methanol–water (3 : 1 (v/v), 20 mL)
was heated under reflux for 2 h. The reaction mixture was then
concentrated under reduced pressure to approximately one
quarter of the original volume and ethyl acetate (30 mL) was
added. Separation of the organic phase, washing with hydro-
chloric acid (1 M, 30 mL), drying over sodium sulphate, fil-
tration and concentration under reduced pressure gave a white
powder. The product was dissolved in diethyl ether–acetonitrile
(1 : 1 (v/v), 30 mL) and the solvents were allowed to slowly
evaporate until approximately 5 mL of liquid remained. The
remaining solvent was removed by decantation, and the crystals
were dried under reduced pressure (20 °C, 0.01 mbar) to afford
5a in 90% yield (228 mg, 716 μmol) as a colourless crystalline
solid. 1H NMR (500.1 MHz, [d6]DMSO): δ = 1.26 (s, 6 H,
C(CH3)2), 1.28 (s, 6 H, C(CH3)2), 1.88 (s, 2 H, CCH2C),
7.22 (d, 1 H, 3J = 8.5 Hz, H-7, Ind), 7.39–7.40 (m, 2 H, H-4 and
H-6, Ind), 7.63 (m, 2 H, H-3/H-5, Benz), 7.95 (m, 2 H, H-2/H-6,
Benz), 13.12 ppm (br. s, 1 H, COOH). 13C NMR (125.8 MHz,
[d6]DMSO): δ = 31.0 (C(CH3)2), 31.1 (C(CH3)2), 42.2 (C-1
or C-3, Ind), 42.4 (C-1 or C-3, Ind), 55.9 (CCH2C), 87.7
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(Ind–CuC), 92.8 (Ind–CuC), 120.1 (C-5, Ind), 123.0 (C-7,
Ind), 125.8 (C-4, Ind), 126.9 (C-4, Benz), 129.5 (C-2/C-6,
Benz), 130.3 (C-1, Benz), 130.4 (C-6, Ind), 131.4 (C-3/C-5,
Benz), 151.4 (C-3a, Ind), 152.3 (C-7a, Ind), 166.7 ppm
(COOH). EI-MS: m/z (%) 318 (44) [M+], 303 (100)
[M+ − CH3]. ESI-HRMS: m/z 317.15484 (found); calcd for
C22H21O2 [M − H]−: 317.15470.
(Si(CH3)2), 89.2 (Ind′′–CuC), 92.3 (Ind′′–CuC), 122.4 (C-5,
Ind′′), 126.5 (C-4, Benz), 129.6 (C-1 and C-2/C-6, Benz), 131.3
(C-7, Ind′′), 131.5 (C-3/C-5, Benz), 131.7 (C-6, Ind′′), 134.0
(C-4, Ind′′), 148.3 (C-3a, Ind′′), 148.8 (C-7a, Ind′′), 166.7 ppm
(COOH). 29Si NMR (99.4 MHz, [d6]DMSO): δ = 14.90,
14.93 ppm. EI-MS: m/z (%) 352 (40) [M+], 337 (100) [M+
−
CH3]. ESI-HRMS: m/z 351.08791 (found); calcd for
C19H19O3Si2 [M − H]−: 351.08782.
4-(1,1,3,3-Tetramethyl-1,3-disilaindan-5-ylethynyl)benzoic acid
(5b). A mixture of 16 (82.0 mg, 224 μmol), potassium hydrox-
ide (126 mg, 2.25 mmol) and methanol–water (3 : 1 (v/v), 5 mL)
was heated under reflux for 2 h. Subsequently, ethyl acetate
(20 mL) and hydrochloric acid (4 M, 10 mL) were added. Sepa-
ration of the organic phase, drying over sodium sulphate, fil-
tration and concentration under reduced pressure gave a white
powder. The product was crystallised from acetonitrile (cooling
of a boiling solution to 20 °C) to afford 5b in 96% yield
6-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-
naphthoic acid (TTNN, 7a). This compound was kindly pro-
vided by Prof. Todd Marder (Universität Würzburg, Germany);
for synthesis see ref. 5a.
6-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-1,4-disilanaphtha-
len-6-yl)-2-naphthoic acid (disila-TTNN, 7b). A mixture of 20
(172 mg, 425 μmol), potassium hydroxide (238 mg, 4.24 mmol)
and methanol–water (3 : 1 (v/v), 8.5 mL) was heated under
reflux for 1 h. Hydrochloric acid (4 M, 10 mL) was then added
to the reaction mixture, followed by dichloromethane (25 mL).
The organic layer was separated, dried over magnesium sulphate,
filtered and allowed to slowly evaporate (20 °C) to give pale
yellow crystals. These were washed with acetone (2 mL) and
dried under reduced pressure (20 °C, 0.03 mbar) to afford 7b in
67% yield (111 mg, 284 μmol) as a colourless crystalline solid.
1H NMR (500.1 MHz, [d6]DMSO): δ = 0.24 (s, 6 H, Si(CH3)2),
1
(75.0 mg, 214 μmol) as a colourless crystalline solid. H NMR
(500.1 MHz, [d6]DMSO): δ = −0.02 (s, 2 H, SiCH2Si), 0.27 (s,
3
6 H, Si(CH3)2), 0.29 (s, 6 H, Si(CH3)2), 7.54 (dd, 1 H, J =
4
7.5 Hz, J = 1.5 Hz, H-6, Ind′), 7.63–7.67 (m, 3 H, H-7 (Ind′)
and H-3/H-5 (Benz)), 7.78 (m, 1 H, H-4, Ind′), 7.96 (m,
2 H H-2/H-6, Benz), 13.14 ppm (br. s, 1 H, COOH). 13C NMR
(125.8 MHz, [d6]DMSO): δ = −2.9 (SiCH2Si), 0.36 (Si(CH3)2),
0.37 (Si(CH3)2), 89.0 (Ind′–CuC), 92.5 (Ind′–CuC), 122.0
(C-5, Ind′), 126.6 (C-4, Benz), 129.6 (C-2/C-6, Benz), 130.5
(C-1, Benz), 131.2 (C-6, Ind′), 131.5 (C-3/C-5, Benz), 131.9
(C-7, Ind′), 134.5 (C-4, Ind′), 150.5 (C-3a, Ind′), 151.4 (C-7a,
Ind′), 166.7 ppm (COOH). 29Si NMR (99.4 MHz, [d6]DMSO):
δ = 9.2, 9.4 ppm. EI-MS: m/z (%) 350 (42) [M+], 335 (100)
[M+ − CH3]. ESI-HRMS: m/z 349.10841 (found); calcd for
C20H21O2Si2 [M − H]−: 349.10856.
3
0.28 (s, 6 H, Si(CH3)2), 1.00 (s, 4 H, SiCH2C), 7.64 (d, 1 H, J
3
4
= 7.5 Hz, H-8, THN), 7.77 (dd, 1 H, J = 7.5 Hz, J = 2.0 Hz,
H-7, THN), 7.90 (m, 1 H, H-5, THN), 7.92 (m, 1 H, H-7,
Naph), 8.00 (m, 1 H, H-3, Naph), 8.09 (m, 1 H, H-4, Naph),
8.20 (m, 1 H, H-8, Naph), 8.29 (m, 1 H, H-5, Naph), 8.62 (m,
1 H, H-1, Naph), 13.08 ppm (s, 1 H, COOH). 13C NMR
(125.8 MHz, [d6]DMSO): δ = −1.53 (Si(CH3)2), −1.51 (Si
(CH3)2), 7.0 (SiCH2C), 7.1 (SiCH2C), 125.1 (C-5, Naph), 125.6
(C-3, Naph), 126.1 (C-7, Naph), 127.0 (C-7, THN), 128.0 (C-2,
Naph), 128.6 (C-4, Naph), 130.0 (C-8, Naph), 130.3 (C-1,
Naph), 131.4 (C-8a, Naph), 131.8 (C-5, THN), 134.1 (C-8,
THN), 135.3 (C-4a, Naph), 139.2 (C-6, THN), 140.0 (C-6,
Naph), 144.7 (C-8a, THN), 146.1 (C-4a, THN), 167.4 ppm
(COOH). 29Si NMR (99.4 MHz, [d6]DMSO): δ = −6.9,
−6.6 ppm. EI-MS: m/z (%) 390 (64) [M+], 375 (72)
[M+ − CH3], 73 (100). ESI-HRMS: m/z 391.15431 (found);
calcd for C23H27O2Si2 [M + H]+: 391.15441.
4-(1,1,3,3-Tetramethyl-2-oxa-1,3-disilaindan-5-ylethynyl)benzoic
acid (6). Compound 18 (72.0 mg, 493 μmol), 12 (150 mg,
30
449 μmol), Pd(PPh3)2Cl2 (3.15 mg, 4.49 μmol) and copper(I)
iodide (855 μg, 4.49 μmol) were dissolved in triethylamine
(10 mL) at 20 °C. The reaction mixture was stirred at this temp-
erature for 2 d, whereupon GC analysis indicated complete con-
sumption of the starting materials. The solvent was then
removed under reduced pressure and the residue was dissolved
in a mixture of tetrahydrofuran (20 mL) and water (10 mL).
Acetic acid was added to this mixture until it reached pH 6 (pH
paper test), followed by addition of dichloromethane (20 mL)
and water (20 mL). The aqueous layer was separated, washed
with dichloromethane (2 × 20 mL) and discarded. Drying of the
combined organic extracts over magnesium sulphate, filtration
and concentration under reduced pressure gave a brown solid.
Purification of the crude product by flash column chromato-
graphy (eluent, dichloromethane–methanol (99 : 1 (v/v))), fol-
lowed by crystallisation from tetrahydrofuran–acetonitrile (1 : 2
(v/v), slow evaporation of the solvents at 20 °C) afforded 6 in
67% yield (106 mg, 301 μmol) as a colourless crystalline solid.
1H NMR (500.1 MHz, [d6]DMSO): δ = 0.32 (s, 6 H, Si(CH3)2),
0.33 (s, 6 H, Si(CH3)2), 7.60 (dd, 1 H, 3J = 7.5 Hz, 4J = 2.0 Hz,
6-(1,1,3,3-Tetramethylindan-5-yl)-2-naphthoic acid (8a). A
mixture of 21 (122 mg, 340 μmol), potassium hydroxide
(191 mg, 3.40 mmol) and methanol–water (3 : 1 (v/v), 17 mL)
was heated under reflux for 7 h. Hydrochloric acid (4 M, 10 mL)
was then added to the reaction mixture, followed by ethyl acetate
(60 mL). The organic layer was separated, dried over magnesium
sulphate, filtered and concentrated under reduced pressure to
yield a fine, white powder. This product was dissolved in
dichloromethane (15 mL) and the solvents were allowed to
slowly evaporate (20 °C) until approximately 3 mL of liquid
remained. The remaining solvent was decanted to afford 8a in
72% yield (84.0 mg, 244 μmol) as a colourless crystalline solid.
1H NMR (500.1 MHz, [d6]DMSO): δ = 1.31 (s, 6 H, C(CH3)2),
1.35 (s, 6 H, C(CH3)2), 1.93 (s, 2 H, CCH2C), 7.29 (d, 1 H, 3J =
7.5 Hz, H-7, Ind), 7.61–7.65 (m, 2 H, H-4 and H-6, Ind), 7.92
(m, 1 H, H-7, Naph), 7.98 (m, 1 H, H-3, Naph), 8.06 (m, 1 H,
3
H-6, Ind′′), 7.66 (m, 2 H, H-3/H-5, Benz), 7.72 (dd, 1 H, J =
5
7.5 Hz, J = 1.0 Hz, H-7, Ind′′), 7.90 (m, 1 H, H-4, Ind′′), 7.97
(m, 2 H, H-2/H-6, Benz), 12.95 ppm (br. s, 1 H, COOH).
13C NMR (125.8 MHz, [d6]DMSO): δ = 0.88 (Si(CH3)2), 0.89
6922 | Org. Biomol. Chem., 2012, 10, 6914–6929
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3
4
H-4, Naph), 8.17 (m, 1 H, H-8, Naph), 8.26 (m, 1 H, H-5,
Naph), 8.61 (m, 1 H, H-1, Naph), 13.04 ppm (s, 1 H, COOH).
13C NMR (125.8 MHz, [d6]DMSO): δ = 31.3 (C(CH3)2),
31.4 (C(CH3)2), 42.0 (C-1 or C-3, Ind), 42.3 (C-1 or C-3, Ind),
56.3 (CCH2C), 121.3 (C-4, Ind), 123.0 (C-7, Ind), 124.8 (C-5,
Naph), 125.5 (C-3, Naph), 126.1 (C-6, Ind), 126.2 (C-7, Naph),
127.8 (C-2, Naph), 128.4 (C-4, Naph), 129.8 (C-8, Naph), 130.3
(C-1, Naph), 131.2 (C-8a, Naph), 135.4 (C-4a, Naph), 138.4
(C-5, Ind), 140.4 (C-6, Naph), 150.8 (C-7a, Ind), 151.7 (C-3a,
Ind), 167.4 ppm (COOH). EI-MS: m/z (%) 344 (46) [M+], 329
(100) [M+ − CH3]. ESI-HRMS: m/z 345.18503 (found); calcd
for C24H25O2 [M + H]+: 345.18491.
H-8), 7.69 (dd, 1 H, J = 8.0 Hz, J = 2.0 Hz, H-7), 7.78 ppm
(d, 1 H, J = 2.0 Hz, H-5). 13C NMR (125.8 MHz, [d6]DMSO):
3
δ = −1.76 (Si(CH3)2), −1.74 (Si(CH3)2), 6.73 (SiCH2C),
6.75 (SiCH2C), 97.1 (C-6), 135.5 (C-8), 136.7 (C-7), 141.2
(C-5), 144.2 (C-8a), 148.7 ppm (C-4a). 29Si NMR (99.4 MHz,
[d6]DMSO): δ = −6.5, −6.4 ppm. EI-MS: m/z (%) 346 (38)
[M+], 331 (100) [M+ − CH3]. Anal. found: C, 42.2; H, 5.6;
calcd for C12H19ISi2: C, 41.61; H, 5.53%.
5-Iodo-1,1,3,3-tetramethylindane (10). Glacial acetic acid
(15.0 mL), concentrated sulphuric acid (98%, 0.8 mL) and water
(3.0 mL) were added to a mixture of 37 (3.00 g, 17.2 mmol),
orthoperiodic acid (785 mg, 3.44 mmol) and iodine (1.75 g,
6.89 mmol of I2). This mixture was stirred at 70 °C for 10 h and
then allowed to cool to 20 °C, whereupon it was diluted with
water (20 mL). Extraction of the mixture with n-hexane (2 ×
20 mL), followed by washing of the combined extracts first with
an aqueous sodium thiosulphate solution (1 M, 40 mL) and then
with an aqueous sodium hydroxide solution (1 M, 40 mL),
drying of the combined organic phases (magnesium sulphate),
filtration and removal of the solvent under reduced pressure
yielded a yellow liquid. This was distilled under reduced
pressure to afford 10 in 64% yield (3.30 g, 11.0 mmol) as a col-
ourless liquid; bp 63 °C (0.16 mbar). 1H NMR (500.1 MHz,
[d6]DMSO): δ = 1.23 (s, 6 H, C(CH3)2), 1.24 (s, 6 H, C(CH3)2),
1.82 (s, 2 H, CCH2C), 6.98 (d, 1 H, 3J = 8.3 Hz, H-7), 7.49 ppm
(m, 2 H, H-4 and H-6). 13C NMR (125.8 MHz, [d6]DMSO): δ =
31.0 (C(CH3)2), 31.1 (C(CH3)2), 42.0 (C-1), 42.3 (C-3), 55.8
(CCH2C), 92.3 (C-5), 125.0 (C-7), 131.3 (C-4 or C-6), 135.4
(C-4 or C-6), 150.6 (C-7a), 153.7 ppm (C-3a). EI-MS: m/z (%)
300 (36) [M+], 285 (100) [M+ − CH3]. EI-HRMS: m/z
300.03683 (found); calcd for C13H17I [M+]: 300.03695.
6-(1,1,3,3-Tetramethyl-1,3-disilaindan-5-yl)-2-naphthoic acid
(8b). A mixture of 22 (85.0 mg, 218 μmol), potassium hydrox-
ide (122 mg, 2.17 mmol) and methanol–tetrahydrofuran–water
(3 : 2 : 1 (v/v), 15 mL) was heated under reflux for 4 h. Dichloro-
methane (20 mL) and hydrochloric acid (4 M, 10 mL) were then
added sequentially to the reaction mixture. The aqueous phase
was separated and extracted with dichloromethane (2 × 20 mL).
Combination of the organic phases, drying over magnesium sul-
phate, filtration and concentration to approximately one third of
the original volume under reduced pressure gave a colourless
solution. The remaining solvent was then allowed to slowly
evaporate (20 °C), and the resulting crystals were washed with
acetone (5 mL)31 and dried under reduced pressure (20 °C,
0.03 mbar) to afford 8b in 96% yield (79.0 mg, 210 μmol) as a
1
colourless crystalline solid. H NMR (500.1 MHz, [d6]DMSO):
δ = 0.01 (s, 2 H, SiCH2Si), 0.30 (s, 6 H, Si(CH3)2), 0.34 (s, 6 H,
3
5
Si(CH3)2), 7.71 (dd, 1 H, J = 7.5 Hz, J = 1.0 Hz, H-7, Ind′),
7.81 (dd, 1 H, 3J = 7.5 Hz, 4J = 2.0 Hz, H-6, Ind′), 7.94 (m, 1 H,
H-7, Naph), 8.00 (m, 1 H, H-3, Naph), 8.02 (m, 1 H, H-4, Ind′),
8.10 (m, 1 H, H-4, Naph), 8.20 (m, 1 H, H-8, Naph), 8.31 (m,
1 H, H-5, Naph), 8.62 (m, 1 H, H-1, Naph) 13.07 ppm (s, 1 H,
5-Iodo-1,1,3,3-tetramethyl-1,3-disilaindane (11). A solution of
31 (822 mg, 3.71 mmol) and isoamylnitrite (870 mg,
7.43 mmol) in diiodomethane (3.7 mL) was stirred at 20 °C for
22 h. The excess diiodomethane was removed via bulb-to-bulb
distillation (46 °C, 1.0 mbar) and discarded. The crude product
was purified by further bulb-to-bulb distillation (100–124 °C,
0.1 mbar), followed by RP-MPLC (eluent, methanol–water
(95 : 5 (v/v)); flow rate, 22 mL min−1; detector wavelength,
250 nm) to afford 11 in 30% yield (364 mg, 1.10 mmol) as a
COOH). 13C NMR (125.8 MHz, [d6]DMSO):
δ
=
−2.6 (SiCH2Si), 0.56 (Si(CH3)2), 0.60 (Si(CH3)2), 125.2 (C-5,
Naph), 125.6 (C-3, Naph), 126.2 (C-7, Naph), 127.6 (C-6, Ind′),
128.0 (C-2, Naph), 128.5 (C-4, Naph), 129.9 (C-8, Naph),
130.26 (C-1, Naph, or C-4, Ind′), 130.27 (C-1, Naph, or C-4,
Ind′), 131.4 (C-8a, Naph), 132.4 (C-7, Ind′), 135.3 (C-4a,
Naph), 139.8 (C-5, Ind′), 140.2 (C-6, Naph), 149.5 (C-7a, Ind′),
150.9 (C-3a, Ind′), 167.4 ppm (COOH). 29Si NMR (99.4 MHz,
[d6]DMSO): δ = 8.6, 9.0 ppm. EI-MS: m/z (%) 376 (42) [M+],
361 (100) [M+ − CH3]. ESI-HRMS: m/z 377.13912 (found);
calcd for C22H25O2Si2 [M + H]+: 377.13876.
1
colourless oil. H NMR (500.1 MHz, [d6]DMSO): δ = −0.06 (s,
2 H, SiCH2Si), 0.24 (s, 6 H, Si(CH3)2), 0.25 (s, 6 H, Si(CH3)2),
7.36 (d, 1 H, 3J = 8.0 Hz, H-7), 7.69 (dd, 1 H, 3J = 8.0 Hz, 4J =
1.8 Hz, H-6), 7.92 ppm (d, 1 H, J = 1.8 Hz, H-4). 13C NMR
4
(125.8 MHz, [d6]DMSO): δ = −3.0 (SiCH2Si), 0.34 (Si(CH3)2),
0.36 (Si(CH3)2), 97.9 (C-5), 133.8 (C-7), 137.0 (C-6), 140.0
(C-4), 149.0 (C-3a), 153.5 ppm (C-7a). 29Si NMR (99.4 MHz,
[d6]DMSO): δ = 9.2, 9.3 ppm. EI-MS: m/z 332 (20) [M+],
317 (100) [M+ − CH3]. Anal. found: C, 39.9; H, 5.2; calcd for
C11H17ISi2: C, 39.76; H, 5.16%.
6-Iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-1,4-disilanaphtha-
lene (9). A solution of 30 (1.07 g, 4.54 mmol) and isoamylnitrite
(1.06 g, 9.07 mmol) in diiodomethane (5.0 mL) was stirred at
20 °C for 20 h. The excess diiodomethane was removed via
bulb-to-bulb distillation (40 °C, 1.5 mbar) and discarded. The
crude product was purified by further bulb-to-bulb distillation
(100–130 °C, 0.05 mbar), followed by RP-MPLC (eluent,
methanol–water (95 : 5 (v/v)); flow rate, 25 mL min−1; detector
wavelength, 240 nm) to give a pale yellow oil. This was passed
through a short silica gel column (eluent, n-hexane) to afford 9
5-Iodo-1,1,3,3-tetramethyl-2-oxa-1,3-disilaindane
(12). A
solution of 29 (1.72 g, 6.13 mmol) in tetrachloromethane (2 mL)
was added in one smooth injection to a stirred solution of iodine
monochloride (1.10 g, 6.78 mmol) in tetrachloromethane (6 mL)
at 0 °C. The reaction mixture was stirred for 10 min at this temp-
erature, diluted with diethyl ether (15 mL), washed with an
aqueous sodium thiosulphate solution (20 mL) and concentrated
1
in 33% yield (527 mg, 1.52 mmol) as a colourless oil. H NMR
(500.1 MHz, [d6]DMSO): δ = 0.17 (s, 6 H, Si(CH3)2), 0.19 (s,
6 H, Si(CH3)2), 0.94 (s, 4 H, SiCH2C), 7.28 (d, 1 H, 3J = 8.0 Hz,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6914–6929 | 6923

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under reduced pressure. The resulting yellow oil was purified by
RP-MPLC (eluent, methanol–water (90 : 10 (v/v)); flow rate,
20 mL min−1; detector wavelength, 240 nm), followed by bulb-
to-bulb distillation (40 °C, 0.03 mbar) to afford 12 in 36% yield
(736 mg, 2.20 mmol) as a colourless crystalline solid; mp
6 H, C(CH3)2), 1.28 (s, 6 H, C(CH3)2), 1.88 (s, 2 H, CCH2C),
3.86 (s, 3 H, C(O)OCH3), 7.23 (d, 1 H, J = 8.6 Hz, H-7, Ind),
3
7.40 (m, 2 H, H 4 and H 6, Ind), 7.66 (m, 2 H, H-3/H-5, Benz′),
7.97 ppm (m, 2 H, H-2/H-6, Benz′). 13C NMR (100.6 MHz, [d6]
DMSO): δ = 31.0 (C(CH3)2), 31.1 (C(CH3)2), 42.2 (C-3, Ind),
42.4 (C-1, Ind), 52.3 (C(O)OCH3), 55.8 (CCH2C), 87.5 (Ind–
CuC), 93.2 (Ind–CuC), 120.0 (C-5, Ind), 123.0 (C-7, Ind),
125.9 (C-4, Ind), 127.4 (C-4, Benz′), 129.0 (C-1 Benz′), 129.4
(C-2/C-6, Benz′), 130.4 (C-6, Ind), 131.5 (C-3/C-5, Benz′),
151.4 (C-3a, Ind), 152.4 (C-7a, Ind), 165.6 ppm (C(O)OCH3).
EI-MS: m/z (%) 332 (46) [M+], 317 (100) [M+ − CH3]. Anal.
found: C, 83.0; H, 7.3; calcd for C23H24O2: C, 83.10; H, 7.28%.
1
75–76 °C. H NMR (400.1 MHz, [d6]DMSO): δ = 0.28 (s, 6 H,
3
Si(CH3)2), 0.30 (s, 6 H, Si(CH3)2), 7.46 (d, 1 H, J = 7.7 Hz,
3
4
H-7), 7.77 (dd, 1 H, J = 7.7 Hz, J = 1.6 Hz, H-6), 8.06 ppm
(d, 1 H, J = 1.6 Hz, H-4). 13C NMR (100.6 MHz, [d6]DMSO):
4
δ = 0.847 (2 C) (Si(CH3)2), 0.853 (2 C) (Si(CH3)2), 98.3 (C-5),
133.2 (C-7), 137.4 (C-6), 139.5 (C-4), 146.7 (C-7a), 151.2 ppm
(C-3a). 29Si NMR (99.4 MHz, [d6]DMSO): δ = 14.3, 15.1 ppm.
EI-MS: m/z (%) 334 (22) [M+], 319 (100) [M+ − CH3]. Anal.
found: C, 35.9; H, 4.5; calcd for C10H15IOSi2: C, 35.93;
H, 4.52%.
Methyl 4-(1,1,3,3-tetramethyl-1,3-disilaindan-5-ylethynyl)ben-
zoate (16). Compound 13 (71.0 mg, 443 μmol), 11 (134 mg,
30
403 μmol), Pd(PPh3)2Cl2 (2.83 mg, 4.03 μmol) and copper(I)
Methyl 4-ethynylbenzoate (13). This compound was syn-
thesised according to ref. 32.
iodide (760 μg, 4.03 μmol) were dissolved in triethylamine
(5 mL) at 20 °C. The reaction mixture was stirred at this tempera-
ture for 17 h, whereupon GC analysis indicated complete con-
sumption of the starting materials. The solvent was then
removed under reduced pressure and the residue was purified by
flash column chromatography (eluent, n-hexane–ethyl acetate
(90 : 10 (v/v))) to give a colourless oil. This oil was crystallised
from acetonitrile (10 mL, slow evaporation of the solvent at
20 °C) to afford 16 in 97% yield (142 mg, 389 μmol) as a col-
Methyl
4-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-1,4-disila-
naphthalen-6-ylethynyl)benzoate (14). Compound 13 (81.0 mg,
30
506 μmol), 9 (160 mg, 462 μmol), Pd(PPh3)2Cl2 (3.24 mg,
4.62 μmol) and copper(I) iodide (880 μg, 4.62 μmol) were dis-
solved in triethylamine (10 mL) at 20 °C. The reaction mixture
was stirred at this temperature for 145 min, whereupon GC
analysis indicated complete consumption of the starting
materials. The solvent was then removed under reduced pressure
and the residue was purified by flash column chromatography
(eluent, n-hexane–ethyl acetate (90 : 10 (v/v))), followed by
recrystallisation from acetonitrile (20 °C) to afford 14 in 82%
yield (144 mg, 380 μmol) as a colourless crystalline solid; mp
1
ourless crystalline solid; mp 97–98 °C. H NMR (500.1 MHz,
CD2Cl2): δ = 0.01 (s, 2 H, SiCH2Si), 0.31 (s, 6 H, Si(CH3)2),
0.32 (s, 6 H, Si(CH3)2), 3.91 (s, 3 H, C(O)OCH3), 7.52 (dd,
3
4
3
1 H, J = 7.5 Hz, J = 1.5 Hz, H-6, Ind′), 7.57 (dd, 1 H, J =
5
7.5 Hz, J = 1.0 Hz, H-7, Ind′), 7.61 (m, 2 H, H-3/H-5, Benz′),
1
7.74 (m, 1 H, H-4, Ind′), 8.02 ppm (m, 2 H, H-2/H-6, Benz′).
13C NMR (125.8 MHz, CD2Cl2): δ = −2.5 (SiCH2Si), 0.4
(Si(CH3)2), 0.5 (Si(CH3)2), 52.5 (C(O)OCH3), 89.1 (Ind′–
CuC), 93.2 (Ind′–CuC), 123.0 (C-5, Ind′), 128.3 (C-4, Benz′),
129.8 (C-2/C-6, Benz′), 130.0 (C-1, Benz′), 131.7 (C-6, Ind′),
131.8 (C-3/C-5, Benz′), 132.0 (C-7, Ind′), 135.1 (C-4, Ind′),
151.2 (C-3a, Ind′), 152.1 (C-7a, Ind′), 166.7 ppm (C(O)OCH3).
29Si NMR (99.4 MHz, CD2Cl2): δ = 9.4, 9.5 ppm. EI-MS: m/z
(%) 364 (33) [M+], 349 (100) [M+ − CH3]. Anal. found: C,
69.4; H, 6.6; calcd for C21H24O2Si2: C, 69.18; H, 6.63%.
93–94 °C. H NMR (400.1 MHz, [d6]DMSO): δ = 0.20 (s, 6 H,
Si(CH3)2), 0.22 (s, 6 H, Si(CH3)2), 0.97 (s, 4 H, SiCH2C),
3.86 (s, 3 H, C(O)OCH3), 7.52 (d, 1 H, 3J = 7.6 Hz, H-7, THN),
7.56 (d, 1 H, 3J = 7.6 Hz, H-8, THN), 7.69 (m, 3 H, H-5 (THN)
and H-3/H-5 (Benz′)), 7.98 ppm (m, 2 H, H-2/H-6, Benz′).
13C NMR (100.6 MHz, [d6]DMSO): δ = −1.7 (Si(CH3)2),
6.8 (SiCH2C), 6.9 (SiCH2C), 52.3 (C(O)OCH3), 88.9 (THN–
CuC), 92.7 (THN–CuC), 121.5 (C-6, THN), 127.1 (C-4,
Benz′), 129.3 (C-1, Benz′), 129.4 (C-2/C-6, Benz′), 130.7 (C-7,
THN), 131.7 (C-3/C-5, Benz′), 133.5 (C-8, THN), 135.9 (C-5,
THN), 145.9 (C-4a, THN), 146.8 (C-8a, THN), 165.6 ppm
(C(O)OCH3). 29Si NMR (79.5 MHz, [d6]DMSO): δ = −6.54,
−6.46 ppm. EI-MS: m/z 378 (30) [M+], 363 (36) [M+ − CH3],
73 (100). Anal. found: C, 69.8; H, 6.9; calcd for C22H26O2Si2:
C, 69.79; H, 6.92%.
Methyl 4-(1,1,3,3-tetramethyl-2-oxa-1,3-disilaindan-5-ylethyn-
yl)benzoate (17). Compound 13 (53.0 mg, 331 μmol), 12
30
(100 mg, 299 μmol), Pd(PPh3)2Cl2 (2.10 mg, 2.99 μmol) and
copper(I) iodide (570 μg, 2.99 μmol) were dissolved in triethyl-
amine (15 mL) at 20 °C. The reaction mixture was stirred at this
temperature for 65 min, whereupon GC analysis indicated com-
plete consumption of the starting materials. The solvent was then
removed under reduced pressure and the residue was purified by
flash column chromatography (eluent, n-hexane–ethyl acetate
(90 : 10 (v/v))), followed by crystallisation from absolute ethanol
(20 °C) to afford 17 in 96% yield (105 mg, 286 μmol) as a col-
ourless crystalline solid; mp 123–125 °C. 1H NMR (500.1 MHz,
[d6]DMSO): δ = 0.32 (s, 6 H, Si(CH3)2), 0.33 (s, 6 H,
Si(CH3)2), 3.86 (s, 3 H, C(O)OCH3), 7.60 (dd, 1 H, 3J = 7.5 Hz,
4J = 1.5 Hz, H-6, Ind′′), 7.69 (m, 2 H, H-3/H-5, Benz′), 7.72
Methyl 4-(1,1,3,3-tetramethylindan-5-ylethynyl)benzoate
(15). Compound 13 (270 mg, 1.69 mmol), 10 (460 mg,
30
1.53 mmol), Pd(PPh3)2Cl2
(10.8 mg, 15.4 mmol) and
copper(I) iodide (2.92 mg, 15.3 mmol) were dissolved in tri-
ethylamine (20 mL) at 20 °C. The reaction mixture was stirred at
this temperature for 16 h, whereupon GC analysis indicated com-
plete consumption of the starting materials. The solvent was then
removed under reduced pressure and the residue was purified by
flash column chromatography (eluent, n-hexane–ethyl acetate
(90 : 10 (v/v))), followed by crystallisation from acetonitrile
(cooling of a hot solution to 20 °C) to afford 15 in 95% yield
(482 mg, 1.45 mmol) as a colourless crystalline solid;
3
5
(dd, 1 H, J = 7.5 Hz, J = 1.0 Hz, H-7, Ind′′), 7.90 (dd, 1 H,
4J = 1.5 Hz, J = 1.0 Hz, H-4, Ind′′), 7.99 ppm (m, 2 H, H-2/H-
5
1
mp 105 °C. H NMR (400.1 MHz, [d6]DMSO): δ = 1.27 (s,
6, Benz′). 13C NMR (125.8 MHz, [d6]DMSO): δ = 0.88
6924 | Org. Biomol. Chem., 2012, 10, 6914–6929
This journal is © The Royal Society of Chemistry 2012

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(Si(CH3)2), 0.89 (Si(CH3)2), 52.3 (C(O)OCH3), 89.0 (Ind′′–
CuC), 92.7 (Ind′′–CuC), 122.3 (C-5, Ind′′), 127.0 (C-4,
Benz′), 129.3 (C-1, Benz′), 129.5 (C-2/C-6, Benz′), 131.3 (C-7,
Ind′′), 131.67 (C-6, Ind′′), 131.68 (C-3/C-5, Benz′), 134.0 (C-4,
Ind′′), 148.3 (C-3a, Ind′′), 149.0 (C-7a, Ind′′), 165.6 ppm (C(O)
OCH3). 29Si NMR (99.4 MHz, [d6]DMSO): δ = 14.91,
14.93 ppm. EI-MS: m/z 366 (%) (28) [M+], 351 (100)
[M+ − CH3]. Anal. found: C, 65.4; H, 6.0; calcd for
C20H22O3Si2: C, 65.53; H, 6.05%.
Schlenk bomb at 20 °C utilising a dry, argon filled glovebox.
The tube was sealed and heated at 80 °C for 19 h, whereupon
GC analysis indicated complete consumption of 10. The reaction
mixture was poured onto ethyl acetate (50 mL), the resulting
mixture was washed with hydrochloric acid (1 M, 2 × 50 mL)
and the combined aqueous washings were extracted with a
further portion of ethyl acetate (50 mL) and discarded. Combi-
nation of the organic extracts, drying over magnesium sulphate,
filtration and concentration under reduced pressure yielded a
brown residue. Purification of this residue by flash column
chromatography (eluent, n-hexane–ethyl acetate (90 : 10 (v/v)))
and subsequent recrystallisation from n-hexane (slow cooling of
a hot solution to 20 °C) afforded 21 in 62% yield (147 mg,
4-Ethynylbenzoic acid (18). This compound was synthesised
according to ref. 33.
Methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
naphthoate (19). This compound was synthesised according to
ref. 34.
1
410 μmol) as a fluffy, white, crystalline solid; mp 156 °C. H
NMR (500.1 MHz, [d6]DMSO): δ = 1.31 (s, 6 H, C(CH3)2),
1.35 (s, 6 H, C(CH3)2), 1.93 (s, 2 H, CCH2C), 3.92 (s, 3 H,
C(O)OCH3), 7.29 (d, 1 H, 3J = 8.0 Hz, H-7, Ind), 7.61–7.64 (m,
2 H, H-4 and H-6, Ind), 7.93 (m, 1 H, H-7, Naph′), 7.99 (m,
1 H, H-3, Naph′), 8.09 (m, 1 H, H-4, Naph′), 8.20 (m, 1 H, H-8,
Naph′), 8.28 (s, 1 H, H-5, Naph′), 8.65 ppm (s, 1 H, H-1,
Methyl 6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-1,4-disila-
naphthalen-6-yl)-2-naphthoate (20). Compound 19 (205 mg,
657 mmol), 9 (250 mg, 722 mmol), Pd(dppf)Cl2 (19.2 mg,
26.2 μmol) and potassium phosphate (348 mg, 1.64 mmol) were
combined with degassed N,N-dimethylformamide (15 mL) and
degassed water (2 mL) in a Schlenk bomb at 20 °C utilising a
dry, argon filled glovebox. The tube was sealed and heated at
80 °C for 16 h, whereupon GC analysis indicated complete con-
sumption of 19. The reaction mixture was poured onto a mixture
of dichloromethane (50 mL) and hydrochloric acid (4 M,
10 mL) and washed with an aqueous sodium chloride solution
(2 × 25 mL). Separation of the organic layer, drying over mag-
nesium sulphate, filtration and concentration under reduced
pressure yielded a brown residue. This residue was purified by
flash column chromatography (eluent, n-hexane–ethyl acetate
(90 : 10 (v/v))). Concentration of the relevant fractions to one
third of the original volume and subsequent cooling of the result-
ing solution to −30 °C afforded 20 in 47% yield (126 mg,
311 μmol) as a colourless crystalline solid following isolation by
Naph′). 13C NMR (125.8 MHz, [d6]DMSO):
δ = 31.3
(C(CH3)2), 31.4 (C(CH3)2), 42.0 (C-1 or C-3, Ind), 42.3 (C-1 or
C-3, Ind), 52.2 (C(O)OCH3), 56.3 (CCH2C), 121.3 (C-4, Ind),
123.0 (C–7, Ind), 124.8 (C-5, Naph′), 125.1 (C-3, Naph′), 126.1
(C-6, Ind), 126.4 (C-7, Naph′), 126.6 (C-2, Naph′), 128.7 (C-4,
Naph′), 129.9 (C-8, Naph′), 130.3 (C-1, Naph′), 131.1 (C-8a,
Naph′), 135.5 (C-4a, Naph′), 138.4 (C-5, Ind), 140.7 (C-6,
Naph′), 150.8 (C-7a, Ind), 151.7 (C-3a, Ind), 166.3 ppm (C(O)-
OCH3). EI-MS: m/z (%) 358 (41) [M+], 343 (100) [M+ − CH3].
ESI-HRMS: m/z 359.20030 (found); calcd for C25H27O2
[M + H]+: 359.20056.
Methyl 6-(1,1,3,3-tetramethyl-1,3-disilaindan-5-yl)-2-naphtho-
ate (22). Compound 19 (251 mg, 804 mmol), 11 (294 mg,
885 mmol), Pd(dppf)Cl2 (23.5 mg, 32.1 μmol) and potassium
phosphate (427 mg, 2.01 mmol) were combined with degassed
N,N-dimethylformamide (10 mL) and degassed water (2 mL) in
a Schlenk bomb at 20 °C utilising a dry, argon filled glovebox.
The tube was sealed and heated at 80 °C for 24 h, whereupon
GC analysis indicated complete consumption of 19. The reaction
mixture was poured onto a mixture of ethyl acetate (40 mL) and
hydrochloric acid (4 M, 10 mL), and the resulting mixture was
washed with an aqueous sodium chloride solution (30 mL).
Separation of the organic layer, drying over sodium sulphate,
filtration and concentration under reduced pressure yielded a
brown residue. Purification of this residue by flash column
chromatography (eluent, n-hexane–ethyl acetate (90 : 10 (v/v)))
and subsequent crystallisation from acetonitrile (slow cooling of
a boiling solution to 20 °C) afforded 22 in 43% yield (135 mg,
1
filtration; mp 167 °C. H NMR (500.1 MHz, CD2Cl2): δ = 0.28
(s, 6 H, Si(CH3)2), 0.30 (s, 6 H, Si(CH3)2), 1.07 (s, 4 H,
SiCH2C), 3.97 (s, 3 H, C(O)OCH3), 7.64 (m, 1 H, H-8, THN),
7.70 (m, 1 H, H-7, THN), 7.81–7.86 (m, 2 H, H-5, THN, and
H-7, Naph′), 7.98 (m, 1 H, H-4, Naph′), 8.05–8.09 (m, 2 H, H-3
and H-8, Naph′), 8.10 (m, 1 H, H-5, Naph′), 8.62 ppm (m, 1 H,
H-1, Naph′). 13C NMR (125.8 MHz, CD2Cl2): δ = −1.5
(Si(CH3)2), −1.4 (Si(CH3)2), 7.75 (SiCH2C), 7.82 (SiCH2C),
52.5 (C(O)OCH3), 125.8 (C-5, Naph′), 126.0 (C-3, Naph′),
126.8 (C-7, Naph′), 127.4 (C-7, THN), 127.9 (C-2, Naph′),
128.7 (C-4, Naph′), 130.2 (C-8, Naph′), 131.0 (C-1, Naph′),
132.1 (C-8a, Naph′), 132.6 (C-5, THN), 134.5 (C-8, THN),
136.2 (C-4a, Naph′), 140.2 (C-6, THN), 141.5 (C-6, Naph′),
145.9 (C-8a, THN), 147.2 (C-4a, THN), 167.3 ppm (C(O)-
OCH3). 29Si NMR (99.4 MHz, CD2Cl2): δ = −6.8, −6.6 ppm.
EI-MS: m/z (%) 404 (24) [M+], 389 (26) [M+ − CH3], 73 (100).
ESI-HRMS: m/z 405.16991 (found); calcd for C24H29O2Si2
[M + H]+: 405.17006.
1
346 μmol) as a fluffy, white, crystalline solid; mp 152 °C. H
NMR (500.1 MHz, CD2Cl2): δ = 0.05 (s, 2 H, SiCH2Si), 0.34
(s, 6 H, Si(CH3)2), 0.36 (s, 6 H, Si(CH3)2), 3.97 (s, 3 H, C(O)
OCH3), 7.70 (dd, 1 H, 3J = 7.5 Hz, 5J = 1.0 Hz, H-7, Ind′), 7.74
3
4
(dd, 1 H, J = 7.5 Hz, J = 1.5 Hz, H-6, Ind′), 7.86 (m, 1 H, H-
4
5
Methyl 6-(1,1,3,3-tetramethylindan-5-yl)-2-naphthoate (21).
Compound 19 (250 mg, 801 mmol), 10 (200 mg, 666 mmol),
Pd(dppf)Cl2 (19.5 mg, 26.6 μmol) and potassium phosphate
(354 mg, 1.67 mmol) were combined with degassed N,N-
dimethylformamide (10 mL) and degassed water (2 mL) in a
7, Naph′), 7.92 (dd, 1 H, J = 1.5 Hz, J = 1.0 Hz, H-4, Ind′),
7.97 (m, 1 H, H-4, Naph′), 8.05–8.08 (m, 2 H, H-3 and H-8,
Naph′), 8.13 (m, 1 H, H-5, Naph′), 8.63 ppm (m, 1 H, H-1,
Naph′). 13C NMR (125.8 MHz, CD2Cl2): δ = −2.2 (SiCH2Si),
0.58 (Si(CH3)2), 0.62 (Si(CH3)2), 52.5 (C(O)OCH3), 125.92
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6914–6929 | 6925

View Article Online
(C-3 or C-5, Naph′), 125.94 (C-3 or C-5, Naph′), 126.9 (C-7,
Naph′), 127.9 (C-2, Naph′), 128.1 (C-6, Ind′), 128.7 (C-4,
Naph′), 130.1 (C-8, Naph′), 131.0 (C-1, Naph′, and C-4, Ind′),
132.0 (C-8a, Naph′), 132.7 (C-7, Ind′), 136.2 (C-4a, Naph′),
140.8 (C-5, Ind′), 141.7 (C-6, Naph′), 150.5 (C-7a, Ind′), 152.0
(C-3a, Ind′), 167.3 ppm (C(O)OCH3). 29Si NMR (99.4 MHz,
CD2Cl2): δ = 8.9, 9.3 ppm. EI-MS: m/z (%) 390 (38) [M+],
375 (100) [M+ − CH3]. ESI-HRMS: m/z 391.15461 (found);
calcd for C23H27O2Si2 [M + H]+: 391.15441.
solution was stirred at this temperature for 2 h, whereupon GC
analysis indicated complete consumption of 24. The reaction
mixture was filtered through a short silica gel column (eluent,
n-hexane) and the filtrate was concentrated under reduced
pressure to give a yellow oil. Purification by RP-MPLC (eluent,
methanol; flow rate, 34 mL min−1; detector wavelength, 240 nm)
gave a white solid, which was crystallised from absolute ethanol
(cooling of a hot solution to 20 °C) to afford 28 in 9% yield
(490 mg, 1.76 mmol) as a colourless crystalline solid; mp 38 °C.
1H NMR (500.1 MHz, CDCl3): δ = −0.05 (s, 2 H, SiCH2Si),
0.28 (s, 9 H, Si(CH3)3), 0.29 (s, 6 H, Si(CH3)2), 0.30 (s, 6 H,
Si(CH3)2), 7.55 (m, 2 H, H–6 and H–7), 7.71 ppm (m, 1 H,
H–4). 13C NMR (125.8 MHz, CDCl3): δ = −2.5 (SiCH2Si),
−1.1 (Si(CH3)3), 0.5 (Si(CH3)2), 0.6 (Si(CH3)2), 131.0 (C-7),
133.5 (C-6), 136.6 (C-4), 140.3 (C-5), 149.4 (C-3a or C-7a),
151.1 ppm (C-3a or C-7a). 29Si NMR (99.4 MHz, CDCl3): δ =
−4.1, 8.7, 8.9 ppm. EI-MS: m/z (%) 278 (5) [M+], 263 (100)
[M+ − CH3]. Anal. found: C, 60.4; H, 9.4; calcd for C14H26Si3:
C, 60.35; H, 9.41%.
1,2-Bis(ethynyldimethylsilyl)ethane (23). This compound was
synthesised according to ref. 6a and stored under dry argon.
Bis(ethynyldimethylsilyl)methane (24). This compound was
synthesised according to ref. 35 and stored under dry argon.
1,3-Diethynyl-1,1,3,3-tetramethyldisiloxane (25). This com-
pound was synthesised according to ref. 36 and stored under dry
argon.
Ethynyltrimethylsilane (26). This compound was commer-
cially available (ABCR) and was used as received.
1,1,3,3-Tetramethyl-5-trimethylsilyl-2-oxa-1,3-disilaindane (29).
A mixture of iodine (51.0 mg, 201 μmol of I2), zinc (130 mg,
2.00 mmol) and acetonitrile (10 mL) was stirred at 20 °C until
the brown colouration disappeared and a grey suspension was
observed. Compound 25 (3.64 g, 20.0 mmol), 26 (2.75 g,
28.0 mmol) and a 0.1 M solution of cobalt(II) iodide in aceto-
nitrile (10.0 mL, 1.00 mmol of CoI2) were then added sequen-
tially in single portions at 20 °C. The resulting dark brown
solution was stirred at this temperature for 18 h, whereupon GC
analysis indicated complete consumption of 25. The reaction
mixture was concentrated under reduced pressure and the residue
was purified by bulb-to-bulb distillation (71–114 °C, 0.15 mbar)
to afford 29 in 63% yield (3.50 g, 12.5 mmol) as a colourless
crystalline solid; mp 49–51 °C. 1H NMR (500.1 MHz, [d6]-
DMSO): δ = 0.24 (s, 9 H, Si(CH3)3), 0.28 (s, 6 H, Si(CH3)2),
0.29 (s, 6 H, Si(CH3)2), 7.54 (dd, 1 H, 3J = 7.2 Hz, 4J = 1.1 Hz,
1,1,4,4-Tetramethyl-6-trimethylsilyl-1,2,3,4-tetrahydro-1,4-di-
silanaphthalene (27). A mixture of iodine (51.0 mg, 201 μmol
of I2), zinc (131 mg, 2.00 mmol) and acetonitrile (40 mL) was
stirred at 20 °C until the brown colouration disappeared and a
grey suspension was observed. Compound 23 (3.89 g,
20.0 mmol), 26 (2.75 g, 28.0 mmol) and a 0.2 M solution of
cobalt(II) bromide in acetonitrile (5.00 mL, 1.00 mmol of CoBr2)
were then added sequentially in single portions at 20 °C. The
resulting dark brown solution was stirred at this temperature for
2 h, whereupon GC analysis indicated complete consumption of
23. The reaction mixture was filtered through a short silica gel
column (eluent, n-hexane) and the filtrate was concentrated
under reduced pressure to give a yellow oil. Purification by
RP-MPLC (eluent, methanol; flow rate, 38 mL min−1; detector
wavelength, 240 nm) gave a white solid, which was crystallised
from absolute ethanol (cooling of a hot solution to 20 °C) to
afford 27 in 34% yield (2.01 g, 6.87 mmol) as a colourless crys-
talline solid; mp 60 °C. 1H NMR (500.1 MHz, CDCl3): δ =
0.21 (s, 6 H, Si(CH3)2), 0.22 (s, 6 H, Si(CH3)2), 0.25 (s, 9 H,
3
5
H–6), 7.60 (dd, 1 H, J = 7.2 Hz, J = 1.0 Hz, H-7), 7.77 ppm
4
5
(“t”, 1 H, J = J = 1.1 Hz, H–4). 13C NMR (125.8 MHz, [d6]-
DMSO): δ = −1.1 (Si(CH3)3), 1.0 (Si(CH3)2), 1.1 (Si(CH3)2),
130.2 (C-7), 133.7 (C-6), 135.6 (C-4), 140.4 (C-5), 146.6
(C-3a), 148.2 ppm (C-7a). 29Si NMR (99.4 MHz, [d6]DMSO):
δ = −4.0, 14.4, 14.7 ppm. EI-MS: m/z (%) 280 (7) [M+],
265 (100) [M+ − CH3]. Anal. found: C, 55.4; H, 8.6; calcd for
C13H24OSi3: C, 55.65; H, 8.62%.
3
Si(CH3)3), 0.99 (s, 4 H, SiCH2Si), 7.47 (dd, 1 H, J = 7.3 Hz,
5J = 0.9 Hz, H-8), 7.49 (dd, 1 H, 3J = 7.3 Hz, 4J = 1.0 Hz, H-7),
7.62 ppm (“t”, 1 H, 4J = 5J = 1.0 Hz, H-5). 13C NMR
(125.8 MHz, CDCl3): δ = −1.54 (Si(CH3)2), −1.45 (Si(CH3)2),
−1.2 (Si(CH3)3), 7.5 (SiCH2C), 7.6 (SiCH2C), 132.6 (C-8),
132.9 (C-7), 138.2 (C-5), 139.8 (C-6), 144.7 (C-4a or C-8a),
146.3 ppm (C-4a or C-8a). 29Si NMR (99.4 MHz, CDCl3): δ =
−7.3, −7.2, −4.2 ppm. EI-MS: m/z (%) 292 (23) [M+],
277 (100) [M+ − CH3]. Anal. found: C, 61.4; H, 9.6; calcd for
C15H28Si3: C, 61.56; H, 9.64%.
(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-1,4-disilanaphthalen-6-yl)-
amine (30). A solution of 33 (2.63 g, 9.94 mmol), diphenoxy-
phosphoryl azide (3.01 g, 10.9 mmol) and triethylamine
(1.1 mL) in toluene (250 mL) was heated under reflux for 17 h,
whereupon GC analysis indicated complete consumption of 33.
Following cooling to 0 °C, a solution of sodium trimethylsilano-
late in dichloromethane24 (1.0 M, 27.0 mL, 27.0 mmol of
NaOSiMe3) was added over a period of 5 min to the stirred solu-
tion. The reaction mixture was stirred at 0 °C for 30 min and
hydrochloric acid (4 M, 20 mL) was added. The aqueous phase
was taken to pH 6 (pH paper test) by gradual addition of an
aqueous sodium hydroxide solution (4 M). Separation of the
organic layer and concentration under reduced pressure gave a
brown solid, which was purified by RP-MPLC (eluent,
1,1,3,3-Tetramethyl-5-trimethylsilyl-1,3-disilaindane (28). A
mixture of iodine (51.0 mg, 201 μmol of I2), zinc (131 mg,
2.00 mmol) and acetonitrile (10 mL) was stirred at 20 °C until
the brown colouration disappeared and a grey suspension was
observed. Compound 24 (3.61 g, 20.0 mmol), 26 (1.97 g,
20.1 mmol) and a 0.1 M solution of cobalt(II) bromide in aceto-
nitrile (10.0 mL, 1.00 mmol of CoBr2) were then added sequen-
tially in single portions at 20 °C. The resulting dark brown
6926 | Org. Biomol. Chem., 2012, 10, 6914–6929
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methanol–water (85 : 15 (v/v)); flow rate, 18 mL min−1; detector
wavelength, 240 nm) and subsequent bulb-to-bulb distillation
(65 °C, 0.05 mbar) to afford 30 in 46% yield (1.07 g,
4.54 mmol) as a colourless crystalline solid; mp 66 °C. 1H NMR
(300.1 MHz, [d6]DMSO): δ = 0.10 (s, 6 H, Si(CH3)2), 0.13 (s,
6 H, Si(CH3)2), 0.88 (s, 4 H, SiCH2C), 5.09 (s, 2 H, NH2),
6.54 (dd, 1 H, 3J = 7.8 Hz, 4J = 2.1 Hz, H–7), 6.68 (d, 1 H, 4J =
filtered and concentrated. The resulting brown oil was purified
by flash column chromatography (eluent, n-hexane) to yield
2.51 g of a yellow oil. This oil was dissolved in acetone (25 mL)
and the solution was added dropwise over 5 min to a stirred
mixture of potassium dichromate (3.97 g, 13.5 mmol), concen-
trated sulphuric acid (4.00 mL), water (12.0 mL) and acetone
(50 mL) at 0 °C. This mixture was stirred and allowed to warm
to 20 °C over a period of 4 h and then poured onto a mixture of
n-hexane (100 mL) and an aqueous solution of sodium hydrox-
ide (4 M, 100 mL). The organic layer was separated and dis-
carded. Concentrated hydrochloric acid was carefully added to
the aqueous phase until it reached pH 2, and this solution was
extracted with dichloromethane (2 × 100 mL). Combination of
the organic washings, drying over magnesium sulphate, filtration
and concentration of the filtrate under reduced pressure yielded a
yellow oil. Purification of the crude product by column
chromatography (eluent, n-hexane–diethyl ether–acetic acid
(80 : 20 : 2 (v/v/v))) afforded 33 in 19% yield (1.03 g,
3.89 mmol, relative to compound 23) as an amorphous white
solid. 1H NMR (500.1 MHz, CD2Cl2): δ = 0.26 (s, 6 H, Si-
(CH3)2), 0.28 (s, 6 H, Si(CH3)2), 1.06 (s, 4 H, SiCH2C),
3
2.1 Hz, H–5), 7.12 ppm (d, 1 H, J = 7.8 Hz, H–8). 13C NMR
(75.5 MHz, [d6]DMSO): δ = −1.5 (Si(CH3)2), −1.0 (Si(CH3)2),
7.3 (SiCH2C), 7.5 (SiCH2C), 114.4 (C-7), 118.5 (C-5), 128.8
(C-6), 134.3 (C-8), 145.3 (C-8a), 148.5 ppm (C-4a). 15N NMR
(30.4 MHz, [d6]DMSO):
δ =
−319.5 ppm. 29Si NMR
(59.6 MHz, [d6]DMSO): δ = −8.7, −7.7 ppm. EI-MS: m/z (%)
235 (55) [M+], 220 (93) [M+ − CH3], 160 (100). H, 13C and
1
29Si data were in agreement with those reported in ref. 6d.
(1,1,3,3-Tetramethyl-1,3-disilaindan-5-yl)amine (31). A solu-
tion of 34 (1.82 g, 7.26 mmol), diphenoxyphosphoryl azide
(2.20 g, 7.99 mmol) and triethylamine (1.2 mL) in toluene
(180 mL) was heated under reflux for 17 h, whereupon GC
analysis indicated complete consumption of 34. Following
cooling to 0 °C, a solution of sodium trimethylsilanolate in
dichloromethane24 (1.0 M, 20.0 mL, 20.0 mmol of NaOSiMe3)
was added over a period of 10 min to the stirred solution. The
reaction mixture was stirred at 0 °C for 30 min and hydrochloric
acid (4 M, 10 mL) was added. The reaction mixture was concen-
trated under reduced pressure and the residue was purified by
bulb-to-bulb distillation (110–125 °C, 0.2 mbar) to afford 31 in
63% yield (1.02 g, 4.61 mmol) as a colourless crystalline solid;
3
5
7.64 (dd, 1 H, J = 7.5 Hz, J = 0.5 Hz, H–8), 8.01 (dd, 1 H,
4
3J = 7.5 Hz, 4J = 2.0 Hz, H–7), 8.21 ppm (dd, 1 H, J = 2.0 Hz,
5J = 0.5 Hz, H–5), COOH not observed. 13C NMR (125.8 MHz,
CD2Cl2): δ = −1.8 (Si(CH3)2), −1.6 (Si(CH3)2), 7.5 (SiCH2C),
7.6 (SiCH2C), 128.6 (C-6), 129.2 (C-7), 133.9 (C-8), 134.8
(C-5), 147.0 (C-8a), 154.1 (C-4a), 172.8 ppm (C(O)OH). 29Si
NMR (99.4 MHz, CD2Cl2): δ = −6.2, −6.1 ppm. EI-MS: m/z
1
(%) 264 (18) [M+], 249 (100) [M+ − CH3]. H, 13C and 29Si
1
mp 37 °C. H NMR (500.1 MHz, [d6]DMSO): δ = −0.15 (s,
NMR data were in agreement with those reported in ref. 6d.
2 H, SiCH2Si), 0.17 (s, 6 H, Si(CH3)2), 0.19 (s, 6 H, Si(CH3)2),
3
4
5.10 (s, 2 H, NH2), 6.57 (dd, 1 H, J = 8.0 Hz, J = 2.0 Hz,
1,1,3,3-Tetramethyl-1,3-disila-5-indanoic acid (34). A mixture
of iodine (102 mg, 402 μmol of I2), zinc (262 mg, 4.01 mmol)
and acetonitrile (20 mL) was heated under reflux until the brown
colouration disappeared and a grey suspension was observed.
Compound 24 (3.61 g, 20.0 mmol), 36 (3.59 g, 28.0 mmol) and
a 0.2 M solution of cobalt(II) bromide in acetonitrile (10.0 mL,
2.00 mmol of CoBr2) were then added sequentially in single por-
tions to the refluxing mixture. The resulting dark green solution
was stirred under reflux for 3.5 h and then at 20 °C for 22 h,
whereupon GC analysis indicated complete consumption of 24.
Hydrochloric acid (1 M, 40 mL) was then added and the reaction
mixture was stirred at 20 °C for 1 h. Subsequently, ethyl acetate
(60 mL) was added and the organic phase was separated and
washed with an aqueous sodium chloride solution (2 × 40 mL).
The aqueous phases were combined, extracted with a further
portion of ethyl acetate (60 mL) and discarded. Both of the
organic phases were combined, dried over magnesium sulphate,
filtered and concentrated. The resulting brown oil was purified
by flash column chromatography (eluent, n-hexane) to yield
3.47 g of a yellow oil. This oil was dissolved in acetone (25 mL)
and the solution was added dropwise over 5 min to a stirred
mixture of potassium dichromate (5.82 g, 19.3 mmol), concen-
trated sulphuric acid (5.80 mL), water (17.5 mL) and acetone
(50 mL) at 0 °C. This mixture was stirred and allowed to warm
to 20 °C over a period of 18 h and then passed through a short
silica gel column (eluent, n-hexane, 250 mL). The organic solu-
tion was washed with an aqueous solution of sodium hydroxide
(4 M, 100 mL) and discarded. Concentrated hydrochloric acid
4
4
H–6), 6.71 (d, 1 H, J = 2.0 Hz, H–4), 7.19 ppm (d, 1 H, J =
8.0 Hz, H-7). 13C NMR (125.8 MHz, [d6]DMSO): δ =
−2.4 (SiCH2Si), 0.6 (Si(CH3)2), 1.2 (Si(CH3)2), 115.3 (C-6),
116.3 (C-4), 132.5 (C-7), 134.0 (C-5), 149.2 (C-3a), 150.6 ppm
(C-7a). 15N NMR (40.6 MHz, [d6]DMSO): δ = −319.3 ppm.
29Si NMR (99.4 MHz, [d6]DMSO): δ = 6.5, 7.5 ppm. EI-MS:
m/z (%) 221 (25) [M+], 206 (100) [M+ − CH3]. Anal. found:
C, 59.8; H, 8.6; N, 6.3; calcd for C11H19NSi2: C, 59.66; H, 8.65;
N, 6.33%.
1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-1,4-disila-6-naphthoic
acid (33). A mixture of iodine (102 mg, 402 μmol of I2), zinc
(262 mg, 4.00 mmol) and acetonitrile (20 mL) was stirred at
20 °C until the brown colouration disappeared and a grey sus-
pension was observed. Compound 23 (3.89 g, 20.0 mmol), 36
(3.59 g, 28.0 mmol) and a 0.2 M solution of cobalt(II) bromide
in acetonitrile (10.0 mL, 2.00 mmol of CoBr2) were then added
sequentially in single portions to the stirred mixture. The result-
ing dark green solution was stirred at 20 °C for 16 h, whereupon
GC analysis indicated complete consumption of 23. Hydro-
chloric acid (4 M, 10 mL) was then added and the reaction
mixture was stirred at 20 °C for 30 min. Subsequently, ethyl
acetate (100 mL) was added and the organic phase was separated
and washed with aqueous sodium chloride solution (3 × 60 mL).
The aqueous phases were combined, extracted with a further
portion of ethyl acetate (100 mL) and discarded. Both of the
organic phases were combined, dried over magnesium sulphate,
This journal is © The Royal Society of Chemistry 2012
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was added to the aqueous phase until it reached pH 2, and this
solution was extracted sequentially with n-hexane (3 × 150 mL)
and diethyl ether (100 mL). Combination of the organic wash-
ings, drying over magnesium sulphate, filtration and concen-
tration of the filtrate under reduced pressure yielded a greeny-
yellow solid. Purification of the crude product by column chrom-
atography (eluent, n-hexane–diethyl ether–acetic acid (80 : 20 : 2
(v/v/v))) afforded 34 in 37% yield (1.86 g, 7.43 mmol, relative
to compound 24) as an amorphous white solid. 1H NMR
(500.1 MHz, [d6]DMSO): δ = 0.00 (s, 2 H, SiCH2Si), 0.27 (s,
containing the DNA binding domain of the yeast transactivator
GAL4 fused to the ligand-binding domain of the corresponding
receptor, and referred to them as Gal4-mRARα (or -β, -γ). Cells
also contained a stably integrated luciferase-reporter gene driven
by a pentamer of the GAL4 recognition sequence termed
“(17m)5-βG-Luc-Neo reporter”. Cells were maintained in
DMEM that contained 5% fetal calf serum (FCS), supplemented
with geneticin G418 (0.8 mg mL−1), puromycin (0.3 μg mL−1
)
and gentamicin (40 μg mL−1).
To determine the RARα, RARβ and RARγ induction potential
of the ligands, an equal number (44 000 cells per well) of the
corresponding cell line was seeded in 48-well plates in 450 μL
of cell culture medium. Cells were allowed to attach to the
bottom, and approximately 5 h later 50 μL of the corresponding
ligand was added. The cells were incubated at 37 °C in 5% CO2
for 16 h. After that, the cells were washed with phosphate
buffered saline (PBS) and lysed in 110 μL of lysis buffer
(25 mM Tris phosphate (pH 7.8), 2 mM EDTA, 1 mM DTT,
10% glycerol and 1% Triton X-100) for 15 min. Equal aliquots
(25 μL) of the cell lysates were transferred in the Optiplate-96
well plate, and the luminescence in RLU (relative luminescence
units) was determined on a MicroLumat LB96P luminometer
(‘Berthold’) after automatic injection of 50 μL of luciferin buffer
(20 mM Tris phosphate (pH 7.8), 1.07 mM MgCl2, 2.67 mM
MgSO4, 0.1 mM EDTA, 33.3 mM DTT, 0.53 mM ATP,
0.47 mM luciferin and 0.27 mM coenzyme A).
3
6 H, Si(CH3)2), 0.28 (s, 6 H, Si(CH3)2), 7.67 (dd, 1 H, J =
5
3
4
7.6 Hz, J = 0.8 Hz, H–7), 7.89 (dd, 1 H, J = 7.6 Hz, J =
4
5
1.6 Hz, H–6), 8.10 (dd, 1 H, J = 1.6 Hz, J = 0.8 Hz, H-4),
12.90 ppm (C(O)OH). 13C NMR (125.8 MHz, [d6]DMSO): δ =
−2.8 (SiCH2Si), 0.3 (Si(CH3)2), 0.4 (Si(CH3)2), 129.1 (C-6),
130.7 (C-5), 131.8 (C-7), 132.0 (C-4), 150.3 (C-3a), 155.8
(C-7a), 167.8 ppm (C(O)OH). 29Si NMR (99.4 MHz, [d6]-
DMSO): δ = 9.06, 9.12 ppm. EI-MS: m/z (%) 250 (4) [M+],
235 (100) [M+ − CH3]. Anal. found: C, 57.4; H, 7.2; calcd for
C12H18O2Si2: C, 57.55; H, 7.24%.
3,3-Diethoxypropyne (36). This compound was commercially
available (ABCR); it was distilled before use and stored at 4 °C
under dry argon.
1,1,3,3-Tetramethylindane (37). This compound was syn-
thesised according to ref. 37.
The receptor activation potential of each test compound was
presented as fold induction measured as ratio of RLU of the
compound over the RLU of the vehicle control (DMEM without
phenol red with gentamicin). All values are represented as the
mean S.E.M. (standard error of the mean) of at least 3 indepen-
dent experiments, with duplicates in each of the experiments.
Crystal structure analyses
Suitable single crystals of 5a, 8b, 15, 17, 28 and 29 were
obtained as described in the respective synthetic procedures.
Compound 5b was crystallised from dichloromethane by slow
evaporation of the solvent at ambient temperature. Compounds
33 and 34 were crystallised from n-hexane by slow evaporation
of the solvent at ambient temperature. The crystals were
mounted in inert oil (perfluoropolyalkyl ether, ABCR) on a
glass fibre and then transferred to the cold nitrogen gas stream of
the diffractometer (Bruker Nonius KAPPA APEX II (15 and 17;
Montel mirror, Mo Kα radiation, λ = 0.71073 Å); Stoe IPDS
(5a, 5b, 8b, 28, 29, 33 and 34; graphite-monochromated Mo Kα
radiation, λ = 0.71073 Å)). The structures were solved by direct
methods.38 The non-hydrogen atoms were refined anisotropi-
cally.38 A riding model was employed in the refinement of the
CH hydrogen atoms. The crystallographic data for the structures
reported herein have been deposited with the Cambridge Crystal-
lographic Date Centre as supplementary publication nos.
CCDC-837993 (5a), CCDC-837994 (5b), CCDC-872960 (8b),
CCDC-837995 (15), CCDC-837996 (17), CCDC-837997 (28),
CCDC-837998 (29), CCDC-837999 (33) and CCDC-838000 (34).
Acknowledgements
We thank Prof. T. B. Marder (Universität Würzburg, Germany)
for the generous provision of a sample of TTNN. J. B. G. G.
thanks the Bayerische Forschungsstiftung for a doctoral student-
ship, Dr Steffen Falgner for advice on the Curtius reaction and
Dr Rolf Janiak for all his help with the HPLC and MPLC
systems. Work in the laboratory of H. G. is supported by the
European Community [contracts LSHC-CT-2005-518417
‘EPITRON’, HEALTH-F4-2009-221952 ‘ATLAS’, LSHM-CT-
2005-018652 ‘CRESCENDO’] and the Ligue National Contre le
Cancer [laboratoire labelisé].
Notes and references
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Transactivation assays
The test compounds were dissolved in DMSO at 10 mM. These
stock solutions were diluted first in ethanol at 1 mM and then
were serially diluted in Dulbecco’s modified Eagle’s medium
(DMEM) without phenol red with gentamicin (40 μg mL−1).
For determination of RAR agonistic activity, HeLa reporter
cell lines were used, stably expressing chimera protein
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