Profluorescent substrates for the screening of olefin metathesis catalysts

Article abstract of DOI:10.3762/bjoc.11.203

Herein we report on a 96-well plate assay based on the fluorescence resulting from the ring-closing metathesis of two profluorophoric substrates. To demonstrate the validity of the approach, four commercially available ruthenium-metathesis catalysts were

Full text of DOI:10.3762/bjoc.11.203

Profluorescent substrates for the screening of olefin
metathesis catalysts
Raphael Reuter and Thomas R. Ward*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1886–1892.
Department of Chemistry, University of Basel, Spitalstrasse 51,
CH-4056 Basel, Switzerland
doi:10.3762/bjoc.11.203
Received: 18 June 2015
Email:
Accepted: 15 September 2015
Published: 12 October 2015
Thomas R. Ward* - thomas.ward@unibas.ch
*
Corresponding author
This article is part of the Thematic Series "Progress in metathesis
chemistry II".
Keywords:
fluorescence; microplate screening; ring closing metathesis
Guest Editor: K. Grela
©
2015 Reuter and Ward; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Herein we report on a 96-well plate assay based on the fluorescence resulting from the ring-closing metathesis of two profluoro-
phoric substrates. To demonstrate the validity of the approach, four commercially available ruthenium-metathesis catalysts were
evaluated in six different solvents. The results from the fluorescent assay agree well with HPLC conversions, validating the useful-
ness of the approach.
Introduction
Since its discovery in the 1950s, olefin metathesis has devel- based on different transition metals have been prepared and
oped into one of the most powerful catalytic reactions both in tailored towards specific applications [12]. With the ultimate
research as well as in industrial applications [1-3]. This is aim of identifying new olefin metathesis catalysts using high-
mostly due to its excellent chemoselectivity, tolerance of many throughput screening, we set out to develop and evaluate
functional groups and its atom economy [4]. Chemists treasure olefinic substrates amenable to a 96-well plate screening
its extraordinary versatility. From the production of polymers format.
[
5,6] and petrochemicals to the synthesis of complex natural
products [7], olefin metathesis has been established as a useful Results and Discussion
tool for solving numerous synthetic challenges. In more recent A quick and highly sensitive analytical method that is suitable
applications, metathesis has also been used in chemical biology, for the fast detection and quantification of small quantities of a
either in the form of an artificial metalloenzyme [8-10] or for product is fluorescence spectroscopy. In particular, biological
the post-translational modification of proteins [11]. To address applications heavily rely on fluorescence-based visualization
these various challenges, a vast number of carbene complexes techniques [13]. For this purpose, a large variety of fluorescent
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Beilstein J. Org. Chem. 2015, 11, 1886–1892.
probes have been developed that react to different chemical
stimuli [14]. Although previous work on the development of
fluorescent olefin metathesis catalysts [15,16] exists, to our
knowledge, the concept of fluorescent probes based on ring-
closing metathesis is new and could be of value to chemical
biologists. Since microplates are a very common and practical
tool for biological applications, we developed a screening assay
in 96-well plate format to quickly evaluate the reaction kinetics
of different commercially available metathesis catalysts. Since
fluorescence spectroscopy is a highly sensitive technique, we
aimed at using a low catalyst concentration (e.g., 100 µM) in a
small reaction volume (150 µL). With this format, only 1 mg
of catalyst is required to perform fifty to a hundred kinetic
experiments.
Figure 1: Catalysts 1–4 tested for the metathesis of profluorescent
substrates.
For this proof-of-principle study, we selected four commer-
cially available, second generation-type catalysts 1–4 dinitroaniline core, acting as a fluorescence quencher [17]. Both
Figure 1). These catalysts were mainly chosen because of their the sulfonamide of the fluorophore and the aniline group of the
(
high stability towards both air and moisture. Catalysts 1 and 2 quencher bear another allyl group. Upon relay ring-closing
are the phosphine-free Grubbs–Hoveyda and Grela-type cata- metathesis, the fluorophore and quencher are disconnected
lysts bearing different isopropoxystyrene ligands. Catalysts 3 resulting in the fluorescent product 7. A similar linker concept
and 4 are phosphine-containing Grubbs-type catalysts with has previously been implemented for a solid-phase linker in the
either a benzylidene ligand or an indenylidene ligand.
synthesis of oligosaccharides [18,19]. The second profluores-
cent molecule selected was diolefin 8, which yields fluorescent
As a model reaction, we selected ring-closing metathesis and 7-hydroxycoumarin (umbelliferone) (9) upon ring-closing
developed two profluorescent substrates that yield a fluorescent metathesis. The synthesis of coumarin derivatives using this ap-
product upon ring-closing metathesis (Scheme 1). Substrate 5 proach was described in previous publications [20,21]. By intro-
consists of a fluorescent 5-methoxynaphthalene-1-sulfonamide ducing an electron donor in the 7-position, a fluorescent prod-
moiety that is connected by an internal double bond to a 2,4- uct is obtained upon ring-closing metathesis [22].
Scheme 1: Two profluorescent substrates yielding fluorescent products upon ring-closing metathesis.
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Synthesis of the profluorescent substrates
a 96-well plate format screening was developed, relying on a
The synthesis of profluorescent substrate 8 leading to umbelli- total volume of 150 µL per experiment and 100 µM catalyst in
ferone after ring-closing metathesis was carried out according to the presence of 10 mM substrate. To demonstrate the versatility
a published, four-step procedure starting from 2,4-dihydroxy- of the method, the kinetics of the ring-closing metathesis with
benzaldehyde (10) with an overall yield of 50% [23,24]. The umbelliferone precursor 8 were determined with different cata-
synthesis of the fluorophore–quencher substrate 5 was achieved lysts 1–4 (Figure 2). It is known that acryloyl ester substrates
relying on two converging synthons (Scheme 2). The fluoro- are poor substrates which typically give low yields with 1st
phore part of the molecule was synthesized starting from generation precatalysts [27]. As the reactions were performed in
sodium 5-methoxynaphthalene-1-sulfonate (11), which was air and with very small volumes, high boiling solvents with
prepared according to a known procedure [25]. It was then different structural features were selected. From the screening,
transformed to the corresponding allyl sulfonamide 12 by the following features were apparent:
reacting the corresponding acid chloride with allylamine. The
quencher part of the molecule was prepared from commercial
-fluoro-2,4-dinitrobenzene (13). Following an alkylation step
1. Grubbs–Hoveyda and Grela catalysts 1 and 2 perform
better for substrate 8 in most solvents.
1
with allyl bromide, it was reacted with an excess of (E)-1,4-
dibromobut-2-ene to selectively afford the mono alkylated
product. A strong base (e.g., NaH) was crucial to achieve
complete deprotonation of the highly deactivated aniline [26].
The fluorophore and quencher parts were finally connected in
high yield relying on a nucleophilic substitution.
2. For solvents that contain a carbonyl or carboxyl function
(i.e., 2-methylpentanone and γ-butyrolactone), the
Grubbs 2nd generation catalyst 3 performs best.
3. In all cases, the initial ring-closing metathesis rates are
highest with precatalyst 2.
The same experiments were conducted with the
Ring-closing metathesis of substrates
fluorophore–quencher substrate 5 (Figure 3). In this case, the
With the aim of miniaturizing and automatizing the screening concentration of the substrate was reduced to 1 mM to miminize
effort for the identification of ring-closing metathesis catalysts, intermolecular quenching of fluorophore 7 by dinitroaniline 6.
Scheme 2: Synthesis of the two profluorescent substrates amenable to ring-closing metathesis.
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Figure 2: Fluorescence evolution resulting from closing metathesis of umbelliferone precursor 8 (λexcitation = 350 nm and λemission = 380 nm).
Different catalysts 1–4 (1: blue; 2: red; 3: green; 4: purple) were screened in different solvents (a: acetic acid; b: 2-methylpentanone; c: toluene;
d: o-xylene; e: γ-butyrolactone; f: anisole).
The following observations can be made:
Conclusion
In summary, two profluorescent substrates, 5 and 8, were
1
. Generally, a higher activity is observed for the Grubbs prepared and fully characterized. Upon ring-closing metathesis,
nd generation catalyst 3 as compared to the umbelli- they produce a fluorescent signal thus allowing a straightfor-
ferone substrate 8. The only exception is when acetic ward screening in a 96-well plate format. The validity of the ap-
acid is used as the solvent. proach was demonstrated by screening four commercially avail-
2
2
3
. The catalyst 4, being nearly inactive for the electron- able catalysts 1–4 in different solvents. Comparison between
poor substrate 8, showed increased activity for substrate the kinetics determined by HPLC and fluorescence showed
5
, especially in acetic acid.
good agreement. These profluorescent substrates could be
. Surprisingly, catalyst 1 was (one of) the worst per- prototypes for more complex structures that could find applica-
forming for this bulky substrate.
tions in ring-closing metathesis for biological applications by
fluorescence microscopy.
To validate the kinetics determined by fluorescence, the reac-
tion progress was monitored by HPLC for umbelliferone Experimental
precursor 8 in acetic acid (Figure 4). Gratifyingly, both the fluo- General Methods: The 1H and 13C NMR spectra were
rescence and HPLC techniques result in very similar trends.
recorded on Bruker 400 MHz and 500 MHz spectrometers. The
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Beilstein J. Org. Chem. 2015, 11, 1886–1892.
Figure 3: Fluorescence evolution resulting from closing metathesis of fluorescence–quencher substrate 5 (λexcitation = 320 nm and λemission = 400
nm). Different catalysts 1–4 (1: blue; 2: red, 3: green, 4: purple) were screened in different solvents (a: acetic acid; b: 2-methylpentanone; c: toluene;
d: o-xylene; e: γ-butyrolactone; f: anisole).
Figure 4: Comparison of kinetics measured by HPLC a) and by a plate reader b) for the ring-closing metathesis of 8 in acetic acid.
chemical shifts are reported in ppm (parts per million). Electro- measured on a Bruker maXis 4G QTOF-ESI spectrometer.
spray ionization mass spectra (ESIMS) were recorded on a HPLC was conducted on a Waters Acquity H-Class Bio UPLC
Bruker FTMS 4.7T bioAPEX II spectrometer. HRMS was device, using a BEH C-18 reversed-phase column. Starting ma-
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terials and reagents were purchased from commercial sources (E)-N-Allyl-N-(4-bromobut-2-en-1-yl)-2,4-dinitroaniline
and used without further purification. HPLC grade solvents (15). To a solution of N-allyl-2,4-dinitroaniline (14, 400 mg,
were used if not mentioned otherwise. For the fluorescence 1.79 mmol, 1.00 equiv) in dry DMF (7 mL), NaH (60% in
measurements, a TECAN Infinite M1000 platereader was used. mineral oil, 143 mg, 3.58 mmol, 2.00 equiv) and (E)-1,4-
dibromobut-2-ene (1.53 g, 7.16 mmol, 4.00 equiv) were added.
N-Allyl-5-methoxynaphthalene-1-sulfonamide (12). To a The mixture was stirred at 70 °C for 16 h. The mixture was
DMF solution (30 mL) of sodium 5-methoxynaphthalene-1- diluted with EtOAc (50 mL), washed with water (2 × 50 mL)
sulfonate (11, 1.30 g, 5.00 mmol, 1.00 equiv), cooled on an ice and dried over MgSO4. The solvent was removed under vacuum
bath, thionyl chloride (1.09 mL, 15.0 mmol, 3.00 equiv) was and the residue was purified by flash column chromatography
added dropwise. After the complete addition, the ice bath was (silica gel, cyclohexane/EtOAc 5:1) to obtain 300 mg of red oil
removed and the reaction was stirred at rt for 3 h. Then, it was (47%). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, 4JHH = 2.7 Hz,
poured onto 300 mL of ice water and extracted with ethyl 1H), 8.21 (dd, 3JHH = 9.4 Hz, 4JHH = 2.7 Hz, 1H), 7.09 (d, 3JHH
acetate (3 × 100 mL). The combined extracts were dried over = 9.4 Hz, 1H), 5.99–5.87 (m, 1H), 5.86–5.70 (m, 2H), 5.33 (d,
MgSO4 and the solvent was removed at reduced pressure. The 3JHH = 10.3 Hz, 1H), 5.28 (d, 3JHH = 17.2 Hz, 1H), 3.86–3.90
residual oil was taken up into DCM (100 mL). Allylamine was (m, 6H); 13C NMR (100 MHz, CDCl3) δ 148.1, 137.9, 137.7,
slowly added to the solution, while stirring. After complete ad- 131.8, 131.3, 128.4, 127.7, 123.7, 120.1, 119.4, 54.6, 53.2,
dition, the reaction mixture was allowed to stir overnight. The 31.0; HRMS [ESI(+)–TOF] m/z: [M + H]+ calcd for
solvent was removed under vacuum and the residue was puri- C13H15BrN3O4, 356.0246; found, 356.0239.
fied by flash column chromatography (silica gel, cyclohexane/
EtOAc 1:1) to obtain a colourless solid (893 mg, 64%). Substrate 5. A round bottom flask was charged with N-allyl-5-
1
H NMR (400 MHz, CDCl3) δ 8.46 (d, 3JHH = 8.4 Hz, 1H), methoxynaphthalene-1-sulfonamide (12, 449 mg, 1.62 mmol,
.22 (d, 3JHH = 8.7 Hz, 1H), 8.15 (s, 1H), 8.14 (d, 3JHH = 7.3 1.00 equiv), (E)-N-allyl-N-(4-bromobut-2-en-1-yl)-2,4-dini-
Hz, 1H), 7.66–7.58 (m, 2H), 7.13 (d, 3JHH = 7.6 Hz, 1H), 5.56 troaniline (15, 610 mg, 1.71 mmol, 1.06 equiv), K2CO3
8
(
(
(
(
ddt, 3JHH = 17.1 Hz, 3JHH = 10.3 Hz, 3JHH = 5.5 Hz, 1H), 5.05 (672 mg, 4.86 mmol, 3.00 equiv) and acetonitrile (20 mL). The
ddt, 3JHH = 17.1 Hz, 2JHH = 1.7 Hz, 4JHH = 1.7 Hz, 1H), 4.91 mixture was stirred at 70 °C overnight and filtered. The filtrate
ddt, 3JHH = 10.3 Hz, 2JHH = 1.5 Hz, 4JHH = 1.5 Hz, 1H), 4.01 was concentrated at reduced pressure and the residue was puri-
s, 3H), 3.45 (d, 3JHH = 5.5 Hz); 13C NMR (100 MHz, CDCl3) fied by flash column chromatography (silica gel, cyclohexane/
δ 155.1, 135.6, 134.2, 128.8, 128.6, 128.3, 126.9, 125.7, 123.8, EtOAc 3:1) to obtain 750 mg of an orange semi-solid (84%).
16.8, 116.2, 105.4, 55.9, 44.8; HRMS [ESI(+)–TOF] m/z: [M 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 4JHH = 2.7 Hz, 1H),
H]+ calcd for C14H16NO3S, 278.0851; found, 278.0845; 8.52 (d, 3JHH = 8.4 Hz, 1H), 8.26 (dd, 3JHH = 7.4 Hz, 4JHH =
Elemental analysis: anal. calcd for C14H15NO3S: C, 60.63; H, 1.3 Hz, 1H), 8.14–8.08 (m, 2H), 7.55–7.46 (m, 2H), 6.94–6.86
.45; N, 5.05; found: C, 60.48; H, 5.58; N, 5.25. (m, 2H), 5.72–5.34 (m, 4H), 5.26 (d, 3JHH = 10.3 Hz, 1H), 5.17
d, 3JHH = 17.1 Hz, 1H), 5.14–5.05 (m, 2H), 4.03 (s, 3H), 3.86
1
+
5
(
N-Allyl-2,4-dinitroaniline (14). A flask was charged with 2,4- (dd, 3JHH = 17.7 Hz, 3JHH = 6.1 Hz, 4H), 3.74 (dd, 3JHH = 17.8
dinitrofluorobenzene (13, 854 mg, 4.59 mmol, 1.00 equiv) and Hz, 3JHH = 5.3 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 155.8,
THF (10 mL). First, triethylamine (710 µL, 5.05 mmol, 147.9, 137.6, 137.4, 134.3, 132.7, 131.4, 130.8, 129.9, 129.5,
1
1
.10 equiv) and then allylamine (378 µL, 5.05 mmol, 128.41, 128.39, 127.61, 127.55, 126.7, 123.6, 123.3, 120.0,
.10 equiv) was added and the mixture was stirred for 2 h at rt 119.3, 119.1, 116.8, 104.8, 55.7, 54.5, 53.2, 49.1, 47.1; HRMS
until the TLC showed complete consumption. The solvent was [ESI(+)–TOF]: [M + H]+ calcd for C27H29N4O7S, 553.1757;
removed under reduced pressure and the residue was purified found, 553.1756; Elemental analysis: anal. calcd for
by flash chromatography (silica gel, cyclohexane/EtOAc 3:1) to C27H28N4O7S: C, 58.69; H, 5.11; N, 10.14; found: C, 58.83; H,
obtain 960 mg of a yellow solid (94%). 1H NMR (400 MHz, 5.45; N, 10.15.
CDCl3) δ 9.15 (d, 4JHH = 2.7 Hz, 1H), 8.69 (bs, 1H), 8.27 (dd,
3
JHH = 9.5 Hz, 4JHH = 2.7 Hz, 1H), 6.92 (d, 3JHH = 9.5 Hz, Ring-closing metathesis in 96-well plates: To each well,
1
1
H), 5.96 (ddt, 3JHH = 17.3 Hz, 3JHH = 10.2 Hz, 3JHH = 5.1 Hz, 142 µL of the selected solvent (cooled at 5 °C to minimize
H), 5.39–5.30 (m, 1H), 4.13–4.08 (m, 1H); 13C NMR (100 evaporation) was pipetted. Then, 5 µL of a 3 mM precatalyst
MHz, CDCl3) δ 148.3, 136.4, 131.6, 130.6, 130.3, 124.2, 118.3, stock solution was added. Finally, 3 µL of the substrate stock
14.3, 45.7; HRMS [ESI(+)–TOF] m/z: [M + H]+calcd for solution was added (for the coumarin substrate 8 a 1 M stock
1
C9H10N3O4, 224.0671; found, 224.0663. Elemental analysis: solution was used, for the fluorophore quencher substrate 5, a
anal. calcd for C9H9N3O4: C, 48.43; H, 4.06; N, 18.83; found: 50 mM stock solution was used). The plate was then sealed with
C, 48.26; H, 4.15; N, 19.08.
transparent plastic foil and analyzed using a fluorescence plate
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Beilstein J. Org. Chem. 2015, 11, 1886–1892.
1
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ChemPhysChem 2012, 13, 4195. doi:10.1002/cphc.201200637
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between the measurements (substrate 5: λexcitation = 320 nm;
λemission = 400 nm; substrate 8: λexcitation = 350 nm;
λemission = 380 nm).
1
doi:10.1055/s-2004-831301
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Supporting Information
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Supporting Information File 1
NMR spectra of synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
2.Xie, L.; Chen, Y.; Wu, W.; Guo, H.; Zhao, J.; Yu, X. Dyes Pigm. 2012,
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Bruneau, C.; Fischmeister, C. Olefin Metathesis in Green Organic
Solvents and without Solvent. In Olefin Metathesis: Theory and
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