Self-immolative aryl phthalate esters

Article abstract of DOI:10.1021/jo301698v

We report that aryl phthalate esters are robust self-immolative linkers. This linker is easy to conjugate and releases output phenols upon cleaving a fluoride-sensitive mask to yield a benign phthalic acid byproduct, making these linkers potentially useful as fluoride sensors and promising for use in biological and materials applications.

Full text of DOI:10.1021/jo301698v

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Self-Immolative Aryl Phthalate Esters
Kaitlyn M. Mahoney, Pratik P. Goswami, and Arthur H. Winter
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301698v • Publication Date (Web): 27 Nov 2012
Downloaded from http://pubs.acs.org on December 11, 2012
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Self-Immolative Aryl Phthalate Esters
Kaitlyn M. Mahoney, Pratik P. Goswami, Arthur H. Winter*
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2101d Hach Hall, Department of Chemistry, Iowa State University, Ames, IA
winter@iastate.edu
Abstract. We report that aryl phthalate esters are robust self-immolative linkers. This
linker is easy to conjugate and releases output phenols upon cleaving a fluoride-sensitive
mask to yield a benign phthalic acid byproduct, making these linkers potentially useful as
fluoride sensors and promising for use in biological and materials applications.
Introduction. Self-immolative linkers have become indispensible molecules for
connecting a cleavable mask to an output cargo molecule. 1-3 Upon an input reaction that
cleaves the mask, self-immolative linkers release their output cargo. Despite their
unsavory moniker, self-immolative linkers have proven to be extremely useful in
enzyme-activated prodrugs,4-12 chemical sensors,2,13-16 traceless linkers,17-20 biological
probes,21-24 and degradable polymers.1,25-33 Released chemical cargoes are often
biomolecules, drugs, or reporters such as fluorescent dyes. Linker structure can aid
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prodrugs by improving stability, solubility, biodistribution, pharmacokinetics,
bioavailability and activation.
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The ideal self-immolative linker does not impose: It is simple, stable, compatible with
water, and transforms into a benign byproduct upon releasing the output cargo.
Furthermore, such linkers should be easy to conjugate, readily adaptable to a variety of
inputs and outputs, and quickly release the output cargo upon the input reaction. In
particular, some common self-immolative linkers suffer from slow release of their output
cargo. New linkers that incorporate these desirable features would be highly useful.
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Scheme 1. Fast hydrolysis of the classic phenyl hydrogen phthalate hydrolysis in water followed by monitoring growth
and decay of phthalic anhydride (kinetic fits can be found in Supporting Information)
The hydrolysis of phenyl hydrogen phthalate is a classic case of neighboring group
participation, the mechanism of which has seen extensive investigation.34-37 Phenyl
hydrogen phthalate is a shelf-stable compound when stored away from moisture, but this
compound hydrolyzes rapidly in water (Scheme 1). It has been determined that the fast
ester hydrolysis of this compound is a case of intramolecular catalysis wherein the
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neighboring carboxylate group displaces the phenol to generate a water-unstable
anhydride that in turn spontaneously hydrolyzes to phthalic acid. In neutral water,
release of phenol is too fast to obtain accurate rate constants using standard UV-Vis
studies (τ < 5 sec), but the rate of release is slowed in more acidic water (τ = 23 sec, pH
5.7). The known favorable kinetics of this hydrolysis led us to test aryl phthalate esters
for use as self-immolative linkers.
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Using a fluoride-sensitive 2-(trimethylsilyl)ethyl ether group to mask the catalytic
carboxyl group, in combination with three phenolic cargos (phenol 1 plus the fluorescent
dyes 7-hydroxycoumarin 2 and 3-(2-benzothiazolyl)-7-hydroxycoumarin 3), we find that
aryl phthalate esters can indeed be exploited as self-immolative linkers. We show that
these linkers can be conjugated easily starting from phthalic anhydride, a cheap industrial
starting material in the manufacture of plastics, and “self-immolate” to ultimately yield
phthalic acid as a biologically benign byproduct upon release of the phenolic output.
Results and Discussion
O
O
O
O
O
SiMe3
O O
SiMe3
O O
SiMe3
O
O
O
O
O
O
O
N
1
3
2
S
Figure 1. Aryl phthalate esters described in this study.
Compounds 1-3 were synthesized and titrated with fluoride ion (Scheme 2). The
1
titration of 1 was followed by H NMR spectroscopy and titrations of 2 and 3 were
followed with fluorescence spectroscopy. The cleavage of the 2-(trimethylsilyl)ethyl
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mask for 2,3 by potassium fluoride (KF) in neat water occurs successfully but is very
slow, requiring excess fluoride ion to achieve reasonable deprotection over several hours
(1 is not very soluble in pure H2O; see Supporting Information for details). Thus, the
titration experiments were performed by initially dissolving 1-3 in organic solvent
(CH3CN or DMSO) with varying equivalents of tetrabutylammonium fluoride (TBAF) to
cleave the mask (which is much more rapid in organic solvent), followed by injection of a
small aliquot of this solution into buffered water for the fluorescence analysis for 2 and 3.
The titration of compound 2 is remarkable because we observe a 730-fold increase in
fluorescence upon complete fluoride deprotection as a consequence of the release of the
highly fluorescent 7-hydroxycoumarin dye. Thus, compound 2 acts as a fluoride sensor.
Curiously, compound 3 shows a decrease in fluorescence during the titration even though
the highly fluorescent free coumarin dye is released. This decrease in fluorescence is due
to the starting ester 3 being highly fluorescent, whereas ester 2 is essentially non-
fluorescent.
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Compounds 1-3 are stable in water/CH3CN/DMSO in the absence of fluoride, with no
decomposition observed after 1 day at room temperature. Additionally, NMR product
analysis after fluoride deprotection indicates that the organic end products are the free
phenolic compound as well as phthalic acid as the byproduct of the self-immolative
linker. Of note, the toxicity of phthalic acid has been studied due to its industrial use in
the synthesis of phthalate plastics and esters; it has not been found to be toxic (LD50
(mouse) is 2.53 g/kg). 38,39 These products lead us to postulate the mechanism of release
shown in Scheme 2. Surprisingly, our titrations indicate that compounds 2,3 require
three equivalents of fluoride to achieve complete deprotection, while 1 requires the
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expected 1 eq. of fluoride. This “excess” F- required for 2,3 is interesting since the
presumed mechanism for TMSE deprotection involves a single fluoride ion adding to the
silicon to eliminate ethane gas and trimethylsilylfluoride. To ensure that this observation
was not an artifact of fluorescence, we added 1 eq. fluoride to 2 and observed only ca.
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1
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33% decomposition of 2 by H NMR. Additionally, F NMR following deprotection
suggest a different product for 1 than for 2,3 (see Supporting Information). Possibly,
deprotection of 2 and 3 proceed through a hypervalent silicon mechanism, although
further work would be needed to verify this mechanistic possibility.
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Figure 2. Fluoride titrations by NMR for 1 (top) and by fluorescence detection for 2
(middle) and 3 (bottom) in pH 7.0 buffer. Plot inserts depict fluorescence (or NMR
integration) at the emission maxima vs. equivalents of tetrabutyl ammonium fluoride.
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-
-
SiMe3
TBAF
O
CO2
CO2
R
O
O
O
O
O
O
O
H2O
O
O
HO
R
R
R
R
HO
O
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R
R
R
Scheme 2. Putative mechanism of decomposition of 1-3 with F- ion.
Conclusion. In conclusion, we have shown that aryl phthalate esters are robust self-
immolative linkers in water using a fluoride sensitive mask as a test case and phenolic
outputs. The phthalate scaffold also appears to be highly promising for latent
fluorophores, given the ~103 fluorescence enhancement upon releasing 7-
hydroxycoumarin. Ester 2 may be useful as an interesting fluoride sensor. The
advantages of this linker include a simple synthesis from inexpensive starting materials
and a biologically benign byproduct. Given the favorable release kinetics of phenol from
phenyl hydrogen phthalate (Scheme 1), the release kinetics of the output phenol may
prove to be favorable, although we cannot directly measure the release directly from 1-3
due to the slow rate of fluoride deprotection of the silyl mask. The possibility of tuning
the rate of release by chemical substitutions to the phthalate ring system, as well as the
scope of this linker for different masking groups and output cargos, is currently under
investigation in our laboratory. Through the use of different masks for the catalytic
carboxylate such as those cleaved by light or enzymes, these phthalate esters may find
use in biological and materials applications. For example, our preliminary studies
indicate that substitution of the 2-(trimethylsilyl)ethyl group in compound 2 with the 2-
nitrobenzyl photocage leads to release of the free coumarin dye upon photolysis in neat
water.
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Synthetic schemes. Compounds 1-3 were prepared from phthalic anhydride (See
Scheme 3). Addition of TMSE to phthalic anhydride yields the TMSE-protected acid
ester, which was further converted to aryl esters 2,3 using the Stieglich DCC/DMAP
coupling procedure. For 1, esterification of phenyl hydrogen phthalate was accomplished
in a similar way using DCC/DMAP conditions.
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O
O
O
SiMe3
SiMe3
HO
toluene
SiMe3
SiMe3
O
OH
O
OAr
O
DCC, DMAP
Ar-OH
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O
O
2, 3
O
O
O
O
O
SiMe3
HO
-
+
1.
Ph-O K
O
O
OH
O
O
DCC, DMAP
2. HCl
O
1
Scheme 3. Synthesis of 1-3.
Experimental procedures. Phenyl hydrogen phthalate, 37 2-(trimethylsilyl)ethyl
hydrogen phthalate, 40 and 3-(2-benzothiazolyl)-7-hydroxycoumarin 41 were prepared by
published procedures. All NMR matched the known spectra.
Synthesis of phenyl 2-(trimethylsilyl)ethyl phthalate 1. Phenyl hydrogen phthalate (1.50 g,
6.21 mmol), 2-trimethylsilylethanol (1 mL, 6.98 mmol) and 4-N,N-
dimethylaminopyridine (0.085 g, 0.69 mmol) were dissolved in dry DMF (4 mL),
followed by continuous stirring of the solution. N,N-dicyclohexylcarbodiimide (1.54g,
7.45 mmol), dissolved in dry DMF (2 mL), was next added to the reaction mixture and
the reaction was stirred under an argon atmosphere overnight. The dicyclohexylurea
byproduct was filtered off as a white solid. The solvent was then removed under reduced
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pressure to yield the crude product as a yellow oil. Flash chromatography (Hex/EtOAc,
90:10) gave the pure final product (0.595 g, 28%) as a colorless oil. (1H NMR, CD3OD,
400 MHz) δ 7.90 (m, 1H), 7.83 (m, 1H), 7.70 (m, 2H), 7.46 (m, 2H), 7.29 (m, 3H), 4.44-
4.40 (m, 2H), 1.09 (m, 2H), 0.04 (s, 9H); (13C NMR, CD3OD, 100MHz) δ 169.1, 167.9,
152.5, 133.9, 133.1, 132.9, 132.7, 130.7, 130.4, 130.2, 127.3, 122.7, 65.4, 18.3, -1.4;
High-res MS(ESI) calculated for formula C19H23O4Si (M+H)+ requires 343.1360; found
343.1360; for formula C19H23O4SiNa ((M+Na)+ requires 365.1180, found 365.1187
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Synthesis of 7-hydroxycoumarinyl 2-(trimethylsilyl)ethyl phthalate 2. 2-
(trimethylsilyl)ethyl hydrogen phthalate (1.29 g, 4.83 mmol), 7-hydroxycoumarin (1.21
g, 4.83 mmol), and 4-dimethylaminopyridine (0.65 g, 5.3 mmol) were dissolved in a
mixture of anhydrous methylene chloride (15 mL) and anhydrous DMF (9 mL). N,N-
dicyclohexylcarbodiimide was quickly added to the reaction mixture and stirred under
argon overnight. Dicyclohexyl urea was filtered off and the filtrate was diluted in 10 mL
of methylene chloride. The solution was washed with brine and then dried over
anhydrous MgSO4. The crude product was collected by evaporation under reduced
pressure and then purified by flash chromatography on silica gel (Hex/EtOAc, 70:30) to
yield 2 (0.65g, 33%) as a white solid: (1H NMR CDCl3, 400 MHz) δ 7.87, (m, 2H), 7.73
(d, 1H, J = 8 Hz), 7.64 (m, 2H), 7.57 (d, 1H, J = 8 Hz), 7.34 (s, 1H), 7.30 (s, 1H), 6.43
(d, 1H, J = 8 Hz), 4.43 (t, 2H, J = 8 Hz), 1.11 (t, 2H, J = 8 Hz), 0.06 (s, 9H); (13C NMR
CDCl3, 100 MHz) δ 167.2, 166.2, 160.7, 155.1, 153.7, 143.2, 132.0, 131.8, 131.7, 129.6,
129.4, 128.9, 118.7, 117.2, 116.5, 110.8, 64.7, 17.7, -1.1. High-res MS (ESI) calcd. for
formula C22H22O6Si (M+H)+ requires 411.1258; found, 411.1261. C22H22O6SiNa
(M+Na)+, requires 433.1078, found 433.1083
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Synthesis of 3-(benzo[d]thiazol-2-yl)-7-hydroxycoumarinyl-2-(trimethylsilyl)ethyl
phthalate 3. 2-(trimethylsilyl)ethyl hydrogen phthalate (50 mg, 0.34 mmol), 3-(2-
benzothiazolyl)-7-hydroxycoumarin (99 mg, 0.34 mmol), and 4-dimethylaminopyridine
(4 mg, 0.034 mmol) were dissolved in DMF (5 mL). N,N-dicyclohexylcarbodiimide (69
mg, 0.34 mmol) was quickly added to the reaction mixture and was stirred under argon
for 12 h. The white solid was filtered off and the DMF was removed by evaporation
under reduced pressure. The crude mixture was purified by preparatory thin-layer
chromatography (200 microns) using a (Hex/EtOAc, 70:30) eluent followed by an
additional prep TLC purification using (Hexane/EtOAc, 50:50) to yield the product 3 (37
mg, 20%) as a yellow solid: (1H NMR CDCl3, 400 MHz) δ 9.11 (s, 1H), 8.12 (d, 1H, J=8
Hz), 8.01 (d, 1H, J = 8 Hz), 7.89 (m, 2H), 7.81 (d, 1H, J = 8 Hz), 7.66 (m, 2H), 7.56 (t,
1H, J = 8 Hz), 7.48 (s, 1H), 7.45 (s, 1H), 7.40 (dd, 2H, J = 4 Hz), 4.45 (t, 2H, J = 8 Hz),
1.12 (t, 2H, J = 8 Hz), 0.07 (s, 9H); (13C NMR CDCl3, 100 MHz) δ 167.1, 166.2, 160.0,
159.9, 154.9, 152.7, 141.24, 137.2, 132.3, 132.1, 131.9, 131.8, 130.6, 129.7, 129.5, 126.9,
125.8, 123.3, 122.1, 120.1, 119.7, 117.3, 110.68, 64.8, 17.7, -1.1. High-res MS (ESI)
calcd. for formula C29H26NO6SSi (M+H)+ requires 544.1245; found, 544.1248.
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1H NMR titration of 1. A stock solution of 1 was prepared (9.05 x 10-2 M) in DMSO-D6
and distributed equally (97 µL) into 12 vials. To these vials was added varying
equivalents of a second stock solution made of 1M TBAF/THF (7.44 x 10-2M) in DMSO-
D6. After 4 h, 0.5 ml D2O was then added to each vial. 1H NMR spectra of each was then
recorded. The titration was repeated three times and the results were averaged.
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Conversion was calculated by measuring the ratio of DMSO-D6 signal integration with
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the integration of the –CH2 peak (δ 4.42 ppm) in 1.
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Fluorescence titration of 2 and 3. A stock solution of 2 was prepared (7.68 x 10-5M) in
acetonitrile and distributed equally (52 µL) into vials. These samples were titrated using
varying equivalents of a 1M TBAF in THF solution for 4 h to ensure complete
deprotection of the TMSE group. The samples were then diluted with 1 mM phosphate
buffered (pH = 7.0) water to 3.0 mL. Excitation was carried out at 370 nm with all
excitation and emission slit widths at 2 nm. The titration was repeated three times and
the data were averaged. The same experimental procedure was used in the titration of
compound 3 except the stock solution (2.3 x 10-6 M) was prepared in DMF, and the
excitation of these scans was carried out at 440 nm.
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Supporting information. All experimental data including kinetic plots, stability tests,
full titration plots, synthetic procedures and compound characterizations. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment We acknowledge the Iowa State VPR office, IPRT, and the
Petroleum Research Fund for financial support.
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