A fluorescent sensor for thymine based on bis-BODIPY containing butanediamido bridges

Article abstract of DOI:10.1039/C9NJ00406H

The sensor for thymine detection has a great significance in the analysis of deoxyribonucleic acid in living organisms. In this work, a series of bis-BODIPY derivatives, namely, 3a-3c with diamido bridges were designed and prepared in yields of 74-77% through a simple procedure. The sensing abilities of compounds 3a-3c for adenine, guanine, cytosine, thymine, glucose, urea and haemoglobin were examined by UV-vis and fluorescence spectra. Sample 3b was demonstrated to be a good selective sensor for thymine among all the other tested species. The detection limit of sample 3b was as low as 1.53 × 10^?6 M for thymine. The competitive experiments suggested that the selective sensor for thymine was influenced slightly by the other species. The proposed sensing mechanism was confirmed by FT-IR, ¹H NMR and MS spectra. Sample 3b exhibited good bioimaging performance with bright green fluorescence in living cell imaging. The significant fluorescence quenching phenomenon after the addition of thymine implied the sensing ability of sample 3b for thymine in living cells.

Full text of DOI:10.1039/C9NJ00406H

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A fluorescent sensor for thymine based on
bis-BODIPY containing butanediamido bridges†
Cite this:DOI: 10.1039/c9nj00406h
abc
Jiahui Bi,a Xiaoyu Ji,a Meiyan Guo,a Hongyu Guo*ab and Fafu Yang
*
The sensor for thymine detection has a great significance in the analysis of deoxyribonucleic acid in living
organisms. In this work, a series of bis-BODIPY derivatives, namely, 3a–3c with diamido bridges were designed
and prepared in yields of 74–77% through a simple procedure. The sensing abilities of compounds 3a–3c for
adenine, guanine, cytosine, thymine, glucose, urea and haemoglobin were examined by UV-vis and fluorescence
spectra. Sample 3b was demonstrated to be a good selective sensor for thymine among all the other tested
species. The detection limit of sample 3b was as low as 1.53 Â 10À6 M for thymine. The competitive experiments
suggested that the selective sensor for thymine was influenced slightly by the other species. The proposed
Received 23rd January 2019,
Accepted 11th March 2019
1
sensing mechanism was confirmed by FT-IR, H NMR and MS spectra. Sample 3b exhibited good bioimaging
DOI: 10.1039/c9nj00406h
performance with bright green fluorescence in living cell imaging. The significant fluorescence quenching
rsc.li/njc
phenomenon after the addition of thymine implied the sensing ability of sample 3b for thymine in living cells.
detection of ions or organic molecules. Among the numerous
fluorophores, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (abbre-
Introduction
Deoxyribonucleic acid (DNA) is an important biomolecule in the viated as BODIPY) and its derivatives have been considered as
living organisms, which encodes genetic information via four favourable fluorescent sensors due to their outstanding charac-
bases: guanine, adenine, thymine and cytosine.1 The changes in teristics and photophysical properties including high excitation
the concentration of these bases may result in mutation or coefficients, high fluorescence efficiencies, high photostabilities,
irregularity in the immune system and may also indicate the very low photo-toxicities, and negligible cytotoxicities.15–21
presence of various diseases such as intellectual disability, As a result, many kinds of BODIPY derivatives were prepared
ageing, cancer, renal failure and cardiovascular diseases.2 There- by introducing various functional groups on the BODIPY skeletons,
fore, the qualitative or quantitative analysis of these changes has which exhibited effective fluorescence sensing abilities for metallic
a great significance.3 Up to now, various analytical methodo- cations such as Hg2+,22,23 Cu2+,24,25 Zn2+,26 Ag+,27 Na+,28 Cd2+,29 and
logies including gas chromatography,4 liquid chromatography,5 K+.30 Lately, some BODIPY-based fluorescent probes were also
fluorescence spectroscopy,6,7 immunocytochemical method,8 reported as effective sensors for organic functional species
capillary electrophoresis,9 and electrochemical methods10–14 including polar biothiols,31 formaldehyde,32 and hydroxyl-
have been used to determine the DNA bases in a variety of amine.33 Although much progress was made in the field of
samples. Generally, most of these methods are expensive and BODIPY-based sensors, no BODIPY-based fluorescent probes for
tedious with complicated preparation processes for detecting thymine have been investigated so far. In this paper, a series of
materials and/or testing samples prior to instrumental analysis. bis-BODIPY derivatives containing diamido bridges were designed
Moreover, there are a few methods concerning the selective and synthesized. The fluorescence sensing abilities of these novel
quantitative analysis of a special DNA base such as thymine BODIPY derivatives for DNA bases were investigated. The results
from biological samples.7 Hence, a simple and effective method suggested that the bis-BODIPY containing butanediamido bridges is
for selectively detecting thymine or other DNA bases is expected. a good selective sensor for thymine, which was observed for the first
In recent years, sensors based on fluorescence changes have time for BODIPY probes. Moreover, it was applied successfully for
attracted much attention due to their simple and efficient the sensitive detection of thymine in living cells.
a College of Chemistry and Materials, Fujian Normal University, Fuzhou 350007,
P. R. China. E-mail: yangfafu@fjnu.edu.cn
Results and discussion
Synthesis
b Fujian Key Laboratory of Polymer Materials, Fuzhou 350007, P. R. China
c Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical
Engineering, Fuzhou 350007, P. R. China
The synthetic routes are illustrated in Scheme 1. According
to previously reported procedures,34 by treating diamines
† Electronic supplementary information (ESI) available: Experimental details,
supporting figures and table. See DOI: 10.1039/c9nj00406h
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Selective detection of thymine as a biochemical sensor
Biomolecules including adenine, guanine, cytosine, thymine,
glucose, urea and haemoglobin were used for the selective
detection of novel bis-BODIPY derivatives 3a, 3b and 3c. The
spectral changes in the UV-vis spectra and fluorescence spectra
of samples 3a, 3b and 3c with these biomolecules were inves-
tigated to determine their binding abilities. The UV-vis spectra
are shown in Fig. S10–S12 (ESI†). It can be seen that the
maximum absorbances of samples 3a, 3b and 3c with different
biomolecules fluctuate significantly (increase in varying
degrees), indicating the strong interactions between samples
3a, 3b and 3c and the tested species. Moreover, Fig. 1 illustrates
the fluorescence spectra of samples 3a, 3b and 3c with different
biomolecules. One can see that all the maximum fluorescence
emission wavelengths of samples 3a, 3b and 3c exhibit no
obvious changes (lem = 513 nm), indicating that the inter-
actions between the samples 3a, 3b and 3c and the tested
species did not influence the conjugated molecular structures
of BODIPY skeletons. Furthermore, the maximum emission
intensities of these spectra exhibited remarkable changes,
suggesting the existence of strong interactions between the
samples 3a, 3b and 3c and the tested species. As shown in
Fig. 1A and C, compared to the fluorescence intensities of
samples 3a and 3c with no tested biomolecules, the intensities
of samples 3a and 3c with all the tested biomolecules decrease
significantly. However, negligible binding selectivity was observed.
The spectrum of sample 3b with tested species exhibits different
changes in comparison with those of samples 3a and 3c. The
fluorescence intensities of sample 3b with adenine, guanine,
cytosine, glucose, urea and haemoglobin show slight decrease
(decreasing ratio of 11–23%) from 540 to 433, 430, 440, 476 and
413, respectively. It was interesting that the fluorescence intensity
of sample 3b with thymine displayed outstanding decrease from
540 to 198 (decreasing ratio of 63%), indicating that it is an
excellent selective sensor for thymine. The fluorescence quantum
yields of sample 3b in the absence of test species and in the
presence of adenine, guanine, cytosine, glucose, urea, haemo-
globin and thymine were measured as 0.93, 0.75, 0.73, 0.77, 0.83,
0.71, 0.86 and 0.33, respectively. These results also implied that
sample 3b possessed selective sensor abilities for thymine. Thus,
the selective sensor abilities of sample 3b for thymine were further
studied in detail by fluorescence titration, 1H NMR titration,
binding ESI-MS spectra, binding FT-IR spectra, competitive
experiments, and application in living cell imaging. The fluores-
cence quenching mechanism was also proposed and confirmed.
Scheme 1 The synthetic routes for target samples 3a, 3b and 3c.
(ethylenediamine, butanediamine and hexamethylendiamine)
with chloroacetic chloride, the corresponding chlorinated
diamido derivatives 1a, 1b and 1c were prepared conveniently.
Also, using 4-hydroxy benzaldehyde and 2,4-dimethyl pyrrole
as starting materials, OH-BODIPY 2 was obtained by sequential
condensation, oxidation, and complexation reactions in the
moderate yield of 25% after rapid columnar chromatography.35
Finally, the target bis-BODIPY derivatives with diamido bridges
3a–3c were synthesized via the ‘‘1+2’’ condensation of compounds
1a–1c with compound 2 in the K2CO3/MeCN system using KI as a
catalyst. The yields obtained after column chromatography were
as high as 74–77%.
The structures of bis-BODIPY derivatives 3a–3c were charac-
terized by 1H NMR spectra, 13C NMR spectra, HR-ESI-MS
1
spectra and elemental analysis (see ESI†). In H NMR spectra,
two singlets for CH3, a pair of doublet and one singlet for
ArH, one singlet for OCH2CO and one broad singlet for NH
certainly suggest that two BODIPY units are bridged by the
diamido spacers. The data of 13C NMR, HR-ESI-MS and
elemental analysis were also in accordance with the structures
of compounds 3a–3c. It was worth noting that unlike the other
reported bis-BODIPY structures,30,36–42 compounds 3a–3c are
the first examples of bis-BODIPY derivatives bridged with soft
Fluorescence titration of thymine
diamido spacers, which is favorable to adjust the positional A fluorescence titration of thymine was performed to explore
orientation of the two BODIPY units when binding guests in the detecting behaviors of sample 3b in detail. The fluorescence
the cavities surrounded by BODIPY units and soft diamido spectra of sample 3b (1 mM) in DMSO/H2O (1 : 9) solutions with
spacers. Moreover, the amido (NH–CQO) groups also con- different concentrations of thymine (1 mM) at lex = 480 nm are
tributed to the binding of the DNA bases based on a strong shown in Fig. 2. By adding a series of different concentrations
hydrogen-bonding action. Thus, the sensing abilities of these of thymine, the fluorescence could be quenched rapidly. For
novel bis-BODIPY derivatives for DNA bases were studied example, when we added 1.0 eq., 2.0 eq. and 5.0 eq. thymine to
in detail.
the solutions, the fluorescence intensities decreased to 37%,
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Fig. 2 Fluorescence spectra of sample 3b (1 mM) in DMSO/H2O (1 : 9)
solutions with different concentrations of thymine (1 mM) at lex = 480 nm.
Inset: The fluorescence images of sample 3b without and with thymine
(5 mM), respectively.
Fig. 3 Fluorescence intensity (513 nm) of sample 3b (1 mM) in DMSO/H2O
(1 : 9) solutions with different concentrations of thymine (1 mM) at lex
480 nm. The inset shows the change in intensity from 0.05 to 0.7 mM
concentrations of thymine.
=
Fig. 1 Fluorescence spectra of samples 3a, 3b and 3c (1 mM) in DMSO/
H2O (1 : 9) solutions with biomolecules (1 mM) at lex = 480 nm. (A) Sample
3a, (B) sample 3b, and (C) sample 3c.
26% and 19%, respectively. Furthermore, Fig. 3 illustrates the plot
of fluorescence intensity at 513 nm versus the concentration of
thymine. The plot between 0.05 eq. and 0.7 eq. of thymine is
enlarged as the inset part, which shows a good linear relationship,
thereby indicating the 1 : 1 binding stoichiometry for sample 3b and
thymine. Based on the calculated formula for the detection limit
DL = K Â Sb1/S (K = 2 or 3; taking the value = 2 here, Sb1 is the
standard deviation of the blank solution and S is the value of the
slope of the standard curve),43 the detection limit could be calculated
as DL = 1.53 Â 10À6 M. This detection limit was low in comparison
with the detection limits of thymine reported in literature,7,13,14
suggesting that sample 3b is a good sensor for thymine.
and metal cations. The results are shown in Fig. 4. One can see that
the fluorescence intensities of sample 3b with thymine fluctuate to
a certain degree after the addition of interference species. The
values of (I0 À I)/(I0 À Ithymine) changed in the range of 1.01–1.08,
implying the slight influence of the interference species on selec-
tively sensing thymine. These interference experiments suggested
that sample 3b is a good selective sensor for thymine under
complicated circumstances containing other competing species.
pH influence on sensing abilities
The sensing stabilities in the pH range of 4–10 were investigated,
as shown in Fig. 5. It can be seen that 3b has good fluorescence
stability at pH 6–8, and the fluorescence intensities decrease
significantly when pH o 6 or pH 4 8. Also, 3b + thymine
Interference experiments
The selective sensing of thymine by sample 3b was further exhibited the strongest fluorescence quenching at pH = 7 and
investigated by interference experiments with various biomolecules remained stable between pH 6 and 8. When pH o 6 or pH 4 8,
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Fig. 6 FT-IR spectra of sample 3b before and after binding thymine (1 : 1).
Fig. 4 Competitive experiments of sample 3b + thymine with interfering
species; [3b] = 1 mM, [thymine] = [interfering species] = 5 mM in DMSO/H2O
(1 : 9) solutions; lex = 480 nm; T = thymine, C = cytosine, Gu = guanine,
A = adenine, Gl = glucose, and U = urea.
Fig. 7 The comparison of 1H NMR spectra of sample 3b (lower), thymine
(upper) and 3b with thymine (1 : 1) (middle).
from a low field to a high field, indicating the strong hydrogen-
bonding action of N–HÁ Á ÁO groups between the sample 3b and
thymine. The signals of ArH in the BODIPY skeleton shift from
5.97 ppm to 6.21 ppm and that of the methyl proton on BODIPY
exhibits a down-field shift, suggesting the existence of p–p
stacking between sample 3b and thymine and the transfer
of p-electron cloud from the BODIPY skeleton (p-donor) to
thymine (p-receptor). Fig. 8 shows the ESI-MS spectra of sample
3b with excess thymine (1 : 5). The results implied that only a
1 : 1 complex compound was observed at m/z of 975.7332.
No other complex peak appeared even when excess thymine
was added. This phenomenon suggested the presence of 1 : 1
binding system for sample 3b with thymine, which was in
accordance with the result of fluorescence titration. Thus,
Fig. 5 The fluorescence intensities of 3b and 3b + thymine in DMSO/H2O
(1 : 9) solutions at different pH values; [3b] = [thymine] = 1 mM, lex = 480 nm.
the fluorescence enhanced significantly, indicating that the
sensing abilities became weak. These results implied that the
pH values greatly influenced the sensing abilities and compound
3b exhibited good sensing properties at pH 6–8 (the normal
pH range of living bodies).
Detection mechanism
The detection mechanism for thymine was investigated via based on the results of FT-IR, 1H NMR and MS spectra of
1
recording FT-IR spectra, H NMR spectra and MS spectra. The sample 3b with thymine, the possible binding model was
FT-IR spectra of sample 3b before and after binding thymine proposed (Fig. 9). Before complexation, the alkyl group of the
are displayed in Fig. 6. By comparing with the FT-IR spectra of diamido bridge was in a random linear conformation, in which
sample 3b and thymine, obvious changes were observed for the distance between the two BODIPY units was too long
the signals of H–NCQO and C–O bonds of sample 3b with to produce p–p stacking and the effect of the fluorescence
thymine. For example, the peak of H–NCQO in thymine and quenching was very weak. However, after complexation with
the CQO in sample 3b at 3391 cmÀ1 and 1682 cmÀ1 shifted to thymine, the distance between the two BODIPY units became
3210 cmÀ1 and 1727 cmÀ1, respectively, indicating the exis- less due to the hydrogen-bonding action between 3b and
tence of hydrogen bonds between sample 3b and thymine. thymine, resulting in enhanced p–p stacking of BODIPY–
Furthermore, the comparison of the 1H NMR spectra of sample thymine–BODIPY, producing photoinduced electron transfer
3b, thymine and 3b with thymine (1 : 1) is shown in Fig. 7. One (PET) and finally strong fluorescence quenching. Due to p–p
can see that the signals of N–H for sample 3b and thymine shift stacking, the aromatic ring plane of thymine was parallel to the
from a high field to a low field and the signals of OCH2CO shift BODIPY plane, due to which NH of thymine could not interact
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Fig. 8 The ESI-MS spectrum of sample 3b with thymine (1 : 5).
Fig. 10 Confocal fluorescence images of MCF-7 cells before and after
incubation with sample 3b (1.0 mM). (A)–(C) MCF-7 cells; (D)–(F) sample
3b-MCF-7 cells; (G)–(I) sample 3b-MCF-7 cells-thymine (5.0 mM). Left
images are bright field images, middle images are fluorescence images,
and right images are the merged images of fluorescence and bright
field (lex = 488 nm). Scale bar is the same for all the images (as shown
in image G).
Fig. 9 The proposed binding mechanism of 3b with thymine.
with 3b, which agreed with the weak shift in the peak of NH of
thymine after complexation. This proposed mechanism not
only was in accordance with the results of the binding spectral
studies but also explained well the fluorescence quenching in
the fluorescence titration experiment. This kind of selective
binding of thymine was observed for BODIPY derivatives for the
first time.
Conclusions
In conclusion, a series of bis-BODIPY derivatives 3a–3c with
diamido bridges were designed and synthesized in yields of
74–77%. The sensing abilities of compounds 3a–3c for bio-
molecules including adenine, guanine, cytosine, thymine,
glucose, urea and haemoglobin were investigated by UV-vis
and fluorescence spectra. The results suggested that sample 3b
is a good selective sensor for thymine. The detection limit for
thymine was as low as 1.53 Â 10À6 M. The other species slightly
influenced the selective sensing of thymine. The proposed
Application in living cell imaging
As thymine is an important biomolecule in living organisms,
it is interesting to investigate the thymine-sensing properties of
sample 3b in living cells, which are usually explored by fluores-
cence living cell imaging.44–46 Therefore, the fluorescences in
living cells with sample 3b or sample 3b and thymine were studied
by confocal laser scanning microscopy (CLSM). On examining the
MCF-7 cell metabolic activity with an MTT assay, it was found that
the cell viability was above 89% under the concentration of 1.0 mM
for 24 h at 37 1C (Fig. S13, ESI†). Then, by incubating with sample
3b for 1 hour at 37 1C in a culture medium, MCF-7 cells were fixed.
1
sensing mechanism was supported by FT-IR spectra, H NMR
spectra and MS spectra. The experiment of living cell imaging
of sample 3b revealed that sample 3b possessed good bioimaging
performance with bright green fluorescence and exhibited
sensing ability for thymine with the feature of fluorescence
quenching, implying the application prospect in thymine detec-
tion in a living body.
The fluorescence signals of living cells were detected at lex
=
488 nm. Fig. 10 illustrates the corresponding fluorescence images.
These images suggest that the cells with sample 3b exhibit bright
green living cell images, indicating that the sample 3b has
excellent bioimaging performance. Moreover, after thymine was
added in the culture medium, the brightness of fluorescence
Experimental
Chemicals and methods
quenched obviously. These changes implied that sample 3b is a All the chemical reagents were obtained from commercial
good fluorescence sensor for thymine in living cells, and they were suppliers and were used directly. TLC analysis was carried out
in accordance with the results of experiments in solution. These on pre-coated glass plates. Column chromatography was per-
results confirmed the good bioimaging abilities of sample 3b to formed using a silica gel (200–300 mesh). NMR spectra were
sense thymine in living cells.
recorded in CDCl3 on a Bruker-ARX 400 instrument at 26 1C
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using tetramethylsilane (TMS) as an internal standard. MS spectra (C48H54B2F4N6O4) [M]+: calcd: 876.4979; found: 876.5011; anal.
were recorded using a Bruker mass spectrometer. Elemental calcd for C48H54B2F4N6O4: C 65.77, H 6.21, N 9.59; found:
analyses were performed using a Vario EL III Elemental Analyzer. C 65.71, H 6.17, N 9.51%.
The UV-vis spectra were measured on a Varian UV-vis spectro-
meter. Fluorescence spectra were recorded in a conventional
MTT assay
quartz cell (10 Â 10 Â 45 nm) at 25 1C on a Hitachi F-4500
Methylthiazolyldiphenyl-tetrazolium (MTT) trials were used
spectrometer equipped with a constant-temperature water bath
and excitation and emission slits 10 nm wide. The fluorescence
absolute quantum yield (FF) was examined on an Edinburgh
Instruments FLS920 Fluorescence Spectrometer with a 6-inch
integrating sphere. Compounds 1a, 1b and 1c were prepared
according to previously reported methods.33 Compound 2 was
synthesized by a reported procedure.29 The MCF-7 cancer cells
were supplied by the School of Pharmacy, Fujian Medical
University.
to explore the toxicity for MCF-7 cancer cells. The inoculated
MCF-7 cancer cells were cultivated at 37 1C and 5% CO2 for
24 hours. Then, 1.0 mM of sample 3b was tracked in the cells
after incubating for 24 h. Furthermore, fostered cells were
washed using PBS buffer and continued fostering for 3 hours in
0.5 mg mLÀ1 MTT–PBS buffer. Finally, 100 mL of DMSO was
added to dissolve the generated formazan crystals, and the
absorption intensity was examined at 490 nm.
The experiment of living cell imaging
Synthetic procedure for compounds 3a, 3b and 3c
Sample 3b (3.0 mg) was dissolved in 1 mL of DMSO and then
diluted using PBS buffer (pH = 7.4) to a concentration of 1.0 mM
for imaging test. The MCF-7 cancer cells were cultivated in the
same conditions as those used for MTT trials mentioned above
for 24 h and then dyed by 1.0 mM of sample 3b. After washing
with PBS buffer, the dyed cells were treated to a solution of
thymine (5.0 mM) for 1 hour at 37 1C. Then, the cells were
imaged by a confocal laser scanning microscope (CLSM, Zeiss
LSM 710, Jena, Germany).
Under an N2 atmosphere, a mixture of compound 1a (1b or 1c,
0.6 mmol), compound 2 (0.41 g, 1.2 mmol), dry K2CO3 (0.41 g,
3 mmol) and KI (0.10 g, 0.6 mmol) was stirred and refluxed in
30 mL of dry MeCN for 24 h. TLC detection suggested the
disappearance of starting materials. After cooling, 50 mL of HCl
solution (1 M) and 60 mL of CH2Cl2 were added to the reaction
system. The obtained mixture was stirred for half an hour and
then, the organic layer was separated. The organic portion was
dried using anhydrous MgSO4 and further concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: CH2Cl2 : petroleum ether = 4 : 1);
bis-BODIPY derivatives 3a, 3b and 3c were collected as red
solids in yields of 74%, 76% and 77%, respectively.
Conflicts of interest
There are no conflicts to declare.
Compound 3a. 1H NMR (400 MHz, CDCl3) d (ppm): 1.37
(s, 12H, CH3), 2.51 (s, 12H, CH3), 3.55 (s, 4H, NCH2), 4.55 (s, 4H,
OCH2), 5.95 (s, 4H, ArH), 7.05 (d, 4H, J = 8.0 Hz, ArH), 7.17
(d, 4H, J = 8.0 Hz, ArH), 7.43 (bs, 2H, NH); 13C NMR (100 MHz,
CDCl3) d (ppm): 14.34, 29.69, 39.80, 67.15, 115.20, 121.29,
128.42, 129.61, 131.66, 141.33, 142.80, 155.28, 157.68, 168.74;
HR-MS (ESI) (C44H46B2F4N6O4) [M + Na]+: calcd: 843.3809;
found: 843.3829; anal. calcd for C44H46B2F4N6O4: C 64.41,
H 5.65, N 10.24; found: C 64.45, H 5.59, N 10.18%.
Acknowledgements
The financial support from the National Natural Science
Foundation of China (no: 21406036), the Fujian Natural Science
Foundation of China (no. 2017J01571), the Fujian Science and
Technology Project (no. 2019N0010), the Fuzhou Science and
Technology Project (2018-G-44) and the Undergraduate Innova-
tion Program of FJNU (2018) are greatly acknowledged.
Compound 3b. 1H NMR (400 MHz, CDCl3) d (ppm): 1.39
(s, 12H, CH3), 1.63 (s, 4H, CH2), 2.54 (s, 12H, CH3), 3.42 (s, 4H,
NCH2), 4.56(s, 4H, OCH2), 5.97 (s, 4H, ArH), 6.83 (bs, 2H, NH),
7.04 (d, 4H, J = 8.0 Hz, ArH), 7.19 (d, 4H, J = 8.0 Hz, ArH);
13C NMR (100 MHz, CDCl3) d (ppm): 15.06, 22.56, 29.52, 38.53,
67.16, 115.54, 121.02, 128.53, 129.65, 131.67, 141.08, 142.62,
155.39, 157.43, 167.91; HR-MS (ESI) (C46H50B2F4N6O4)
[M + Na]+: calcd: 871.4106; found: 871.4142; anal. calcd for
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