Development of new quinoline-based photo-labile groups for photo-regulation of bioactive molecules

Article abstract of DOI:10.1016/j.tetlet.2010.01.071

A series of quinoline-based photo-removable protecting (caging) groups were synthesized for the development of new chemical tools to photo-regulate bioactive molecules in living cells and tissues with improved properties. Compared with the recently developed 8-bromo-7-hydroxyquinolinyl (BHQ) chromophore, change of the bromine substituent to a pyridine group led to a new photo-labile group (3′-PyHQ) with an increased water solubility, a lower self-fluorescence, and a higher photolysis efficiency. It was proposed that the replacement of a halogen group by a pyridine-like heterocycle may provide a general strategy to improve the existing photo-caging groups.

Full text of DOI:10.1016/j.tetlet.2010.01.071

Tetrahedron Letters 51 (2010) 1609–1612
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of new quinoline-based photo-labile groups
for photo-regulation of bioactive molecules
a,b,
Yi-Ming Li a,b, Jing Shi b, Rong Cai b, Xiao-Yun Chen b, Qing-Xiang Guo b, , Lei Liu
*
*
a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
b Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of quinoline-based photo-removable protecting (caging) groups were synthesized for the devel-
opment of new chemical tools to photo-regulate bioactive molecules in living cells and tissues with
improved properties. Compared with the recently developed 8-bromo-7-hydroxyquinolinyl (BHQ) chro-
mophore, change of the bromine substituent to a pyridine group led to a new photo-labile group (30-
PyHQ) with an increased water solubility, a lower self-fluorescence, and a higher photolysis efficiency.
It was proposed that the replacement of a halogen group by a pyridine-like heterocycle may provide a
general strategy to improve the existing photo-caging groups.
Received 9 October 2009
Revised 11 January 2010
Accepted 22 January 2010
Available online 28 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Photo-labile protecting groups offer an ideal method for regu-
lating cellular functions with a high spatiotemporal resolution
and therefore, have become increasingly important in the biologi-
cal research. ‘Caging’ is a specific term which describes the use of a
photolytic chromophore to encapsulate bioactive molecules in an
inactive form whose activity can be restored by photo-irradiation.
A variety of molecular structures, such as 2-nitrobenzyl,2 1-(4,5-
dimethoxy-2-nitrophenyl)-ethyl,3,4 4,5-dimethoxy-2-nitrobenzyl,5
6-bromo-7-hydroxy-coumarin-4-yl-methyl,6 [7-(diethyl-amino)-
coumarin-4-yl]-methyl,7 and 7-dinitro-indolinyl8 have been devel-
oped as photo-caging groups. They have been successfully used to
photo-regulate metal ions (such as calcium),9 neurotransmit-
ters,5,10 carboxylic acids,11,12 proteins,13–16 nucleotides,17–19 pep-
tides,20 RNAs,6,21 and DNAs.22–31 Nevertheless, the existing
photo-caging groups are still limited by various unfavorable prop-
erties including poor water solubility, high self-fluorescence, and/
or lower photolysis sensitivity.
To solve the problems, Dore and co-workers recently developed
the BHQ (8-bromo-7-hydroxyquinoline) group based on the quin-
oline structure. Up to now BHQ has been successfully utilized for
the photo-releasing of acetate, phosphates and diol groups that
are commonly found in bioactive molecules such as neurotrans-
mitters.1,11,12 Compared with the previous photo-caging groups,
BHQ demonstrates many favorable photo-chemical and photo-
physical properties such as a larger two-photon cross-section, an
improved water solubility, and a higher uncaging quantum yield.
These properties are highly important for the study of living cells
and tissue cultures.10
In the present study we seek to generate an improved photo-la-
bile protecting group with a better water solubility, a lower self-
fluorescence, and a higher photolysis sensitivity as compared to
BHQ. To this end we synthesize a series of BHQ derivatives (1–7,
Fig. 1) to cage acetate as a model bioactive compound. Note that
during the course of our study Dore and co-workers also examined
the possibility to improve BHQ by the substitution changes.12 They
reported that swapping the bromine substituent for a nitro, cyano,
or chloro or exchanging the hydroxy for dimethylamino or sulfhy-
dryl significantly alters the photo-chemical and photo-physical
properties of the quinoline chromophore. Compared with Dore’s
work, our strategy to modify BHQ is different as shown below.
Our first strategy was to change the position of the electron-
donating hydroxyl group from the 7-position to the 6-position.
The rationale for this strategy is the previously proposed solvent-
Br
HO
HO
OAc
OAc
HO
N
N
OAc
N
1
2
3
7-HQ-OAc
6-HQ-OAc
5-BHQ-OAc
OAc
HO
N
N
R
OAc
N
N
R =
N
4
6-DMAQ-OAc
6
7
5
* Corresponding authors. Tel.: +86 10 62780027; fax: +86 10 62771149.
E-mail addresses: qxguo@ustc.edu.cn (Q.-X. Guo), lliu@mail.tsinghua.edu.cn (L.
Liu).
PhHQ-OAc 3'-PyHQ-OAc 4'-PyHQ-OAc
Figure 1. Quinoline-based photo-removable protecting groups.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.071

1610
Y.-M. Li et al. / Tetrahedron Letters 51 (2010) 1609–1612
compound 6 (30-PyHQ-OAc) was synthesized from 2-methylquino-
hv
lin-7-ol (Scheme 2). First, bromination of 2-methylquinolin-7-ol
with Br2 in acetic acid gave 12 in 78% yield. Protection of the
7-OH group by the MOMCl provided 13 in 93% yield. Subsequently
compound 14 was obtained by Suzuki cross-coupling between 13
and pyridine-3-ylboronic acid (yield = 74%). Removal of the MOM
protecting group with 35% HCl in CH3OH provided 15 in 89% yield.
Re-protection of the 7-OH group by t-butyldiphenylsilyl chloride
gave 16 in 79% yield. Oxidation of the 2-methyl group by the
SeO2 afforded 17 in 84% yield, which was reduced by NaBH4 to pro-
duce 18 in 89% yield. Esterification of 18 with acetic anhydride pro-
vided 19 in 72% yield. Finally, the removal of the silyl protecting
group with TBAF in THF gave 6 in 64% yield. Note that we had to
use both the MOM and TDBPS protecting groups in the synthesis,
because TDBPS-protected compound could not undergo Suzuki
coupling possibly due to the steric hinderance, whereas the
MOM-group cannot survive the SeO2 oxidation. The compounds
5 and 7 were synthesized by using similar synthetic procedures.
The UV–vis spectra reveal that compounds 3 and 4 have charac-
teristic absorbance peaks similar to BHQ-OAc, although the kmax
value for compounds 1, 2, and 5–7 are slightly lower (Fig. 3). On
the other hand, significant differences are observed for the fluores-
cence spectra of these compounds (Fig. 4). Compared to BHQ-OAc,
compounds 2, 6, and 7 exhibit a much lower fluorescence emission.
In particular, compound 2 shows almost no self-fluorescence. A
lower self-fluorescence of 2, 6, and 7 should facilitate the applica-
tion of these photo-caging groups when they are used together
with other fluorescent indicators.1 Note that the dimethylamino-
substituted compound (4) exhibits the strongest emission bands
at 498 nm. This observation is consistent with the previous studies
on similar compounds by Dore and co-workers.12
OAc
OAc
OAc
O
N
O
N
Br
Br
BHQ-OAc
O
N
Br
(a)
O
O
hv
OAc
OAc
OAc
N
N
Br
Br
Br
O
better through-bond
conjugation?
N
(b)
Figure 2. Proposed mechanism for the BHQ photolysis reaction.
assisted photoheterolysis (SN1) reaction mechanism for the photo-
releasing of the BHQ group.32 As shown in Figure 2a, irradiation of
BHQ-OAc should lead to a singlet excited state which can cleavage
its carbon–oxygen bond to generate a zwitterion-like intermediate.
If this mechanism is correct, placement of an electron-donating hy-
droxyl group at the 6-position should increase the stability of the
zwitterion-like intermediate (Fig. 2b) and thereby, improve the
properties of the photo-caging group.
On the basis of the above proposal, we synthesized compounds
1–4. To provide an example for the synthesis, 6-HQ-OAc (2) was
prepared from 2-methylquinolin-6-ol. As shown in Scheme 1, pro-
tection of the 6-OH of 2-methylquinolin-6-ol by t-butyldiphenylsi-
lyl chloride gave 8 in 85% yield. Oxidation of the methyl group of 8
by using SeO2 in 1,4-dioxane provided 9 in 78% yield. Reduction of
9 by NaBH4 in EtOH afford 10 in 80% yield. Esterification of 10 with
acetic anhydride gave 11 in 67% yield. Finally, the removal of the
silyl protecting group with TBAF produced 2 in 65% yield. The com-
pounds 1, 3, and 4 were also synthesized by using similar synthetic
procedures.
It has been demonstrated that successful use of ‘caged’ com-
pounds in cellular studies requires satisfactory solubility in aque-
ous solutions at moderately high ionic strength.1 Thus the water
solubility of compounds 1–7 was determined by measuring the
fluorescence or absorption intensity as a function of their concen-
trations, respectively.33–35 As shown in Figure 5, the solubility of
compound 6 in water (0.5% DMSO) is 250 lM, which is nearly
10-fold higher than the parent compound, BHQ-OAc. Besides, com-
pounds 1–3 have better water solubility to various degrees. The re-
sults supported our proposal that the solubility of a photo-caging
group can be improved by the incorporation of heterocycles. Note
that the solubility of compound 4 is fairly low (less than 5 lM) and
it has a high self-fluorescence. Therefore, we concluded that 4
could not be suitable for further applications.
Furthermore, we studied the photolysis efficiency of com-
pounds 1–7. Upon photolysis with 365 nm photons under simu-
lated physiological conditions in KMOPS (100 mM KCl, 10 mM
MOPS, pH 7.2), BHQ-OAc and compounds 1–7 were all converted
Our second approach to improve the BHQ group was to incorpo-
rate an aromatic heterocycle into the chromophore. The advantage
of this approach is twofold: (1) the presence of an aromatic hetero-
cycle such as pyridine may improve water solubility; (2) the aro-
matic heterocycle may improve photon cross-section and
quantum yield because it enlarges the conjugation plane. Thus
TBDPSO
imidazole/TBDPSCl
HO
DMF
85%
N
N
8
TBDPSO
SeO2
1,4-dioxane
TBDPSO
NaBH4
EtOH
O
OH
N
80%
78%
N
10
9
TBDPSO
TBAF
HO
Ac2O/pyridine
67%
THF
OAc
OAc
65%
N
N
2
11
Scheme 1. The synthesis of 6-HQ-OAc (2).

Y.-M. Li et al. / Tetrahedron Letters 51 (2010) 1609–1612
1611
MOMCl,
K2CO3
Br2
HOAc
acetone
HO
N
MOMO
N
HO
N
78%
93%
Br
Br
12
13
K2CO3 aq.
toluene/EtOH
Pd(PPh3)4
HCl/CH3OH
89%
MOMO
N
HO
N
pyridin-3-ylboronic acid
74%
N
N
15
14
DMF
imidazole
TBDPSCl
SeO2
1,4-dioxane
NaBH4
EtOH
O
TBDPSO
N
TBDPSO
N
89%
84%
79%
N
N
16
17
Ac2O
pyridine
TBAF
THF
HO
N
TBDPSO
N
TBDPSO
N
OAc
OH
OAc
64%
72%
N
N
N
18
19
6
Scheme 2. The synthesis of 30-PyHQ-OAc (6).
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
250
200
BHQ-OAc
1 (7-HQ-OAc)
2 (6-HQ-OAc)
3 (5-BHQ-OAc)
4 (6-DMAQ-OAc)
5 (PhHQ-OAc)
6 (3'-PyHQ-OAc)
7 (4'-PyHQ-OAc)
150
100
50
0
7
6
3
5
2
6-HQ
250
300
350
400
450
1
7-HQ
4'-PyHQ
3'-PyHQ
BHQ
5-BHQ PhHQ
Wavelength (nm)
Figure 5. The water solubility of BHQ-OAc and compounds 1–3, 5–7 (aqueous
solutions with 0.5% DMSO).
Figure 3. UV–vis spectra of BHQ-OAc and compounds 1–7 (100 lM in KMOPS).
450
nearly 1.5 times faster than BHQ-OAc, which is possibly due to
their large uncaging cross-section. On the other hand, compounds
1 and 2 photolyze slightly more slowly than the parent compound
BHQ-OAc. Finally, it is surprising to observe that compound 3 does
not photolyze efficiently. We considered that the high photolysis
sensitivity may contribute to a lower phototoxicity in the study
of biomolecules.
BHQ-OAc
1 (7-HQ-OAc)
2 (6-HQ-OAc)
3 (5-BHQ-OAc)
4 (6-DMAQ-OAc)
5 (PhHQ-OAc)
6 (3'-PyHQ-OAc)
7 (4'-PyHQ-OAc)
400
350
300
250
200
150
100
50
Summarizing the above results,36–42 we can conclude that com-
pounds 2 (6-HQ-OAc) and 6 (30-PyHQ-OAc) are better photo-caging
groups than BHQ-OAc. Both 2 and 6 exhibit much lower self-fluo-
rescence. They both show dramatically better water solubility. Fur-
thermore, 6 photolyzes about 1.5 times faster than BHQ-OAc,
although 2 photolyzes slightly more slowly than BHQ-OAc. Given
the fact that BHQ represents one of the best photo-caging groups
available at the present stage, we believe that our newly developed
photo-caging groups (i.e., 6-HQ and 30-PyHQ) may find important
applications for photo-regulation of various bioactive molecules
under physiological conditions. Furthermore, we have demon-
strated in the present study that the replacement of a halogen
0
400
450
500
550
600
650
700
Wavelength (nm)
Figure 4. Fluorescence spectra of BHQ-OAc and compounds 1–7 (50
kex = 365 nm).
lM in KMOPS,
to the corresponding hydroxy derivative and acetate. The speed of
each photo-chemical reaction was monitored by HPLC measure-
ments. The results (Fig. 6) indicated that compounds 5–7 photolyze

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Y.-M. Li et al. / Tetrahedron Letters 51 (2010) 1609–1612
14. Wu, N.; Deiters, A.; Cropp, T. A.; King, D.; Schultz, P. G. J. Am. Chem. Soc. 2004,
100
90
80
70
60
50
40
30
20
10
126, 14306.
15. Mayer, G.; Muller, J.; Mack, T.; Freitag, D. F.; Hover, T.; Potzsch, B.; Heckel, A.
ChemBioChem 2009, 10, 654.
16. Chou, C.; Young, D. D.; Deiters, A. Angew. Chem., Int. Ed. 2009, 48, 5950.
17. Woll, D.; Smirnova, J.; Galetskaya, M.; Prykota, T.; Buhler, J.; Stengele, K. P.;
Pfleiderer, W.; Steiner, U. E. Chem. Eur. J. 2008, 14, 6490.
18. Furuta, T.; Takeuchi, H.; Isozaki, M.; Takahashi, Y.; Kanehara, M.; Sugimoto, M.;
Watanabe, T.; Noguchi, K.; Dore, T. M.; Kurahashi, T.; Iwamura, M.; Tsien, R. Y.
ChemBioChem 2004, 5, 1119.
19. Sven Geibel, A. B. Biophys. J. 2000, 79, 1346.
20. Rothman, D. M.; Petersson, E. J.; Vazquez, M. E.; Brandt, G. S.; Dougherty, D. A.;
Imperiali, B. J. Am. Chem. Soc. 2005, 127, 846.
BHQ-OAc
1 (7-HQ-OAc)
2 (6-HQ-OAc)
3 (5-BHQ-OAc)
5 (PhHQ-OAc)
6 (3'-PyHQ-OAc)
7 (4'-PyHQ-OAc)
21. Richards, J. L.; Tang, X. J.; Turetsky, A.; Dmochowski, I. J. Bioorg. Med. Chem. Lett.
2008, 18, 6255.
22. Ghosn, B.; Haselton, F. R.; Gee, K. R.; Monroe, W. T. Photochem. Photobiol. 2005,
81, 953.
23. Heckel, A.; Mayer, G. J. Am. Chem. Soc. 2005, 127, 822.
24. Mayer, G.; Krock, L.; Mikat, V.; Engeser, M.; Heckel, A. ChemBioChem 2005, 6,
1966.
0
20
40
60
80 100 120 140 160
Time (s)
Figure 6. Time courses for the photolysis of BHQ-OAc and compounds 1–7 at
365 nm.
25. Shah, S.; Rangarajan, S.; Friedman, S. H. Angew. Chem., Int. Ed. 2005, 44, 1328.
26. Dmochowski, I. J.; Tang, X. J. Biotechniques 2007, 43, 161.
27. Shestopalov, I. A.; Sinha, S.; Chen, J. K. Nat. Chem. Biol. 2007, 3, 650.
28. Shah, S.; Friedman, S. H. Oligonucleotides 2007, 17, 35.
29. Tang, X. J.; Maegawa, S.; Weinberg, E. S.; Dmochowski, I. J. J. Am. Chem. Soc.
2007, 129, 11000.
group by a pyridine-like heterocycle may provide a general strat-
egy to improve the existing photo-caging groups.
30. Li, Y.; Shi, J.; Luo, Z.; Jiang, H.; Chen, X.; Wang, F.; Wu, X.; Guo, Q. Bioorg. Med.
Chem. Lett. 2009, 19, 5368.
31. Young, D. D.; Govan, J. M.; Lively, M. O.; Deiters, A. ChemBioChem 2009, 10,
1612.
Acknowledgment
This study was supported by the NSFC (Grant Nos. 90713009
and 20932006).
32. An, H. Y.; Ma, C. S.; Nganga, J. L.; Zhu, Y.; Dore, T. M.; Phillips, D. L. J. Phys. Chem.
A 2009, 113, 2831.
33. Kim, H. M.; Choo, H. J.; Jung, S. Y.; Ko, Y. G.; Park, W. H.; Jeon, S. J.; Kim, C. H.;
Joo, T. H.; Cho, B. R. ChemBioChem 2007, 8, 553.
34. Kim, H. M.; Jeong, B. H.; Hyon, J. Y.; An, M. J.; Seo, M. S.; Hong, J. H.; Lee, K. J.;
Kim, C. H.; Joo, T.; Hong, S. C.; Cho, B. R. J. Am. Chem. Soc. 2008, 130, 4246.
35. Kim, H. M.; Kim, B. R.; Choo, H. J.; Ko, Y. G.; Jeon, S. J.; Kim, C. H.; Joo, T.; Cho, B.
R. ChemBioChem 2008, 9, 2830.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.071.
36. Compound 1: 1H NMR (400 MHz, CDCl3, d ppm) 7.94 (d, J = 8.3, 1H), 7.30 (d,
J = 8.9, 1H), 7.24 (d, J = 1.6, 1H), 7.21 (d, J = 8.3, 1H), 6.77 (dd, J = 8.8, 2.1, 1H),
5.29 (s, 2H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3, d ppm) 170.8, 159.6, 155.3,
147.9, 137.6, 128.8, 122.0, 120.0, 116.5, 108.3, 66.3, 20.9.
37. Compound 2: 1H NMR (400 MHz, CDCl3, d ppm) 8.03 (dd, J = 11.7, 9.1, 2H), 7.43
(d, J = 8.5, 1H), 7.34 (dd, J = 9.1, 2.6, 1H), 7.14 (d, J = 2.6, 1H), 5.38 (s, 2H), 2.17 (s,
3H); 13C NMR (100 MHz, DMSO, d ppm) 170.3, 155.7, 152.8, 142.2, 135.2, 130.2,
128.7, 122.4, 119.9, 108.4, 66.9, 20.8.
References and notes
1. (a) Lee, H.-M.; Larson, D. R.; Lawrence, D. S. ACS Chem. Biol. 2007, 4, 619; (b)
Meng, X.; Chen, X.; Fu, Y.; Guo, Q. Prog. Chem. 2008, 20, 2034; (c) Ellis-Davies, G.
C. R. Nat. Methods 2007, 4, 619.
2. Schade, B.; Hagen, V.; Schmidt, R.; Herbrich, R.; Krause, E.; Eckardt, T.; Bendig, J.
J. Org. Chem. 1999, 64, 9109.
3. Monroe, W. T.; McQuain, M. M.; Chang, M. S.; Alexander, J. S.; Haselton, F. R. J.
Biol. Chem. 1999, 274, 20895.
4. Cambridge, S. B.; Geissler, D.; Calegari, F.; Anastassiadis, K.; Hasan, M. T.;
Stewart, A. F.; Huttner, W. B.; Hagen, V.; Bonhoeffer, T. Nat. Methods 2009, 6,
527.
5. Furuta, T.; Wang, S. S. H.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E.
M.; Denk, W.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 1193.
6. Ando, H.; Furuta, T.; Tsien, R. Y.; Okamoto, H. Nat. Genet. 2001, 28, 317.
7. Hagen, V.; Frings, S.; Wiesner, B.; Helm, S.; Kaupp, U. B.; Bendig, J. ChemBioChem
2003, 4, 434.
8. Fedoryak, O. D.; Sul, J. Y.; Haydon, P. G.; Ellis-Davies, G. C. R. Chem. Commun.
2005, 3664.
9. Momotake, A.; Lindegger, N.; Niggli, E.; Barsotti, R. J.; Ellis-Davies, G. C. R. Nat.
Methods 2006, 3, 35.
38. Compound 3: 1H NMR (400 MHz, CDCl3, d ppm) 8.38 (d, J = 8.7, 1H), 7.99 (d,
J = 9.2, 1H), 7.54 (d, J = 8.7, 1H), 7.50 (d, J = 9.2, 1H), 5.38 (s, 2H), 2.19 (s, 3H);
13C NMR (100 MHz, DMSO, d ppm) 170.3, 153.7, 152.9, 142.7, 134.2, 129.7,
127.6, 121.9, 121.1, 103.3, 66.4, 20.8.
39. Compound 4: 1H NMR (400 MHz, CDCl3, d ppm) 7.99–7.91 (m, 2H), 7.39–7.32
(m, 2H), 6.80 (d, J = 2.8, 1H), 5.32 (s, 2H), 3.08 (s, 6H), 2.16 (s, 3H); 13C NMR
(100 MHz, CDCl3, d ppm) 170.9, 151.5, 148.9, 135.0, 129.8, 129.2, 120.3, 119.8,
104.9, 67.9, 40.8, 21.1.
40. Compound5: 1H NMR (400 MHz, DMSO, d ppm) 8.21 (d, J = 8.4, 1H), 7.81 (d,
J = 8.9, 1H), 7.41 (d, J = 4.2, 4H), 7.38 (d, J = 8.9, 1H), 7.31 (dq, J = 8.9, 4.2, 1H),
7.26 (d, J = 8.4, 1H), 5.15 (s, 2H), 1.97 (s, 3H); 13C NMR (100 MHz, DMSO, d ppm)
170.5, 155.9, 155.6, 146.9, 137.0, 135.8, 132.0, 128.4, 127.4, 126.5, 122.4, 121.9,
119.2, 116.01, 66.6, 20.8.
41. Compound6: 1H NMR (400 MHz, DMSO, d ppm) 10.20 (s, 1H), 8.61 (dd, J = 2.1,
0.7, 1H), 8.50 (dd, J = 4.8, 1.7, 1H), 8.28 (d, J = 8.4, 1H), 7.88 (d, J = 8.9, 1H), 7.85–
7.80 (m, 1H), 7.45 (ddd, J = 7.8, 4.8, 0.7, 1H), 7.39 (d, J = 8.9, 1H), 7.31 (d, J = 8.4,
1H), 5.17 (s, 2H), 2.02 (s, 3H); 13C NMR (100 MHz, DMSO, d ppm) 170.2, 156.1,
155.8, 152.1, 147.0, 146.4, 139.1, 137.0, 131.3, 129.0, 122.6, 121.7, 119.0, 118.5,
116.1, 66.3, 20.6.
10. Nikolenko, V.; Poskanzer, K. E.; Yuste, R. Nat. Methods 2007, 4, 943.
11. (a) Fedoryak, O. D.; Dore, T. M. Org. Lett. 2002, 4, 3419; (b) Zhu, Y.; Pavlos, C. M.;
Toscano, J. P.; Dore, T. M. J. Am. Chem. Soc. 2006, 128, 4267.
12. Davis, M. J.; Kragor, C. H.; Reddie, K. G.; Wilson, H. C.; Zhu, Y.; Dore, T. M. J. Org.
Chem. 2009, 74, 1721.
42. Compound 7: 1H NMR (400 MHz, DMSO, d ppm) 10.28 (s, 1H), 8.60 (dd, J = 4.4,
1.6, 2H), 8.28 (d, J = 8.4, 1H), 7.89 (d, J = 8.9, 1H), 7.43 (dd, J = 4.4, 1.6, 2H), 7.38
(d, J = 8.9, 1H), 7.31 (d, J = 8.4, 1H), 5.17 (s, 2H), 2.00 (s, 3H); 13C NMR (100 MHz,
DMSO, d ppm) 170.2, 156.2, 155.6, 148.5, 146.1, 143.8, 137.0, 129.4, 127.1,
121.6, 119.3, 119.0, 116.2, 66.3, 20.7.
13. Tang, X.; Richards, J. L.; Peritz, A. E.; Dmochowski, I. J. Bioorg. Med. Chem. Lett.
2005, 15, 5303.