A facile Garratt-Braverman cyclization route to intercalative DNA-binding bis-quinones

Article abstract of DOI:10.1016/j.tetlet.2011.10.030

Bispropargyl ethers (both symmetrical and non-symmetrical) equipped with 1,4-dimethoxyaryl groups were synthesized. Under strongly basic conditions (KOBu^t/toluene/reflux), these ethers underwent Garratt-Braverman type cyclization to the tetrame

Full text of DOI:10.1016/j.tetlet.2011.10.030

Tetrahedron Letters 53 (2012) 19–22
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A facile Garratt–Braverman cyclization route to intercalative DNA-binding
bis-quinones
⇑
⇑
Partha Sarathi Addy, Sansa Dutta, Kumar Biradha , Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bispropargyl ethers (both symmetrical and non-symmetrical) equipped with 1,4-dimethoxyaryl groups
were synthesized. Under strongly basic conditions (KOBut/toluene/reflux), these ethers underwent Garr-
att–Braverman type cyclization to the tetramethoxy bi-aryl systems in high yields presumably via the
bisallenes. The products could be successfully converted to the bis-quinones via CAN-mediated demeth-
ylation cum oxidation. This two-step protocol offers a simple route to bis-quinones, connected by C1–C20
bonds, in good yields. Fluorescence based EB-displacement assay, CD spectroscopy and viscosity mea-
surements confirmed the DNA-binding ability of the synthesized quinones via intercalation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 May 2011
Revised 5 October 2011
Accepted 7 October 2011
Available online 23 October 2011
Organic reactions involving formation of two carbon–carbon
bonds in high yields, either concerted or stepwise are extremely
attractive in synthesis.1,2 Diels–Alder and related cycloadditions
are by far the best examples of concerted formation of two C–C
bonds with extensive applications.3 The logical targets using such
reactions are cyclic compounds that include alicyclic, aromatic,
or heterocyclic derivatives which are all important for various rea-
sons. Garratt–Braverman cyclization4 involving diradical as the
intermediate5 and discovered about 30 years ago forms two C–C
bonds at the same time. But its synthetic potential is yet to be fully
explored. It is only recently6 that applications of GB cyclization
have started to appear. In an effort to expand the synthetic scope
further, we have selected a synthetic target the bis-quinone core
with C1–C20 connectivity between the two quinonoid moieties as
it can be found7 in several natural products like 1–3 (Fig. 1) as a
synthetic target. Herein we describe our results.
OR
OR
.
.
OR
O
O
O
O
OR
OR
OR
O
O
RO
O
RO
R
P
Q
OR
OR
OR
O
C
O
C
OR
OR
RO
OR
RO
T
S
Scheme 1. Retro synthetic analysis using GB cyclization.
O
O
O
O
O
A
B
C
A
D
O
O
OH
O
HO
O
O
O
O
MeO
O
O
O
O
OH
HO
2
1
3
Figure 1. The naturally occurring bis-quinones.
⇑
Corresponding authors.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.030

20
P. S. Addy et al. / Tetrahedron Letters 53 (2012) 19–22
to structures 1–3. It may be mentioned that bis-quinones are
O
constantly drawing interest because of their biological profile8
which includes anticancer, antimalarial, and anti-HIV activities.
They also have a variety of other applications, for example as
probe9 for studying the biochemical processes and materials for
data recording, storage, and reproduction.10
THPO
OTHP
O
O
i
+
86%
THPO
12
4
13
1:1
O
H
One aspect that did bother us initially was concerning with the
lower double bond character of the C2–C3 bond in a naphthalene
system. This might prevent self quenching of the intermediate
diradical R (Scheme 1) involving the C2–C3 bond. In order to clarify
this point, we first subjected the unsymmetrical bispropargyl
ethers 4–6 to GB cyclization conditions (K tert-butoxide, toluene,
reflux). Interestingly, the compound 4 smoothly cyclized to the
product involving the C1–C2 bond with greater double bond char-
acter. In addition, another product via an intramolecular 1,5-H-
shift, often observed in GB cyclization, was also isolated. But no
normal GB product involving the C2–C3 bond could be isolated
from the reaction. When the participation of the C1–C2 double
bond was blocked by incorporating a substituent at C-1 as shown
in 5, the reaction followed only the intramolecular 1,5-H-shift
pathway. It is only when the H required for such 1,5-shift was
missing like in 6 that the standard GB-product 15, formed via the
C2–C3 double bond was isolated in 94% yield (Scheme 2).
As a follow-up of this result and with an aim to prepare the
biaryl skeleton, we carried out the GB cyclization of various bis-
propargyl ethers11 having 1,4-dialkoxy naphthalene/benzene moi-
ety with no possibility of 1,5-shift. Gratifyingly, all the ethers
produced only the GB products in good yields (Scheme 3). In those
cases where mixture of products was obtained, the individual
isomers were separated by silica gel column chromatography and
carried to the next step.
OMe
OMe
OMe
.
.
O
C
i
O
60%
OTHP
C
OMe
OMe
OMe
5b
OTHP
OTHP
5
5a
O
OMe
OMe
OMe
i
O
O
94%
OTHP
OMe
OMe
OMe
14
15
6
i = KOBut/Toluene/reflux
Scheme 2. Importance of double bond character.
The retro synthesis of the target bis-quinone core is shown in
Scheme 1. The bispropargylic ether moiety was needed to do the
isomerization to the bisallene and subsequent GB cyclization to
construct the critical C–C bonds. The product of GB cyclization,
namely the cyclic ether, can also be further functionalized, for
example, to lactone6 or anhydride.
To our knowledge although a large plethora of bis-quinones,
both natural and unnatural are known, most of them have a differ-
ent connectivity between the two quinones. Several elegant meth-
ods do exist for the synthesis of their core structure. However, to
our knowledge, there is no report yet on the synthetic approaches
The products of GB cyclization, namely the dimethoxy com-
pounds, underwent smooth demethylation followed by in situ
oxidation with CAN12 to produce the bis-quinones in 70–78% yield
O
O
O
O
O
O
O
O
O
O
9
O
8
7
O
70%
60%
O
O
92%
O
O
O
O
O
O
O
O
O
O
17
18
16
O
O
O
O
O
O
O
O
10
93%
11
O
O
78%
+
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3:1
21
19
20
Scheme 3. Result of GB cyclization.

P. S. Addy et al. / Tetrahedron Letters 53 (2012) 19–22
21
O
O
O
O
O
O
O
O
i
O
O
O
i
O
O
O
O
O
O
77%
O
O
O
78%
23
22
19
18
O
O
O
O
O
O
O
O
i
i
O
O
O
O
O
O
O
O
O
O
O
O
70%
75%
21
20
25
24
i CAN, Acetonitrile, rt, 30 min
Scheme 4. Result of oxidative demethylation for the synthesis of bis-quinones (CAN/acetonitrile/rt/30 min).
(Scheme 4).13 Considering the complexity of the bis-quinones, our
method offers a simple and efficient strategy to synthesize such
targets.
The structures of the GB products 16–21 were confirmed by
NMR and mass spectroscopy.14 Thus in the 1H NMR, the peri H at
C-1 appeared as a singlet in the characteristic region of d 8–8.5.
The formation of bis-quinone core was reflected by the absence
of methyl signals in 1H/13C spectra as well as appearance of four
carbonyl signals in the region of d 180–190. Final confirmation of
the structure came from the X-ray structure of one of the bis-qui-
none 22 (Fig. 2).
ments.21 Upon titration of the ethidium bromide-DNA complex
with the bis-quinones, considerable decrease in the fluorescence
intensity was observed, which is characteristic of the intercalative
mode of binding (Fig. 3). The highest decrease was observed for the
compound 25 followed by compounds 23, 22, and 24. Circular
dichroism studies furthermore substantiate the mode of interac-
tion of the compounds with the asymmetric environment of the
DNA helix. CD spectra were collected for ct-DNA starting from
200 to 350 nm. Gradual addition of the synthesized ligands to
the solution of the ct-DNA led to perturbations of both the positive
and the negative bands at 277 and 245 nm, respectively. Here
again, the increase in ellipticity at 277 nm, primarily associated
with reduced DNA winding angle,22,23 was maximum for the ana-
log 25 and 23 with pendant benzoquinone moiety.
The results obtained for viscosity measurements of DNA which
showed an increase in viscosity with increasing amounts of the
synthesized ligands (bis-quinones) also supported the intercalative
mode of binding. The analog 25 is intercalated into the ct-DNA
maximally followed by 23, 22, and 24, a trend observed earlier in
fluorescence and CD studies.24
The well known intercalation properties of quinones, especially
the anthraquinones,15 prompted us to study the DNA-binding
activities of the synthesized compounds using the established
techniques of fluorescence,16 CD,17–20 and viscosity measure-
In conclusion, we have developed a high yielding GB route to
bis-quinones (a hybrid of anthra/naphtha/benzo quinone) with a
C1–C20 connectivity. Fluorescence based EB-displacement assay,
100
compound 22
95
compound 23
compound 24
90
compound 25
85
80
75
70
65
60
0
5
10 15 20 25 30 35 40
compound (µM)
Figure 3. Relative fluorescence intensity decrease of EB (2.26
competitive binding of the synthesized compounds to ct DNA (20
l
M) induced by the
M).
Figure 2. X-ray structure of bis-quinone 22.
l

22
P. S. Addy et al. / Tetrahedron Letters 53 (2012) 19–22
10. Facchetti, A.; Marks, T. J.; Yan, H. PCT Int. Appl. 2008, WO.2008085942 A2
20080717.
CD spectroscopy, and viscosity measurements confirmed the DNA-
binding ability of the synthesized quinines. The mode of binding
was also shown to be intercalative.
11. These were prepared by O-alkylation of the substituted propargyl alcohols
with the bromides of the other arm of the ether in presence of NaH in THF.
12. (a) Richardson, W. H. In Oxidation in Organic Chemistry; Wiberg, K. B., Ed.;
Academic: New York, 1965. Part A, Chapter IV; (b) Ho, T.-L. Synthesis 1973, 347;
(c) Jacob, P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N., Jr. J. Org. Chem. 1976,
41, 3627; (d) Hauser, F. M.; Prasanna, S. J. Am. Chem. Soc. 1981, 103, 6378; (e)
Godard, A.; Rocca, P.; Fourquez, J. M.; Rovera, J. C.; Marsais, F.; Queguiner, G.
Tetrahedron Lett. 1993, 34, 7919; (f) Kitahara, Y.; Nakahara, S.; Shimizu, M.;
Yonezawa, T.; Kubo, A. Heterocycles 1993, 36, 1909.
Acknowledgments
Department of Science and Technology, Govt. of India, is
thanked for a research grant and also for 400 MHz and X-ray facil-
ities under the IRPHA and FIST programmes. PSA is grateful to CSIR,
Govt. of India for a fellowship.
13. Controlled oxidation can give rise to monoquinone. This aspect is currently
under investigation.
14. Selected spectral data: For 4-(1,4-Dimethoxy-naphthalen-2-yl)-5,10-
dimethoxy-1,3-dihydro-anthra[2,3-c]furan (18): State: Yellow gummy mass;
Yield 67%; dH (200 MHz, CDCl3): 8.39–8.36 (2H, m), 8.29 (1H, s), 8.22–8.16 (2H,
m), 7.67–7.46 (4H, m), 6.85 (1H, s), 5.40 (2H, s), 5.06 (1H, d, J = 14 Hz), 4.91 (1H,
d, J = 14 Hz), 4.21 (3H, s), 3.54 (3H, s), 3.40 (3H, s); dC (50 MHz, CDCl3): 150.9,
150.0, 148.5, 145.9, 139.5, 137.5, 129.4, 128.7, 127.5, 126.6, 126.2, 125.9, 125.6,
125.4, 125.2, 124.9, 123.7, 123.5, 122.5, 122.3, 113.5, 105.9, 94.7, 73.5, 63.2,
61.2, 55.9; MS: m/z 467 [MH+]; HRMS: Calcd for C30H26O5+H+ 467.1859, found
467.1863.
Supplementary data
Supplementary data (Spectral data.) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2011.
10.030.
For 4-(2,5-Dimethoxy-phenyl)-5,8-dimethoxy-1,3-dihydro naphtha [2,3-
c]furan (19): State: White gummy mass; yield 93%; dH (400 MHz, CDCl3):
8.15 (1H, s), 7.28 (1H, s), 6.89–6.84 (3H, m), 6.75–6.68 (3H, m), 5.32 (2H, s),
4.96 (1H, d, J = 13 Hz), 4.84 (1H, d, J = 13 Hz), 3.99 (3H, s), 4.78 (3H, s), 3.65 (3H,
s), 3.43 (3H, s); dC (100 MHz, CDCl3): 153.0, 151.4, 150.6, 149.9, 138.7, 137.0,
132.6, 127.4, 114.9, 114.6, 113.2, 112.2, 111.3, 106.3, 103.3, 73.8, 73.4, 56.4,
56.3, 55.8, 55.7; MS: m/z 367 [MH+]; HRMS: Calcd for C22H22O5+H+ 367.1546,
found 367.1548.
References and notes
1. (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: New York,
1996; (b) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New
York, 1995.
2. (a) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967; (b) Tietze, L. F.;
Brasche, G.; Gericke, K. In Domino Reactions in Organic Synthesis; Tietze, L. F.,
Ed.; Wiley-VCH: Weinheim, 2007.
For
4-(1,4-Dioxo-1,4-dihydro-naphthalen-2-yl)-1,3-dihydro-anthra[2,3-
3. (a) Kobayashi, S. Cycloaddition Reactions in Organic Synthesis; Wiley-VCH, 2001;
(b) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1990.
4. (a) Braverman, S.; Segev, D. J. Am. Chem. Soc. 1974, 96, 1245; (b) Garratt, P. J.;
Neoh, S. B. J. Org. Chem. 1979, 44, 2667; (c) Cheng, Y. S. P.; Garratt, P. J.; Neoh, S.
B.; Rumjanek, V. H. Isr. J. Chem 1985, 26, 101; (d) Braverman, S.; Duar, Y.; Segev,
D. Tetrahedron Lett. 1976, 17, 3181; (e) Zafrani, Y.; Gottlieb, H. E.; Sprecher, M.;
Braverman, S. J. Org. Chem. 2005, 70, 10166.
c]furan-5,10-dione (22): State: Golden yellow crystal; mp: 215 °C; Yield 78%;
dH (400 MHz, CDCl3): 8.37 (1H, s), 8.34 (1H, d, J = 1.6 Hz), 8.29 (1H, d,
J = 1.6 Hz), 8.19–8.17 (1H, m), 8.12 (1H, dd, J = 7.6 Hz, 1.2 Hz), 7.89–7.74 (4H,
m), 6.86 (1H, s), 5.31 (2H, s), 5.27 (1H, d, J = 14 Hz), 5.04 (1H, d, J = 14 Hz); dC
(100 MHz, CDCl3): 184.5, 183.1, 182.9, 182.5, 150.6, 146.0, 145.2, 134.7, 134.4,
134.0, 133.9, 133.3, 132.6, 132.5, 132.4, 32.0, 131.6, 129.0, 127.5, 127.2, 127.1,
126.8, 126.4, 121.2, 74.1, 72.8; MS: m/z 407 [MH+]; HRMS: Calcd for
C
26H14O5+H+ 407.0920, found 407.0922.
5. Maji, M.; Mallick, D.; Mondal, S.; Anoop, A.; Bag, S. S.; Basak, A.; Jemmis, E. D.
Org. Lett. 2011, 13, 888.
For 4-(3,6-Dioxa-cyclohexa-1,4-dienyl)-1,3-dihydro-naptho[2,3-c]furan-5,8-
dione (23): State: Light yellow gummy mass; Yield 77%; dH (400 MHz,
CDCl3): 8.09 (1H, s), 7.01–6.91 (3H, m), 6.86 (1H, d, J = 10.4 Hz), 6.62 (1H, s),
5.28 (2H, bs), 5.19 (1H, d, J = 13.6 Hz), 4.96 (1H, d, J = 13.6 Hz); dC (100 MHz,
CDCl3): 186.6, 184.9, 184.6, 184.2, 147.7, 145.9, 144.9, 138.9, 137.9, 137.2,
132.9, 130.4, 129.8, 127.5, 120.6, 74.0, 72.6; MS: m/z 307 [MH+]; HRMS: Calcd
for C18H10O5+H+ 307.0606, found 307.0607.
6. Mondal, S.; Maji, M.; Basak, A. Tetrahedron Lett. 2011, 52, 1183.
7. (a) Hassanean, H. A.; Ibraheim, Z. Z.; Takeya, K.; Horawa, H. Die Pharmazie 2000,
55, 317; (b) Eyong, K. B.; Krohn, K.; Hussain, H.; Folefoc, G. N.; Nkengfack, A. E.;
Schultz, B.; Hu, Q. Chem. Pharm. Bull. 2005, 53, 616; (c) Aguinaldo, A. M.;
Ocampo, O. P. M.; Bowden, B.; Gray, A. I.; Waterman, P. G. Phytochemistry 1993,
33, 933.
15. (a) Riahi, S.; Ganjali, M. R.; Norouzi, P. J. Theo. Comp. Chem. 2008, 7, 317; (b)
Qiao, C.; Bi, S.; Sun, Y.; Song, D.; Zhang, H.; Zhou, W. Spectrochim. Acta Part A
Mol. Biomol. Spectrosc. 2008, 70A, 136; (c) Guin, S. P.; Das, S.; Mandal, C. P. J.
Soln. Chem. 2011, 40, 492.
8. (a) Alemayehu, G.; Abegaz, B.; Kraus, W. Phytochemistry 1998, 85, 528; (b)
Russel, A. R.; Day, I. A.; Pilley, A. B.; Leavy, J. P.; Warrener, N. R. J. Chem. Soc.,
Chem. Commun. 1987, 1631; (c) Bystrykh, L. V.; Fernandez-Moreno, M. A.;
Herrema, J. K.; Malpartida, F.; Hopwood, D. A.; Dijkhuizen, L. J. Bacteriol. 1996,
178, 2238; (d) Shimatani, T.; Kumagaya, K.; Hosoya, N.; Natsume, Y.; Ishiyama,
T.; Japanese Patent 2 003 238 555, 2003; (e) Ostlind, D. A.; Mochales, S. U.S.
Patent 5 017 603, 1991; (f) Shibata, S.; Morishita, E.; Takeda, T.; Sakata, K.
Tetrahedron Lett. 1966, 40, 4855; (g) Chakrabarty, S.; Roy, M.; Hazra, B.;
Bhattacharya, R. K. Cancer Lett. 2002, 188, 85; (h) Adeniyi, B. A.; Fong, H. H.;
Pezzuto, J. M.; Luyengi, L.; Odelola, H. A. Phytother. Res. 2000, 14, 112; (i) Singh,
P. D.; Johnson, J. H.; Aklonis, C. A.; Bush, K.; Fisher, S. M.; O’Sullivan, J. J. Antibiot.
1985, 38, 706; (j) Meselhy, M. R.; Kadota, S.; Tsubono, K.; Kusai, A.; Hattori, M.;
Namba, T. Tetrahedron Lett. 1994, 35, 583; (k) Costa, M.; Aurea, C.; Silva, M. S.;
Alves, A. C.; Seabra, R. M. Nat. Prod. Lett. 1999, 13, 269; (l) Kapadia, G. J.;
Balasubramanian, V.; Tokuda, H.; Konoshima, T.; Takasaki, M.; Koyama, J.;
Tagahaya, K.; Nishino, H. Cancer Lett. 1997, 113, 47; (m) Hirakawa, K.; Ogiue, E.;
Motoyoshiya, J.; Yajima, M. Phytochemistry 1986, 25, 1494.
16. Lepecq, J. B.; Paoletti, C. J. Mol. Biol. 1967, 27, 87.
17. Rodger, A.; Ismail, M. A. Introduction to circular dichroism. In
Spectrophotometry and Spectrofluorimetry; Gore, M. G., Ed.; Oxford University
Press: New York, 2000.
18. Rajendran, A.; Nair, B. U. Biochim. Biophys. Acta 2006, 1760, 1794.
19. Jain, S. S.; Polak, M.; Hud, N. V. Nucleic Acids Res. 2003, 31, 4608.
20. Mergny, J. L.; Duval-Valentin, G.; Nguyen, C. H.; Perrouault, L.; Faucon, B.; Rougee,
M.; Montenay-Garestier, T.; Bisagni, E.; Helene, C. Science 1992, 256, 1681.
21. Kelly, J. M.; Tossi, A. B.; McConnell, D. J.; OhUigin, C. Nucleic Acids Res. 1985, 13,
6017.
22. Johnson, B. B.; Dahl, K. S.; Tinoco, I., Jr.; Ivanov, V. I.; Zhurkin, V. B. Biochemistry
1981, 20, 73.
23. Chan, A.; Kilkuskie, R.; Hanlon, S. Biochemistry 1979, 84.
24. The CD spectra and the viscosity trends are included in the Supplementary
data.
9. (a) Tyson, D. S.; Carbaugh, A. D.; Ilhan, F.; Santos-Perez, J.; Meader, M. A. Chem.
Mater. 2008, 20, 6595; (b) Meader, M. A.; Tyson, D. S.; Ilhan, F. U.S. Pat. Appl.
Publ. 2008, US 20080242870 A1 20081002; (c) Meader, M. A.; Tyson, D. S.;
Carbaugh, A. D. PMSE Preprints 2008, 98, 130.