Novel syntheses of aryl quinoxaline C-nucleoside analogs by mild and efficient three-component sequential reactions

Article abstract of DOI:10.1039/c4cc01448k

Novel syntheses of C-nucleoside analogs with aryl quinoxalines as nucleobase surrogates have been accomplished by mild and efficient three-component sequential reactions in high yields with a wide scope of substrates. The mechanism was clarified by isolation of novel sugar 1,2-diketone derived from oxidation of the corresponding alkyne. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01448k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Novel syntheses of aryl quinoxaline C-nucleoside
analogs by mild and efficient three-component
sequential reactions†
Cite this: Chem. Commun., 2014,
50, 5771
Received 25th February 2014,
Accepted 11th April 2014
Fuyi Zhang,*a Yuan Xi,a Yanhui Lu,a Liming Wang,a Linwei Liu,a Jinliang Li‡a and
Yufen Zhaoab
DOI: 10.1039/c4cc01448k
www.rsc.org/chemcomm
Novel syntheses of C-nucleoside analogs with aryl quinoxalines as nature between hydrophilic and hydrophobic species are there-
nucleobase surrogates have been accomplished by mild and effi- fore the most promising candidates for efficient incorporation
cient three-component sequential reactions in high yields with a into DNA and extension of the duplex.7a,b,8 Quinoxalines and
wide scope of substrates. The mechanism was clarified by isolation their derivatives are very important benzoheterocycles, showing
of novel sugar 1,2-diketone derived from oxidation of the corre- a broad spectrum of significant biological activity such as anti-
sponding alkyne.
inflammatories,9 antivirals,10 antibacterials,11 kinase inhibi-
tors,12 anti-HIV13 and DNA cleaving agents.14 These have made
C-Nucleosides and their analogs are the widely studied com- them privileged structures in combinatorial drug discovery
pounds, in which the C–C bond between the heterocycle and libraries and a number of methods are available for the synthesis
the sugar moiety is resistant to bacterial hydrolases and enables of quinoxalines.15 Although the parent quinoxalines are easily
these molecules to interfere with DNA and RNA synthases.1 prepared, the corresponding substituted compounds are con-
Many of these compounds display a potent biological activity.2 siderably more challenging. The sugar substituted quinoxaline
The use of non-natural nucleobases and the designed surro- by the C–C bond (called the quinoxaline C-nucleoside) remains
gates to synthesize C-nucleoside analogs is a frequently applied sparse. In continuation of our interest in the syntheses of
approach. Amongst these numerous base analogs, hydrophobic biologically active carbohydrate analogues16 and C-substituted
aryl groups and polycyclic aryl groups as nucleobase surrogates sugar analogues,17 herein, for the first time, we present a general
are of particular interest due to their biological activities2a,b and and efficient synthesis of novel C-nucleoside analogs with aryl
their use in the extension of the genetic alphabet.3 Because of quinoxalines as nucleobase surrogates.
the increased propensity to p-stacking and favorable desolva-
The terminal sugar alkynes 1a (Scheme 1) prepared according to
tion energy compared to canonical hydrophilic nucleobases, the known procedure18 were initially treated with 4-iodobiphenyl
these aryl groups form pairs selectively with the same or other
hydrophobic nucleobases in oligonucleotide duplexes.4 In this
way, the aryl C-nucleosides have been used to explore base
stacking in DNA–DNA duplexes after their incorporation into
DNA-oligomers via phosphoramidite chemistry or to explore
the molecular interactions in DNA–protein recognition pro-
cesses5 and the reaction mechanisms of DNA repair enzymes.6
The crucial importance of minor-groove interactions of the
synthetic nucleobase with the enzyme has been found recently.7
The triphosphates of hetaryl C-nucleosides possessing equivocal
a The College of Chemistry and Molecular Engineering, The Key Lab of Chemical
Biology and Organic Chemistry, Zhengzhou University, Zhengzhou 450052, China.
E-mail: zhangfy@zzu.edu.cn; Fax: +86-371-67763845; Tel: +86-371-67763845
b College of Chemistry and Chemical Engineering, The Key Lab for Chemical Biology
of Fujian Province, Xiamen University, Xiamen, Fujian 361005, China
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data or other electronic formats. See DOI: 10.1039/c4cc01448k
Scheme 1 The synthesis of 2aa and the reaction sequence.
‡ Present address: Henan Purui Pharmaceutical Technology Co., ltd.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5771--5773 | 5771

View Article Online
Communication
ChemComm
in the presence of Pd(PPh3)2Cl2 and CuI at rt under N2 for the presence of 5–10 mol% of Lewis acid (Table 1, entries 1–3).
1.5 h. TLC showed the complete conversion of 1a, indicating that Only a trace of 5 was produced using the two different palla-
the Sonogashira coupling reaction was finished. The solution dium catalysts at 80 1C and 30% yield was obtained when FeBr3
was evaporated to remove Et3N, and then CH2Cl2 was added was used as a catalyst. Prolonged reaction time and increasing
and washed with water. NaIO4, MeCN and catalytic amounts the reaction temperature resulted in the complicated reactions.
of RuCl3ꢀ3H2O were added and then treated with 1,2-phenylene- KMnO4 and H5IO6 as oxidants also did not work well and 5 was
diamine at rt to give 2aa in 88% yield.
generated in 28–40% yield, respectively (Table 1, entries 4–6).
In order to clarify this mechanism, the reaction was stopped We were pleased to find that RuCl3ꢀ3H2O/NaIO4 was a very
by evaporating the reaction mixture to dryness before 1,2-phenylene- efficient oxidation system for converting 3 into 5 at rt (Table 1,
diamine was added. Fortunately, the product 1,2-diketone 5 entries 7–9). It was optimized and a yield of 90% was finally
(Scheme 1) was isolated. In this way, the reactants undergo
a Sonogashira coupling reaction, with subsequent oxidation
followed by condensation as the three main steps. The reaction
sequence starts with Pd(PPh3)2Cl2 and CuI catalyzed coupling
Table 2 The scope of substrates for the syntheses of various aryl
quinoxaline C-nucleoside analogsa
between 1a and 4-iodobiphenyl to produce sugar biphenyl
alkyne 3. RuO4 generated in situ from catalytic amounts of
RuCl3, H2O and an excess of sodium periodate attacks the triple
bond of 3 to form the intermediate 4. The sugar 1,2-diketone 5
is produced after eliminatioꢁn of RuO2 from 4. The RuO2 is
Entry
Product yieldb, time
Entry
Product yieldb, time
subsequently oxidized by IO4 to give RuO4 which participates
in the next oxidation recycle. The condensation of 5 with
1,2-phenylenediamine gives the desired product 2aa. The struc-
tures of 2aa and 5 were characterized by 1H NMR, 13C NMR,
DEPT-135, 2D NMR, HRMS and IR spectra.
1
5
In the optimization studies for the synthesis of 2aa from 1a,
we found that the best results for the Sonogashira coupling
reaction were obtained with 1.1 equivalent of 4-iodobiphenyl,
1.0 equivalent of 1a and 5 mol% of Pd(PPh3)2Cl2 and CuI each.
The reaction was complete within 1.5 h at rt. Increasing the
reaction temperature diminished the yield, probably due to
the deprotection of 1,2-O-isopropylidene in the presence of
Pd(PPh3)2Cl2 and CuI as Lewis acid. For conversion of sugar
alkyne into sugar 1,2-diketone, although the oxidation system
for diarylalkynes has been presented,19 the elevated tempera-
ture, prolonged reaction time and acidic media are not suitable
for the sugar alkyne having sensitive functional groups.
Hitherto, no oxidation of sugar alkyne into the corresponding
1,2-diketone has been reported. In order to get a mild oxidation
system suitable for 3 and the other fragile sugar alkynes, we
used the isolated intermediate 3 as the starting material to
explore the oxidation system. DMSO as an oxidant was used in
2
6
3
7
Table 1 The oxidation of 3 to 5 under various conditionsa
T
Yielda
(%)
Entry Oxidation system
(1C) Time
1
2
3
4
5
6
7
8
9
PdCl2, DMSO
PdI2, DMSO
FeBr3, DMSO
KMnO4, H2O, MeCN
KMnO4, H2O, acetone
H5IO6, MeOH
80 4 h
80 4.5 h
80 2 h
60 2 h
60 2 h
60 2 h
Trace
Trace
30
28
35
4
40
RuCl3ꢀ3H2O, NaIO4, H2O, CH2Cl2
rt
rt
15 min 65
10 min 72
5 min 90b
RuCl3ꢀ3H2O, NaIO4, H2O, MeCN
RuCl3ꢀ3H2O, NaIO4, H2O, CH2Cl2, MeCN rt
a
Reaction conditions: 0.81 mmol of aryl iodide, 0.8 mmol of terminal
a
b
Isolated yield. The reaction was performed on a 0.5 mmol scale sugar alkyne, 5 mol% of each Pd(PPh3)2Cl2 and CuI, 3 ml of Et3N, 4 ml
using RuCl3ꢀ3H2O (1.3 mol%) and NaIO4 (3.0 equiv.) in the tricomponent of CH2Cl2, 2 ml of MeCN, 1.3% mol of RuCl3ꢀH2O, 2.4 mmol of NaIO4,
b
solvent (H2O/CH2Cl2/MeCN = ca. 1 :10: 5).
0.81 mmol of 1,2-phenylenediamine, rt. Isolated yield.
5772 | Chem. Commun., 2014, 50, 5771--5773
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
ˇ
ˇ
2 Selected examples: (a) J. Stambask´y, M. Hocek and P. Kocovsk´y,
attained in the presence of 1.3 mol% of RuCl3ꢀ3H2O and 3.0
equivalent of NaIO4 by use of tricomponent solvent of H2O,
CH2Cl2 and MeCN (ca. 1 : 10 : 5) within 5 min.
´
ˇ
Chem. Rev., 2009, 109, 6729; (b) M. Popsavin, S. Spaic, M. Svircev,
´
´
´
V. Kojic, G. Bogdanovic, V. Pejanovic and V. Popsavin, Tetrahedron,
2009, 65, 7637; (c) A. B.-A. El-Gazzar, H.-N. Hafez and H.-S. Abbas,
Eur. J. Med. Chem., 2009, 44, 4249; (d) A. B.-A. El-Gazzar, H.-N. Hafez
and G. A. M.-S. Nawwar, Eur. J. Med. Chem., 2009, 44, 1427.
3 (a) E.-T. Kool, J.-C. Morales and K.-M. Guckian, Angew. Chem., Int. Ed.,
2000, 39, 990; (b) E.-T. Kool, Acc. Chem. Res., 2002, 35, 936; (c) A.-A.
Henry and F. E. Romesberg, Curr. Opin. Chem. Biol., 2003, 7, 727.
4 Selected examples: (a) K.-M. Guckian, T.-R. Krugh and E.-T. Kool,
J. Am. Chem. Soc., 2000, 122, 6841; (b) Y.-Q. Wu, A.-K. Ogawa,
M. Berger, D.-L. McMinn, P.-G. Schultz and F.-E. Romesberg,
J. Am. Chem. Soc., 2000, 122, 7621; (c) J. Parsch and J.-W. Engels,
J. Am. Chem. Soc., 2002, 124, 5664; (d) J.-S. Lai, J. Qu and E.-T. Kool,
Angew. Chem., Int. Ed., 2003, 42, 5973; (e) J.-S. Lai and E.-T. Kool,
J. Am. Chem. Soc., 2004, 126, 3040.
5 Selected examples: (a) T.-J. Matray and E.-T. Kool, Nature, 1999,
399, 704; (b) A.-K. Ogawa, Y.-Q. Wu, D.-L. McMinn, J.-Q. Liu, P.-G.
Schultz and F.-E. Romesberg, J. Am. Chem. Soc., 2000, 122, 3274;
(c) C.-Z. Yu, A.-A. Henry, F.-E. Romesberg and P.-G. Schultz, Angew.
Chem., Int. Ed., 2002, 41, 3841.
6 Selected examples: (a) K. Kwon, Y.-L. Jiang and J.-T. Stivers, Chem.
Biol., 2003, 10, 351; (b) D.-J. Krosky, F. Song and J.-T. Stivers,
Biochemistry, 2005, 44, 5949.
7 (a) Y. Kim, A.-M. Leconte, Y. Hari and F.-E. Romesberg, Angew.
Chem., Int. Ed., 2006, 45, 7809; (b) A.-M. Leconte, S. Matsuda, G.-T.
Hwang and F.-E. Romesberg, Angew. Chem., Int. Ed., 2006, 45, 4326;
(c) N. Joubert, R. Pohl, B. Klepetarova and M. Hocek, J. Org. Chem.,
2007, 72, 6797.
8 A.-M. Leconte, S. Matsuda and F.-E. Romesberg, J. Am. Chem. Soc.,
2006, 128, 6780.
9 R. Sarges, H.-R. Howard, R.-C. Browne, L.-A. Label, P.-A. Seymour
and K.-B. Koe, J. Med. Chem., 1990, 33, 2240.
To explore the generality of this method and to synthesize
various aryl quinoxaline C-nucleoside analogs, various terminal
sugar alkynes and substituted aryl iodides were used to perform
this sequence, which were summarized in Table 2 (the structures
of 1a–1g are shown in pages 2–4 in the ESI†). The sequence
proceeds smoothly to give the corresponding products in high
yields. All the aryl iodides having electron-donating, electron-
withdrawing and electron-neutral substituents can be used
throughout this reaction sequence without difficulties. Gener-
ally, aryl iodide with electron-withdrawing substituents gives the
lowest yield (for example R = CN, Table 2, entry 1, entries 3–7)
and that having electron-donating groups is superior to the
others (for example entry 6, 2fa, 2ff). All the sugar alkynes can
be coupled efficiently to produce the aryl quinoxaline C-nucleoside
analogs. However, D-fructose derived 1e takes longer reaction time
and gives lower yield (Table 2, entry 5) than that of the other
cyclic sugar alkynes, probably due to the steric hindrance of
di-O-isopropylidene. The acyclic sugar alkyne 1g has a less clean
reaction and gives lower yield than 1f, because of the bulky
triphenylmethyl group at the 40-position and its easy deprotec-
tion in the presence of Lewis acid. All the new compounds were
characterized by 1H NMR, 13C NMR, DEPT-135, 2D NMR, HRMS
and IR.
´ˇ
´
10 F. Rong, S. Chow, S. Yan, G. Larson, Z. Hong and J. Wu, Bioorg. Med.
Chem. Lett., 2007, 17, 1663.
In summary, novel syntheses of C-nucleoside analogs with aryl
quinoxalines as nucleobase surrogates have been accomplished
from various terminal sugar alkynes by mild and efficient sequen-
tial Sonogashira coupling/oxidation/condensation reactions in high
yields. This method has a wide scope of substrates including
various substituted aryl iodides as well as cyclic and acyclic terminal
sugar alkynes. The reaction mechanism was clarified by isolation
of the novel product, the first example of oxidation of sugar
alkyne into the corresponding 1,2-diketone. In addition, these aryl
quinoxaline C-nucleoside analogs are optically pure. They are the
precursors of the tetrahydroquinoxaline derivatives which have also
shown great potential for drug development. Thus, a lot of optically
pure tetrahydroquinoxaline derivatives can be obtained if these
quinoxaline C-nucleoside analogs are hydrogenated.
11 (a) L.-E. Seitz, W.-J. Suling and R.-C. Reynolds, J. Med. Chem., 2002,
45, 5604; (b) A. Jaso, B. Zarranz, I. Aldana and A. Monge, J. Med.
Chem., 2005, 48, 2019.
12 M.-R. Myers, W. He, B. Hanney, N. Setzer, M.-P. Maguire, A. Zulli,
G. Bilder, H. Galzcinski, D. Amin, S. Needle and A. Spada, Bioorg.
Med. Chem. Lett., 2003, 13, 3091.
13 X. Hui, J. Desrivot, C. Bories, P.-M. Loiseau, X. Franck, R. Hocquemiller
and B. Fidadere, Bioorg. Med. Chem. Lett., 2006, 16, 815.
14 (a) K. Toshima, R. Takano, T. Ozawa and S. Matsumura, Chem. Commun.,
2002, 212; (b) L.-S. Hegedus, M.-M. Greenberg, J.-J. Wendling and J.-P.
Bullock, J. Org. Chem., 2003, 68, 4179.
15 Selected examples: (a) A.-R. Katritzky, D. Zhang and K. Kirichenko,
J. Org. Chem., 2005, 70, 3271; (b) J. Cai, J.-P. Zou, X.-Q. Pan and
W. Zhang, Tetrahedron Lett., 2008, 49, 7386; (c) S. Chandrasekhar,
N. K. Reddy and V. P. Kumar, Tetrahedron Lett., 2010, 51, 3623;
(d) E. Merkul, J. Dohe, C. Gers, F. Rominger and T. J. J. Muller,
Angew. Chem., Int. Ed., 2011, 50, 2966.
16 (a) D.-L. Ma, T. Y.-T. Shum, F. Zhang, C.-M. Che and M. Yang, Chem.
Commun., 2005, 4675; (b) Q. Zhang, J. Sun, Y. Zhu, F. Zhang and
B. Yu, Angew. Chem., Int. Ed., 2011, 50, 4933; (c) J. Yu, J. Sun, Y. Niu,
R. Li, J. Liao, F. Zhang and B. Yu, Chem. Sci., 2013, 4, 389.
17 (a) H.-M. Liu, F. Zhang and J. Zhang, Carbohydr. Res., 2001, 334, 323;
(b) H.-M. Liu, F. Zhang, J. Zhang and S. Li, Carbohydr. Res., 2003,
338, 1737; (c) H.-M. Liu, F. Zhang and S. Wang, Org. Biomol. Chem.,
2003, 1, 1641; (d) H.-M. Liu, F. Zhang and D.-P. Zou, Chem.
Commun., 2003, 2044; (e) F. Zhang, H. Liu, Y.-F. Li and H.-M. Liu,
Carbohydr. Res., 2010, 345, 839; ( f ) Q. Zhang, J. Sun, F. Zhang and
B. Yu, Eur. J. Org. Chem., 2010, 3579; (g) H. Liu, F. Zhang, J.-P. Li,
X. Yan, H.-M. Liu and Y.-F. Zhao, J. Chem. Crystallogr., 2011,
41, 1228; (h) F. Zhang, H. Liu, Y. Sheng and H.-M. Liu, Chin.
J. Chem., 2012, 30, 195; (i) F. Zhang, L. Wang, C. Zhang and
Y. Zhao, Chem. Commun., 2014, 50, 2046.
18 (a) E.-J. Cory and P.-L. Fuchs, Tetrahedron Lett., 1972, 13, 3769; (b) J.-M. J.
Tronchet, A. Gonzalez, J.-B. Zumwald and F. Perret, Helv. Chim. Acta,
1974, 57, 1505.
19 (a) C.-J. Walsh and B.-K. Mandal, J. Org. Chem., 1999, 64, 6102; (b) M.-S.
Yusubov, G.-A. Zholobova, S.-F. Vasilevsky, E.-V. Tretyakov and D.-W.
Knight, Tetrahedron, 2002, 58, 1607; (c) Z. Wan, C.-D. Jones, D. Mitchell,
J.-Y. Pu and T.-Y. Zhang, J. Org. Chem., 2006, 71, 826.
This work was supported by the National Natural Science Founda-
tion of China (No. 21272219, 20972142) and the State Key Laboratory
of Bio-organic and Natural Products Chemistry, CAS (08417).
Notes and references
1 Selected examples: (a) J.-A. Walker, W. Liu, D.-S. Wise, J.-C. Drach
and L.-B. Townsend, J. Med. Chem., 1998, 41, 1236; (b) S. Aketani,
K. Tanaka, K. Yamamoto, A. Ishihama, H. Cao, A. Tengeiji,
S. Hiraoka, M. Shiro and M. Shionoya, J. Med. Chem., 2002,
45, 5594; (c) Q.-P. Wu and C. Simons, Synthesis, 2004, 1533;
(d) S. Matsuda, J.-D. Fillo, A.-A. Henry, P. Rai, S.-J. Wilkens, T.-J.
Dwyer, B.-H. Geierstanger, D.-E. Wemmer, P.-G. Schultz, G. Spraggon
and F.-E. Romesberg, J. Am. Chem. Soc., 2007, 129, 10466; (e) A.-M.
Leconte, G.-T. Hwang, S. Matsuda, P. Capek, Y. Hari and F.-E.
Romesberg, J. Am. Chem. Soc., 2008, 130, 2336; ( f ) M. F.-A. Adamo
and R. Pergoli, Curr. Org. Chem., 2008, 12, 1544; (g) A.-M. Leconte,
N. Joubert, M. Hocek and F.-E. Romesberg, ChemBioChem, 2008,
ˇ
9, 2796; (h) M. Stefko, R. Pohl and M. Hocek, Tetrahedron, 2009,
65, 4471.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5771--5773 | 5773