A concise and versatile synthesis of viridicatin alkaloids from cyanoacetanilides

Article abstract of DOI:10.1021/ol900255g

The efficient synthesis of 3-hydroxy-4-arylquinolin-2(1H)-ones through one-pot Knoevenagel condensation/epoxidation of cyanoacetanilides followed by decyanative epoxide-arene cyclization is described. A convergent assembly with functionalized aldehydes allows for rapid synthesis with diverse substitution patterns. Isolation of 3-hydroxy-4-arylquinolin-2(1H)-ones is readily accomplished by precipitation and filtration.

Full text of DOI:10.1021/ol900255g

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1603-1606
A Concise and Versatile Synthesis of
Viridicatin Alkaloids from
Cyanoacetanilides
Yusuke Kobayashi* and Takashi Harayama*
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity,
Sanuki-shi, Kagawa 769-2193, Japan
ykobayashi@kph.bunri-u.ac.jp; harayama@kph.bunri-u.ac.jp
Received February 6, 2009
ABSTRACT
The efficient synthesis of 3-hydroxy-4-arylquinolin-2(1H)-ones through one-pot Knoevenagel condensation/epoxidation of cyanoacetanilides
followed by decyanative epoxide-arene cyclization is described. A convergent assembly with functionalized aldehydes allows for rapid synthesis
with diverse substitution patterns. Isolation of 3-hydroxy-4-arylquinolin-2(1H)-ones is readily accomplished by precipitation and filtration.
Functionalized 4-arylquinolin-2(1H)-ones 1 (Figure 1) con-
stitute a valuable class of biologically active molecules,1-3
including an orally active antitumor agent1 that is currently
undergoing human clinical trials. In particular, the biological
activities of 3-hydroxy-4-arylquinolin-2(1H)-one derivatives
2, including several natural products such as viridicatin (3),4
viridicatol (4),5 and 3-O-methylviridicatin (5),6 have attracted
much attention in recent years.7-9 Compounds 3-5 were
first isolated as fungal metabolites in the 1950s and 1960s,4-6
but their biological activities remained unexplored until 1998,
when Heguy and co-workers reported that 5 inhibits the
replication of human immunodeficiency virus (HIV) induced
by tumor necrosis factor (TNF-R) with an IC50 of 2.5 µM.7
More recently, Desaubry and co-workers reported on the
structure-activity relationships of 5.8 In addition, a series
of 3-hydroxy-4-arylquinolin-2(1H)-ones 2 have been found
to act as maxi-K channel openers with antibacterial activity.9
However, surprisingly, the synthesis of derivatives 2 has
(1) (a) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny,
Y. A.; Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004,
479. (b) Andresen, B. M.; Couturier, M.; Cronin, B.; D’Occhio, M.; Ewing,
M. D.; Guinn, M.; Hawkins, J. M.; Jasys, V. J.; LaGreca, S. D.; Lyssikatos,
J. P.; Moraski, G.; Ng, K.; Raggon, J. W.; Stewart, A. M.; Tickner, D. L.;
Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. Org. Process Res. DeV.
2004, 8, 643
.
(2) For recent reports, see: (a) Cheng, P.; Zhang, Q.; Ma, Y.-B.; Jiang,
Z.-Y.; Zhang, X.-M.; Zhang, F.-X.; Chen, J.-J. Bioorg. Med. Chem. Lett.
2008, 18, 3787. (b) Capell, B. C.; Olive, M.; Erdos, M. R.; Cao, K.; Faddah,
D. A.; Tavarez, U. L.; Conneely, K. N.; Qu, X.; San, H.; Ganesh, S. K.;
Chen, X.; Avallone, H.; Kolodgie, F. D.; Virmani, R.; Nabel, E. G.; Collins,
F. S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 15902. (c) Wall, M. J.; Chen,
J.; Meegalla, S.; Ballentine, S. K.; Wilson, K. J.; DesJarlais, R. L.; Schubert,
C.; Chaikin, M. A.; Crysler, C.; Petrounia, I. P.; Donatelli, R. R.; Yurkow,
E. J.; Boczon, L.; Mazzulla, M.; Player, M. R.; Patch, R. J.; Manthey, C. L.;
Molloy, C.; Tomczuk, B.; Illig, C. R. Bioorg. Med. Chem. Lett. 2008, 18,
(4) (a) Cunnigham, K. G.; Freeman, G. G. Biochem. J. 1953, 53, 328.
(b) Bracken, A.; Pocker, A.; Raistrick, H. Biochem. J. 1954, 57, 587. (c)
Luckner, M.; Mothes, K. Tetrahedron Lett. 1962, 3, 1035.
(5) (a) Luckner, M.; Mothes, K. Arch. Pharm. Berlin 1963, 296, 18.
(b) Mohammed, Y. S.; Luckner, M. Tetrahedron Lett. 1963, 4, 1953.
(6) Austin, D. J.; Myers, M. B. J. Chem. Soc. 1964, 1, 1197.
2097
.
(3) (a) Hewawasam, P.; Fan, W.; Ding, M.; Flint, K.; Cook, D.;
Goggings, G. D.; Myers, R. A.; Gribkoff, V. K.; Boissard, C. G.; Dworetzky,
S. I.; Starret, J. E.; Lodge, N. J. J. Med. Chem. 2003, 46, 2819. (b) Cappelli,
A.; Mohr, G. la P.; Gallelli, A.; Rizzo, M.; Anzini, M.; Vomero, S.;
Mennuni, L.; Ferrari, F.; Makovec, F.; Menziani, M C.; Benedetti, P. G.
(7) Heguy, A.; Cai, P.; Meyn, P.; Houck, D.; Russo, S.; Michitsch, R.;
Pearce, C.; Katz, B.; Bringmann, G.; Feineis, D.; Taylor, D. L.; Tyms, A. S.
AntiViral Chem. Chemother. 1998, 9, 149
(8) Ribeiro, N.; Tabaka, H.; Peluso, J.; Fetzer, L.; Nebigil, C.; Dumont,
S.; Muller, C. D.; De´saubry, L. Bioorg. Med. Chem. Lett. 2007, 17, 5523
(9) Sit, S.-Y.; Meanwell, N. A. U.S. Patent 5,892,045, 1999
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.
.
10.1021/ol900255g CCC: $40.75
Published on Web 03/03/2009
2009 American Chemical Society

that the CN groups would function not only as electron-
withdrawing groups at the condensation step (7 + 8 f 6)
but also as leaving groups at the cyclization step (6 f 2).
Here, we describe a novel and flexible protocol for the
synthesis of functionalized 3-hydroxy-4-arylquinolin-2(1H)-
ones 2. The salient features of our method are as follows:
(1) a variety of cyanoacetanilides 7 and aldehydes 8 are
readily available; (2) only three steps are required beginning
from the starting materials, and the rapid synthesis of 2 with
diverse substitution patterns is possible; (3) facile isolation
of 2 is accomplished by a simple aqueous workup.
Figure 1. Biologically active 4-arylquinolin-2(1H)-one derivatives.
We first examined the reaction between cyanoacetanilide
(7a) and benzaldehyde (8a) (Scheme 2). After a brief survey
remained largely unexplored: only a few methods have been
reported, including the condensation of aryldiazomethanes
with isatins,10 transformation of cyclopenin,11 Friedla¨nder-
type condensations,1-3,12 and Pd-catalyzed coupling reac-
tions.13,14 These strategies, unfortunately, suffer from the
disadvantages that the starting materials are only available
in limited supply and that the process of varying the R2 and
R3 groups of 2 is cumbersome and lengthy. The development
of a novel method for the synthesis of derivatives 2 with
complete control over both R2 and R3 substituents would
therefore be of significant value.
Scheme 2. Optimized Conditions for the Synthesis of
3-Hydroxy-4-arylquinolin-2(1H)-ones 2
Our strategy for the synthesis of 2 is outlined in Scheme
1, where 2 is obtained from 6 via oxidative cyclizations. In
Scheme 1. Strategy for the Synthesis of
3-Hydroxy-4-arylquinolin-2(1H)-ones 2
of reaction conditions, we found that the desired 3-hydroxy-
4-arylquinolin-2(1H)-one 2aa16 was obtained in 84% yield
by the H2SO4-mediated cyclization of epoxide 9aa,17-19
which was, in turn, synthesized from 7a in good yield by
the one-pot Knoevenagel condensation/epoxidation. Knoev-
enagel condensation was best performed under mild condi-
tions using piperidine as the catalyst (10-15 mol % of
piperidine, DMF, rt, 48 h), and one-pot epoxidation pro-
ceeded efficiently under optimized conditions20 (t-BuOOH,
KF, rt, 24 h). It was noted that both 9aa and 2aa were
(16) All spectral data were in full accord with those reported in the
literature; see the Supporting Information.
(17) For reviews of Friedel-Crafts and related reactions, see: (a) Olah,
G. A.; Krishnamurti, R.; Prakash, G. S. S. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
Chapter 1.8. (b) Olah, G. A. Friedel-Crafts and Related Reactions;
turn, 6 can be readily prepared by Knoevenagel condensation
of cyanoacetanilides15 7 with aldehydes 8. We hypothesized
Interscience Publishers: New York, 1964
(18) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006
.
.
(19) For a review of epoxide-arene cyclizations, see: (a) Taylor, S. K.
Org. Prep. Proced. Int. 1992, 24, 245. For recent examples, see: (b) Islas-
Gonza´lez, G.; Benet-Buchholz, J.; Maestro, M. A.; Riera, A.; Perica`s, M. A.
J. Org. Chem. 2006, 71, 1537. (c) Kraus, G. A.; Kim, I. Org. Lett. 2003,
5, 1191. (d) Nagumo, S.; Miyoshi, I.; Akita, H.; Kawahara, N. Tetrahedron
Lett. 2002, 43, 2223. (e) Yang, L.; Deng, G.; Wang, D.-X.; Huang, Z.-T.;
Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9, 1387. (f) Johansen, M. B.;
Leduc, A. B.; Kerr, M. A. Synlett 2007, 2593. (g) Marcos, R.; Rodr´ıguez-
Escrich, C.; Herrer´ıas, C. I.; Perica`s, M. A. J. Am. Chem. Soc. 2008, 130,
16838. (h) Nagumo, S.; Ishii, Y.; Sato, G.; Mizukami, M.; Imai, M.;
Kawahara, N.; Akita, H. Tetrahedron Lett. 2009, 50, 26. For a recent
example of related cyclizations, see: (i) Wipf, P.; Maciejewski, J. P. Org.
(10) (a) Eistert, B.; Selzer, H. Z. Naturforsch. 1962, 17b, 3. (b) Luckner,
M.; Mohammed, Y. S. Tetrahedron Lett. 1964, 5, 1987.
(11) (a) Smith, H. W.; Rapoport, H. J. Am. Chem. Soc. 1969, 91, 6083.
(b) Martin, P. K.; Rapoport, H.; Smith, H. W.; Wong, J. L. J. Org. Chem.
1969, 34, 1359.
(12) (a) For a review, see: Cheng, C.-C.; Yan, S.-J. The Friedla¨nder
Synthesis of Quinolines. In Organic Reactions; Dauben, W. C., Ed.; J. Wiley
& Sons: New York, 1982; Vol. 28, p 37. (b) Terada, A.; Yabe, Y.; Miyadera,
T.; Tachikawa, R. Chem. Pharm. Bull. 1973, 21, 807
(13) Arshad, N.; Hashim, J.; Kappe, C. O. J. Org. Chem. 2008, 73, 4755
(14) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433
(15) Cyanoacetanilides (7a-f) were prepared by reacting cyanoacetic
acid with the corresponding aniline up to a 20-g scale (77-96% yields).
For experimental details, see the Supporting Information.
.
.
.
Lett. 2008, 10, 4383.
(20) When H2O2 was used as the oxidant instead of t-BuOOH, we
observed partial hydrolysis of the CN group of 9aa.
1604
Org. Lett., Vol. 11, No. 7, 2009

obtained as precipitates by simple aqueous workup and could
be purified by recrystallization.
With the optimized conditions identified, we examined the
substrate scope of the reaction with respect to both the
nitrogen (R1) and the aromatic (R2) substituents of cyanoac-
etanilides 7 (Table 1).21 The reaction showed remarkable
result, the reactions of 9ea and 9fa, which have electron-
withdrawing groups such as Br and Cl on the aromatic rings,
proceeded slowly at room temperature; however, the reac-
tions were completed within 24 h to afford the corresponding
quinolinones 2ea and 2fa in respective yields of 85% and
92% (entries 5 and 6). These halogenated products could in
principle be further functionalized by way of transition-metal-
catalyzed coupling reactions. As we expected, the isolation
of all products 2ba-2fa was readily accomplished by
precipitation and filtration.
Table 1. Substrate Scope of Cyanoacetanilides 7a
We used the same strategy, one-pot Knoevenagel/epoxi-
dation followed by epoxide-arene cyclization, to synthesize
a variety of 3-hydroxy-4-arylquinolin-2(1H)-ones 2 by vary-
ing the R3 groups (Table 2). One-pot reactions of cyanoac-
entry
7 (R1, R2)
9 (yield,b %)
2 (yield, %)
2ba (40c)
2ca (72c)
2ca (82c)
2da (99f)
Table 2. Substrate Scope of Aldehydes 8
1
2
3e
4
5
6
7b (Bn, H)
7c (PMB,d H)
7c
7d (PMB, Me)
7e (PMB, Br)
7f (Me, Cl)
9da (49)
9ea (88)
9fa (69)
2ea (85f, g
)
2fa (92f, g
)
a Unless otherwise noted, all reactions were carried out with 3.0 mmol
of 7. b Isolated yields in two steps from 7. c Isolated yields in three steps
from 7. d PMB ) 4-methoxybenzyl. e Carried out with 30 mmol of 7c.
f Isolated yields from 9. g 9ea and 9fa were consumed in 24 h.
entry
7 (R1)
8 (R3)
9 (yielda) 2 (yield, %)
2cb (59b)
1
2
3
4
5
6
7
7c (PMBd) 8b (3-HOC6H4)
7a (Me)
7a
7a
7a
7a
7a
8c (4-MeOC6H4) 9ac (70)
2ac (89c)
2ad (90c)
2ae (86c,e
2af (0c)
8d (1-naphthyl)
8e (4-BrC6H4)
8f (4-CF3C6H4)
8f
9ad (87)
9ac (86)
9ac (78)
9af
tolerance to a range of substituents with markedly different
steric and electronic properties (entries 1-6). We first
examined the reactions of the more readily deprotected N-Bn
and N-PMB derivatives 7b and 7c (entries 1 and 2). Although
the one-pot reactions of 7b and 7c worked equally well, we
could not obtain the corresponding epoxides 9 as precipitates.
However, by telescoping22 the reaction sequence (7 f 9 f
2), 2ba and 2ca were obtained as white solids in 40% and
72% overall yields, respectively. Notably, the large-scale
reactions can be conducted easily and inexpensively. For
example, the reactions proceeded cleanly and efficiently to
afford 8.7 g of 2ca when carried out with 30 mmol (8.4 g)
of 7c (entry 3). To expand the utility of this reaction, we
next examined the effect of the substituents R2 on the
aromatic rings (entries 4-6). The substituents R2 were found
to have little effect on the one-pot Knoevenagel condensation/
epoxidation, and the desired epoxides 9da-9fa were ob-
tained as white solids in moderate-to-good yields. Subsequent
epoxide-arene cyclization of epoxide 9da bearing an electron-
rich aryl group took place smoothly to afford the desired
quinolinone 2da in 99% yield (entry 4). In contrast to this
)
2af (71c,f
)
8g (2-thienyl)
2ag (38b)
a Isolated yields in two steps from 7. b Isolated yields in three steps
from 7. c Isolated yields from 9. d PMB ) 4-methoxybenzyl. e 9ae was
consumed in 24 h. f 9af was treated in trifluoroacetic acid at 100 °C (reflux)
for 24 h.
etanilides 7 with substituted arylaldehydes (8b-g) generally
produced good-to-excellent yields. The subsequent cycliza-
tions of epoxides having electron-rich aromatic rings were
found to have beneficial effects on rate, affording the
corresponding quinolinones in 59-78% overall yields (en-
tries 1-3). It should be noted that no protection was required
for the phenolic -OH in H2SO4-mediated epoxide-arene
cyclization (entry 1). In contrast, epoxides 9ae and 9af
bearing electron-withdrawing substituents R3 proved less
reactive (entries 4-6). For example, when 9af was treated
with 10 equiv of H2SO4 for 24 h, cyclization did not proceed
at all (entry 5), suggesting such substituents inhibit the
generation of carbocation species at benzylic positions. Its
efficient conversion, however, could be achieved by refluxing
in trifluoroacetic acid for 24 h (entry 6). Moreover, this
methodology could be applied to the heteroaromatic aldehyde
8g, and the desired quinolinone 2ag was obtained, albeit in
somewhat lower yield (entry 7).
(21) Note that a tertiary anilide must be used to ensure a smooth
annulation reaction. This is because the reaction of the secondary anilide
(R1 ) H) does not proceed at all, most probably due to conformational
reasons; see: (a) Pederson, B. F.; Pederson, B. Tetrahedron Lett. 1965, 2995.
(b) Nanjan, M. J.; Kannappan, V.; Ganesan, R. Indian J. Chem. 1979, 18B,
461. (c) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177.
(22) The term “telescoping” has been used before to describe sequential
multistep/multipot processes with shortened or omitted isolation procedures
for the involved intermediates; see, e.g.: Dale, D. J.; Draper, J.; Dunn, P. J.;
Hughes, M. L.; Hussain, F.; Levett, P. C.; Ward, G. B.; Wood, A. S. Org.
Process Res. DeV. 2002, 6, 767.
Finally, the conversion of the resulting N-PMB derivatives
to quinolinones with free N-H functions was examined
(Scheme 3). Under acidic conditions, 2ca and 2cb were
Org. Lett., Vol. 11, No. 7, 2009
1605

reactions are widely available or can be readily prepared,
thus greatly enhancing the synthetic potential of the method.
The development of synthetic applications is under investiga-
tion and will be reported in due course.
Scheme 3. Deprotection of N-PMB Derivatives
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (Start-up) (Y.K.) from
Japan Society for the Promotion of Science.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
readily deprotected to afford 3 and 4 in 73% and 64% yields,
respectively.
OL900255G
In summary, we have demonstrated an efficient approach
to the synthesis of the biologically active 3-hydroxy-4-
arylquinolin-2(1H)-ones 2 by fully exploiting the CN
groups23 of the cyanoacetanilides 7. Substrates for the
(23) For recent examples of other reactions fully exploiting the CN
groups, see: (a) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978. (b) Nakao, Y.;
Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc.
2008, 130, 12874.
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Org. Lett., Vol. 11, No. 7, 2009