Two-step total syntheses of Canthin-6-one alkaloids: New one-pot sequential Pd-catalyzed Suzuki-Miyaura coupling and Cu-catalyzed amidation reaction

Article abstract of DOI:10.1021/ol100300s

Chemical Equation Presented Canthin-6-one (1) and nine analogues including the naturally occurring 9-methoxycanthin-6-one (2) and amaroridine (3) are prepared rapidly and in high yields via a convergent non-classical strategy that focuses on construction of the central ring B. The strategy relies on concomitant Pd-catalyzed Suzuki-Miyaura C-C coupling followed by a Cu-catalyzed C-N coupling that can be achieved either stepwise or in a new one-pot protocol starting from the appropriate 8-bromo-1,5-naphthyrldine.

Full text of DOI:10.1021/ol100300s

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1352-1355
Two-Step Total Syntheses of
Canthin-6-one Alkaloids: New One-Pot
Sequential Pd-Catalyzed
Suzuki-Miyaura Coupling and
Cu-Catalyzed Amidation Reaction
Andreas Gollner†,‡ and Panayiotis A. Koutentis*,†
Department of Chemistry, UniVersity of Cyprus, P.O. Box 20537, 1678 Nicosia,
Cyprus, and Cyano Research Corporation Ltd., P.O. Box 28670, 2081 Nicosia, Cyprus
koutenti@ucy.ac.cy
Received February 4, 2010
ABSTRACT
Canthin-6-one (1) and nine analogues including the naturally occurring 9-methoxycanthin-6-one (2) and amaroridine (3) are prepared rapidly
and in high yields via a convergent “non-classical” strategy that focuses on construction of the central ring B. The strategy relies on concomitant
Pd-catalyzed Suzuki-Miyaura C-C coupling followed by a Cu-catalyzed C-N coupling that can be achieved either stepwise or in a new
one-pot protocol starting from the appropriate 8-bromo-1,5-naphthyridine.
Canthinones are ꢀ-carboline alkaloids that have an ad-
ditional ring fusion affording a tetracyclic core (Figure
1). Canthinone 1, first isolated by Haynes in 1952,1 has a
promising biological profile;1b,2 as such, its synthesis has
generated significant interest. Over 40 natural occurring
analogues have now been reported,1b,2 e.g., 9-methoxycan-
thin-6-one (2),3 amaroridine (3),4 or the more complex
curtisin (4).5
canthinone to afford indole synthons could therefore be
considered as “classical”. We required a convergent and
flexible synthesis that was suitable for the rapid generation
of a diverse compound library for biological studies. In light
(2) (a) Murakami, C.; Fukamiya, N.; Tamura, S.; Okano, M.; Bastow,
K. F.; Tokuda, H.; Mukainaka, T.; Nishino, H.; Lee, K.-H. Bioorg. Med.
Chem. 2004, 12, 4963. (b) Thouvenel, C.; Gantier, J.-C.; Duret, P.; Fourneau,
C.; Hocquemiller, R.; Ferreira, M.-E.; Rojas de Arias, A.; Fournet, A.
Phytother. Res. 2003, 17, 678. (c) Soriano-Agaton, F.; Lagoutte, D.; Poupon,
E.; Roblot, F.; Fournet, A.; Gantier, J.-C.; Hocquemiller, R. J. Nat. Prod.
2005, 68, 1581. (d) Ouyang, Y.; Koide, K.; Ohmoto, T. Phytochemistry
1994, 36, 1543. (e) Zapesochnaya, G. G.; Pervykh, L. N.; Kurkin, V. A.
Chem. Nat. Compd. 1991, 27, 336. (f) Vetrichelvan, T.; Jegadeesan, M.
Ethnopharmacol. 2002, 80, 103. (g) Hsieh, P.-W.; Chang, F.-R.; Lee, K.-
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R.; Ihara, M. Chem. Pharm. Bull. 2005, 53, 653. (i) O’Donnell, G.; Gibbons,
S. Phytother. Res. 2007, 21, 653.
The known reported syntheses of canthinones6 all start
from either indoles or tryptophans. The retrosynthesis of
† University of Cyprus.
‡ Cyano Research Corporation Ltd.
(1) (a) Haynes, H. F.; Nelson, E. R.; Price, J. R. Aust J. Res., Ser. A
1952, 5, 387. (b) For a review, see: Ohmoto, T.; Koike, K. In The Alkaloids;
Brossi, A., Ed.; Academic: New York, 1989; Vol. 36, p 135.
10.1021/ol100300s  2010 American Chemical Society
Published on Web 03/01/2010

dioxane gave the key precursor 8-bromo-1,5-naphthyrid-
2(1H)-one (6) that can be prepared in multigram batches (5
g).
Scheme 2. Preperation of Key Naphthyridines 6 and 9
Figure 1. Structure and chemical numbering of canthin-6-one (1)
and selected examples from over 40 natural analogues.
of this, we reevaluated the retrosynthesis of canthinone 1
and identified a nonclassical route that revolved around
constructing ring B via transition-metal C-C and C-N
coupling chemistry.
For the stepwise approach, the desired 8-(2-chlorophenyl)-
2-methoxynaphthyridine 10 was prepared from 8-bromo-2-
methoxynaphthyridine 9 and 2-chlorophenylboronic acid via
a Suzuki-Miyaura coupling. Initial efforts using either
Pd(Ph3P)4 or Pd(OAc)2 in aqueous dioxane and K2CO3
suffered from formation of either significant amounts of
biphenyls or protodehalogenation of the naphthyridine,
respectively. The latter problem could be resolved with the
use of anhydrous toluene as solvent. After additional ef-
forts, the reaction proceeded in excellent yield when
Pd(dppf)Cl2·CH2Cl2 was used together with K2CO3 in a
dioxane/H2O solvent system (Table 1, entry 1). Refluxing
the 8-aryl-2-methoxynaphthyridine 10 with aqueous HCl in
dioxane gave the naphthyridone 11 in 90% yield. On
completion (by TLC) of the Suzuki-Miyaura reaction, the
direct addition of aqueous HCl to the mixture followed by
1 h at reflux allowed both steps to be achieved in one-pot.
To our delight, the final C-N coupling worked using
Buchwald‘s conditions,8 [CuI (5 mol %), DMEDA (10 mol
Adding the A ring at the end of the synthesis can introduce
flexibility for modifying the C8-C11 positions (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Canthin-6-one (1)
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6211.
This could be achieved by an intermolecular C-C coupling
followed by an intramolecular C-N coupling, either via a
stepwise or a one-pot procedure. The stratergy required
access to 1,5-naphthyridines 5 and 6, which can be prepared
from cheap 6-methoxypyridin-3-amine (7).
The aminopyridine 7 was converted into comercially
available 8-bromo-2-methoxy-1,5-naphthyridine (9) in three
steps (Scheme 2).7 Demethylation using aqueous HBr in
(3) (a) Kardono, L. B. S.; Angerhofer, C. K.; Tsauri, S.; Padmawinata,
K.; Pezzuto, J. M.; Kinghorn, D. J. Nat. Prod. 1991, 54, 1360. (b)
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Remuinan-Blanco, M. J. WO2009090222, 2009.
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124, 7421.
Org. Lett., Vol. 12, No. 6, 2010
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Table 1. Stepwise Synthesis of Canthin-6-one Alkaloids via 8-Bromonaphthyridine 9
a Reagents and conditions: ArB(OH)2 (1.2 equiv), Pd(dppf)Cl2·CH2Cl2 (2 mol %), K2CO3 (2 equiv), dioxane/H2O (3:1), reflux. b Reagents and conditions:
ArB(OH)2 (1.5 equiv), Pd(dppf)Cl2·CH2Cl2 (4 mol %), K2CO3 (2 equiv), dioxane/H2O (3:1), reflux. c Reagents and conditions: HCl concd, H2O, dioxane.
d Reagents and conditions: ArB(OH)2 (1.2 equiv), Pd(dppf)Cl2·CH2Cl2 (2 mol %), K2CO3 (2 equiv), dioxane/H2O (3:1), reflux, then HCl, reflux. e Reagents
and conditions: ArB(OH)2 (1.5 equiv), Pd(dppf)Cl2·CH2Cl2 (5 mol %), K2CO3 (2 equiv), dioxane/H2O (3:1), reflux, then HCl, reflux. f Reagents and conditions:
CuI (5 mol %), DMEDA (10 mol %), Cs2CO3 (2 equiv), H2O (2 equiv), dioxane, reflux. g Reagents and conditions: CuI (10 mol %), DMEDA (20 mol %),
Cs2CO3 (2 equiv), H2O (2 equiv), dioxane, reflux.
%) as ligand, and H2O (2 equiv) in dioxane at reflux], in
only 15 min and in 99% yield. The first approach, therefore,
gave canthinone 1 in only five steps and in 70% overall yield
starting from aminopyridine 7.
9-Methoxycanthin-6-one (2)3 and 11-methoxycanthin-6-one
(amaroridine, 3)4 represent natural products that to our
knowledge have not been previously synthesized.
In an effort to further simplify the synthesis, we targeted
an ambitious one-pot protocol for canthinones from 8-bromo-
1,5-naphthyridone 6. A variety of nitrogen heterocycles have
been prepared using domino, tandem, or one-pot transition-
metal-catalyzed coupling procedures.10 However, very few
sequential transition-metal-catalyzed coupling reactions are
known that use two different catalyst systems in the same
pot since many transformations are catalyst and/or ligand
specific.11 Combining such protocols can greatly facilitate
the rapid preparation of compound libraries.
Since there are a wide variety of 2-chlorophenylboronic
acids,9 we prepared several canthinone analogues in a similar
manner (Table 1, column 1). 2,3-, 2,4-, and 2,5-disubstituted
phenylboronic acids reacted smoothly to give arylnaphthy-
ridines 12-16. Even the sterically demanding 2-chloro-6-
methoxyphenylboronic acid gave the analogue 18 in good
yield. 2,6-Dichlorophenylboronic acid, however, gave a
mixture of the 8-arylnaphthyridine 17 and mainly unreacted
starting material, which was difficult to separate. The
subsequent demethylations (Table 1, column 2) could be
performed using HCl in good yields for arylnaphthyridones
19-24.
Satisfied with the Suzuki-Miyaura coupling of the bro-
monaphthyridine 9, we initially applied the same conditions
(10) For recent examples, see: (a) Candito, D. A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 6713. (b) Fayol, A.; Fang, Y.-Q.; Lautens, M.
Org. Lett. 2006, 8, 4203. (c) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7,
3449. (d) Furuta, T.; Kitamura, Y.; Hahimoto, A.; Fujii, S.; Tanaka, K.;
Kan, T. Org. Lett. 2007, 9, 183. (e) Kitamura, Y.; Yashikawa, S.; Furuta,
T.; Kan, T. Synlett 2008, 377. (f) Ferraccioli, R.; Carenzi, D.; Motti, E.;
Catellani, M. J. Am. Chem. Soc. 2006, 128, 722. (g) Ferraccioli, R.; Carenzi,
D.; Rombola`, O.; Catellani, M. Org. Lett. 2004, 6, 4759.
The one-pot coupling/demethylation method was unfavor-
able for the 8-dichlorophenylnaphthyridones 19, 20, and 22,
which partly suffered protodehalogenation.
Finally, the C-N coupling using CuI (10 mol %) and
DMEDA (20 mol %)8 gave six new canthinone alkaloids 2,
3, and 25-28 in good overall yields (Table 1, column 3).
(11) (a) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J.
Org. Chem. 2006, 71, 260. (b) Collot, V.; Bovy, R.; Rault, S. Tetrahedron
Lett. 2000, 41, 9053. (c) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004,
126, 13906.
(9) Seventy-seven substituted 2-chlorophenylboronic acids are comer-
cially available (SciFinder 11 January, 2010).
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Org. Lett., Vol. 12, No. 6, 2010

applied to other 2-chlorophenylboronic acids: 2-Chloro-4-
methylphenylboronic acid gave excellent yields of canthinone
29 (Table 2, entry 3), while reactions with less activated 2,3-,
2,4-, and 2,5-disubstituted phenylboronic acids gave good
conversions and yields when 2 equiv of arylboronic acids
and higher catalyst loadings were used (Table 2, entries 2
and 4-9). With the sterically demanding 2,6-disubstituted
phenylboronic acids the C-C coupling did not work,
preventing access to the 11-substituted canthinones via this
route. Using this new one-pot protocol, we produced nine
canthinones 1, 2, and 25-31 sporting various substituents
on the A ring quickly and in excellent yields of 71-95%
(Table 2).
Table 2. One-Pot Synthesis of Canthin-6-ones
In conclusion, two high-yielding and flexible syntheses
of canthin-6-one (1) were developed and optimized. The first
provided a five-step synthesis of canthinone 1 in an overall
yield of over 70% via cheap 6-methoxypyridin-3-amine (7)
and in only two steps from comercially available precursor
8-bromo-2-methoxynaphthyridine 9 (89%). The second was
a simple and useful one-pot protocol that involved a
sequential application of a Pd-catalyzed Suzuki-Miyaura
coupling followed by a Cu-catalyzed amidation that could
be of general use for synthetic chemists. In total, 10
canthinones including the first syntheses of naturally occuing
9-methoxycanthin-6-one (2) and amaroridine (3) were re-
ported.
a Reagents and conditions: (i) Pd(dppf)Cl2.CH2Cl2 (2 mol %), ArB(OH)2
(1.1 equiv), K2CO3 (3 equiv), dioxane/H2O (3:1), 0.5 h; (ii) CuI (5 mol %),
DMEDA (10 mol %), dioxane/H2O (3:1), 15 min. b Reagents and conditions:
(i) Pd(dppf)Cl2·CH2Cl2 (5 mol %), ArB(OH)2 (2 equiv), K2CO3 (3 equiv),
dioxane/H2O (3:1), 80 min; (ii) CuI (10 mol %), DMEDA (20 mol %),
dioxane/H2O (3:1), 40 min. c Recovery of naphthyridone 6 (12%). d Recovery
of naphthyridone 6 (80%).
Acknowledgment. The authors wish to thank the Cyprus
Research Promotion Foundation (Grant No. EΠIXEIPHΣEIΣ/-
EΦAPM/0308/19) and the following organizations in Cyprus
for generous donations of chemicals and glassware: The State
General Laboratory, the Agricultural Research Institute, and
the Ministry of Agriculture. Furthermore, we thank the A. G.
Leventis Foundation for helping to establish the NMR facility
at the University of Cyprus.
to the reaction of 8-bromo-1,5-naphthyridone 6 and 2-chlo-
rophenylboronic acid and obtained 8-(2-chlorophenyl)naph-
thyrid-2(1H)-one 11 in high yield. Our initial hopes that the
final C-N coupling would be catalyzed by the already
present Pd species did not materialize. Nevertheless, on
completion of the Suzuki-Miyaura reaction (by TLC), the
addition to the refluxing mixture of a preformed deep blue
complex of CuI (5 mol %) and DMEDA (10 mol %) in
dioxane gave in only 20 min canthinone 1 in near-quantitative
yield (Table 2).12 The one-pot protocol was successfully
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) The simultaneous addition of both the Pd and Cu catalysts at the
start of the reaction gave mainly recovered naphthyridone 6. More
information can be found in the Supporting Information.
OL100300S
Org. Lett., Vol. 12, No. 6, 2010
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