Extraction, hemisynthesis, and synthesis of canthin-6-one analogues. Evaluation of their antifungal activities

Article abstract of DOI:10.1021/np050250z

Zanthoxylum chiloperone var. angustifolium was investigated. Alkaloids 1-3 from the canthin-6-one series were characterized. Derivatives 7-28 were prepared by hemisynthesis or total synthesis. All compounds were tested for in vitro antifungal activities against five pathogenic fungal strains. Analogues of canthin-6-one did not show better antifungal activities. 2005 American Chemical Society and American Society of Pharmacognosy.

Full text of DOI:10.1021/np050250z

© Copyright 2005 by the American Chemical Society and the American Society of Pharmacognosy
Volume 68, Number 11
November 2005
Full Papers
Extraction, Hemisynthesis, and Synthesis of Canthin-6-one Analogues.
Evaluation of Their Antifungal Activities
Flor Soriano-Agato´n,† Delphine Lagoutte,† Erwan Poupon,*,† Franc¸ois Roblot,† Alain Fournet,§
Jean-Charles Gantier,‡ and Reynald Hocquemiller†
Laboratoire de Pharmacognosie Associe´ au CNRS (UMR 8076, BioCIS) and Laboratoire de Biologie et Controˆle des
Organismes Parasites, Centre d’EÄ tudes Pharmaceutiques, Universite´ Paris-Sud 11, 5 Rue Jean-Baptiste Cle´ment, 92296
Chaˆtenay-Malabry, France, and De´partement “Ressources Vivantes”, US 084 (Biodival), Institut de Recherche pour le
De´veloppement (IRD), 213 Rue Lafayette, 75480 Paris Cedex 10, France
Received July 12, 2005
Zanthoxylum chiloperone var. angustifolium was investigated. Alkaloids 1-3 from the canthin-6-one series
were characterized. Derivatives 7-28 were prepared by hemisynthesis or total synthesis. All compounds
were tested for in vitro antifungal activities against five pathogenic fungal strains. Analogues of canthin-
6-one did not show better antifungal activities.
The canthin-6-one alkaloids are a subclass of â-carboline
alkaloids with an additional D-ring. Canthin-6-one 1 was
first isolated in 1952 by Haynes et al. from Australian
Pentaceras australis (Rutaceae).1,2 Since then, more than
forty members of this class of alkaloids have been reported
from several plants primarily of the Rutaceae2,3 and
Simaroubaceae2,4 families, but also from Malvaceae,2 Ama-
ranthaceae,2 Caryophyllaceae,2,5 Zygophyllaceae,6 and re-
cently from fungi (Boletus curtisii Berk.).7 Several of these
alkaloids have been bioassayed and show interesting
pharmacological activities.2,8,9 Canthin-6-one and some
derivatives isolated from Zanthoxylum chiloperone var.
angustifolium displayed interesting antifungal activities.3b,10
We wanted to further investigate these observations by
screening additional natural canthin-6-ones and also hemi-
synthetic and synthetic analogues of 1.
Results and Discussion
one var. angustifolium Engl. (Rutaceae) yielded three
known alkaloids (canthin-6-one 1, 5-methoxycanthin-6-one
(2), and canthin-6-one N-oxide (3)). Two other compounds
Silica gel chromatography of the CH2Cl2 extract of air-
dried and ground bark material of Zanthoxylum chiloper-
were also isolated. Compounds 4 and 5 were cis-avicennol
* To whom correspondence should be addressed. Tel: +33-1-46 83 55
and trans-avicennol, two pyranocoumarins previously iso-
lated from other species of Zanthoxylum such as Z. el-
ephantiasis Macfad.11 Norchelerythrine (6) was also char-
acterized from this extract.12
86. Fax: +33-1-46 83 53 99. E-mail: erwan.poupon@cep.u-psud.fr.
† Laboratoire de Pharmacognosie, Universite´ Paris-Sud 11.
‡ Laboratoire de Biologie et Controˆle des Organismes Parasites, Univer-
site´ Paris-Sud 11.
§ Institut de Recherche pour le De´veloppement.
10.1021/np050250z CCC: $30.25
© 2005 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/26/2005

1582 Journal of Natural Products, 2005, Vol. 68, No. 11
Scheme 1. Hemisynthesis of Canthin-6-one Analoguesa
Soriano-Agato´n et al.
Scheme 3. Synthesis of Canthin-6-one Analoguesa
a Reagents and conditions: (i) RX (excess), rt (7: 50%; 8: 50%; 9: 50%);
(ii) mCPBA (3 equiv), CH2Cl2, rt, 18 h (75%).
Scheme 2. Hemisynthesis of 5-Aminocanthin-6-onesa
a Reagents and conditions: NaN3 (15 equiv), ZnBr2 (15 equiv), H2O/DMF,
reflux, 48 h (10: 70%; 11: 40%).
Our efforts were first directed to exploring the possibili-
ties of chemical modifications starting from natural 1. A
few analogues were prepared using simple reactions (Scheme
1). A series of N-3 alkyl derivatives were prepared by
reacting 1 with excess haloalkanes. In these conditions,
water-soluble 7-9, bearing respectively a methyl, an
n-propyl, and a bromoethane moiety, were obtained in 50%
yield. Larger amounts of canthin-6-one N-oxide (3) for
needed biological assays were also prepared by oxidation
of 1 with meta-chloroperbenzoic acid in CH2Cl2 or alter-
natively with hydrogen peroxide in acetic acid, affording 3
in 75% yield. An original amination reaction, involving
sodium azide and a zinc salt, was also exploited toward
the synthesis of two 4-aminated analogues (10, 11) from
respectively 1 and 2 (Scheme 2).13
Our interest in canthin-6-one and analogues for extended
biological assays has taken us to search for a flexible and
low-cost method of preparation,14 using tryptamines as
starting materials. The retrosynthetic analysis for the
construction of their basic framework is depicted in Figure
1. The key step in our synthesis is to access an ap-
propriately substituted â-carboline precursor promoted by
a Bischler-Napieralski cyclization. Thus, total synthesis
of canthin-6-one and analogues is depicted in Scheme 3.
Exposure of tryptamines 12a-d to succinic anhydride in
CH2Cl2 at room temperature afforded the corresponding
amides 13a-d. Esterification of the latter with catalytic
Amberlyst H-15 in MeOH afforded methyl esters 14a-d
in almost quantitative yields over the two steps. Treatment
of amides 14a-d in the Bischler-Napieralski conditions
using POCl3 afforded cyclization to produce imines 15a-
d.15 Reaction conditions of this crucial step, especially in
terms of solvent and temperature, were extensively studied.
The best conditions appeared to be the use of 3 equiv of
POCl3 in refluxing benzene for 2 h;16 other conditions
resulted in substantial decomposition with little or no
a Reagents and conditions: (i) succinic anhydride (1.1 equiv), CH2Cl2,
rt, 18 h (13a: 98%, 13b: 99%, 13c: 98%, 13d: 98%); (ii) Amberlyst 15
(20% w/w), MeOH, reflux, 18 h (14a: 98%, 14b: 98%, 14c: 98%, 14d: 98%);
(iii) POCl3 (3 equiv), C6H6, reflux, 1 h; and then (iv) DBU (3 equiv), CH2Cl2,
rt, 18 h (1: 80%, 16: 70%, 17: 80%, 18: 20% in two steps).
formation of the desired compounds. With our key inter-
mediates in hand, the final step, i.e., the intramolecular
cyclization, was accomplished by exposure of imines 15a-d
(which were normally not isolated) to a strong hindered
base such as diazabicycloundecene (DBU) in CH2Cl2 at
room temperature, which led directly to canthin-6-ones 1
and 16-18 in good overall yields (60% overall yield for 1).
Interestingly, complete oxidation (i.e., C-1/C-2 and C-4/C-5
bonds) of the tetracyclic structures occurred spontaneously
probably by contact with air, and no intermediates could
be isolated. Some points to be stressed are the following.
Attempts to circumvent the esterification step were disap-
pointing, resulting, however, in the final isolation of 1 but
with a 3-fold decreased overall yield. Imines 15a-d ap-
peared to be quite unstable, and their purification re-
mained problematic; rapid filtration of the crude reaction
mixture over silica gel was chosen as a good compromise
between purity and yield. In the case of 1 we were able to
fully characterize the imine intermediate 15a (see Experi-
mental Section).
To further explore the scope of our synthetic strategy,
benzo[e]canthin-6-one (21) was targeted as well as 22, a
difluoro analogue. Tryptamine was reacted with phthalic
anhydrides as depicted in Scheme 4 to afford the corre-
sponding amides 19a,b in quantitative yield. This time no
esterification step was required: 19a,b were directly
treated with POCl3 in benzene, leading probably to benzoyl
chlorides 20a,b, which were not isolated, but were directly
exposed to DBU in CH2Cl2 at room temperature, affording
2117 and 22. As observed in the case of 1 and 16-18,
oxidation of the C-1/C-2 bond occurred spontaneously. Two
other 4,5-substituted derivatives were prepared according
to the same process. Compounds 25 and 28, with respec-
tively a cyclohexane ring and a pyrazine, were obtained
but in modest yields (Scheme 5).
Compounds were tested for their antifungal activities
against selected fungi. The results are presented in Table
1. Ketoconazole has MIC values that are about one-third
Figure 1. Synthetic approach for 1.

Synthesis of Canthin-6-one Analogues
Journal of Natural Products, 2005, Vol. 68, No. 11 1583
Table 1. Antifungal Screening of Canthin-6-one Analogues
MIC (µM L-1
)
Candida
albicans
Cryptococcus
neoformans
Saccharomyces
cerevisae
Trychophyton
mentagrophytes
Aspergillus
fumigatus
compound
1
2
3
4
5
8
9
56.8
>200
>200
146.0
146.0
124.0
>200
53.2
100.0
13.1
>200
2.9
14.2
50.0
14.2
50.0
53.0
>200
>200
124.0
7.7
53.2
50.0
13.1
>200
5.9
7.1
6.3
14.2
50.0
>200
>200
>200
>200
>200
106.0
200.0
13.1
>200
nt
>200
>200
>200
>200
>200
>200
>200
13.1
nt
>200
>200
106.0
>200
nt
10
16
17
18
>200
5.9
nt
23.5
nt
94.2
ketoconazole
Scheme 4. Synthesis of Benzo[4,5]canthin-6-onesa
Scheme 5. Synthesis of Analogues 25 and 28a
a Reagents and conditions: (i) anhydride (1.1 equiv), CH2Cl2, rt, 18 h
(19a: 98%, 19b: 98%); (ii) POCl3 (3 equiv), C6H6, reflux, 1 h; and then (iii)
DBU (3 equiv), CH2Cl2, rt, 18 h (21: 80%, 22: 50%).
of those of 1 against Aspergillus fumigatus and Trichophy-
ton mentagrophytes var. interdigitale. Against Cryptococcus
neoformans and Saccharomyces cerevisiae, the MIC of
ketoconazole was more than double compared to 1. Against
Candida albicans, 1 showed only moderate activity (MIC:
56.8 µM) compared to ketoconazole (MIC: 2.9 µM). The
5-methoxy analogue 2 was less active against T. mentago-
phytes, and N3-substituted derivatives were not active.
Concerning substitutions on the canthine skeleton: com-
pound 17 was the most interesting, with conserved or
increased activity. The presence of a methyl or a methoxy
respectively at positions 2 and 9 appeared to be detrimen-
tal.
a Reagents and conditions: (i) anhydride (1.1 equiv), CH2Cl2, rt, 18 h
(19a: 98%, 19b: 98%); (ii) POCl3 (3 equiv), C6H6, reflux, 1 h; and then (iii)
DBU (3 equiv), CH2Cl2, rt, 18 h (25: 50%, 28: 50%).
Structure-activity relationships for the antifungal activ-
ity still remain unclear. All compounds possessing substi-
tutions at the 4 and 5 positions showed decreased activity.
Hence, a free double bond at this position is more or less
essential for the antifungal activity. Structure-activity
relationships are depicted in Figure 2. When tested for
antifungal ability, no activity was detected for any of the
synthetic intermediates.
In conclusion, the methodology presented herein repre-
sents a convenient entry into functionalized canthin-6-one
alkaloids. Access to hemisynthetic molecules was possible
in one step from natural canthinones. Concerning total
synthesis, the sequences of reactions described above
provide efficient synthetic routes to canthin-6-one and other
canthinone derivatives in three or four steps and satisfac-
tory to very good overall yields (60% for the preparation of
1) with an original DBU-mediated cyclization followed by
Figure 2. Structure-activity relationships for antifungal activity.
spontaneous aromatization. The procedures are easily
suitable for scale-up. The canthinone derivatives described
in this study did not exhibit improved antifungal activity
compared to canthin-6-one 1.
Experimental Section
General Experimental Procedures. Yields refer to chro-
matographically and spectroscopically homogeneous materials,
unless otherwise stated. All reactions were carried out under
an argon atmosphere. Reactions were monitored by TLC

1584 Journal of Natural Products, 2005, Vol. 68, No. 11
Soriano-Agato´n et al.
1
carried out on Merck Kieselgel silica gel plates (60F-254) using
UV light as visualizing agent, and sulfuric vanillin or Dragen-
dorff reagent and heat was used as developing agent. Merck
Kieselgel silica gel (60, particle size 40-63 µm) was used for
flash chromatography. NMR spectra were recorded on a AR
200 P or a AM-400 Bruker spectrometer and calibrated using
undeuterated solvent as an internal reference. IR spectra were
recorded on a Vector 22 Bruker spectrometer, and values are
reported in cm-1 units. Mass spectra were recorded at “Labo-
ratoire de Spectrome´trie de Masse”, ICSN, Gif-sur-Yvette,
France.
Plant Material. Stem bark of Zanthoxylum chiloperone var.
angustifolium Engl. was collected by Alain Fournet, in Para-
guay near Piribebuy, Department of Cordillera, and identified
by N. Soria (Department of Botany, National University of
Asuncion, Paraguay). A voucher specimen (AF 917) has been
deposited at the Herbarium of Chemical Sciences Faculty,
Asuncion, Paraguay.
mg, 50%). 8: orange powder, mp >260 °C; H NMR (DMSO-
d6, 400 MHz) δ 9.22 (1H, d, J ) 6.3 Hz, H-2), 8.93 (1H, d, J )
6.3 Hz, H-1), 8.67 (1H, d, J ) 10.0 Hz, H-4), 8.59 (1H, d, J )
8.0 Hz, H-11), 8.55 (1H, d, J ) 8.0 Hz, H-8), 7.98 (1H, t, J )
8.0 Hz, H-9), 7.75 (1H, t, J ) 8.0 Hz, H-10), 7.41 (1H, d, J )
10.0 Hz, H-5), 4.99 (2H, t, J ) 7.5 Hz, H-R), 1.91 (2H, qu, J )
7.5 Hz, H-â), 1.37 (2H, m, J ) 7.5 Hz, H-γ), 0.92 (3H, t, J )
7.5, -Me); 13C NMR (DMSO-d6, 100 MHz) δ 157.4 (C-6), 142.3
(C-2), 141.0 (C-7a), 139.0 (C-11b), 134.3 (C-9), 133.7 (C-5),
133.5 (C-3b), 132.5 (C-3a), 130.0 (C-4), 126.9 (C-10), 125.6 (C-
11), 122.5 (C-11a), 119.2 (C-1), 116.5 (C-8), 54.8 (C-R), 33.3
(C-â), 18.8 (C-γ), 13.3 (C-Me); ESIMS m/z 277 [M]+; HRESIMS
m/z 277.1339 (calcd for C18H17N2O, 277.1341).
N3-Bromoethylcanthin-6-one, Bromide Salt (9). Can-
thin-6-one 1 (25 mg, 0.11 mmol) was dissolved in Br(CH2)2Br
(3 mL). The mixture was then refluxed for 48 h. A precipitate
was formed upon cooling and was filtered and washed with
CH2Cl2 (25 mg, 50%). 9: green powder, mp >260 °C; IR (film,
CH2Cl2) νmax 3395, 2987, 1682, 1655, 1445, 1334, 1181, 829,
788, 758 cm-1; 1H NMR (D2O, 200 MHz) δ 8.81 (1H, d, J ) 6.4
Hz, H-2), 8.41 (1H, d, J ) 6.4 Hz, H-1), 8.27 (1H, d, J ) 10.2
Hz, H-4), 8.16-8.06 (2H, m, H-8, H-11), 7.62 (1H, d, J ) 8.0
Hz, H-9), 7.41 (1H, d, J ) 8.0 Hz, H-10), 7.12 (1H, d, J ) 10.2
Hz, H-5), 5.51 (2H, t, J ) 5.8 Hz, H-R), 4.19 (2H, d, J ) 5.8
Hz, H-â); ESIMS m/z 327 [M]+; HRESIMS m/z 327.0139 (calcd
for C16H12N2O, 327.0133).
Extraction and Isolation. Powdered, dried stem bark of
Z. chiloperone var. angustifolium (1.5 kg) was basified with
ammonia, extracted in a Soxhlet apparatus separately, and
successively with CH2Cl2 and MeOH for 3 days to afford 28
and 35 g of crude extracts. All extracts were evaluated for
antifungal activity, and the CH2Cl2 extract showed strong
antifungal activity.
Therefore, the CH2Cl2 extract was subjected to silica gel
flash column chromatography, eluted with CH2Cl2/ethyl ac-
etate (8:2), to obtain 30 fractions. Fractions 2-5 were combined
and rechromatographed (cyclohexane/CH2Cl2/AcOEt, 60:35:5)
to give in the order of elution 6 (5 mg), 4 (110 mg), and 5 (30
mg). Fractions 14-24 were combined to provide 1 (1.1 g), as
white needles after recrystallization from acetone. Fractions
24-28 were combined and rechromatographed (AcOEt/CH2-
Cl2/MeOH, 8:1:1) to give 2 (150 mg) and then 3 (10 mg).
Canthin-6-one N-Oxide (3). Canthin-6-one 1 (50 mg, 0.2
mmol) was dissolved in CH2Cl2 (35 mL), and the system was
cooled to 5 °C. m-CPBA (3 equiv) was added, and the solution
was then stirred at room temperature for 18 h. The reaction
was quenched with H2O, and organic fractions were washed
successively with an aqueous saturated solution of NaHCO3
(5 × 40 mL) and then a saturated NaCl solution (2 × 30 mL).
The organic fraction was dried over Na2SO4, solvent was
removed under reduced pressure, and the crude mixture was
purified by flash chromatography (CH2Cl2/MeOH, 99:1) to
furnish 3 as a yellow powder (40 mg, 75%). 3: yellow powder,
mp 243-245 °C; IR (film, CH2Cl2) νmax 1677, 1432, 1329, 1299,
Preparation of 4-Aminocanthin-6-ones (10, 11). Can-
thin-6-one 1 (160 mg, 0.7 mmol) or 5-methoxycanthin-6-one
(2) (25 mg, 0.11 mmol) was dissolved in H2O/DMF (9:1, 5 mL).
NaN3 (15 equiv, for 1: 10 mmol, 700 mg; for 2: 1.65 mmol,
110 mg) and ZnBr2 (15 equiv, for 1: 10 mmol, 2.45 g, for 2:
1.65 mmol, 370 mg) were added, and the solution was heated
under reflux for 48 h. CH2Cl2 was added to the cooled solution,
the organic layer was washed successively with H2O (5 × 40
mL) and a saturated NaCl solution (2 × 30 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude
mixture was purified by flash chromatography (MeOH/CH2-
Cl2, 9:1) to furnish 10 (118 mg, 70%) or 11 (12 mg, 40%).
4-Aminocanthin-6-one (10): yellow crystalline powder
(CH2Cl2), mp 199-200 °C; IR (film, CH2Cl2) νmax 3254, 1673,
1612, 1580, 1556, 1443, 1313, 837, 785, 742 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 8.68 (1H, d, J ) 5.1 Hz, H-2), 8.64 (1H, d,
J ) 8.0 Hz, H-8), 8.06 (1H, d, J ) 8.0 Hz, H-11), 7.69 (1H, d,
J ) 5.1 Hz, H-1), 7.66 (1H, t, J ) 8.0 Hz, H-9), 7.51 (1H, t, J
) 8.0 Hz, H-10), 7.0 (1H, s, H-5), 4.98 (2H, s, -NH); 13C NMR
(CDCl3, 100 MHz) δ 156.2 (C-6), 145.9 (C-2), 142.4 (C-4), 139.1
(C-7a), 138.8 (C-3a), 130.1 (C-9), 129.1 (C-3b), 126.4 (C-11a),
125.86 (C-11b), 125.7 (C-10), 122.5 (C-11), 116.8 (C-8), 112.0
(C-1), 106.8 (C-5); ESIMS m/z 236 [M+H]+; HRESIMS m/z
236.0822 (calcd for C14H10N3O, 236.0824).
4-Amino-5-methoxycanthin-6-one (11): yellow powder,
Rf ) 0.3 (CH2Cl2/MeOH, 85:15); IR (film, CH2Cl2) νmax 3073,
2925, 2854, 2599, 1689, 1436, 1200, 730 cm-1; 1H NMR (CD3-
OD, 200 MHz) δ 8.43 (1H, d, J ) 5.8 Hz, H-2), 8.19 (1H, d, J
) 8.0 Hz, H-8), 8.10 (1H, d, J ) 5.8 Hz, H-1), 7.64-7.62 (2H,
m, H-9, H-11), 7.36-7.28 (1H, dt, J ) 8.0, 3.2 Hz, H-10), 3.02
(3H, s, -OMe); ESIMS m/z 266 [M + H]+; HRESIMS m/z
266.0934 (calcd for C15H12N3O2, 266.0930).
Preparation of Tryptamides 13a-d. General Proce-
dure. The requisite tryptamine 12a (10 mmol, 1.6 g) or 12b-d
(12b: 0.1 g, 0.53 mmol; 12c: 0.1 g, 0.46 mmol; 12d: 0.1 g,
0.57 mmol) was dissolved in dry CH2Cl2 (20 mL). Succinic
anhydride (1.1 equiv, respectively for cases a-d: 1.1 g, 58 mg,
50 mg, 63 mg) was added slowly. The reaction was stirred at
room temperature for 18 h. The resulting precipitate was
filtered, washed with a small amount of CH2Cl2, and dried to
furnish tryptamides 13a-d (13a: 2.5 g, 98%; 13b: 140 mg,
99%; 13c: 130 mg, 98%; 13d: 150 mg, 98%).
1
1140, 826, 779, 749 cm-1; H NMR (CDCl3, 400 MHz) δ 8.65
(1H, d, J ) 8.0 Hz, H-8), 8.38 (1H, d, J ) 10.0 Hz, H-4), 8.34
(1H, d, J ) 6.6 Hz, H-2), 7.99 (1H, d, J ) 8.0 Hz, H-11), 7.82
(1H, d, J ) 6.6 Hz, H-1), 7.64 (1H, t, J ) 8.0 Hz, H-9), 7.53
(1H, t, J ) 8.0 Hz, H-10), 6.92 (1H, d, J ) 10.0 Hz, H-5); 13C
NMR (CDCl3, 100 MHz) δ 140.0 (C-7a), 134.0 (C-3b), 133.0
(C-4), 132.1 (C-11b), 130.0 (C-9), 129.6 (C-10), 129.1 (C-3a),
128.4 (C-2), 126.3 (C-5), 123.7(C-11a), 121.8 (C-11), 117.7 (C-
8), 117.4 (C-1); ESIMS m/z 237 [M + H]+.
N3-Methylcanthin-6-one, Iodide Salt (7). Canthin-6-one
1 (50 mg, 0.22 mmol) was dissolved in CH3I (3 mL). The
mixture was then stirred at room temperature for 48 h. The
precipitate was filtered and washed with CH2Cl2 (40 mg, 50%).
7: orange powder, mp 238-241 °C; IR (film, CH2Cl2) νmax 1684,
1655, 1448, 1340, 1142, 815, 787, 766 cm-1; 1H NMR (DMSO-
d6, 400 MHz) δ 9.18 (1H, d, J ) 6.3 Hz, H-2), 8.90 (1H, d, J )
6.3 Hz, H-1), 8.57 (3H, m, H-8, H-4, H-11), 7.96 (1H, t, J ) 7.8
Hz, H-9), 7.73 (1H, t, J ) 7.8 Hz, H-10), 7.41 (1H, d, J ) 10.0
Hz, H-5), 4.64 (3H, s, -Me); 13C NMR (DMSO-d6, 50 MHz) δ
158.0 (C-6), 142.7 (C-2), 141.4 (C-7a), 136.1 (C11-b), 134.7 (C-
9), 133.7 (C-5), 133.3 (C-3b), 130.2 (C-3a), 130.2 (C-4), 127.4
(C-10), 125.7 (C-11), 122.5 (C-11a), 119.1 (C-1), 116.8 (C-8),
44.3 (N-Me); ESIMS m/z 235 [M]+; HRESIMS m/z 235.2602
(calcd for C15H11N2O, 235.2615).
13a: yellow crystalline powder (CH2Cl2), mp 128-130 °C;
IR (film, CH2Cl2) νmax 3394, 3271, 2939, 1686, 1638, 1226, 1172,
1
833, 739, 669, 623 cm-1; H NMR (CD3OD, 400 MHz) δ 7.54
N3-Butylcanthin-6-one, Iodide Salt (8). Canthin-6-one
1 (50 mg, 0.22 mmol) was dissolved in CH3(CH2)2I (3 mL). The
mixture was then refluxed for 48 h. A precipitate was formed
upon cooling and was filtered and washed with CH2Cl2 (47
(1H, d, J ) 8.0 Hz, H-4), 7.31 (1H, d, J ) 8.0 Hz, H-7), 7.10-
7.07 (2H, m, H-2, H-6), 7.0-6.99 (1H, dt, J ) 8.0, 0.92 Hz,
H-5), 3.45 (2H, t, J ) 7.3 Hz, H-9), 2.91 (2H, t, J ) 7.3 Hz,
H-8), 2.56 (2H, t, J ) 6.9 Hz, H-13), 2.42 (2H, t, J ) 6.9 Hz,

Synthesis of Canthin-6-one Analogues
Journal of Natural Products, 2005, Vol. 68, No. 11 1585
H-12); 13C NMR (CD3OD, 50 MHz) δ 174.2 (C-14), 171.1 (C-
11), (136.6 C-b), 127.6 (C-a), 122.9 (C-2), 121.2 (C-6), 118.8
(C-5), 118.5 (C-4), 112.2 (C-3), 111.7 (C-7), 40.8 (C-9), 30.5 (C-
12), 29.6 (C-13), 25.5 (C-8); ESIMS m/z 283 [M + Na]+;
HRESIMS m/z 283.1053 (calcd for C14H16N2O3Na, 283.1059).
13b: yellow crystalline powder (CH2Cl2), mp 101-103 °C;
IR (film, CH2Cl2) νmax 3384, 3260, 1718, 1640, 1211, 792, 638
m/z 327 [M + Na]+; HRESIMS m/z 327.1320 (calcd for
C16H20N2O4Na, 327.1321).
14c: white crystalline powder (CH2Cl2), mp 124-126 °C; IR
(film, CH2Cl2) νmax 2925, 2360, 2341, 1727, 1626, 1250, 1203,
1040, 802 cm-1; 1H NMR (CD3OD, 400 MHz) δ 7.49-7.45 (1H,
m, H-4), 7.02 (1H, s, H-2), 7.01 (1H, dd, J ) 10.0, 2.0 Hz, H-7),
6.79-6.74 (1H, m, H-5), 3.44 (2H, t, J ) 7.3 Hz, H-9), 3.34
(3H, s, -OMe), 2.89 (2H, t, J ) 7.3 Hz, H-8), 2.56 (2H, t, J )
6.9 Hz, H-13), 2.44 (2H, t, J ) 6.9 Hz, H-12); 13C NMR (CD3-
OD, 50 MHz) δ 175.1 (C-14), 174.0 (C-11), 160.5 (C-6), 158.0
(C-b), 126.2 (C-a), 124.6 (C-2), 120.9 (C-4), 112.5 (C-3), 109.0
(C-5), 99.2 (C-7), 52.9 (-OMe), 42.2 (C-9), 32.2 (C-8), 31.0 (C-
12), 26.9 (C-13); ESIMS m/z 315 [M + Na]+; HRESIMS m/z
315.1125 (calcd for C15H17FN2O3Na, 315.1121).
1
cm-1; H NMR (CD3OD, 400 MHz) δ 7.20 (1H, d, J ) 8.8 Hz,
H-7), 7.02 (1H, d, J ) 2.4 Hz, H-4), 6.97 (1H, s, H-2), 6.74 (1H,
dd, J ) 8.8, 2.4 Hz, H-6), 3.77 (3H, s, -OMe), 3.43 (2H, t, J )
7.2 Hz, H-9), 2.86 (2H, t, J ) 7.2 Hz, H-8), 2.55 (2H, t, J ) 7.0
Hz, H-13), 2.39 (2H, t, J ) 7.0 Hz, H-12); 13C NMR (CD3OD,
50 MHz) δ 176.8 (C-14), 174.6 (C-11), 155.1 (C-5), 133.5 (C-
b), 129.3 (C-a), 124.8 (C-2), 113.5 (C-7), 113.4 (C-3), 113.1 (C-
6), 102.0 (C-4), 57.2 (-OMe), 41.6 (C-9), 32.1 (C-12), 31.0 (C-
13), 26.6 (C-8); ESIMS m/z 313 [M + Na]+; HRESIMS m/z
313.1166 (calcd for C15H18N2O4Na, 313.1164).
13c: white crystalline powder (CH2Cl2), mp 103-105 °C; IR
(film, CH2Cl2) νmax 3396, 2937, 1686, 1633, 1255, 1208, 1149,
950, 807 cm-1; 1H NMR (CD3OD, 200 MHz) δ 7.18 (1H, t, J )
8.0 Hz, H-4), 6.74 (1H, s, H-2), 6.69 (1H, d, J ) 2.0 Hz, H-7),
6.52-6.41 (1H, dt, J ) 8.0, 2.0 Hz, H-5), 3.10 (2H, t, J ) 7.2
Hz, H-9), 3.0 (2H, t, J ) 7.2 Hz, H-8), 2.59 (2H, t, J ) 6.9 Hz,
H-13), 2.09 (2H, t, J ) 6.9 Hz, H-12), 13C NMR (CD3OD, 50
MHz) δ 175.6 (C-14), 175.3 (C-11), 164.3 (C-4), 159.6 (C-b),
126.4 (C-a), 124.8 (C-2), 121.1 (C-4), 114.4 (C-3), 109.1 (C-5),
99.2 (C-7), 42.2 (C-9), 32.5 (C-8), 30.6 (C-12), 27.0 (C-13);
ESIMS m/z 301 [M + Na]+; HRESIMS m/z 301.0963 (calcd
for C14H15FN2O3Na, 301.0964).
13d: yellow amorphous powder; IR (film, CH2Cl2) νmax 3387,
2926, 1711, 1618, 1532, 1338, 1231, 1168, 741 cm-1; 1H NMR
(CD3OD, 200 MHz) δ 7.44 (1H, d, J ) 8.0 Hz, H-4), 7.18 (1H,
d, J ) 8.0 Hz, H-7), 6.96-6.81 (3H, m, H-2, H-5, H-6), 4.07
(1H, q, J ) 6.5 Hz, H-9), 2.83-2.58 (2H, m, H-8), 2.36 (2H, t,
J ) 6.0 Hz, H-13), 2.26 (2H, t, J ) 6.0 Hz, H-12), 0.92 (3H, d,
J ) 6.5 Hz, -Me); 13C NMR (CD3OD, 50 MHz) δ 174.6 (C-14),
174.5 (C-11), 138.6 (C-b), 129.9 (C-a), 124.9 (C-2), 123.0 (C-5),
120.4 (C-6), 120.3 (C-4), 113.4 (C-3), 113.0 (C-7), 48.1 (C-9),
33.6 (C-8), 32.7 (C-12), 31.3 (C-13), 21.0 (-Me); ESIMS m/z
297 [M + Na]+; HRESIMS m/z 297.12165 (calcd for C15H18N2O3-
Na, 297.1215).
Preparation of Methyl Esters 14a-d. General Proce-
dure. The requisite tryptamide 13a (7.6 mmol, 2.0 g), 13b
(0.48 mmol, 140 mg), 13c (0.45 mmol, 130 mg) or 13d (0.55
mmol, 150 mg) was dissolved in MeOH (60 mL). Catalytic
Amberlyst H-15 (20% w/w) was added, and the solution was
heated under reflux for 18 h. The solvent was removed under
reduced pressure. The crude product was crystallized from
diisopropyl ether to furnish 14a-d (14a: 2.0 g, 98%; 14b: 140
mg, 98%; 14c: 130 mg, 98%; 14d: 150 mg, 98%).
14d: white amorphous powder; IR (film, CH2Cl2) νmax 2361,
1
1732, 1650, 1456, 1265, 1167, 733, 702 cm -1; H NMR (CD3-
OD, 400 MHz) δ 7.57 (1H, d, J ) 8.0 Hz, H-4), 7.30 (1H, d, J
) 8.0 Hz, H-7), 6.07-7.96 (3H, m, H-2, H-5, H-6), 4.19 (1H, q,
J ) 6.6 Hz, H-9), 3.30 (3H, s, -OMe), 2.77-2.83 (2H, m, H-8),
2.53 (2H, t, J ) 6.0 Hz, H-13), 2.39 (2H, t, J ) 6.0 Hz, H-12),
1.11 (3H, d, J ) 6.6 Hz, -Me); 13C NMR (CD3OD, 50 MHz) δ
174.7 (C-14), 174.5 (C-11), 137.4 (C-b), 128.9 (C-a), 124.1 (C-
2), 122.4 (C-5), 119.9 (C-6), 119.6 (C-4), 112.3 (C-3), 112.3 (C-
7), 52.7 (-OMe), 47.0 (C-9), 32.7 (C-8), 31.8 (C-12), 30.3 (C-
13), 20.8 (C-Me); ESIMS m/z 311 [M + Na]+; HRESIMS m/z
311.1370 (calcd for C16H20N2O3Na, 311.1372).
Preparation of Imines 15a-d. General Procedure. The
requisite ester 14a (0.91 mmol, 250 mg), 14b (0.46 mmol, 140
mg), 14c (0.41 mmol, 120 mg), or 14d (0.52 mmol, 150 mg)
was dissolved in benzene (10 mL, CAUTION). The solution
was cooled to 5 °C. POCl3 (3 equiv, for 14a: 420 mg, 2.73 mmol;
14b: 210 mg, 1.38 mmol; 14c: 190 mg, 1.23 mmol; 14d: 190
mg, 1.23 mmol) was added dropwise, and the solution was
heated under reflux for 1 h and then cooled to room temper-
ature. Solvents were removed under reduced pressure to
furnish imines 15a-d (15a: 140 mg, 60%; 15b: 90 mg, 60%;
15c: 70 g, 55%; 15d: 60 mg, 40%), which were used in the
next reaction without further purification due to instability.
15a was purified by a rapid flash chromatography (CH2Cl2/
MeOH, 95:5).
15a: unstable brown oil; IR (film, CH2Cl2) νmax 2850, 1698,
1632, 1182, 1040, 748 cm-1 1H NMR (CD3OD, 200 MHz) δ
;
7.90 (1H, s, -NH), 7.69 (1H, d, J ) 8.0 Hz, H-5), 7.49 (1H, d,
J ) 8.0 Hz, H-8), 7.45 (1H, t, J ) 8.0, H-7), 7.15 (1H, t, J )
8.0 Hz, H-6), 3.89 (2H, t, J ) 8.7 Hz, H-3), 3.65 (5H, m, H-1′,
-OMe), 3.27 (2H, t, J ) 8.7 Hz, H-4), 2.91 (2H, t, J ) 7.0 Hz,
H-2′); 13C NMR (CD3OD, 50 MHz) δ 172.5 (C-3′), 169.0 (C-d),
142.6 (C-c), 129.9 (C-7), 126.2 (C-b), 125.1 (C-a), 122.5 (C-5),
122.3 (C-6), 113.8 (C-8), 52.1 (-OMe), 43.2 (C-1′), 31.1 (C-4),
28.3 (C-3), 19.5 (C-2′); ESIMS m/z 257 [M + H]+.
14a: white crystalline powder (CH2Cl2), mp 101-102 °C; IR
(film, CH2Cl2) νmax 3336, 3282, 2862, 1721, 1651, 1538, 1258,
1221, 1188, 936, 800 cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.30
(1H, s, -NH), 7.58 (1H, d, J ) 7.8 Hz, H-4), 7.35 (1H, d, J )
7.8 Hz, H-7), 7.18 (1H, t, J ) 7.8 Hz, H-6), 7.10 (1H, t, J ) 7.8
Hz, H5), 7.04 (1H, s, H-2), 5.30 (1H, s, -NH), 3.64 (3H, s,
-OMe), 3.57 (2H, t, J ) 6.5 Hz, H-9), 2.95 (2H, t, J ) 6.5 Hz,
H-8), 2.63 (2H, t, J ) 6.8 Hz, H-13), 2.39 (2H, t, J ) 6.8 Hz,
H-12); 13C NMR (CDCl3, 50 MHz) δ 173.4 (C-14), 172.7 (C-
11), 136.6 (C-b), 127.3 (C-a), 122.1 (C-2), 121.8 (C-6), 120.8
(C-5), 117.8 (C-4), 111.7 (C-3), 110.7 (C-7), 57.0 (-OMe), 40.0
(C-9), 29.9 (C-12), 28.7 (C-13), 24.7 (C-8); ESIMS m/z 297 [M
+ Na]+; HRESIMS m/z 297.1216 (calcd for C15H18N2 O3Na,
297.1215).
Preparation of Canthin-6-ones (1, 16-18). General
Procedure. The requisite imine 15a (0.51 mmol, 130 mg), 15b
(0.31 mmol, 90 mg), 15c (0.25 mmol, 70 mg), or 15d (0.11
mmol, 30 mg) was dissolved in CH2Cl2 (30 mL). DBU (3 equiv,
respectively for a-d: 230 mg, 140 mg, 115 mg, 50 mg) was
added, and the solution was then stirred at room temperature
for 18 h. The reaction was quenched with H2O (10 mL), and
the organic fraction was washed successively with H2O (5 ×
40 mL) and a saturated NaCl solution (2 × 30 mL), dried over
Na2SO4, and concentrated under reduced pressure. The mix-
ture was purified by flash chromatography (CH2Cl2/MeOH,
99.5:0.5) to furnish canthin-6-ones 1 and 16-18 (1: 100 mg,
80%; 16: 60 mg, 70%; 17: 50 mg, 80%; 18: 4 mg, 20%).
14b: white crystalline powder (CH2Cl2), mp 105-110 °C; IR
(film, CH2Cl2) νmax 3328, 2952, 2860, 1720, 1651, 1440, 1213,
Canthin-6-one (1): yellow crystalline powder (CH2Cl2), mp
161-163 °C; IR (film, CH2Cl2) νmax 1673, 1434, 1141, 841, 793,
1
1
860, 794, 640 cm-1; H NMR (CD3OD, 400 MHz) δ 7.20 (1H,
746 cm-1; H NMR (CDCl3, 400 MHz) δ 8.70 (1H, d, J ) 5.0
d, J ) 8.8 Hz, H-7), 7.02 (1H, s, H-4), 6.99 (1H, s, H-2), 6.73
(1H, d, J ) 8.8 Hz, H-6), 3.78 (3H, s, Ar-OMe), 3.43 (2H, t, J
) 7.0 Hz, H-9), 3.34 (3H, s, -OMe), 2.88 (2H, t, J ) 7.0 Hz,
H-8), 2.54 (2H, t, J ) 6.0 Hz, H-13), 2.42 (2H, t, J ) 6.0 Hz,
H-12); 13C NMR (CD3OD, 50 MHz) δ 175.4 (C-14), 174.6 (C-
11), 155.4 (C-5), 133.9 (C-b), 129.5 (C-a), 124.9 (C-2), 113.6 (C-
7), 113.5 (C-3), 113.2 (C-6), 102.1 (C-4), 57.2 (Ar-OMe), 52.9
(-OMe), 42.0 (C-9), 32.1 (C-12), 30.9 (C-13), 26.8 (C-8); ESIMS
Hz, H-2), 8.50 (1H, d, J ) 8.0 Hz, H-8), 7.98 (1H, d, J ) 8.0
Hz, H-11), 7.90 (1H, d, J ) 9.8 Hz, H-4), 7.80 (1H, d, J ) 5.0
Hz, H-1), 7.59 (1H, t, J ) 8.0 Hz, H-9), 7.42 (1H, t, J ) 8.0 Hz,
H-10), 6.88 (1H, d, J ) 9.8 Hz, H-5); 13C NMR (CDCl3, 100
MHz) δ 159.2 (C-6), 145.6 (C-2), 139.3 (C-4), 139.1 (C-7a), 135.9
(C-3a), 131.7 (C-3b), 130.6 (C-9), 129.9 (C-11b), 128.7 (C-5),
125.4 (C-10), 124.1 (C-11a), 122.4 (C-11), 117.0 (C-8), 116.1
(C-1); ESIMS m/z 243 [M + Na]+.

1586 Journal of Natural Products, 2005, Vol. 68, No. 11
Soriano-Agato´n et al.
10-Methoxycanthin-6-one (16): yellow crystalline powder
(CH2Cl2), mp 203-205 °C; IR (film, CH2Cl2) νmax 2924, 2359,
1672, 1302, 1222, 1001, 846 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 8.81 (1H, d, J ) 5.0 Hz, H-2), 8.55 (1H, d, J ) 9.0 Hz, H-8),
8.05 (1H, d, J ) 9.8 Hz, H-4), 7.96 (1H, d, J ) 5.0 Hz, H-1),
7.57 (1H, d, J ) 2.1 Hz, H-11), 7.27 (1H, dd, J ) 9.0, 2.1 Hz,
H-9), 6.98 (1H, d, J ) 9.8 Hz, H-5), 3.96 (3H, s, -OMe); 13C
NMR (CDCl3, 100 MHz) δ 159.2 (C-6), 158.1 (C-10), 145.0 (C-
2), 138.7 (C-4), 136.0 (C-3a), 133.8 (C-7a), 132.5 (C-3b), 131.0
(C-11b), 129.4 (C-5), 125.8 (C-11a), 118.3 (C-9), 118.1 (C-8),
116.4 (C-1), 106.7 (C-11), 56.0 (-OMe); ESIMS m/z 251 [M +
H]+; HRESIMS m/z 251.0825 (calcd for C15H11N2O2, 251.0821).
9-Fluorocanthin-6-one (17): yellow crystalline powder
(CH2Cl2), mp 155-158 °C; IR (film, CH2Cl2) νmax 2925, 2360,
m, H-14), 1.35-1.31 (1H, m, H-15); 13C NMR (CDCl3, 50 MHz)
δ 178.0 (C-18), 175.2 (C-11), 136.4 (C-b), 127.2 (C-a), 122.5 (C-
2), 121.9 (C-6), 119.1 (C-5), 118.4 (C-4), 112.2 (C-3), 111.4 (C-
7), 44.3 (C-17), 42.7 (C-12), 39.8 (C-9), 27.2 (C-13), 26.9 (C-8),
24.9 (C-16), 24.1 (C-15), 23.0 (C-14); ESIMS m/z 337 [M + Na]+.
26: yellow crystalline powder (CH2Cl2), mp 105-107 °C; IR
(film, CH2Cl2) νmax 3052, 1726, 1531, 1359, 1094, 742 cm-1; 1H
NMR (CD3OD, 400 MHz) δ 8.79 (1H, d, J ) 2.4 Hz, H-15),
8.63 (1H, d, J ) 2.4 Hz, H-14), 7.56 (1H, t, J ) 8.0 Hz, H-4),
7.33 (1H, t, J ) 8.0 Hz, H-7), 7.15-6.95 (3H, m, H-2, H-5, H-6),
3.68 (1H, t, J ) 7.3 Hz, H-9), 3.23 (1H, t, J ) 7.3 Hz, H-9),
3.13-3.04 (2H, m, H-8); 13C NMR (CD3OD, 50 MHz) δ 172.7
(C-18), 165.6 (C-11), 152.3 (C-12), 146.5 (C-17), 143.7 (C-14),
143.5 (C-15), 137.9 (C-b), 128.5 (C-a), 124.3 (C-6), 123.6 (C-5),
122.3 (C-2), 119.6 (C-4), 112.5 (C-7), 110.5 (C-3), 41.3 (C-9),
26.1 (C-8); ESIMS m/z 311 [M + H]+.
Preparation of 21, 22, 25, and 28. General Procedure.
The requisite tryptamide (19a: 250 mg, 0.81 mmol; 19b: 170
mg, 0.5 mmol, 23: 300 mg, 0.95 mmol; 26: 0.31 mg, 0.96
mmol) was treated under Bischler-Napieralski reaction condi-
tions as described above for 14a (POCl3: XXX equiv; for 19a:
371 mg, 2.43 mmol; 19b: 230 mg, 1.5 mmol; 23: 436 mg, 2.85
mmol; 26: 440 mg, 2.88 mmol). The crude mixture of the imine
(20a: 140 mg; 20b: 90 mg; 24: 200 mg, 27: 160 mg) was
dissolved in dry CH2Cl2 (20 mL), and DBU (3 equiv, for 20a:
1.4 mmol, 210 mg; 20b: 0.83 mmol, 130 mg; 24: 2 mmol, 310
mg; 27: 1.6 mmol, 250 mg) was added. The mixture was then
stirred at room temperature for 18 h, and the reaction was
quenched with H2O (10 mL). The organic layer was washed
successively with H2O (5 × 40 mL) and then a saturated NaCl
solution (2 × 30 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure, and the crude product was
purified by flash chromatography (CH2Cl2 for 21, 22, 25 and
CH2Cl2/MeOH, 97:3, for 28) to give 21 (40 mg, 80%), 22 (60
mg, 50%), 25 (110 mg, 50%), and 28 (60 mg, 50%).
1674, 1637, 1448, 1306, 1140, 843, 829, 815 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 8.83 (1H, d, J ) 5.0 Hz, H-2), 8.41 (1H,
dd, J ) 8.7, 2.2 Hz, H-8), 8.09 (2H, m, H-4, H-11), 7.96 (1H, d,
J ) 5.0 Hz, H-1), 7.29 (1H, dd, J ) 8.7, 2.2 Hz, H-10), 6.99
(1H, d, J ) 10.0 Hz, H-4); 13C NMR (CDCl3, 100 MHz) δ 165.0
(C-6), 159.8 (C-9), 145.52 (C-2), 140.0 (C-7a), 139.53 (C-4),
135.71 (C-3a), 132.1 (C-3b), 130.08 (C-11b), 129.04 (C-5), 123.95
(C-11), 120.58 (C-11a), 116.22 (C-1), 113.89 (C-10), 105.17 (C-
8); ESIMS m/z 239 [M + H]+; HRESIMS m/z 239.0624 (calcd
for C14H8FN2O, 239.0621).
2-Methylcanthin-6-one (18): yellow amorphous powder;
1H NMR (CDCl3, 200 MHz) δ 8.71 (1H, d, J ) 8.0 Hz, H-8),
8.28 (1H, s, H-1), 8.11 (1H, d, J ) 8.0 Hz, H-11), 7.89 (1H,
H-4), 7.74-7.66 (1H, t, J ) 8.0 Hz, H-9), 7.57-7.49 (1H, t, J
) 8.0 Hz, H-10), 6.49 (1H, d, J ) 9.2 Hz, H-5); ESIMS m/z
235 [M + H]+; HRESIMS m/z 235.0876 (calcd for C15H11N2O,
235.0871).
Tryptamides 19a,b, 23, and 26. General Procedure.
Tryptamine (for 19a: 1.6 g, 0.01 mol; 19b: 0.08 g, 0.5 mmol;
23: 160 mg, 1 mmol; 26: 1.1 mmol, 165 mg) was dissolved in
dry CH2Cl2 (20 mL) with the requisite anhydride (1.1 equiv,
phthalic anhydride: 11 mmol, 1.630 g; difluorophthalic anhy-
dride: 0.55 mmol, 85 mg; cyclohexanedicarboxylic anhydride:
1.1 mmol, 170 mg; pyrazine dicarboxylic anhydride: 1.1 mmol,
165 mg). The reaction was stirred at room temperature for 18
h. The resulting precipitate was filtered, washed with a small
amount of CH2Cl2, and dried to furnish 19a (3.0 g, 98%), 19b
(170 mg, 98%), 23 (310 mg, 98%), and 26 (300 mg, 98%).
19a: yellow crystalline powder (CH2Cl2), mp 123-125 °C;
IR (film, CH2Cl2) νmax 3371, 1693, 1637, 1540, 1277, 1267, 730
Benzo[e]canthin-6-one (21): white crystalline powder
(CH2Cl2), mp 228-230 °C; IR (film, CH2Cl2) νmax 1681, 1444,
1339, 1272, 874, 756, 739 cm-1; 1H NMR (CDCl3, 400 MHz) δ
8.81 (1H, d, J ) 5.0 Hz, H-2), 8.75 (1H, m, H-8, H-12), 8.61
(1H, d, J ) 8.0 Hz, H-15), 8.10 (1H, d, J ) 8.0 Hz, H-11), 7.91
(1H, d, J ) 5.0 Hz, H-1), 7.87 (1H, t, J ) 8.0 Hz, H-13), 7.76-
7.68 (2H, m, H-9, H-14), 7.51 (1H, t, J ) 8.0 Hz, H-10); 13C
NMR (CDCl3, 100 MHz) δ 159.4 (C-6), 144.9 (C-2), 139.4 (C-
7a), 136.0 (C-5), 134.7 (C-4), 133.5 (C-13), 130.6 (C-9), 130.5
(C-11b), 130.5 (C-3b), 130.1 (C-14), 129.5 (C-3a), 129.2 (C-15),
125.3 (C-10), 124.9 (C-11a), 123.5 (C-12), 122.4 (C-11), 117.5
(C-8), 115.1 (C-1); ESIMS m/z 271 [M + H]+; HRESIMS m/z
271.0873 (calcd for C18H11N2O2, 271.0871).
1
cm-1; H NMR (CD3OD, 400 MHz) δ 7.90 (1H, d, J ) 8.0 Hz,
H-13), 7.60 (1H, d, J ) 8.0 Hz, H-4), 7.52-7.41 (2H, m, H-14,
H-15), 7.33-7.29 (2H, m, H-7, H-16), 7.08-7.06 (2H, m, H-2,
H-6), 6.99 (1H, t, J1 ) 8.0 Hz, H-5), 3.63 (2H, t, J ) 7.4 Hz,
H-9), 3.06 (2H, t, J ) 7.4 Hz, H-8); 13C NMR (CD3OD, 50 MHz)
δ 173.3 (C-18), 170.4 (C-11), 140.5 (C-17), 138.9 (C-b), 138.9
(C-12), 133.6 (C-14), 132.9 (C-13), 132.0 (C-a), 131.9 (C-16),
131.3 (C-2), 129.6 (C-6), 124.4 (C-5), 123.1 (C-4), 120.2 (C-15),
114.2 (C-3), 113.1 (C-7), 42.8 (C-9), 26.7 (C-8); ESIMS m/z 331
[M + Na]+; HRESIMS m/z 331.1057 (calcd for C18H16N2O3Na,
331.1059).
12,15-Difluoro[e]canthin-6-one (22): white crystalline
powder (CH2Cl2), mp >260 °C; Rf ) 0.9 (CH2Cl2/MeOH, 9:1);
IR (film, CH2Cl2) νmax 2361, 2341, 1693, 1479, 1336, 841, 749,
1
699 cm-1; H NMR (CDCl3, 400 MHz) δ 8.98 (1H, d, J ) 5.0
Hz, H-2), 8.79 (1H, d, J ) 7.8 Hz, H-8), 8.14 (1H, d, J ) 7.8
Hz, H-11), 8.0 (1H, d, J ) 5.0 Hz, H-1), 7.74 (1H, t, J ) 7.8
Hz, H-9), 7.63-7.57 (2H, m, H-10, H-14), 7.41 (1H, dt, J )
10.5 Hz, 1.5 Hz, H-13); 13C NMR (CDCl3, 100 MHz) δ 162.0
(C-6), 159.0 (C-15), 154.5 (C-12), 146.0 (C-2), 145.5 (C-3b),
143.5 (C-3a), 139.0 (C-7a), 131.0 (C-9), 130.5 (C-11b), 124.9
(C-11a), 122.5 (C-11), 119.0 (C-4), 118.7 (C-14), 118.5 (C-13),
118.0 (C-5), 117.0 (C-8), 115.5 (C-1); ESIMS m/z 329 [M + Na]+;
HRESIMS m/z 329.0505 (calcd for C18H8F2N2ONa, 329.0502).
Cyclohexyl[e]canthin-6-one (25): yellow crystalline pow-
der (CH2Cl2), mp 201-203 °C; IR (film, CH2Cl2) νmax 3060,
2934, 2360, 1706, 1661, 1638, 1443, 1333, 750 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 8.77 (1H, d, J ) 5.0 Hz, H-2), 8.65 (1H, d,
J ) 8.0 Hz, H-8), 8.06 (1H, d, J ) 8.0 Hz, H-11), 7.87 (1H, d,
J ) 5.0 Hz, H-1), 7.67 (1H, 1H, t, J ) 8.0 Hz, H-9), 7.48 (1H,
t, J ) 8.0 Hz, H-10), 3.18 (2H, s, H-12), 2.78 (2H, s, H-15),
1.92 (4H, s, H-13, H-14); 13C NMR (CDCl3, 100 MHz) δ 160.0
(C-6), 145.5 (C-5), 144.8 (C-2), 139.5 (C-7a), 136.9 (C-3a), 135.0
(C-4), 130.5 (C-9), 130.1 (C-3b), 129.8 (C-11b), 125.2 (C-10),
124.7 (C-11a), 122.5 (C-11), 117.2 (C-8), 115.3 (C-1), 24.4 (C-
15), 23.9 (C-12), 22.0 (C-14), 21.3 (C-13); ESIMS m/z 297 [M
+ Na]+; HRESIMS m/z 297.3060 (calcd for C18H14N2ONa,
297.3063).
19b: white amorphous powder; IR (film, CH2Cl2) νmax 3352,
1
2494, 1702, 1611, 1468, 1260, 830, 746 cm-1; H NMR (CD3-
OD, 400 MHz) δ 7.59 (1H, d, J ) 7.7 Hz, H-4), 7.32 (1H, d, J
) 7.7 Hz, H-7), 7.29-7.22 (2H, m, H-14, H-15), 7.11 (1H, s,
H-2), 7.09 (1H, t, J ) 7.7 Hz, H-6), 6.99 (1H, t, J ) 7.7 Hz,
H-5), 3.62 (2H, t, J ) 7.5 Hz, H-9), 3.04 (2H, t, J ) 7.5 Hz,
H-8); 13C NMR (CD3OD, 50 MHz) δ 166.4 (C-11), 165.4 (C-
18), 159.7 (C-12), 158.5 (C-17), 154.7 (C-13), 153.6 (C-16), 138.0
(C-b), 128.6 (C-a), 123.6 (C-2), 122.3 (C-6), 120.8 (C-14), 120.2
(C-15), 119.6 (C-5), 119.2 (C-4), 113.1 (C-3), 112.3 (C-7), 42.0
(C-9), 26.0 (C-8); ESIMS m/z 367 [M + Na]+; HRESIMS m/z
367.0874 (calcd for C18H14F2N2O3Na, 367.0870).
23: white crystalline powder (CH2Cl2), mp 98-100 °C; IR
(film, CH2Cl2) νmax 3399, 2932, 2858, 1701, 1530, 1188, 1129,
741 cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, H-1), 7.60
(1H, d, H-4), 7.37 (1H, d, H-7), 7.20 (1H, t, H-6), 7.10 (1H, t,
H-5), 7.0 (1H, s, H-2), 6.0 (1H, s, -NH), 3.64-3.55 (2H, m,
H-9), 2.99-2.91 (2H, m, H-8), 2.86 (1H, m, H-12), 2.52-2.50
(1H, m, H-17), 2.19-2.17 (1H, m, H-13), 1.81-1.73 (1H, m,
H-16), 1.61-1.50 (4H, m, H-13, H-14, H-15, H-16), 1.44 (1H,

Synthesis of Canthin-6-one Analogues
Journal of Natural Products, 2005, Vol. 68, No. 11 1587
(7) Bro¨ckelmann, M. G.; Dasenbrock, J.; Steffan, B.; Steglich, W.; Wang,
Y.; Raabe, G.; Fleischhuaer. Eur. J. Org. Chem. 2004, 4856-4863.
(8) 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, 4963-4968.
Pyrazine[e]canthin-6-one (28): brown crystalline powder
(CH2Cl2), mp 250-253 °C; IR (film, CH2Cl2) νmax 1699, 1430,
1355, 1276, 1146, 784 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.15
(1H, d, J ) 1.6 Hz, H-14), 9.07, (1H, d, J ) 1.6 Hz, H-13), 9.02
(1H, d, J ) 5.2 Hz, H-2), 8.82 (1H, d, J ) 8.0 Hz, H-8), 8.15
(1H, d, J ) 8.0 Hz, H-11), 8.09 (1H, d, J ) 5.2 Hz, H-1), 7.78
(1H, t, J ) 8.0 Hz, H-9), 7.58 (1H, t, J ) 8.0 Hz, H-10); 13C
NMR (CDCl3, 100 MHz) δ 157.1 (C-6), 148.6 (C-14), 147.4 (C-
5), 147.5 (C-4), 146.7 (C-13), 145.9 (C-2), 141.6 (C-3a), 139.0
(C-7a), 134.1 (C-3b), 132.1 (C-11-b), 131.4 (C-9), 126.2 (C-10),
124.7 (C-11a), 122.7 (C-11), 117.8 (C-8), 117.3 (C-1); ESIMS
m/z 295 [M + Na]+; HRESIMS m/z 295.0593 (calcd for C16H8N4-
ONa, 295.0596).
(9) Ferreira, M. E.; Rojas de Arias, A.; Torres de Ortiz, S.; Inchausti, A.;
Nakayama, H.; Thouvenel, C.; Hocquemiller, R.; Fournet, A. J.
Ethnopharmacol. 2002, 80, 199-202.
(10) Thouvenel, C.; Gantier, J.-C.; Duret, P.; Fourneau, C.; Hocquemiller,
R.; Ferreira, M.-E.; Rojas de Arias, A.; Fournet, A. Phytother. Res.
2003, 17, 678-680.
(11) See for example: Gray, A. I.; Waigh, R. D.; Waterman, P. G.
Phytochemistry 1977, 16, 1017-1018.
(12) Also previously isolated from other Zanthoxylum species, see ref 3b.
(13) A full account of this new reaction will be disclosed in due course.
(14) (a) For recent examples of access to the general canthine skeleton,
see: Lindsley, C. W.; Bogusky, M. J.; Leister, W. H.; McLain, R. T.;
Robinson, R. G.; Barnett, S. F.; Defeo-Jones, D.; Ross, C. W., III;
Hartman, G. D. Tetrahedron Lett. 2005, 46, 2779-2782. Lindsley,
C. W.; Wisnoski, D. D.; Wang Y.; Leister W. H.; Zhao, Z. Tetrahedron
Lett. 2003, 44, 4495-4498. van Maarseveen, J. H.; Mulders, S. J. E.;
Aben, R. W. M.; Kruse, C. G.; Scheeren, H. W. Tetrahedron 1995, 51,
4841-4852. Benson, S. C.; Snyder, J. K. J. Org. Chem. 1992, 57,
5285-5287. (b) For recent access to the canthin-6-one skeleton, see
inter alia: Suzuki, H.; Adachi, M.; Ebihara, Y.; Gyoutoku, H.; Furuya,
H.; Murakami, Y.; Okuno, H. Synthesis 2005, 28-32. Condie, G. C.;
Bergman, J. J. Heterocycl. Chem. 2004, 41, 531-540. Condie, G. C.;
Bergman, J. Eur. J. Org. Chem. 2004, 1286-1297. Czerwinski, K.
M.; Zificsak, C. A.; Stevens, J.; Oberbeck, M.; Randlett, C.; King, M.;
Mennen, S. Synth. Commun. 2003, 33, 1225-1231. Koike, K.;
Yoshino, H.; Nikaido, T. Heterocycles 1999, 51, 315-323. Ro¨ssler, U.;
Blechert, S.; Steckhan, E. Tetrahedron Lett. 1999, 40, 7075-7078.
Markgraf, J. H.; Finkelstein, M.; Cort, J. R. Tetrahedron 1996, 52,
461-470. Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M. J. Org.
Chem. 1989, 54, 2170-2178. For previous synthetic work, see ref 2.
(15) For the use of POCl3 in Bischler-Napieralski cyclizations in different
reaction conditions, see, inter alia: (a) Snyder, H. R.; Werber, F. X.
J. Am. Chem. Soc. 1950, 72, 2962-2965. (b) Spenser, I. D.; Can. J.
Chem. 1959, 37, 1851-1858. (c) Rosenkranz, H. J.; Botyos, G. Justus
Lieb. Ann. Chem. 1966, 691, 159-164. (d) Whittaker, N. J. Chem.
Soc. 1969, 85-89. (e) Oehl, R.; Lenzer, G.; Rosenmund, P. Chem. Ber.
1976, 109, 705-709. (f) Fujii, T.; Ohba, M. Heterocycles 1988, 47, 525-
539. (g) Martin, S. F.; Benage, A.; Hunter, J. E. J. Am. Chem. Soc.
1988, 110, 5-5927. (h) Torisawa, Y.; Hashimoto, A.; Nakagawa, M.;
Seki, H.; Hara, R.; Hino, T. Tetrahedron 1991, 38, 8067-8078. (i)
Desmae¨le, D.; Mekouar, K.; d′Angelo, J. J. Org. Chem. 1997, 62,
3890-3901. (j) Radchenko, O. S.; Novikov, L. M.; Elyakov, G. B.
Tetrahedron Lett. 1997, 30, 5339-5342. (k) Alves, J. C. F.; Simas, A.
B. C.; Costa, P. R. R. Tetrahedron: Asymmetry 1999, 10, 297-306.
(16) For a similar case, where benzene (caution) was chosen as the solvent
for a Bischler-Napieralski cyclization, see: Santos, L. S.; Pilli, R.
A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283-1289.
Biological Assays. The antifungal activity was evaluated
by a bioautographic method, and the minimal inhibitory
concentrations (MIC) were estimated. Details of the assay were
described previously.10
Microorganisms. The following microorganisms were used
for the determination of the MIC: Candida albicans CIP
(Collection de l’Institut Pasteur) 4872 (ATCC 10231 ) NIH
3147); Saccharomyces cerevisiae CPCM (Collection de Phar-
macie de Chaˆtenay-Malabry) 116.85 (ATCC 26.01); Crypto-
coccus neoformans H99;18 Aspergillus fumigatus 04-486;18 and
Trichophyton mentagrophytes var. interdigitale CPCM 06.99.
References and Notes
(1) Haynes, H. F.; Nelson, E. R.; Price, J. R. Aust. J. Sci. Res., Ser. A
1952, 5, 387-400.
(2) Review: Ohmoto, T.; Koike, K. In The Alkaloids; Brossi, A., Ed.;
Academic: New York, 1989; Vol. 36, pp 135-170.
(3) For a recent examples from Rutaceae, see inter alia: (a) Rahman,
M. M.; Islam, M. A.; Khondkar, P.; Gray, A. I. Biochem. Syst. Ecol.
2005, 33, 91-96. (b) He, W.; Van Puyvelde, L.; De Kimpe, N.;
Verbruggen, L.; Anthonissen, K.; Van der Flaas, M.; Bosselaers, J.;
Mathenge, S. G.; Mulida, F. P. Phytother. Res. 2002, 16, 66-70.
(4) For recent examples from Simaroubaceae, see inter alia: (a) Sima-
rouba glauca DC.: Rivero-Cruz J. F.; Lezutekong, R.; Lobo-Echeverri,
T.; Ito, A.; Mi, Q.; Chai, H.-B.; Soejarto, D. D.; Cordell, G. A.; Pezzuto,
J. M.; Swanson, S. M.; Morelli, I.; Kinghorn, A. D. Phytother. Res.
2005, 19, 136-140. (b) Eurycoma longifolia Jack: Kuo, P.-C.; Shi,
L.-S.; Damu, A. G.; Su, C.-R.; Huang, C.-H.; Ke, C.-H.; Wu, J.-B.; Lin,
A.-J.; Bastow, K. F.; Lee, K.-H.; Wu, T.-S. J. Nat. Prod. 2003, 66,
1324-1327, and references therein.
(17) Compound 21 was previously prepared with a mercuric acetate-
mediated oxidation step, see: Shipchandler, M. T.; Mitscher, L. A. J.
Heterocycl. Chem. 1971, 8, 695-696. In the course of the revision of
the manuscript, another access to benzocanthinones was published,
see: Markgraf, J. H.; Dowst, A. A.; Hensley, L. A.; Jakobsche, C. E.;
Kaltner, C. J.; Webb, P. J.; Zimmerman, P. W. Tetrahedron 2005,
61, 9102-9110.
(5) For a recent example from Caryophyllaceae (Drymaria diandra Bl.):
Hsieh, P.-W.; Chang, F.-R.; Lee, K.-H.; Hwang, T.-L.; Chang, S.-M.;
Wu, Y.-C. J. Nat. Prod. 2004, 67, 1175-1177.
(6) Peganum nigellastrum Bunge, Zygophyllaceae: Ma, Z.-Z.; Hano, Y.;
Nomura, T.; Chen, Y.-J. Phytochemistry 2000, 53, 1075-1078.
(18) Kindly provided by F. Dromer, CNRMA, Institut Pasteur, Paris,
France.
NP050250Z