A concise total synthesis of the natural carbazole clauraila A

Article abstract of DOI:10.1080/14786419.2012.751599

A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is described. The approach is designed on the basis of the key regioselective Diels-Alder reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to give the corresponding adduct 2. The latter is converted to functionalised diarylamine 8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed double C-H bond activation process in a fairly good overall yield. 2013

Full text of DOI:10.1080/14786419.2012.751599

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Natural Product Research: Formerly
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A concise total synthesis of the natural
carbazole clauraila A
Rafael Bautista a , Adriana Benavides a , Hugo A. Jiménez-Vázquez
a & Joaquín Tamariz a
a Departamento de Química Orgánica, Escuela Nacional de
Ciencias Biológicas, Instituto Politécnico Nacional. Prol. Carpio y
Plan de Ayala, 11340, México, D.F. Mexico
Published online: 12 Mar 2013.
To cite this article: Natural Product Research (2013): A concise total synthesis of the natural
carbazole clauraila A, Natural Product Research: Formerly Natural Product Letters, DOI:
10.1080/14786419.2012.751599
To link to this article: http://dx.doi.org/10.1080/14786419.2012.751599
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Natural Product Research, 2013
http://dx.doi.org/10.1080/14786419.2012.751599
A concise total synthesis of the natural carbazole clauraila A
´ ´ ´
Rafael Bautista, Adriana Benavides, Hugo A. Jimenez-Vazquez and Joaquın Tamariz*
´ ´ ´ ´
Departamento de Quımica Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico
´
Nacional. Prol. Carpio y Plan de Ayala, 11340 Mexico, D.F. Mexico
(Received 20 August 2012; final version received 13 November 2012)
A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is
described. The approach is designed on the basis of the key regioselective Diels-Alder
reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to
give the corresponding adduct 2. The latter is converted to functionalised diarylamine
8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed
double CZH bond activation process in a fairly good overall yield.
Keywords: 1-methoxycarbazoles; 4,5-dimethylene-2-oxazolidinone dienes; clauraila
A; Pd(II) cyclisation; CZH bond activation
1. Introduction
Among the new naturally occurring clauraila carbazoles recently extracted from the roots of
Clausena harmandiana (Rutaceae), clauraila A (1) exhibits a significant selective cytotoxicity
against human lung cancer cells (NCI-H187), but not against normal cells (Songsiang,
Thongthoom, Boonyarat, & Yenjai, 2011). Interestingly, this plant is currently used in Thai
traditional folk medicine for treating headaches, stomach aches and stomach sickness (Yenjai
et al., 2000).
Clauraila A (1) is a 1-oxygenated carbazole, as are many biologically active carbazoles
¨
isolated from the Clausena genus (Knolker & Reddy, 2002, 2008). Both the 1-methoxy and 3-
formyl groups seem to be the responsible pharmacophores for its anticancer activity (Songsiang
et al., 2011). Owing to the broad and important pharmacological activity and applications in
´ ´
materials science (Sridharan, Martın, & Menendez, 2009) of carbazoles, an intense effort has
¨
been generated for accomplishing the synthesis of natural carbazoles (Knolker & Reddy, 2002,
2008; Schmidt, Reddy, & Knolker, 2012), including clauraila A (1) (Yang, Zhou, Wang, & Ren,
¨
¨
2011) and clausine Q (Fuchsenberger, Forke, & Knolker, 2011), among other 1,7-dioxygenated
carbazole alkaloids.
Previously we described a novel methodology for the preparation of the carbazole scaffold
(Mandal, Delgado, & Tamariz, 1998), which was applied to the total synthesis of 1-
methoxycarbazoles such as mukonine (Zempoalteca & Tamariz, 2002), murrayanine,
murrayafoline A (Benavides, Peralta, Delgado, & Tamariz, 2004; Bernal & Tamariz, 2007),
6-methoxymurrayanine, clausenine (Bernal, Benavides, Bautista, & Tamariz 2007) and
glycozolicine, mukolidine and mukoline (Bautista, Bernal, Montiel, Delgado, & Tamariz, 2011).
Considering the relevant anticancer activity of carbazole 1 and the interest in testing the
*Corresponding author. Email: jtamariz@woodward.encb.ipn.mx
q 2013 Taylor & Francis

2
R. Bautista et al.
Scheme 1. Retrosynthetic analysis of naturally occurring carbazole 1.
versatility and effectiveness of our methodology, we herein report a new total synthesis of 1,
involving the exo-2-oxazolidinone diene 3 in a Diels-Alder cycloaddition, which provides the
corresponding adduct 2, followed by an efficient transformation to the carbazole alkaloid natural
product (Scheme 1).
2. Results and discussion
Preparation of diene 3 involved the condensation of diacetyl (5) with 3-methoxyphenylisocya-
nate (6) under the reported reaction conditions (Bernal et al., 2007) to afford the desired product
in 61% yield (Scheme 2). The modest yield was due to the instability of this new diene, which
contrasts with all the similar dienes nowadays described (Fuentes et al., 2005; Mandal et al.,
1997). Consequently, once the workup is finished, the crude mixture must be immediately
purified and the product kept refrigerated to avoid its decomposition.
The Diels-Alder cycloaddition of diene 3 to acrolein (4) under Lewis acid catalysis
ðBF3·OEt2Þ; at low temperature (2788C) for 25 min, yielded a mixture of the para/meta (relative
position of the formyl group with respect to the nitrogen atom in the cyclohexene ring) adducts
1
2a/2b (98:2) in high regioselectivity (Scheme 2), as determined in the crude mixture by H
NMR. This mixture was separated by column chromatography to obtain the desired adduct 2a in
high yield (90%) as a stable colourless oil. Aromatisation of the cyclohexene ring moiety of
adduct 2a was carried out with 4,5-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in dry dioxane
at 708C for 12 h to furnish benzoxazol-2-one 7 in 74% yield (Scheme 2).
With the aim of isolating diarylamine 8a, saponification of 7 was carried out under mild
conditions (KOH, EtOH/H2O, 208C, 2 h) (Scheme 3). Although 8a was identified by 1H NMR of
Scheme 2. Synthesis of benzoxazol-2-one 7 from 2-oxazolidinone diene 3.

Natural Product Research
3
Scheme 3. Transformation of benzoxazol-2-one 7 to natural carbazole 1.
the crude mixture, its instability under the purification conditions over silica gel or neutral
alumina did not allow us to obtain a sample pure enough to be characterised. This is probably
due to its propensity to be oxidised to polar quinoid side-products (Mandal et al., 1998).
Therefore, following the previous methodology (Bautista et al., 2011), 7 was hydrolysed under
the same mild conditions and, without purification, the resulting crude mixture was treated with
methyl iodide along with K2CO3, affording diarylamine 8b in high yield (91%).
The insertion of the benzene rings of diarylamine 8b to give the natural product 1 was
attempted by the Pd(II)-catalysed oxidative cyclisation, via a double CZH activation process
¨
(Bauer & Knolker, 2012; Bedford & Betham, 2006; Campeau & Fagnou, 2006; Knolker, 2005,
2009; Knolker & Frohner, 1998; Knolker, Frohner, & Reddy, 2002; Knolker & Knoll, 2003;
¨
¨
¨
¨
¨
¨
¨
¨
¨
¨
Knolker, & Reddy, 2003; Krahl, Jager, Krause, & Knolker, 2006) in accordance with a known
¨
¨
protocol (Forke, Krahl, Krause, Schlechtingen, & Knolker, 2007; Schmidt & Knolker, 2009;
Sridharan et al., 2009). However, instead of the desired product, the decarbonylated compound 9
was obtained in good yield (70%) (Table 1, entry 1), in agreement with our previous results
(Bautista et al., 2011). In order to avoid the loss of the formyl group, the reaction was carried out
under similar conditions but with a decreased reaction temperature (Table 1, entry 2). Indeed, the
change of temperature furnished the desired product 1, albeit in a modest yield (60%). An
improvement of the yield was accomplished when 8b was subjected to Pd(II)-promoted insertion
¨
conditions (Table 1, entry 3), by using stoichiometric amounts of Pd(OAc)2 (Knolker &
O’Sullivan, 1994), to give carbazole 1 in 75% yield. Spectroscopic data and mp of 1 were in
agreement with those reported for the natural (Songsiang et al., 2011) and synthetic product
(Yang et al., 2011).
Table 1. Yields of carbazoles 1 and 9 obtained by Pd(II) insertion of diarylamine 8b.a
Pd(OAc)2
(mol equiv.)
Cu(OAc)
(mol equiv.)2
MW
(watts)
Entry
Solvent
T (8C)
t
Product (%)b
1
2
3
0.1
0.1
1.1
2.5
2.5
–
DMF
DMF
AcOH
100
100
–
130
90
140
70 min
3 h
24 h
9 (70)
1 (60)
1 (75)
a Reaction conditions: 8b (1.0 mol equiv.).
b After column chromatography.

4
R. Bautista et al.
3. Experimental
3.1. General
Melting points (uncorrected) were determined with an electrothermal capillary melting point
apparatus. IR spectra were recorded on a Perkin-Elmer 2000 spectrophotometer. 1H (500 MHz)
and 13C (125 MHz) NMR spectra were recorded on a Varian VNMR System instruments, with
TMS as internal standard. Mass spectra (MS) and high-resolution mass spectra (HR-MS) were
obtained, in electron impact (EI) (70 eV) mode on Thermo-Finnigan Polaris Q and on Jeol JSM-
GcMateII spectrometers, respectively. Microwave (MW) irradiation was carried out on a CEM
MW reactor. Analytical thin-layer chromatography was carried out using E. Merck silica gel 60
F254 coated 0.25 plates, visualised by a long- and short-wavelength UV lamp. Flash column
chromatography was carried out over Natland International Co. silica gel, N.C. 27709, USA
(230–400 mesh). All air moisture sensitive reactions were carried out under nitrogen using
oven-dried glassware. Dioxane was freshly distilled over sodium, and DMF and methylene
chloride over calcium hydride, prior to use. Acetone was dried by distillation after treatment
with potassium permanganate, followed by a second distillation over anhydrous sodium
sulphate. K2CO3 and Li2CO3 were dried overnight at 2008C prior to use. Triethylamine was
freshly distilled from KOH. All other reagents were used without further purification.
3.2. Procedures
3.2.1. 3-(3-Methoxyphenyl)-4,5-dimethylene-1,3-oxazolidin-2-one (3)
A mixture of 5 (0.49 g, 5.7 mmol) in anhydrous dioxane (15 mL), triethylamine (1.15 g,
11.4 mmol) and Li2CO3 (4.22 g, 57.0 mmol) was kept in the dark and stirred at 208C under N2
atmosphere for 1 h. Then, a solution of 6 (1.270 g, 8.55 mmol) in anhydrous dioxane (10 mL) was
added over a period of 1 h and stirred for 24 h at 208C. The mixture was filtered over Celite, the
residue washed with CH2Cl2 (3 £ 15 mL) and the solvent was removed under vacuum. The
residue was purified by column chromatography over silica gel impregnated with triethylamine
(10%) (10 g/g of crude, hexane–EtOAc, 95:5), to give 0.75 g (61%) of 3 as a colourless oil. Rf
0.37 (hexane–EtOAc, 4:1); IR (KBr): nmax 1777, 1664, 1634, 1517, 1405, 1292, 1255, 1058,
988, 881, 832 cm21; 1H NMR (500 MHz, CDCl3): d 3.83 (s, 3H, OCH3), 4.39 (d, J ¼ 3.0 Hz, 1H,
H-6), 4.76 (d, J ¼ 3.0 Hz, 1H, H-6), 4.92 (d, J ¼ 3.5 Hz, 1H, H-7), 4.97 (d, J ¼ 3.5 Hz, 1H, H-7),
6.88 (t, J ¼ 2.5 Hz, 1H, H-20), 6.91–6.98 (m, 2H, H-40, H-60), 7.40 (t, J ¼ 8.5 Hz, 1H, H-50); 13C
NMR (125 MHz, CDCl3): d 55.5 (OCH3), 84.7 (C-6), 86.9 (C-7), 112.6 (C-20), 114.6 (C-40),
119.0 (C-60), 130.4 (C-50), 134.0 (C-10), 138.8 (C-4), 148.8 (C-5), 152.2 (C-2), 160.6 (C-30);
MS (70 eV): m/z (%) 217 (Mþ, 100), 186 (27), 158 (33), 133 (34), 121 (69), 103 (54), 77 (20);
HR-MS (EI): m/z [Mþ] Anal. Calcd for C12H11NO3: 217.0739; found: 217.0739.
3.2.2. 6-Formyl-3-(3-methoxyphenyl)-2,3,4,5,6,7-hexahydrobenzoxazol-2-one (2a)
To a stirred solution of 3 (0.200 g, 0.92 mmol) in anhydrous CH2Cl2 (20 mL), at 2788C under N2
atmosphere, 4 (0.155 g, 2.76 mmol) and BF3·Et2O (0.026 g, 0.18 mmol) were added dropwise,
and the mixture was stirred for 25 min at the same temperature. The mixture was diluted with
CH2Cl2 (15 mL) and poured into H2O (10 mL). The organic layer was washed with a 5%
aqueous solution of NaHCO3 (2 £ 5 mL) and with a 5% aqueous solution of NH4Cl (2 £ 5 mL),
dried (Na2SO4) and the solvent was removed under vacuum, giving a mixture of 2a/2b (98:2).
The residue was purified by column chromatography over silica gel (20 g, hexane–EtOAc, 8:2),
to give 0.23 g (90%) of 2a as a colourless oil. Rf 0.14 (hexane–EtOAc, 7:3); IR (film): nmax
1760, 1713, 1604, 1495, 1396, 1266, 1252, 1041, 997, 736 cm21; 1H NMR (500 MHz, CDCl3):
d 1.87-1.98 (m, 1H, H-5), 2.12–2.22 (m, 1H, H-5), 2.35–2.43 (m, 2H, H-4), 2.68–2.87 (m, 2H,

Natural Product Research
5
H-6, H-7), 3.81 (s, 3H, OCH3), 6.82–6.94 (m, 3H, H-20, H-40, H-60), 7.29–7.36 (m, 1H, H-50),
9.73 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3): d 19.2 (C-4), 20.7 (C-7), 21.7 (C-5), 45.4
(C-6), 55.4 (CH3O), 111.1 (C-20), 113.4 (C-40), 117.2 (C-60), 120.9 (C-3a), 130.1 (C-50), 133.3
(C-7a), 134.8 (C-10), 154.3 (C-2), 160.3 (C-30), 201.6 (CHO); MS (70 eV): m/z (%) 273 (Mþ,
71), 245 (44), 200 (31), 173 (42), 160 (44), 147 (100), 107 (13), 77 (22); HR-MS (EI): m/z [Mþ]
Anal. Calcd for C15H15NO4: 273.1001; found: 273.1005.
3.2.3. 6-Formyl-3-(3-methoxyphenyl)-2,3-dihydrobenzoxazol-2-one (7)
A mixture of 2a (0.150 g, 0.55 mmol) in anhydrous dioxane (15 mL) and DDQ (0.25 g,
1.1 mmol) was placed in a threaded ACE glass pressure tube with a sealed Teflon screw cap, and
heated at 708C for 12 h. The mixture was filtered on a Bu¨chner funnel packed with Celite (lower
layer) and silica gel (upper layer) (2:3), and washed with CH2Cl2 (4 £ 15 mL). The solvent was
removed under vacuum, and the residue was purified by column chromatography over silica gel
(20 g/g of crude, hexane–EtOAc, 95:5) to give 0.11 g (74%) of 7 as a white solid. Rf 0.41
(hexane–EtOAc, 7:3); mp 134–1358C; IR (KBr): nmax 1788, 1684, 1606, 1498, 1451, 1282,
1248, 1165, 997, 820, 784 cm21; 1H NMR (500 MHz, CDCl3): d 3.87 (s, 3H, OCH3), 7.03 (ddd,
J ¼ 8.5, 2.5, 1.0 Hz, H-40), 7.08 (dd, J ¼ 2.5, 2.0 Hz, 1H, H-20), 7.12 (ddd, J ¼ 8.5, 2.0, 1.0 Hz,
H-60), 7.22 (d, J ¼ 8.0 Hz, H-4), 7.49 (t, J ¼ 8.5 Hz, 1H, H-50), 7.75 (dd, J ¼ 8.0, 1.5 Hz, 1H,
H-5), 7.80 (d, J ¼ 1.5 Hz, 1H, H-7), 9.97 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3): d 55.5
(OCH3), 109.6 (C-4), 109.8 (C-7), 111.0 (C-20), 114.6 (C-40), 117.1 (C-60), 128.2 (C-5), 130.7
(C-50), 132.2 (C-6), 133.5 (C-10), 136.3 (C-3a), 142.8 (C-7a), 152.7 (C-2), 160.6 (C-30), 190.3
(CHO); MS (70 eV): m/z (%) 269 (Mþ, 100), 268 (58), 240 (6), 224 (13), 182 (14), 154 (26), 127
(7), 77 (8); HR-MS (EI): m/z [Mþ] Anal. Calcd for C15H11NO4: 269.0688; found: 269.0683.
3.2.4. 3-Methoxy-4-(3-methoxyphenylamino)benzaldehyde (8b)
A mixture of 7 (0.121 g, 0.45 mmol) and KOH (0.10 g, 1.8 mmol) in a mixture of EtOH–H2O
(7:3) (10 mL) was stirred at 208C for 2 h. The mixture was neutralised with 10% aqueous
solution of HCl, and was extracted with CH2Cl2 (2 £ 20 mL). The organic layer was dried
(Na2SO4) and the solvent was removed under vacuum. The residue was mixed with MeI
(0.097 g, 0.68 mmol) and K2CO3 (0.094 g, 0.68 mmol) in anhydrous acetone (20 mL), and was
heated to reflux for 2 h. The solvent was removed under vacuum, the residue was purified by
column chromatography over silica gel (20 g/g of crude, hexane–EtOAc, 9:1) to give 0.105 g
(91%) of 8b as a pale yellow oil. Rf 0.48 (hexane–EtOAc, 7:3); IR (film): nmax 3302, 1668, 1596,
1510, 1461, 1302, 1251, 1157, 1126, 1031, 813, 730 cm21; 1H NMR (500 MHz, CDCl3): d 3.81
(s, 3H, OCH3-30), 3.96 (s, 3H, OCH3-3), 6.66 (ddd, J ¼ 8.0, 2.5, 1.0 Hz, 1H, H-40), 6.72 (br s, 1H,
NH), 6.80 (dd, J ¼ 2.5, 2.0 Hz, 1H, H-20), 6.83 (br dd, J ¼ 8.0, 2.0 Hz, 1H, H-60), 7.26
(t, J ¼ 8.0 Hz, 1H, H-50), 7.28 (d, J ¼ 8.0 Hz, 1H, H-5), 7.35 (dd, J ¼ 8.0, 1.5 Hz, 1H, H-6), 7.38
(d, J ¼ 1.5 Hz, 1H, H-2), 9.76 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3): d 55.3 (OCH3-C30),
55.8 (OCH3-C3), 107.2 (C-20), 107.7 (C-2), 109.0 (C-40), 110.6 (C-5), 113.7 (C-60), 127.8 (C-6),
127.9 (C-1), 130.2 (C-50), 140.0 (C-4), 141.2 (C-10), 147.1 (C-3), 160.6 (C-30), 190.4 (CHO); MS
(70 eV): m/z (%) 257 (Mþ, 100), 242 (29), 211 (73), 198 (31), 183 (16), 154 (14), 121 (20); HR-
MS (EI): m/z [Mþ] Anal. Calcd for C15H15NO3: 257.1052; found: 257.1057.
3.2.5. 3-Formyl-1,7-dimethoxy-9H-carbazole (Clauraila A) (1)
3.2.5.1. Method A. A mixture of 8b (0.100 g, 0.39 mmol) and Pd(OAc)2 (0.105 g, 0.47 mmol) in
glacial acetic acid (6.5 mL) was placed in a threaded ACE glass pressure tube with a sealed
Teflon screw cap, under N2 atmosphere. The mixture was stirred and heated to 1408C for 24 h in

6
R. Bautista et al.
the dark, then filtered over Celite. The mixture was diluted in toluene (10 mL) and the solvent
was removed under vacuum. This procedure was repeated twice. The residue was purified by
column chromatography over silica gel (10 g/g of crude, hexane–EtOAc, 95:5), to give 0.074 g
(75%) of 1 as a pale yellow solid.
3.2.5.2. Method B. A mixture of 8b (0.100 g, 0.39 mmol) and Pd(OAc)2 (0.008 g, 0.039 mmol)
and Cu(OAc)2 (0.177 g, 0.98 mmol) in dry DMF (0.5 mL) was stirred and heated to 908C for 3 h
under MW irradiation (100 W). The mixture was filtered over Celite, diluted in toluene (10 mL)
and the solvent was removed under vacuum. This evaporation procedure was repeated twice.
The residue was purified by column chromatography over silica gel (10 g/g of crude, hexane–
EtOAc, 95:5), to give 0.06 g (60%) of 1 as a pale yellow solid. Rf 0.45 (hexane–EtOAc, 7:3); mp
183–1848C [175–1778C (Songsiang et al., 2011); 183–1858C (Yang et al., 2011)]; IR (film):
1
nmax 3380, 3157, 1656, 1608, 1498, 1329, 1263, 1220, 1142, 1032, 845, 750 cm21; H NMR
(500 MHz, (CD3)2SO–CDCl3, 1:1):d 3.80 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.74 (dd, J ¼ 9.0,
2.0 Hz, 1H, H-6), 6.96 (d, J ¼ 2.0 Hz, 1H, H-8), 7.44 (s, 1H, H-2), 7.81 (d, J ¼ 9.0 Hz, 1H, H-5),
8.24 (s, 1H, H-4), 10.01 (s, 1H, CHO), 10.90 (br s, 1H, NH); 13C NMR (125 MHz, (CD3)2SO–
CDCl3, 1:1): 54.27 d (OCH3), 54.31 (OCH3), 94.1 (C-8), 104.6 (C-2), 107.7 (C-6), 114.1 (C-4),
115.8 (C-4a), 119.7 (C-5), 120.7 (C-4), 122.3 (C-9a), 131.6 (C-3), 140.6 (C-8a), 143.7 (C-1),
157.9 (C-7), 191.0 (CHO); MS (70 eV): m/z (%) 255 (Mþ, 91), 240 (100), 212 (29), 184 (22),
169 (13), 140 (9), 127 (7), 113 (4); HR-MS (EI): m/z [Mþ] Anal. Calcd for C15H13NO3:
255.0895; found: 255.0899.
3.2.6. 1,7-Dimethoxy-9H-carbazole (9)
A mixture of 8b (0.100 g, 0.39 mmol) and Pd(OAc)2 (0.0087 g, 0.039 mmol) and Cu(OAc)2
(0.177 g, 0.98 mmol) in dry DMF (0.5 mL) was stirred and heated to 1308C for 70 min under MW
irradiation (100 W). The mixture was filtered over Celite, diluted in toluene (10 mL) and the
solvent was removed under vacuum. This evaporation procedure was repeated twice. The
residue was purified by column chromatography over silica gel (10 g/g of crude, hexane–
EtOAc, 95:5), to give 0.062 g (70%) of 9 as a white solid. Rf 0.62 (hexane–EtOAc, 7:3); mp
164–1658C [164–1668C (Bedford & Betham, 2006)]; IR (film): nmax 3412, 1632, 1619, 1579,
1504, 1450, 1320, 1280, 1263, 1244, 1157, 1097, 777 cm21; 1H NMR (500 MHz, CDCl3): d 3.87
(s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.83 (d, J ¼ 8.0 Hz, 1H, H-2), 6.84 (dd, J ¼ 8.5, 2.0 Hz, 1H,
H-6), 6.90 (d, J ¼ 2.0 Hz, 1H, H-8), 7.12 (t, J ¼ 8.0 Hz, 1H, H-3), 7.57 (d, J ¼ 8.0, 1H, H-4),
7.89 (d, J ¼ 8.5 Hz, 1H, H-5), 8.17 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3): d 55.5 (OCH3),
55.6 (OCH3), 94.8 (C-8), 105.0 (C-2), 108.3 (C-6), 112.2 (C-4), 117.6 (C-4a), 119.9 (C-3), 121.2
(C-5), 124.5 (C-4b), 129.6 (C-9a), 140.5 (C-8a), 145.5 (C-1), 159.0 (C-7); MS (70 eV): m/z (%)
227 (Mþ, 100), 212 (30), 184 (70), 169 (13), 141 (18); HR-MS (EI): m/z [Mþ] Anal. Calcd for
C14H13NO2: 227.0946; found: 227.0945.
4. Conclusions
The total synthesis of the naturally occurring and anticancer alkaloid clauraila A (1) is described.
The synthetic pathway starts from the exo-2-oxazolidinone diene 3, through a regioselective
Diels-Alder reaction, followed by transformation of adduct 2a to the diarylamine precursor 8b.
The B-ring of the desired natural product 1 was generated via the CZH bond activation reaction
of 8b, catalysed or assisted by Pd(OAc)2 to give 1 in fairly good overall yields (22–28%). More
severe conditions of the Pd(II)-catalysed reaction resulted in the deformylated carbazole 9.
Therefore, modulating the reaction temperature can selectively lead to the diaryl insertion with
or without decarbonylation of the carbazole framework.

Natural Product Research
7
Acknowledgements
We thank Alberto Jerezano for his help in spectrometric analyses, and Bruce A. Larsen for reviewing the
English in the manuscript. J.T. acknowledges SIP/IPN (Grants 20110172 and 20120830) and CONACYT
(Grant 83446) for financial support. R.B. thanks CONACYT for awarding graduate scholarships, and SIP/
IPN (PIFI) for scholarship complements. H.A.J.-V. and J.T. are fellows of the EDI-IPN and COFAA-IPN
programmes.
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