The first total synthesis of potent antitumoral (±)-mafaicheenamine A, unnatural 6-fluoromafaicheenamine A and expedient synthesis of clausine e

Article abstract of DOI:10.1039/c6ra03242g

The first total synthesis of potent antitumoral mafaicheenamine A (1) and its unnatural analogue, 6-fluoromafaicheenamine A (2) have been accomplished. An expedient synthesis of clausine E, a key intermediate in the course of synthesis of 1 and 2, was ach

Full text of DOI:10.1039/c6ra03242g

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The first total synthesis of potent antitumoral (±)-mafaicheenamine A, unnatural 6-
fluoromafaicheenamine A and expedient synthesis of clausine E
a
a,b
a
Yasir Abbas , Muhammad Mansha and Nisar Ullah*
aChemistry Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi
Arabia. Tel: +966 13 8607527. Fax: +966 13 860 4277. E-mail: nullah@kfupm.edu.sa
bCentre of Research Excellence in Nanotechnology, King Fahd University of Petroleum and
Minerals, Dhahran, Saudi Arabia
Abstract
The first total synthesis of potent antitumoral mafaicheenamine A (1) and its unnatural analogue,
6
-fluoromafaicheenamine A (2) have been accomplished. An expedient synthesis of clausine E, a
key intermediate in the course of synthesis of 1 and 2, was achieved in three steps from
commercially available methyl 4-amino-3-(benzyloxy)benzoate (10) by copper-catalyzed N-
arylation with aryllead triacetate followed by cyclodehydrogenation of the resultant diarylamine
under palladium(II) acetate catalysis. Moreover, palladium-catalyzed O-prenylation of clausine E
and subsequent o-Claisen rearrangement under microwave irradiation rendered the advanced
intermediate, C-prenylated phenol, which was eventually subjected to oxidative cyclization to
construct the dihydroisocoumarin unit, leading to the synthesis of 1 and 2 in 12% and 15% overall
yield, respectively, from 10.
1

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Keywords Carbazole alkaloids, natural products, Claisen rearrangement, cyclodehydrogenation,
oxidative cyclization, antitumoral agents
Introduction
Cancer is one of the most leading causes of mortality. Despite of enormous efforts devoted to its
prevention and treatment, it remains the second leading cause of death. As such discovery and
development of anticancer agents has attracted a great deal of attention by several pharmaceutical
companies as well as non-profit organizations [1]. A recent study has revealed that since 1940s to
date 48.6% approved anticancer agents were either natural products or directly derived there from.
The study concluded that natural products as sources of novel structures are indispensable in
anticancer lead-finding research [2].
Naturally occurring carbazole alkaloids are known to exhibit numerous pharmacological activities
including anti-bacterial [3], anti-malarial [4], anti-tuberculosis [4] and anti-HIV [5]. In addition,
they have shown potent cytotoxic activity against several cancer cell lines such as prostate cancer
[
[
6], breast cancer [7], oral cavity cancer and small-cell lung cancer [8, 7b] and human leukemia
9]. Owing to the great utility of carbazoles, considerable efforts have been devoted to their
isolation from natural sources [10] as well as on the development of methods for their synthesis
11].
[
In an effort towards to discover new bioactive compounds, phytochemical investigation of twigs
of Clausena lansium has led the isolation and characterization of a new carbazole alkaloid,
mafaicheenamine A (1) (Fig. 1) [12]. Compound 1 was evaluated for its antitumor activity against
three human cancer cell lines namely: breast cancer (MCF7), oral cavity cancer (KB), and small
lung cancer (NCI-H187). While exhibiting moderate activity against KB (1C50 = 7.68 μg/mL) and
2

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NCI-H187 (1C50 = 13.27 μg/mL), compound 1 showed potent activity against MCF7 (1C50 = 2.96
μg/mL).
Substitution of aromatic and heteroaromatic rings with fluorine substituent is a common practice
in drug discovery. The incorporation of fluorine into a molecule can improve drug potency [13],
target selectivity [14] and also can address issues associated with drug metabolism [15]. In a
previous study, the effect of aromatic fluorine substitution in a series of thrombin inhibitors was
investigated. The study revealed that incorporation of fluorine at C-4 of phenyl ring significantly
enhanced the activity compared to when it was introduced at other positions of the phenyl ring.
The high potency of 4-fluorophenyl derivative was rationalized due to the dipolar C–F…H–C

and C–F…C=O interactions between the 4-fluorophenyl ring and the enzyme’s active site [16]. In
our continuing interest in the synthesis of bioactive natural products [17], we now wish to disclose
the first total synthesis of 1 and its unnatural analogue, 6-fluoromafaicheenamine A 2 (Fig. 1). An
expedient synthesis of clausine E, a key intermediate in the course of synthesis of 1 and 2, was
also accomplished and describe herein.
Fig. 1 Chemical structures of mafaicheenamine A (1) and 6-fluoromafaicheenamine A (2)
Results and discussion
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The synthesis of compound 1 was envisioned from intermediate 9 which was to be transformed to
by the operations of olefin metathesis followed by oxidative cyclization. To this end, ester 3 was
reacted with allyl bromide in DMF, using K CO as a base, to produce the known ester 4 [18]. The
1
2
3
Claisen rearrangement of 4 to the corresponding C-allyl phenol in ortho-dichlorobenzene, N,N-
dimethylaniline or DMF either by conventional heating or under microwaves was very low
o
yielding (32%), requiring prolonged heating and higher reaction temperature (˃ 150 C). In all
attempts the reaction led to the recovery of either hydrolyzed acid (in case of N,N-dimethylaniline)
or starting material (in case of ortho-dichlorobenzene and DMF). Consequently, the nitro group of
4
was reduced with iron powder in a mixture of ethanol, acetic acid and water promoted by
ultrasonic irradiation, generating 5 in high yield (90%) [19]. The initial attempts of Claisen
rearrangement of intermediate 5 in N,N-dimethylaniline under conventional heating or microwave
irradiation were very sluggish, resulting the formation of only 10% of the desired product.
o
However, with an optimized condition the reaction in DMF under microwave irradiation at 180 C
for 2 h gave the desired rearranged phenol 6 in high yield (85%). The chemoselective methylation
on the phenolic OH of 6 with diazomethane in diethyl ether did not go to the completion even with
the use excess of diazomethane; the desired 7 was formed in a low yield (15%) along with the
recovery of 6. In the second attempt, methylation was realized by stirring the solution of 6 in DMF
with 1.3 equivalent of K
The amount of K CO and short reaction time (1.5 h) was critical to obtain the desired 7 in high
yield (73%). The N-arylation of ester 7 with bromobenzene under Buchwald-Hartwig conditions
Pd(dba) , BINAP) rendered the desired 8 in a very low yield (16%). The reaction become
relatively cleaner when the combination of Pd(OAc) and JohnPhos were used as catalyst and
2
CO
3
for 0.5 h followed by the addition of 1.2 equivalent of iodomethane.
2
3
(
2
2
ligand, respectively but column chromatography purifications turned out to be tedious and the
4

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desired 8 was obtained in 20% yield. Consequently, N-arylation of ester 7 was realized under
Barton conditions [20], using phenylead triacetate and copper(II) acetate as a catalyst to furnish
the desired 8 in good yield (66%). Cyclodehydrogenation of 8 in acetic acid or DMF with catalytic
or stoichiometric amounts of palladium(II) acetate and copper(II) acetate using either thermal
induction [21] or microwave heating [22] at elevated temperatures did not yield the desired 9, the
decomposition of 8 was observed in all cases (Scheme 1).
Scheme 1: Synthesis of intermediate 9
Failure in cyclodehydrogenation of 8 led us revised our synthetic strategy as outlined in scheme 2.
N-arylation of commercially available ester 10 with phenylead triacetate under Barton conditions
furnished the desired 11 in good yield (67%). The key step of cyclodehydrogenation on 11 was
o
performed in acetic acid at 100 C, using palladium(II) acetate as a catalyst to furnish the desired
1
3 in good yield (60%). Removal of O-benzyl protection of 13 with catalytic hydrogenation
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produced 15 (clausine E) in 34% overall yield from 10. Despite the fact that six procedures for the
synthesis of clausine E are known [23], our synthetic method provide an efficient access to the
synthesis of clausine E in an overall high yielding reactions sequence from a commercially
available starting material [24]. Next, Pd-catalyzed allylation of 15 at room temperature proceeded
to give, after filtration, 17 which in turn was subjected as is to Claisen rearrangement under the
o
optimized condition in DMF, using microwave irradiation at 180 C for 2 h to afford the desired
C-prenylated phenol 19 in 82% yield (over two steps). The chemoselective methylation on the
phenolic OH of 19 was realized with iodomethane in DMF followed by the hydrolysis of the ester
function under basic condition produced the desired 23 in 57% overall yield from 19 (Scheme 2).
With compound 23 in hand, we next moved towards the construction of the dihydroisocoumarin
unit of 1 [25]. To this end, acid 23 was treated with m-CPBA in CH
2
Cl followed by work-up with
2
saturated NaHCO readily generated the desired 1 in 78% yield (Scheme 2). All the spectral data
3
of 1 matched with those of natural mafaicheenamine A [12].
6

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Scheme 2: Synthesis of mafaicheenamine A (1) and 6-fluoromafaicheenamine A (2)
Keeping in view the aforementioned importance and utility of fluorine substituents in drug
discovery, the usefulness of our synthetic approach was extended towards the synthesis of 6-
fluoromafaicheenamine A (2), an unnatural analogue of 1. As depicted in Scheme 2, 6-
fluoroclausine E (16) was synthesized from 10 by the reaction sequence of N-arylation with 4-
fluorophenylead triacetate, palladium(II) acetate mediated cyclodehydrogenation and removal of
benzyl protection with catalytic hydrogenation. Likewise intermediate 22 was originated from 16
by the operations of Pd-catalyzed allylation, Claisen rearrangement and O-methylation. Finally
7

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basic hydrolysis of ester function of 22 followed by oxidative cyclization furnished the desired 2
in 15% overall yield from 10 in eight steps (Scheme 2).
Experimental
General. Melting Points were determined on a Büchi apparatus (Büchi Labortechnik AG,
Switzerland) and are uncorrected. Elemental analysis was carried out on a Perkin Elmer Elemental
Analyzer Series 11 Model 2400 (PerkinElmer Inc. USA). IR spectra were recorded on a Perkin
1
13
Elmer 16F PC FTIR spectrophotometer (PerkinElmer Inc. USA). H and C NMR spectra were
measured in CDCl and d -DMSO using TMS as internal standard on a JEOL JNM-LA 500 MHz
3
6
spectrometer (JEOL USA Inc.). Analytical TLC was carried out on silica gel 60 F254 plates (E.
Merck); column chromatography was carried out on silica gel (200-400 mesh, E. Merck).
Synthesis of Methyl 3-(allyloxy)-4-aminobenzoate (5)
To a suspension of 4 (0.3 g, 1.3 mmol) in a mixture of glacial acetic acid (4 mL), ethanol
(4 mL) and water (2 mL) was added reduced iron powder (0.37 g, 6.6 mmol). The resulting
suspension was exposed to ultrasonic irradiation at 30 °C for 3 h and the mixture was filtered to
remove the iron residue, which was washed with ethyl acetate (30 mL). The filtrate was added 2M
KOH (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were
washed with brine (2 x 30 mL) and water (3 x 50 mL), dried over anhydrous Na
2
SO and
4
concentrated under reduced pressure. The crude residue was resolved on silica column, eluting
with hexanes:ethyl acetate (80:20) to afford the title compound 5 as a bright yellow oil. Yield: 0.25
g, 90%; IR (neat): 3373, 3312, 3025, 2946, 1682, 1608, 1573, 1571, 1426, 1363, 1302, 1208, 1136,
-1 1
1
101 cm ; H-NMR (500 MHz, CDCl
3
): δ 3.85 (s 3H, OCH
3
), 4.28 (br. s, 2H, NH ), 4.60 (d, J =
2
8

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5
1
.5 Hz, 2H, OCH
2
CH=CH
2
), 5.30 (dd, J = 1.5, 10.3 Hz, 1H, OCH
2
CH=CH
2
), 5.41 (dd, J = 1.5,
7.1 Hz, 1H, OCH
2
CH=CH
2
), 6.07 (m, 1H, OCH
2
CH=CH ), 6.67 (d, J = 8.2 Hz, 1H, H-5), 7.45
2
13
(
d, J = 1.8 Hz, 1H, H-2), 7.54 (dd, J = 1.7, 8.2 Hz, 1H, H-6); C-NMR (125.7 MHz, CDCl
3
): δ
), 112.59, 113.27, 117.86, 119.39, 124.21, 132.98, 141.32,
44.95, 167.22 (C=O). Anal. Calcd for C11 : C, 63.76; H, 6.32; N, 6.76%. Found: C, 63.72;
5
1
1.66 (OCH
3
), 69.23 (OCH
2
CH=CH
2
H13NO
3
H, 6.35; N, 6.71.
Synthesis of Methyl 2-allyl-4-amino-3-hydroxybenzoate (6)
In a microwave reaction vessel, through a solution of 5 (2 g, 9.7 mmol) in DMF (4 ml) was
bubbled nitrogen for 1 min and vessel was then placed inside CEM Discover S-Class microwave
o
synthesizer where it was exposed to microwaves at 180 C (260 W) for 2 h. After completion of
the reaction, the mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL) and
then washed with brine (5 x 10 mL), dried over anhydrous Na
2
SO , filtered and concentrated under
4
vacuum. Column chromatography purifications of the yellow oily material, eluting with
hexanes:ethyl acetate (50:50) to obtain compound 6 as an off white solid. Yield: 1.7 g, 85%; m.p.
o
-
9
1-92 C; IR (neat): 3408, 3313, 3002, 2947, 1693, 1601, 1493, 1441, 1277, 1191, 1100, 1015 cm
1; 1
H-NMR (500 MHz, CDCl
): δ 3.82 (s, 3H, OCH
), 3.89 (d, J = 6.1 Hz, 2H, ArCH
CH=CH
), 6.60 (d,
): δ 31.64
), 112.44, 116.13, 119.13, 125.49, 126.88 136.45, 139.87, 142.00,
67.82 (C=O). Anal. Calcd for C11 : C, 63.76; H, 6.32; N, 6.76%. Found: C, 63.71; H, 6.34;
N, 6.72.
),
3
3
2
2
4
.12 (br. s, 2H, NH
J = 8.2 Hz, 1H, H-5), 7.50 (d, J = 8.2 Hz, 1H, H-6); C-NMR (125.7 MHz, CDCl
ArCH CH=CH ), 51.57 (OCH
2
), 5.15-5.19 (m, 2H, OCH
2
CH=CH
2
), 6.06 (m, 1H, OCH
2
CH=CH
2
1
3
3
(
2
2
3
1
H13NO
3
Synthesis of Methyl 2-allyl-4-amino-3-methoxybenzoate (7)
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In a solution of 6 (0.2 g, 0.97 mmol) in DMF (5 mL) was added K
2
CO
3
(0.27 g, 1.93 mmol)
and after being stirred for 30 minutes at room temperature, iodomethane (0.1 mL, 1.45 mmol) was
added and the reaction mixture was further stirred for 1 h at room temperature. The mixture was
diluted with water (30 mL) and then extracted with ethyl ether (2 x 15 mL). The combined organic
layers was washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na
2
SO
4
and evaporated under reduced pressure. Column chromatography of the light yellow oily material
on silica gel eluting with petroleum ether:ethyl acetate (90:10) gave the title compound 7 as a dark
o
pink crystalline solid. Yield: 0.16 g, 76%; m.p. 89-90 C; IR (neat): 3505, 3374, 3026, 2938, 1687,
-1 1
1
612, 1427, 1335, 1261, 1029 cm ; H-NMR (500 MHz, CDCl
H, OCH ), 3.85 (d, J = 5.8 Hz, 2H, ArCH CH=CH ), 4.95-5.00 (m, 2H, ArCH
CH=CH ), 6.62 (d, J = 8.2 Hz, 1H, H-5), 7.64 (d, J = 8.2 Hz, 1H, H-6); C-NMR
125.7 MHz, CDCl ): δ 30.73 (ArCH CH=CH ), 51.47 (OCH ), 59.92 (OCH ), 112.59, 114.52,
19.49, 128.60, 135.98 137.88, 143.89, 145.10, 167.42 (C=O). Anal. Calcd for C12 : C,
5.14; H, 6.83; N, 6.33%. Found: C, 65.10; H, 6.86; N, 6.28.
Synthesis of Methyl 2-allyl-3-methoxy-4-(phenylamino)benzoate (8)
To a solution of compound 7 (0.25 g, 1.12 mmol) in dry CH Cl
phenyllead triacetate (0.67 g, 1.47 mmol) followed by the addition of copper(II) acetate (0.04 g,
.22 mmol) and the reaction was stirred at room temperature for 24 h until the reaction was
3
): δ 3.75 (s, 3H, OCH
3
), 3.83 (s,
3
3
2
2
2
CH=CH
2
), 6.05
1
3
(
m, 1H, ArCH
2
2
(
3
2
2
3
3
1
6
H15NO
3
2
2
(15 mL) was added
0
completed (TLC analysis). The mixture was filtered through a pad of celite and the filtrate was
concentrated under reduced pressure. The residues was resolved on silica column, eluting with
petroleum ether:ethyl acetate (90:10) to get the title compound 8 as a pale yellow oil. Yield: 0.22
-1 1
g, 66%; IR (neat): 3345, 3075, 2996, 1707, 1588, 1497, 1430, 1254, 1135, 1036 cm ; H-NMR
(
500 MHz, CDCl ): δ 3.82 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.91 (d, J = 5.6 Hz, 2H,
3
3
3
1
0

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ArCH
2
CH=CH
2
), 5.00-5.04 (m, 2H, ArCH
2
CH=CH
2
), 6.07 (m, 1H, ArCH
2
CH=CH ), 6.47 (br. s,
2
1
H, NH), 7.09 (t, J = 5.6 Hz, 1H, Ar-H), 7.14 (d, J = 8.6 Hz, 1H, Ar-H), 7.22 (d, J = 8.4 Hz, 2H,
1
3
Ar-H), 7.36 (m, 2H, Ar-H), 7.68 (d, J = 8.6 Hz, 1H, Ar-H); C-NMR (125.7 MHz, CDCl
3
): δ
), 110.70, 114.67, 120.54, 120.64, 122.99,
26.04, 128.33, 128.39, 129.46, 135.72, 137.78, 140.71, 141.06, 146.21, 167.32 (C=O). Anal.
: C, 72.71; H, 6.44; N, 4.71%. Found: C, 72.66; H, 6.49; N, 4.65.
3
1
0.90 (ArCH
2
CH=CH
2
), 51.54 (OCH
3
), 60.65 (OCH
3
Calcd for C18
H19NO
3
Synthesis of Methyl 3-(benzyloxy)-4-(phenylamino)benzoate (11)
Following the same procedure adopted for the synthesis of 8, the reaction of compound 10
with phenyllead triacetate gave the title compound 11 as colorless crystalline solid. Yield: 0.26 g,
o
6
1
7%; m.p. 119-120 C; IR (neat): 3399, 3024, 2946, 1692, 1587, 1515, 1493, 1440, 1418, 1380,
-1 1
347, 1268, 1221, 1101 cm ; H-NMR (500 MHz, CDCl
Ph), 6.56 (br. s, 1H, NH), 7.08 (t, J = 7.3 Hz, 1H, Ar-H), 7.21-7.24 (m, 3H, Ar-H), 7.33-7.36
m, 2H, Ar-H), 7.39 (m, 1H, Ar-H), 7.42-7.45 (m, 2H, Ar-H), 7.48 (d, J = 7.0 Hz, 1H, Ar-H), 7.62
3
): δ 3.90 (s, 3H, OCH ), 5.19 (s, 2H,
3
OCH
2
(
(
1
3
dd, J = 1.8, 8.2 Hz, 1H, Ar-H), 7.65 (d, J = 1.6 Hz, 1H, Ar-H); C-NMR (125.7 MHz, CDCl
3
): δ
Ph), 111.02, 112.46, 115.35, 119.85, 120.36, 121.14, 123.19, 124.19,
27.96, 128.37, 128.71, 129.41. 129.57, 136.34, 138.64 140.53, 145.68, 156.03, 167.18 (C=O).
: C, 75.66; H, 5.74; N, 4.20%. Found: C, 75.61; H, 5.78; N, 4.15.
5
1
1.81 (OCH
3
), 70.90 (OCH
2
Anal. Calcd for C21
H
19NO
3
Synthesis of Methyl 3-(benzyloxy)-4-((4-fluorophenyl)amino)benzoate (12)
Following the same procedure adopted for the synthesis of 8, the reaction of compound 10
with 4-fluorophenyllead triacetate gave the title compound 12 as a brown thick oil. Yield: 0.29 g,
7
1
6
0%; IR (neat): 3408, 3033, 2947, 1890, 1706, 1593, 1559, 1525, 1501, 1432, 1351, 1268, 1204,
-1 1
155, 1124, 1097 cm ; H-NMR (500 MHz, CDCl
3
): δ 3.88 (s, 3H, OCH
3
), 5.17 (s, 2H, OCH Ph),
2
.44 (br. s, 1H, NH), 7.01-7.05 (m, 3H, Ar-H), 7.11-7.17 (m, 2H, Ar-H), 7.38-7.49 (m, 5H, Ar-H),
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1
3
7
.42 (t, J = 7.3 Hz, 2H), 7.62 (dd, J = 1.8, 8.2 Hz, 1H, Ar-H), 7.65 (d, J = 1.6 Hz, 1H, Ar-H); C-
NMR (125.7 MHz, CDCl ): δ 51.79 (OCH ), 70.89 (OCH Ph), 110.38, 112.38, 116.02, 116.21,
19.73, 123.86, 124.24, 128.03, 128.41, 128.72, 136.29, 136.40 139.27, 145.41, 159.19 (d, J =
43.0 Hz, C-6), 167.11 (C=O). Anal. Calcd for C21 : C, 71.78; H, 5.16; N, 3.99%. Found:
3
3
2
1
2
H18FNO
3
C, 71.73; H, 5.19; N, 3.93.
Synthesis of methyl 1-(benzyloxy)-9H-carbazole-3-carboxylate (13)
Under nitrogen atmosphere, to a solution of 8 (0.95 g, 2.85 mmol) in glacial acetic acid (60 mL)
o
was added palladium(II) acetate (1.3 g, 5.7 mmol) and the mixture was heated at 100 C for 24 h.
The solvent was removed under reduced pressure and the residue was purified by flash
chromatography on silica gel, eluting with petroleum ether:ethyl acetate (80:20) to afford 13 as a
o
colorless crystalline solid. Yield: 0.5 g, 55%; m.p. 149-150 C; IR (neat): 3358, 3032, 2946, 1678,
-1 1
1
629, 1583, 1495, 1406, 1344, 1309, 1230, 1149, 1092 cm ; H-NMR (500 MHz, CDCl
s, 3H, OCH ), 5.31 (s, 2H, OCH Ph), 7.27 (m, 1H, Ar-H), 7.39 (d, J =7.3 Hz, 1H, Ar-H), 7.42-
.47 (m, 4H, Ar-H), 7.53 (d, J = 7.3 Hz, 2H, Ar-H), 7.72 (d, J = 1.6 Hz, 1H, Ar-H), 8.11 (d, J =7.9
3
): δ 3.99
(
3
2
7
13
Hz, 1H, Ar-H), 8.51 (d, J = 1.6 Hz, 1H, Ar-H), 8.53 (br. s, 1H, NH); C-NMR (125.7 MHz,
CDCl ): δ 52.06 (OCH ), 70.71 (OCH Ph), 107.86, 111.23, 116.48, 120.30, 120.77, 121.89,
23.75, 123.79, 126.41, 128.16, 128.44, 128.72, 136.44, 139.53, 144.29, 167.92 (C=O). Anal.
Calcd for C21 : C, 76.12; H, 5.17; N, 4.23%. Found: C, 76.08; H, 5.21; N, 4.17.
3
3
2
1
H17NO
3
Synthesis of Methyl 1-(benzyloxy)-6-fluoro-9H-carbazole-3-carboxylate (14)
Following the same procedure adopted for the synthesis of 13, the cyclodehydrogenation
of compound 12 in acetic acid gave the title compound 14 as a colorless solid. Yield: 0.09 g, 59%;
o
m.p. 172-176 C; IR (neat): 3325, 2939, 1687, 1608, 1582, 1480, 1455, 1433, 1407, 1325, 1300,
-1 1
1
275, 1249, 1167, 1095, 1017 cm ; H-NMR (500 MHz, CDCl
3
): δ 3.97 (s, 3H, OCH ), 5.27 (s,
3
1
2

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2
H, OCH
2
Ph), 7.17 (td, J = 2.4, 9.1 Hz, 1H), 7.35-7.45 (m, 4H, Ar-H), 7.51 (d, J = 7.0 Hz, 2H,
Ar-H), 7.69 (d, J = 1.3, 1H, Ar-H), 7.72 (dd, J = 8.2, 1.6 Hz, 1H, Ar-H), 8.42 (d, J = 1.2, 1H, Ar-
1
3
H), 8.51 (br. s, 1H, NH); C-NMR (125.7 MHz, CDCl
3
): δ 52.11 (OCH
06.31, 106.50, 108.04, 111.81, 111.90, 114.23, 114.44, 116.58, 121.89, 123.39, 124.34, 128.16,
28.47, 128.73, 134.08, 135.78, 136.28, 144.36, 159.42 (d, J = 249.0 Hz, C-6), 167.76 (C=O).
: C, 72.20; H, 4.62; N, 4.01%. Found: C, 72.17; H, 4.65; N, 3.96.
3
), 70.69 (OCH Ph),
2
1
1
Anal. Calcd for C21
H
16FNO
3
Synthesis of Methyl 1-hydroxy-9H-carbazole-3-carboxylate (15)
To a suspension of 13 (0.48 g, 1.44 mmol) in a mixture of THF (20 mL) and ethanol (20 mL) was
added palladium on activated carbon (0.05 g, 10% wet basis) and the reaction mixture was
subjected to hydrogenation in a Parr apparatus at 50 psi for 5 h. The mixture was filtered through
a pad of celite, and the filtrate was concentrated under vacuum and loaded on a silica column,
eluting petroleum ether:ethyl acetate (66:33) afforded 15 as a white solid. Yield: 0.32 g, 91%. The
spectral data of 15 matched with those of earlier values [23].
Synthesis of Methyl 6-fluoro-1-hydroxy-9H-carbazole-3-carboxylate (16)
Following the same procedure adopted for the synthesis of 15, the title compound 16 was
obtained as a white solid from the O-debenzylation of 14. Yield: 0.2 g, 95%; m.p. 220-221; IR
-1 1
(
neat): 3388, 3078, 2952, 1711, 1664, 1634, 1496, 1292, 1252, 1169 cm ; H-NMR (500 MHz,
DMSO-d ): δ 3.91 (s, 3H, OCH ), 7.31 (td, J = 1.6, 8.8 Hz, 1H, Ar-H), 7.52 (d, J = 1.3 Hz, 1H,
Ar-H), 7.55 (dd, J = 4.2, 8.8 Hz, 1H, Ar-H), 8.10 (d, J = 7.9 Hz, 1H, Ar-H), 8.38 (d, J = 1.3 Hz,
6
3
1
3
1
H, Ar-H), 10.35 (br. s, 1H, NH), 11.64 (s, 1H, OH); C-NMR (125.7 MHz, DMSO-d
6
): δ 51.75
(
OCH ), 106.33, 110.29, 112.56, 112.63, 113.72, 113.92, 114.63, 120.58, 123.10, 124.34, 136.63,
3
1
3
42.99, 159.12 (d, J = 247.0 Hz, C-6), 166.98 (C=O). Anal. Calcd for C14
H
10FNO : C, 64.86; H,
3
.89; N, 5.40%. Found: C, 64.82; H, 3.94; N, 5.35.
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Synthesis of methyl 1-hydroxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carboxylate (19)
To a solution of compound 15 (0.45 g, 1.87 mmol) and isobutyl 2-methylbut-3-en-2-yl
carbonate (0.61 g, 2.76 mmol) in THF (12 mL) at room temperature was added
tetrakis(triphenylphosphine)palladium (0.036 g, 0.03 mmol) and the mixture was stirred at room
temperature for 6 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the whole
was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The
residue was purified by silica gel column chromatography, eluting with petroleum ether:ethyl
acetate (80:20) to give O-allyl ether 17, which was used as is in the next reaction. In a microwave
reaction vessel, a solution of 17 in DMF (2 ml) was bubble through nitrogen for 1 min and vessel
was then placed inside CEM Discover S-Class microwave synthesizer where it was exposed to
o
microwaves at 180 C (260 W) for 2 h. After completion of the reaction and work up the residue
was purified on silica gel column chromatography, eluting with hexanes:ethyl acetate (66:33) to
o
get the title compound 19 as a white crystalline solid. Yield: 0.47 g, 82%; m.p. 131-132 C; IR
(
neat): 3482, 3313, 2928, 1701, 1646, 1608, 1490, 1443, 1347, 1288, 1253, 1226, 1160, 1039 cm-
1; 1
H-NMR (500 MHz, CDCl
): δ 1.68 (s, 3H, CH
), 1.83 (s, 3H, CH
), 3.92 (s, 3H, OCH ), 3.97
3
3
3
3
(
d, J = 5.8 Hz, 2H, ArCH
2
-), 5.29 (m, 1H, ArCH
2
CH=C(CH
3
2
) ), 5.66 (br. s, 1H, OH), 7.25 (m, 1H,
Ar-H), 7.41-7.46 (m, 2H, Ar-H), 8.04 (d, J =7.6 Hz, 1H, Ar-H), 8.37 (d, J = 1.2 Hz, 1H, Ar-H),
1
3
8
5
1
6
.43 (br. s, 1H, NH); C-NMR (125.7 MHz, CDCl
3
): 18.10 (CH
3
), 25.75 (CH
3
), 25.96 (CH ),
2
1.95 (OCH ), 111.12, 115.36, 116.88, 119.96, 120.51, 121.76, 122.37, 122.51, 123.70, 126.15,
3
31.90, 132.24, 137.23, 139.82, 140.37, 168.95 (C=O). Anal. Calcd for C19
.19; N, 4.53%. Found: C, 73.72; H, 6.24; N, 4.48.
H19NO : C, 73.77; H,
3
Synthesis of Methyl 6-fluoro-1-hydroxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-
carboxylate (20)
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Following the same procedure adopted for the synthesis of 19, O-allylation of 16 followed
by Claisen rearrangement in DMF under microwave irradiation gave the title compound 20 a white
o
solid. Yield: 0.35 g, 85%; m.p. 121-122 C; IR (neat): 3486, 3383, 2922, 1708, 1661, 1609, 1494,
-1 1
1
3
453, 1433, 1347, 1288, 1253, 1220, 1166, 1031 cm ; H-NMR (500 MHz, DMSO-d
H, CH ), 1.81 (s, 3H, CH ), 3.86 (s, 3H, OCH ), 3.92 (d, J = 5.8 Hz, 2H, ArCH -), 5.26 (m, 1H,
CH=C(CH ), 7.23 (td, J = 2.1, 8.8 Hz, 1H, Ar-H), 7.53 (dd, J = 4.3, 8.5 Hz, 1H, Ar-H),
6
): δ 1.69 (s,
3
3
3
2
ArCH
2
)
3 2
7
.95 (dd, J = 2.1, 9.7 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H), 9.20 (br. s, 1H, NH), 11.09 (s, 1H, OH);
13C-NMR (125.7 MHz, DMSO-d
): δ 18.12 (CH
), 25.77 (CH
), 25.95 (CH
), 51.97 (OCH ),
6
3
3
2
3
1
1
06.03 (d, J = 23.86 Hz), 112.53, 113.53 (d, J = 24.89 Hz), 114.36, 116.13, 120.83, 121.55, 123.76,
31.95, 134.08, 136.43, 137.61, 140.34, 159.32 (d, J = 245 Hz, C-4), 168.16 (C=O). Anal. Calcd
: C, 69.71; H, 5.54; N, 4.28%. Found: C, 69.65; H, 5.59; N, 4.22.
for C19
H18FNO
3
Synthesis of Methyl 1-methoxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carboxylate
(21)
Following the same procedure adopted for the synthesis of 7, the reaction of compound 19
with iodomethane gave the title compound 21 as colorless crystalline solid. Yield: 0.20 g, 71%;
o
m.p. 129-133 C; IR (neat): 3334, 2936, 1707, 1685, 1626, 1605, 1568, 1494, 1430, 1389, 1342,
-
1 1
1
242, 1097 cm ; H-NMR (500 MHz, CDCl
m, 8H, 2 x OCH , ArCH -), 5.24 (m, 1H, ArCH
m, 2H, Ar-H), 8.07 (d, J = 7.9 Hz, 1H, Ar-H), 8.58 (br. s, 1H, NH), 8.46 (s, 1H, Ar-H); C-NMR
125.7 MHz, CDCl ): δ 18.10 (CH ), 25.74 (CH ), 25.96 (CH ), 51.96 (OCH ), 61.08 (OCH ),
11.12, 120.16, 120.20, 120.46, 122.37, 122.66, 123.91, 124.19, 126.28, 131.28, 133.21, 135.57,
39.95, 143.22, 168.80 (C=O). Anal. Calcd for C20 : C, 74.28; H, 6.55; N, 4.33%. Found:
3
): δ 1.69 (s, 3H, CH
3
), 1.82 (s, 3H, CH
3
), 3.91-3.96
(
(
(
3
2
2
CH=C(CH ), 7.25 (m, 1H, Ar-H), 7.42-7.45
3 2
)
1
3
3
3
3
2
3
3
1
1
H21NO
3
C, 74.23; H, 6.60; N, 4.27.
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Synthesis of Methyl 6-fluoro-1-methoxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-
carboxylate (22)
Following the same procedure adopted for the synthesis of 7, the reaction of compound 20
with iodomethane gave the title compound 22 as a white solid. Yield: 0.15 g, 84%; m.p. 115-116
oC; IR (neat): 3395, 2967, 1692, 1631, 1609, 1587, 1485, 1434, 1377, 1345, 1320, 1274, 1230,
-
1 1
1
3
187, 1167, 1040 cm ; H-NMR (500 MHz, CDCl
3
): δ 1.69 (s, 3H, CH
3
), 1.82 (s, 3H, CH
3
), 3.91-
.96 (m, 8H, 2 x OCH , ArCH -), 5.22 (m, 1H, ArCH
3
2
2
CH=C(CH ), 7.17 (td, J = 2.4, 8.8 Hz, 1H,
3 2
)
Ar-H), 7.37 (dd, J = 4.2, 8.8 Hz, 1H, Ar-H), 7.68 (dd, J = 2.4, 8.8 Hz, 1H, Ar-H), 8.25 (br. s, 1H,
1
3
NH), 8.40 (s, 1H, Ar-H); C-NMR (125.7 MHz, CDCl
CH ), 52.00 (OCH ), 61.17 (OCH ), 106.35 (d, J = 24.90), 111.66 (d, J = 9.34), 114.13 (d, J =
4.90), 120.33, 122.28, 122.68, 123.93, 124.61, 124.68, 131.52, 133.81, 136.07, 136.55, 143.29,
3
): δ 18.12 (CH
3
), 25.77 (CH ), 25.94
3
(
2
3
3
2
1
4
57.89 (d, J = 236.54, C-6), 168.47 (C=O). Anal. Calcd for C20
H
20FNO : C, 70.37; H, 5.91; N,
3
.10%. Found: C, 70.33; H, 5.95; N, 4.06.
Synthesis of 1-Methoxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carboxylic acid (23)
To a solution of 21 (0.01 g, 0.30 mmol) in a mixture of MeOH (2 mL) and THF (1 mL)
was added a solution of KOH (15 mL, 30% in H
ºC. The reaction was cooled to room temperature, acidified to pH 4 with 2M HCl and then extracted
with ethyl acetate (2 x 30 mL). The organic layer was dried over anhydrous Na SO and evaporated
2
O) and the mixture was heated overnight at 50
2
4
under reduced pressure. The residue was passed through a pad of silica, eluting with hexanes:ethyl
acetate (50:50) to afford compound 23 as a white crystalline solid. Yield: 80%, m.p. 176-177 ºC;
-1 1
IR (neat): 3337, 3062, 2925, 1675, 1610, 1448, 1406, 1278, 1236, 1031 cm ; H-NMR (500 MHz,
CD OD): δ 1.57 (s, 3H, CH ), 1.72 (s, 3H, CH ), 3.83 (s, 3H, OCH ), 3.85 (d, J = 5.5 Hz, 1H,
ArCH -), 5.14 (m, 1H, ArCH CH=C(CH ), 7.08 (td, J = 1.1, 7.95 Hz, 1H, Ar-H), 7.28 (td, J =
3
3
3
3
2
2
)
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1
1
.2, 7.35 Hz, 1H, Ar-H), 7.39 (d, J = 7.9 Hz, 1H, Ar-H), 7.93 (d, J = 7.95 Hz, 1H, Ar-H), 8.37 (s,
1
3
H, Ar-H); C-NMR (125.7 MHz, CD
), 120.62, 120.95, 121.00, 123.13, 123.73, 124.79, 125.65, 127.08, 131.50, 133.87, 137.05,
42.10, 144.72, 172.09 (C=O). Anal. Calcd for C19 : C, 73.77; H, 6.19; N, 4.53%. Found:
3
OD): δ 18.20 (CH
3
), 25.94 (CH
3
), 26.65 (CH ), 61.35
2
(OCH
3
1
H19NO
3
C, 73.72; H, 6.24; N, 4.48.
Synthesis of 6-Fluoro-1-methoxy-2-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carboxylic
acid (24)
Following the same procedure adopted for the synthesis of 23, the basic hydrolysis of 22
gave the title compound 24 as a white crystalline solid from. Yield: 0.084 g, 77%; m.p. 196-197
ºC; IR (neat): 3455, 3040, 2913, 1664, 1634, 1612, 1588, 1569, 1489, 1443, 1376, 1342, 1317,
-
1 1
1
3
8
277, 1243, 1192, 1170, 1098 cm ; H-NMR (500 MHz, CD
H, CH ), 3.91-3.96 (s, 5H, OCH , ArCH -), 5.22 (m, 1H, ArCH
.8 Hz, 1H, Ar-H), 7.43 (dd, J = 4.3, 8.8 Hz, 1H, Ar-H), 7.70 (dd, J = 2.4, 8.8 Hz, 1H, Ar-H), 8.45
3
OD): δ 1.65 (s, 3H, CH
3
), 1.79 (s,
3
3
2
2
CH=C(CH ), 7.14 (td, J = 2.4,
3 2
)
1
3
(
s, 1H, Ar-H); C-NMR (125.7 MHz, CD
OCH ), 106.53 (d, J = 23.86), 113.05 (d, J = 9.34), 114.64 (d, J = 25.93), 121.28, 123.29, 125.34,
25.42, 125.79, 131.63, 134.35, 138.10, 138.41, 144.79, 158.96 (d, J = 234.47, C-6), 171.92
C=O). Anal. Calcd for C19 : C, 69.71; H, 5.54; N, 4.28%. Found: C, 69.67; H, 5.58; N,
3
OD): δ 18.19 (CH
3
), 25.92 (CH
3
), 26.66 (CH
2
), 61.35
(
3
1
(
H18FNO
3
4
.22.
Synthesis of 3-(2-Hydroxypropan-2-yl)-5-methoxy-3,4-dihydropyrano[4,3-b]carbazol-
(6H)-one (1)
To an ice-cold solution of 23 (0.025 g, 0.081 mmol) in anhydrous CH
1
2
Cl (5 mL) was
2
added m-CPBA (0.021 g, 0.122 mmol) and the reaction was stirred for 2 h at room temperature.
After the completion of reaction (TLC analysis) the solvent was evaporated under vacuum and
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residue was diluted with H
organic extracts were washed with saturated NaHCO
mL) and brine (6 mL). The organic phase was dried over Na
2
O (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined
solution (2 x 6 mL) followed by water (6
SO and evaporated under vacuum.
3
2
4
The residue was purified by silica column, eluting with hexanes:ethyl acetate (50:50) to get the
title compound 1 as a light brown solid. Yield: 0.02 g, 78%. All the spectral data of 1 matched
1
with those of natural mafaicheenamine A [12]. H-NMR (500 MHz, acetone-d
6
): δ 1.37 (s, 3H, H-
4
'/ H-5'), 1.38 (s, 3H, H-4'/H-5'), 3.01 (dd, J = 12.5, 16.4 Hz, 1H, H-1'b), 3.47 (dd, J = 2.5, 16.4
Hz, 1H, H-1'a), 3.98 (s, 3H, OCH ), 4.30 (dd, J = 2.5, 12.6 Hz, 1H, H-2'), 7.25 (ddd, J = 1.3, 7.4,
3
8
.1 Hz, 1H, H-6), 7.47 (ddd, J = 1.2, 7.3, 8.1 Hz, 1H, H-7), 7.56 (d, J = 8.1 Hz, 1H, H-8), 8.24 (d,
13
J = 8.1 Hz, 1H, H-5), 8.60 (s, 1H, H-4), 10.95 (br. s, 1H, NH); C-NMR (125.7 MHz, acetone-
): δ 23.30 (C-1'), 25.29 (C-5'), 26.86 (C-4'), 61.39 (OCH ), 71.28 (C-3'), 85.21 (C-2'), 112.62
C-8), 118.04 (C-3), 119.92 (C-4), 121.09 (C-6), 121.52 (C-5), 124.46 (C-4a), 124.93 (C-4b),
d
6
3
(
1
27.59 (C-7), 129.69 (C-2), 137.50 (C-9a), 141.68 (C-8a), 142.17 (C-1), 166.49 (C-10).
Natural mafaicheenamine A [12]
1H-NMR (400 MHz, acetone-d
H, H-1'b), 3.47 (dd, J = 2.4, 16.4 Hz, 1H, H-1'a), 3.99 (s, 3H, OCH
H, H-2'), 7.26 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H, H-6), 7.46 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H, H-7), 7.56
): δ 1.37 (s, 6H, H-4', H-5'), 3.02 (dd, J = 12.4, 16.4 Hz,
6
1
1
3
), 4.29 (dd, J = 2.4, 12.4 Hz,
(d, J = 8.0 Hz, 1H, H-8), 8.23 (d, J = 8.0 Hz, 1H, H-5), 8.59 (s, 1H, H-4), 10.96 (br. s, 1H, NH);
13C-NMR (100 MHz, acetone-d
): δ 23.2 (C-1'), 25.3 (C-5'), 26.8 (C-4'), 61.3 (OCH ), 71.2 (C-3'),
6
3
8
5.1 (C-2'), 112.5 (C-8), 118.0 (C-3), 119.8 (C-4), 121.0 (C-6), 121.5 (C-5), 124.4 (C-4a), 124.9
(C-4b), 127.5 (C-7), 129.6 (C-2), 137.4 (C-9a), 141.6 (C-8a), 142.1 (C-1), 166.4 (C-10).
Synthesis of 9-Fluoro-3-(2-hydroxypropan-2-yl)-5-methoxy-3,4-dihydropyrano[4,3-
b]carbazol-1(6H)-one (2)
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Following the same procedure adopted for the synthesis of 1, the oxidative cyclization of
4 gave the title compound 2 as a white crystalline solid from. Yield: 0.036 g, 80%; m.p. 276-277
2
ºC; IR (neat): 3506, 3218, 2989, 2971, 2933, 1691, 1634, 1612, 1584, 1506, 1482, 1385, 1362,
-
1 1
1
323, 1293, 1265, 1240, 1216, 1166, 1121, 1080, 1045 cm ; H-NMR (500 MHz, CD
s, 3H, CH ), 1.39 (s, 3H, CH ), 3.00 (dd, J = 12.8, 16.4 Hz, 1H, H-1'b), 3.45 (dd, J = 16.4, 2.7 Hz,
H, H-1'a), 3.98 (s, 3H, OCH ), 4.29 (dd, J = 2.7, 12.8 Hz, 1H, H-2'), 7.20 (dd, J = 6.4, 8.8 Hz,
H, Ar-H), 7.48 (dd, J = 4.3, 8.8 Hz, 1H, Ar-H), 7.80 (dd, J = 2.4, 8.8 Hz, 1H, Ar-H), 8.55 (s, 1H,
3
OD): δ 1.38
(
3
3
1
1
3
1
3
Ar-H); C-NMR (125.7 MHz, CD
3
OD): δ 21.96 (C-1'), 23.69 (CH
0.41 (C-3'), 84.53 (C-2'), 105.55 (d, J = 24.90), 111.94 (d, J = 9.34), 113.98 (d, J = 25.98), 115.65,
19.32, 123.66, 123.86 (d, J = 9.33), 123.89, 128.53, 137.06, 137.84, 141.09, 157.79 (d, J =
35.50, C-6), 167.49 (C=O). Anal. Calcd for C19 : C, 66.46; H, 5.28; N, 4.08%. Found:
3
), 24.94 (CH
3
), 59.99 (OCH ),
3
7
1
2
H18FNO
4
C, 66.40; H, 5.33; N, 4.03.
Conclusions
In conclusion, the first total synthesis of mafaicheenamine A, an antitumoral carbazole alkaloid
having potent activity against breast cancer cell lines and moderate activities against oral cavity
cancer and small lung cancer have been described. In addition, owing to high importance and
utility of fluorine substituents in drug discovery, the synthesis of unnatural 6-
fluoromafaicheenamine A has also been achieved. Moreover, our synthetic approach furnishes an
expedient synthesis of clausine E, a key intermediate in the course of synthesis of mafaicheenamine
A and 6-fluoromafaicheenamine A.
Acknowledgements
The research facilities and financial support by KFUPM Grant No: SB131009 are gratefully
acknowledged.
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0

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1
1
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