First total synthesis of bauerine C

Article abstract of DOI:10.1080/00397910701575426

The first total synthesis of Bauerine C, a unique indoloquinazoline alkoloid, has been achieved from readily available 2,3-dichloroaniline. The key step is the Japp-Klingmann condensation between 2,3-dichloroaniline and ethyl-2-acetyl-5-phthalimido pentanoate to get 3-[(2,3-dichlorophenyl)- hydrozono]-pipiridin-2-one, which cyclizes to 7,8-dichloro-2,3,4,9-tetrahydro- β-carbolin-1-one, which can be methylated by dimethyl sulphate to give 7,8-dichloro-9-methyl 2,3,4,9-tetrahydro-β-carbolin-1-one. This N-methyl derivative is then subjected to dehydrogenation with 2,3-dichloro-5,6-dicayano- 1,4-benzoquinone (DDQ) to give the target compound Bauerine C. Copyright Taylor & Francis Group, LLC.

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First Total Synthesis of Bauerine C
Y. Lingam a , D. Muralimohan Rao b , Dipal R. Bhowmik a & Aminul Islam a
a Custom Pharmaceutical Services , Dr. Reddy's Laboratories Limited ,
Hyderabad, India
b College of Engineering, Jawaharlal Nehru Technological University ,
Kakinada, Andhra Pradesh, India
Published online: 14 Dec 2007.
To cite this article: Y. Lingam , D. Muralimohan Rao , Dipal R. Bhowmik & Aminul Islam (2007) First Total
Synthesis of Bauerine C, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:24, 4313-4318, DOI: 10.1080/00397910701575426
To link to this article: http://dx.doi.org/10.1080/00397910701575426
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Synthetic Communicationsw, 37: 4313–4318, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575426
First Total Synthesis of Bauerine C
Y. Lingam
Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Hyderabad, India
D. Muralimohan Rao
College of Engineering, Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh, India
Dipal R. Bhowmik and Aminul Islam
Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Hyderabad, India
Abstract: The first total synthesis of Bauerine C, a unique indoloquinazoline alkoloid,
has been achieved from readily available 2,3-dichloroaniline. The key step is the Japp–
Klingmann condensation between 2,3-dichloroaniline and ethyl-2-acetyl-5-phthalimido
pentanoate to get 3-[(2,3-dichlorophenyl)-hydrozono]-pipiridin-2-one, which cyclizes
to 7,8-dichloro-2,3,4,9-tetrahydro-b-carbolin-1-one, which can be methylated by
dimethyl sulphate to give 7,8-dichloro-9-methyl 2,3,4,9-tetrahydro-b-carbolin-1-one.
This N-methyl derivative is then subjected to dehydrogenation with 2,3-dichloro-5,6-
dicayano-1,4-benzoquinone (DDQ) to give the target compound Bauerine C.
Keywords: Bauerine C, cyclization, indoloquinazoline alkaloid, Japp–Klingmann
condensation, methylation
INTRODUCTION
Three new chloro-containing b-carbolines, Bauerines A–C,[1] have been
isolated from the terrestrial blue-green alga Dichothrix baueriana. These
Received in India May 8, 2007
Address correspondence to Aminul Islam, Custom Pharmaceutical Services,
Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad 500 049,
India. E-mail: aminulislam@drreddys.com
4313

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Y. Lingam et al.
alkaloids show activity against herpes simplex virus type 2. The biological
activity of Bauerine C has attracted considerable interest in its total
synthesis. Bauerine C is an attractive target, exhibiting antiviral activity and
cytotoxic activity. In connection with our ongoing interest in the total
synthesis of b-carboline natural products, here we report the total synthesis
of Bauerine C. To the best of our knowledge, this is the first report on total
synthesis of Bauerine C. We report here a potentially significant route to
Bauerine C, which is not only short but also experimentally simple,
involving Japp–klingmann condensation as the key step.
During the course of our process research on Zolmitriptan,[2] we
encounter 2,3,4,9-tetrahydro-1H-b-carboline-1-one as an impurity. The
b-carboline derivatives that have various biological activities motivated us
to explore this work further to synthesis different b-carboline derivatives.
The b-carboline moiety is a core structure in various synthetic pharma-
ceuticals displaying a broad spectrum of biological activities. b-Carbolines,
conformationally constrained tryptamine analogs, are a fascinating and under-
investigated class of compounds. It is worth mentioning that the basic skeleton
present in our isolated compounds is interesting, as some biologically active
compounds such as incasan,[3] canthin,[4a] manzamine,[4b] and rutecarpine[5]
possess this skeleton. These can be prepared by this methodology, and we
envisioned a short synthesis of b-carbolines (Figs 1 and 2).
RESULTS AND DISCUSSION
In the first instance, the readily available intermediate ethyl-2-acetyl-5-phtha-
limido pentanoate[6] on Japp–Klingmann reaction with a diazonium salt of
dichloro aniline and hydrazine hydrate treatment gives 1 in moderate yield.
We have followed the known and reported literature procedure for the
Figure 1. Bauerine A (R ¼ H), Bauerine B (R ¼ Cl).
Figure 2. Bauerine C.

First Total Synthesis of Bauerine C
4315
preparation of ethyl-2-acetyl-5-phthalimido pentanoate.[6] The cyclization
using hydrazine hydrate in ethanol furnished the intermediate 1, which was
purified by column chromatography. Phthalyl hydrazide was the major
by-product in this reaction. Compound 1, on treatment with formic acid in
toluene under reflux condition for 12 h, gives compound 2 in good yield.
Alkylation has been tried with methyl iodide in presence of sodium hydride
as a base but resulted in a dimethylated product. The reaction conditions
were changed, and 7,8-dichloro-2,3,4,9-tetrahydro-1H-b-carbolin-1-one 2
was treated with dimethyl sulphate in the presence of sodium methoxide to
give 7,8-dichloro-9-methyl-2,3,4,9-tetrahydro-1H-b-carbolin-1-one
3 in
good yield. This was further dehydrogenated by DDQ in 1,4-dioxane at
room temperature to give the crude Bauerine C, which was purified by
column chromatography using a mixture of ethyl acetate and petroleum
ether as eluent to give pure Bauerine C 4 in moderate yield. The spectroscopic
data of Bauerine C are in agreement with those described in the literature.[1]
The key reactions leading to total synthesis of Bauerine C are schematically
shown in Scheme 1.
In conclusion, we report here the first concise total synthesis of Bauerine
C. Our present approach is applicable to the synthesis of more b-carbolines
targets. Several analogs of b-carbolines derivatives have been prepared and
are currently undergoing biological studies. The synthesis and evaluation of
the biological activities of Bauerine C analogs will be reported in due course.
EXPERIMENTAL
General Methods
1H NMR spectra were determined in CDCl3, and DMSO-d6 solution on Varian
Gemini 200-MHz spectrometers. Proton chemical shifts (d) are relative to
Scheme 1. Reagents and conditions: (i) NaOAc/EtOH, NaNO2, con. HCl; (ii)
.
NH2NH2 H2O/EtOH; (iii) HCOOH/toluene; (iv) (CH3)2SO4, NaOMe, acetone; (v)
DDQ, 1-4 dioxane.

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Y. Lingam et al.
tetramethylsilane (TMS, d 0.00) as internal standard and expressed in parts per
million (ppm). Spin multiplicities are given as s (singlet), d (doublet),
t (triplet), and m (multiplet). Coupling constants (J) are given in hertz.
Melting points were determined using a scientific capillary melting-point
apparatus and are uncorrected. Mass spectra were obtained on a HP-5989A
mass spectrometer. Thin-layer chromatography (TLC) was performed on
silica-gel plates (SRL 230–400 mesh). All the solvents used were commer-
cially available and was distilled before use.
Preparation of 3-[(2,3-Dichlorophenyl)-hydrozono]-pipiridin-2-one (1)
Part A.
Ethyl 2-acetyl-5-phthalimidopentanoate (10.2 g, 0.0306 mmol) and ethanol
(100 ml) were taken into a four-neck, round-bottom flask. To this, 20.6 g
(8.3 mmol) of sodium acetate were added while stirring the mixture for
5 min; the resulting solution was then stirred at room temperature for 1 h.
Part B.
2,3-Dichloro aniline (5.0 g, 0.0306 mmol), 12.5 ml of ethanol, and 18.5 ml of
water were taken into another four-neck, round-bottom flask, stirred, and
cooled to 08C. To this solution, 16.0 ml of concentrated hydrochloric acid
were added during 30 min while stirring. The reaction mixture was allowed
to stir at 08C for 10 min. A freshly prepared solution of sodium nitrite
[2.3 g, (1.1 mmol) in 10 ml water] was slowly added to the reaction mixture
at 0–58C and stirred for 30 min.
The part A reaction mass was cooled to 08C, and part B reaction mass was
added to this. The resulting mixture was stirred at room temperature for 3 h.
After completion of the reaction (TLC), the mixture was extracted with
dichloromethane, the organic layer was evaporated to dryness, and 25 ml of
ethanol were added to the residue. The mixture was heated to reflux while
ethanolic hydrochloric acid (10%) was added to the mixture at reflex. The
reaction mixture was stirred for 2 h at reflux temperature. After completion
of the reaction, the mixture was cooled to room temperature. The solid was
filtered and washed with precooled ethanol to give 6 g of the intermediate,
which was taken in 2.6 ml of ethanol. Hydrazine hydrate (2.6 g) was added.
The resulting reaction mixture was stirred at 458C for 2 h. After completion
of the reaction, the mass was cooled to room temperature, and 2 ml of concen-
trated hydrochloric acid was added. The yellow solid was obtained, which was
then purified by column chromatography using a mixture of ethyl acetate and
pet. ether as an eluent to yield 2.2 g (26%) of compound 1. 1H NMR
(200 MHz, CDCl3) d 13.35 (s, 1H), 7.52 (d, 1H), 7.25 (t, 1H), 6.99 (d, 1H),
6.02 (s, 1H), 3.44 (d, 2H), 3.76 (d, 2H), 2.07 (m, 2H), MS (CI method)

First Total Synthesis of Bauerine C
4317
271.8 (M þ 1). Anal. calcd. for C11H11Cl2N3O (271.03); C, 48.55; H, 40.72;
N, 15.44. Found: C, 48.72; H, 40.82; N, 15.56. MS (CI method) 271.8
(M þ 1).
Preparation of 7,8-Dichloro-2,3,4,9-dihydro-1H-b-carbolin-1-one (2)
3-[(2,3-Dichlorophenyl)-hydrozono]-pipiridin-2-one (1.0 g, 0.0036 mmol) and
toluene (10 ml) were taken in a round-bottom flask, and formic acid (0.33 g,
0.0072 mmol) was added slowly to the reaction mixture. The reaction was
heated to reflux and stirred for 12 h. The solvent was evaporated, the residue
was neutralized with ammonia solution, and the resulting mixture was
extracted with ethyl acetate. The organic layer was dried over sodium
sulphate and evaporated to give 0.48 g (52%) of compound 2. 1H NMR
(200 MHz, CDCl3) d 9.1 (s, 1H), 7.44 (d, 2H), 5.64 (s, 1H), 3.74 (t, 2H),
3.04 (t, 2H). Anal. calcd. for C11H8Cl2N2O (254); C, 51.79; H, 3.16; N,
10.98. Found: C, 51.82; H, 3.26; N, 10.99. MS (CI method) 255 (M þ 1).
Preparation of 7,8-Dichloro-9-methyl-2,3,4,9-tetrahydro-1H-b-
carbolin-1-one (3)
Compound 2 (0.45 g, 0.0017 mmol), 50% solution of sodium hydroxide
(2.0 ml), and 5.0 ml of methanol were taken in a round-bottom flask and
stirred for 30 min at 608C. The solvent was evaporated, 10 ml of acetone
were added to the residue, and 120 mg (0.0019 mmol) of methyl sulfide
were added slowly to this. The reaction mixture was heated to reflux and
stirred at this temperature for 12 h. The reaction mass was evaporated and
extracted with 20 ml of chloroform. The organic layer was washed with
water, dried over sodium sulphate, and concentrated to dryness. The crude
residue was then purified by column chromatography using a mixture of
ethyl acetate and pet. ether as an eluent to yield 120 mg (37%) of
1
compound 3. H NMR (200 MHz, CDCl3 þ DMSO-d6) d 7.45 (d, 1H), 7.23
(d, 1H), 7.12 (s, 1H), 4.50 (s, 3H), 3.61 (m, 2H), 2.98 (t, 2H). Anal. calcd.
for C11H8Cl2N2O (268): C, 53.55; H, 3.75; N, 10.41. Found: C, 53.62; H,
3.83; N, 10.63. MS (CI method) 269 (M þ 1).
Preparation of 7,8-Dichloro-9-methyl-2,9-dihydro-1H-b-carbolin-
1-one (4)
Compound 3 (0.100 g, 0.00037 mmol), 10 ml of 1,4-dioxane, and 0.253 g
(0.0011 mmol) of DDQ were taken in a round-bottom flask and stirred at
room temperature for 2 h. Ten ml of 10% sodium hydroxide solution were
added to the reaction mass, stirred for 30 min, and extracted with 20 ml of

4318
Y. Lingam et al.
chloroform. The organic layer was washed with water, dried over sodium
sulphate, and concentrated. The residue was purified by column chromato-
graphy using a mixture of ethyl acetate–pet. ether as an eluent to yield
0.060 g (61%) of compound 4. 1H NMR (400 MHz, CDCl3) d 11.32
(s, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.31 (d, 1H), 7.04 (s, 1H), 6.84 (d, 1H),
4.72 (s, 3H). Anal. calcd. for C12H8Cl2N2O (266.11); C, 53.96; H, 3.02; N,
10.49. Found: C, 53.98; H, 3.10; N, 10.52. MS (CI method) 267 (M þ 1).
ACKNOWLEDGMENT
The authors thank Dr. Reddy’s Laboratories, Ltd., for supporting this work
and Abhijit Mukherjee and Vilas Dahanukar of Custom Pharmaceutical
Services for their constant help and encouragement. Cooperation extended
by colleagues from the analytical division is gratefully acknowledged.
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