Synthesis of tetrahydro-β-carbolines, β-carbolines, and natural products, (±)-harmicine, eudistomin U and canthine by reductive Pictet Spengler cyclization

Article abstract of DOI:10.1016/j.tetlet.2015.09.052

Reductive Pictet Spengler cyclization was used for the synthesis of naturally occurring β-carbolines, eudistomin U, and canthine. Other biologically important β-carbolines as well as tetrahydro-β-carboline, such as (±)-harmicine were also synthesized usin

Full text of DOI:10.1016/j.tetlet.2015.09.052

Accepted Manuscript
Synthesis of tetrahydro-β-carbolines, β-carbolines, and natural products, (± ±-
harmicine, eudistomin U and canthine by reductive Pictet Spengler cyclization
Deepali S. Pakhare, Radhika S. Kusurkar
PII:
S0040-4039(15±30094-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.052
TETL 46724
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 June 2015
14 September 2015
15 September 2015
Please cite this article as: Pakhare, D.S., Kusurkar, R.S., Synthesis of tetrahydro-β-carbolines, β-carbolines, and
natural products, (± ±-harmicine, eudistomin U and canthine by reductive Pictet Spengler cyclization, Tetrahedron
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Tetrahedron Letters
Synthesis of tetrahydro-β-carbolines, β-carbolines, and natural products, (±)-
harmicine, eudistomin U and canthine by reductive Pictet Spengler cyclization
Deepali S. Pakhare, Radhika S. Kusurkar*
Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune - 411 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Reductive Pictet Spengler cyclization was used for the synthesis of naturally occurring β-
carbolines, eudistomin U, and canthine. Other biologically important β-carbolines as well as
tetrahydro-β-carboline, such as (±)-harmicine were also synthesized using the same strategy.
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Eudistomin U
canthine
(±)-harmicine
reductive Pictet Spengler cyclization
Introduction
reductive Pictet Spengler cyclization using nitrile and tryptamine
in presence of hydrogenation conditions.
β- Carboline alkaloids constitute a large group of natural and
synthetic indole alkaloids. The interest of chemists in the
development of new methods for the synthesis of β-carboline
alkaloids is mainly due to their broad spectrum of biological
In this paper, we report the synthesis of biologically active,
three natural products, eudistomin
U (3d), canthine (8),
harmicine (10) and three other unnatural β-carbolines, 3a-c using
reductive Pictet Spengler cyclization.
1a-c
1d
effects and presence in pharmaceuticals.
Results and discussion
4
-6
The reductive Pictet Spengler cyclization where nitrile is
used instead of an aldehyde was visualized for the synthesis of
natural and unnatural THβCs and β-carbolines. Thus, reaction of
tryptamine with benzonitrile (1a) in presence of 10% Pd/C in
acetic acid under hydrogen atmosphere, at room temperature
7
resulted in THβC 2a (Table 1). Similar reaction using 2-
cyanopyridine and 3-cyanopyridine furnished THβCs 2b and 2c
8a
respectively. Subsequently, THβC 2a was dehydrogenated
using KMnO , to produce β-carboline 3a while compounds 2b
Figure 1. Structures of β-carbolines and tetrahydro-β-carboline
alkaloids.
4
8b
and 2c were aromatized to 3b and 3c using 10% Pd/C in good
yield. The same strategy using indole-3-carbonitrile furnished
THβC 2d, which on aromatization using 10% Pd/C resulted into
the formation of eudistomin U (3d). For aromatization of 2a, the
2
The Pictet Spengler condensation is one of the most
important strategies available for the synthesis of tetrahydro-β-
carbolines (THβCs) which further can be dehydrogenated to β-
carboline alkaloids. After the discovery of Pictet Spengler
9
use of Pd/C was avoided due to the reported possibility of
3
a
3b
3c
reaction, various Bronsted acids , Lewis acids , enzymes ,
breakage of the ring during the dehydrogenation. All the
synthesized compounds were characterized using spectral data
3d
microwave reaction conditions etc. were used for this reaction.
1
0a-g
and comparison with reported
values.
While targeting polyfunctional compounds, difficulty in the
preparation of the polyfunctional aldehydes, use of corrosive
CF COOH, and lower yields of the reactions, confines the scope
3
4
of classical Pictet Spengler reaction. Literature survey revealed
an interesting modification for the synthesis of THβCs by

2
o
Table 1. Reductive Pictet Spengler reaction of tryptamine with
nitriles 1a-d and further dehydrogenation
NaH, THF, rt, overnight, 92%; c) conc. HCl, EtOH, 50 C, 2 h,
90% (crude compound); d) 10% Pd/C, H , CH COOH, 24 h, rt;
2
3
e) 10% Pd/C, Toluene, reflux, 24 h, 60% (starting from
compound 5).
In order to synthesize harmicine, trypatamine was treated with
4
-bromobutyronitrile which gave compound 9 with the
12
preferential monosubstitution at primary nitrogen (Scheme 2).
Further intramolecular reductive Pictet Spengler reaction gave
harmicine 10 (55%), along with reduced product 11 (40%).
Scheme 2. Synthesis of harmicine. Reagents and conditions: a)
4
2 3
-bromobutyronitrile, K CO , EtOH, reflux, 6 h, 95%; b) 10%
Pd/C, H , CH COOH, rt, 40 h, 10 (55%), 11 (40%).
2
3
3,4
According to the reported mechanism of reductive Pictet
Spengler reaction, in the present case, initially the nitrile group
was hydrogenated to protonated imine 9a under acetic acid
condition. Further cyclization (might be assisted by Pd catalyst),
loss of ammonia and Pictet Spengler reaction furnished
compound 10. This was accompanied with the hydrogenation of
protonated imine in compound 9a to get compound 11 as shown
in Scheme 3.
For the synthesis of other target molecules, such as canthine
and harmicine, use of aliphatic nitriles was envisioned. Thus,
amino group of trypatamine was protected using (Boc) O to give
2
N-Boc compound 4 in 94% yield (Scheme 1). Treatment of
compound 4 with 4-bromobutyronitrile in THF in presence of
11a,b
NaH gave selectively N-substituted
group was deprotected using conc. HCl in ethanol to get amine 6
crude compound 95%). Being an amine, it was difficult to purify
compound 5. Further, Boc
(
using chromatographic separation. After removing ethanol on
rotary evaporator, pH of the reaction mixture was adjusted to 11-
1
2 by 5M NaOH and it was extracted with dichloromethane to
Scheme 3. Possible Mechanism of the formation of 10 and 11.
1
obtain an oily product. It showed H NMR consistent with the
structure of amine 6 and its HRMS confirmed (M+H) 228.1498
18 3
for molecular formula C14H N . Thus, it was used for further
Conclusion
transformation without purification. Subsequently, stirring the
compound 6 in acetic acid under hydrogen atmosphere, furnished
an oily product by intramolecular reductive Pictet Spengler
reaction. The efforts to purify the product by column
Reductive Pictet Spengler reaction has been used successfully
for the synthesis of naturally occurring biologically active
tetrahydro-β-carbolines, harmicine (10), β carbolines, eudistomin
U (3d), canthine (8) and some pharmacologically important β-
carbolines 3a, 3b, and 3c.
chromatography, gave
a complex mixture indicating the
instability of this oily product. Therefore, it was used as such for
the further reaction of aromatization using 10% Pd/C which
furnished canthine 8 in 60% yield starting from compound 5.
Acknowledgments
We are thankful to Mrs. Shital Bansode and Mr. Dattatraya
Ukale for NMR spectra and Mr. Rahul Yewale for HRMS.
D.S.P. is thankful to CSIR, New Delhi for financial assistance
through fellowship and contingency.
Supplementary data
Supplementary data associated with this article can be found,
in the online version.
Scheme 1. Synthesis of canthine. Reagents and conditions: a)
3 2
Et N, (Boc) O, Dioxane, rt, 3 h, 94%; b) 4-bromobutyronitrile,

References and notes
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1
0% Pd/C (0.2 mmol) in one portion. The mixture was
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made basic with aqueous NH
dichloromethane. The combined organic layers were dried
on Na SO and solvent was evaporated. The residue was
3
and then extracted with
2
4
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aluminium oxide using dichloromethane: methanol as an
eluent to give tetrahydro-β-carboline.
8) General procedure for aromatization of THβC to
β-carboline: (a) To a solution of THβC (1 mmol) in
acetone was added KMnO
4
(4 mmol) cautiously

2
Graphical Abstract
Synthesis of tetrahydro-β-carbolines,
β-
carbolines, and natural products, (±)-harmicine,
eudistomin U and canthine by reductive Pictet
Spengler cyclization
Deepali S. Pakhare and Radhika S. Kusurkar*