An efficient one-pot decarboxylative aromatization of tetrahydro-β-carbolines by using N-chlorosuccinimide: total synthesis of norharmane, harmane and eudistomins

Article abstract of DOI:10.1039/c5ra16221a

A facile method for the synthesis of a variety of β-carbolines and their natural products such as norharmane (2a), harmane (2b), eudistomins I, N, T, and U (6, 7, 9 and 10, respectively) has been successfully developed via a decorboxylative aromatization tool by employing N-chlorosuccinimide (NCS) as a mild and efficient reagent. Gratifyingly, this reagent system proceeds in a one-pot manner and converted all the tetrahydro-β-carboline acids into their corresponding decorboxylative aromatic products with good to excellent yields. Additionally, this system works well in the case of tetrahydro-β-carboline esters to produce their aromatic partners in high yields.

Full text of DOI:10.1039/c5ra16221a

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An efficient one-pot decarboxylative aromatization of tetrahydro-
β-carbolines by using N-chlorosuccinimide: Total synthesis of
norharmane, harmane and eudistomins
Received 00th January 20xx,
Accepted 00th January 20xx
Ahmed Kamal,*a,b,c Manda Sathish,a A. V. G. Prasanthi,b Jadala Chetna,b Yellaiah Tangella,a Vunnam
Srinivasulu,a Nagula Shankaraiahb and Abdullah Alarific
DOI: 10.1039/x0xx00000x
www.rsc.org/
A facile method for the synthesis of a variety of β-carbolines and their natural products such as norharmane (2a), harmane
(2b), eudistomins I, N, T, and U (6, 7, 9 and 10) respectively has been successfully developed via decorboxylative
aromatization tool by employing N-chlorosuccinimide (NCS) as a mild and efficient reagent. Gratifyingly, this reagent
system proceeds in a one-pot manner and converted all the tetrahydro-β-carboline acids into their corresponding
decorboxylative aromatic products with good to excellent yields. Additionally, this system works well in case of tetrahydro-
β-carboline esters to produce their aromatic partners in high yields.
MnO2,19 SeO2,20 palladium on carbon21 and sulfur22 with excess
usage of the oxidants as well as prolonged reaction time. Other
organic oxidants like DDQ23 and chloranil24 were also used for
Introduction
It is well-known that β-carboline alkaloids having a tricyclic planar
ring system are found in various synthetic/natural indole alkaloids.1
This class of compounds (norharmane, harmane and harmine) are
originally isolated from Peganum harmala and a group of β-
carbolines,2 termed as eudistomins (eudistomine I, N, T and U) are
isolated from ascidians.3,4 Most of these alkaloids exhibit
antibacterial,5 antimalarial,6 antitumor,7anti-HIV8 activities, and also
shows binding affinity towards 5-hydroxy serotonin receptors,9
monoamine oxidase10 and benzodiazepine receptors11 in the central
nervous system. In light of these medicinal properties, there is a
need for the development of mild and efficient methods towards
the synthesis of β-carboline and their natural products. In recent
years, we have been involved in the total syntheses of several
natural/unnatural β-carboline alkaloids such as arborescidine
alkaloids, quinolactacin B, PDE5 inhibitor, etc.12 Moreover, the β-
carboline ring system has also been used as versatile synthetic
intermediates in the development of pharmaceutically useful
motifs.13
aromatization but the yields are not satisfactory. However, most of
these methods require expensive reagents and drastic reaction
conditions that lack environmental safety. Hence, the development
of inexpensive, operationally simple and environmentally safe
protocols that could be carried out under milder reaction conditions
are valuable.
Next, N-halosuccinimides (NXS, X = Cl, Br and I) are considered
as haloginating and mild oxidizing agents that can be used as a
source of halogen in radical reactions for various electrophilic
additions25,26as well as for mild oxidations.27 Earlier, Roy and co-
workers have reported the decarboxylative halogenation of α,β-
unsaturated carboxylic acids by using NXS.28 Later, Kuang and co-
workers have reported the stereoselective decarboxylative
bromination of α,β-unsaturated carboxylic acids by using NBS and
lithium acetate under microwave conditions.29 However, N-
chlorosuccinimide (NCS) is a versatile and cost effective reagent for
the mild oxidation as well as halogenation, having lesser toxicity
than other oxidants.30 Moreover, the by-product succinimide is
highly soluble in water (1 g/3 mL at 25 oC),31 easy to remove from
reaction mixture during the work-up and also in large-scale
reactions the succinimide from aqueous phase can be converted
into the starting reagent N-chlorosuccinimide by treating with the
sodium hypochlorite to make the method sustainable.32 Recently,
trichloroisocyanuric acid (TCCA) is also being used for aromatization
of tetrhydro-β-carboline esters,33 but the draw-back of this reagent
The decarboxylative aromatization is one of the most attractive
transformations
in the organic synthesis.14
However,
decarboxylative aromatization of tetrahydro β-carbolines that
involves C−H bond formaꢀon has received considerably less
attention. A common method for the decarboxylative aromatization
employs transition-metal oxidants at higher temperatures.15,16 In
16
the past, this transformation was achieved by using K2Cr2O7 in
acetic acid under heating for prolonged reaction times in presence
of persulfate employing catalytic silver (Ag+/S2O8 ).17 Generally,
o
-
is solubility of its by-product cyanuric acid (0.27 g/100 ml at 25 C)
in water. Based on these observations, we were prompted to look
Pictet–Spengler reaction followed by decarboxylative aromatization
is the most widely studied method to access β-carbolines.18 On the
other hand, aromatization of the tetrahydro-β-carboline
carboxylate is reported to be carried out by using mild oxidants like
for
a straightforward, operationally simple and high yielding
protocol for the synthesis of β-carbolines using N-
chlorosuccinimide. Therefore, we herein report a new one-pot
decarboxylative aromatization tandem aromatization strategy for
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the synthesis of several β-carbolines and their alkaloids such as
After establishing optimal conditions, we studied the reactivity
norharmane (2a), harmane (2b), eudistomin I (6), eudistomin N (7), of various tetrahydro-β-carboline acids differing at position-1 and
eudistomin T (9) and eudistomin U (10) in excellent yields. In the results are shown in Table 2. The substrates tetrahydro-β-
addition, this method was also successfully applied for the carboline acids successfully synthesized by Pictet-Spengler reaction
aromatization of tetrahydro-β-carboline ester into their of L-tryptophan and substituted benzaldehydes. Typically, the
corresponding β-carboline esters in high yields.
substituents on tetrahydro-β-carboline acids slightly affected the
yields, wherein good yields are observed in case of aromatic and
heteroaromatic rings at position-1 compared to aliphatic
substitutions (entry 1, 2, 3 and 4, Table 2). From Table 2, it is
observed that the nature of substituents at position-1 considerably
influence the yields of the products. For example, substrates with
electron-rich groups afforded noticeably high yields compared to
electron-poor groups (entry 14 and 15, Table 2). Interestingly, the
tetrahydro-β-carboline acids with fused ring systems like napthyl
and phenanthryl groups also provided excellent yields (entry 17 and
18, Table 2), howevermoderate yields are observed in case of
subsrtates with phenoxy substitutions at position-1 (entry 10 and
11, Table 2). Moreover, the natural β-carboline alkaloids
norharmane (2a) and harmane (2b) are synthesized successfully by
using this protocol with appreciable yields (entries 1 and 2, Table 2).
Results and Discussion
In this study, we have initially tested the feasibility of the reaction
of 1i with N-halosuccinimides (NXS, X = Cl, Br and I, 1.5 equiv.) in
the presence of TEA (2 equiv.) and THF as a solvent at ambient
temperature for 12 h. It was observed that the product 2i obtained
in moderate yields 60%, 53% and 48% (entry 1, 2, 3, Table 1) with
different reagents. Later, when we enhanced the stoichiometric
ratio of NXS (2.1 equiv.) and TEA (2.5 equiv.), the desired products
were obtained in good yields 85%, 78% and 70% (entry 4, 5, 6, Table
1) respectively. Gratifyingly, the startingmaterials were completely
consumed and even the reaction time was also decreased to 30
min. However, increase in the stoichiometric ratio of NXS (3 equiv.)
reagent had no effect on yields and even the chlorinated product
was not observed in this reaction process. Based on these model
experiments, 2.1 equiv. of NCS was found to be slightly superior in
comparison to NBS or NIS, and as well cost effective. The effect of
solvent on the reaction was also studied by using various solvents
such as THF, CH3CN, 1,4-dioxane, DMF, DMSO, CH2Cl2 and it was
observed that the product was obtained in 30 min with higher
yields in the case of DMF as solvent (Table 1).
Table 2 One-pot decorboxylative aromatization for the synthesis of β-carbolines 2a–t
and 8 by using NCSa.
Table 1 Optimization of the reaction conditions for the synthesis of β-carbolines.a
Entry
1
R
H
product
yield (%)b
80
norharmane (2a)
2
Me
harmane(2b)
82
3
n-propyl
2c
2d
2e
2f
78
4
4-methoxybenzyl
Phenyl
90
5
85
6
p-tolyl
88
7
p-methoxy phenyl
3,4,5-trimethoxy phenyl
4-hydroxy-3-methoxy phenyl
3-hydroxyphenyl
4-chlorophenyl
4-fluorophenyl
4-cyanophenyl
4-nitrophenyl
Piperonyl
2g
2h
2i
93
8
92
9
83
10
11
12
13
14
15
16
17
18
19
20
21
2j
78
Entry
NXS
equiv.
time (h)
solvent
yield (%)b
2k
2l
80
83
1
2
NCS
NBS
NIS
1.5
1.5
1.5
2.1
2.1
2.1
3.0
2.1
2.1
2.1
2.1
2.1
12
12
12
1
THF
THF
60c
53c
48c
85
78
70
85
65
71
92
88
68
2m
2n
2o
2p
2q
2r
2s
2t
81
79
3
THF
91
4
NCS
NBS
NIS
THF
Napthyl
94
5
1
THF
9-phenanthryl
3-pyridyl
95
6
1
THF
91
7
NCS
NCS
NCS
NCS
NCS
NCS
1
THF
4-fluoro-3-methoxyphenyl
4-trifluorotolyl
N-boc-2-phenethylamino
88
8
1
acetonitrile
1,4-dioxane
DMF
85
9
1
8
80
10
11
12
0.5
1
a1 (1 mmol) in DMF, NCS (2.1 equiv.) and TEA (2.5 equiv.) stirred for 30 min at rt.
b Isolated yield.
DMSO
DCM
1
aTetrahydro-β-carboline acid (1i, 1 equiv.), NXS and TEA. bIsolated yield. cStarting
material was recovered.
2 | J. Name., 2012, 00, 1-3
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Scheme 1 Total synthesis of eudistomin I (6), eudistomin N (7), eudistomin T (9) and eudistomin U (10) by using NCS.
Inspired by the above results, we were prompted to apply this deprotection of boc group using 2N HCl in 1,4-dioxane to afford the
method for the synthesis of marine β-carboline alkaloids like hydrochloride salt . Salt was produced the eudistomin I ( ) under
5
5
6
eudistomins I, N, T and U. Eudistomin I, N and T were isolated from optimized reaction conditions by using NCS in 70% yield.
Caribbean tunicate Eudistoma Olivaceum and shows strong antiviral Interestingly, it was observed that decarboxylation, aromatization
and antimicrobial activities.3b,34 In 1987, the total synthesis of and imine formation were successfully achieved in a one-pot
eudistomin I was reported,3b,35 while Rinehart and co-workers in manner (Scheme 1).
order to characterize the alkaloid isolated eudistomin N, described
Next, the synthesis of eudistomin N (
7
) was achieved by the
the synthesis of this bromo-β-carbolines.3b,36 Moreover, edustomin Pictet-Spengler reaction of L-tryptophan (
1
) and formaldehyde
N was found to be the most potent antiviral agent even compared followed by decarboxylative aromatization under optimized
to harmine.37 Whereas, eudistomin T was isolated in 1987 by Kinzer reaction conditions with NCS to afford norharmane (2a). The
and Cardellina II,38 another marine β-carboline alkaloid eudistomin bromination of 2a with NBS in acetic acid afforded the eudistomin
U was isolated from the marine ascidian lissoclinum fragile and was
N (7) and it is important to note that the overall yield is
reported to posses antimicrobial as well as anticancer activities with considerably higher (91%, Scheme 1).
strong DNA binding potential.4 Both these eudistomins T and U
Subsequently, the total synthesis of eudistomin T (9) was also
succumbed to their total synthesis six times.39,40 Overall, from the carried out with the acid catalyzed Pictet-Spengler condensation of
literature it was observed that the syntheses of such β-carbolines L-tryptophan with N-Boc phenylalaninal and further reaction with
rarely involve decarboxylative aromatization and often utilized NCS provided compound
8. This compound (8) was taken for
either metal catalysts, drastic conditions or prolonged reaction deprotection of Boc group with 2N HCl in 1,4-dioxane to afford the
times and with lower yields to construct the core skeleton. In sight corresponding amine, which was subsequently treated directly with
of these aspects, we were driven to synthesize these natural β- sodium hypochlorite to produce eudistomin T (9, 88%, Scheme 1).
carbolines from the commercially available starting materials which
could be a efficient route with higher yields than the previously
reported syntheses.
Finally, we also carried out the total synthesis of eudistomin U
(
10) with commercially available L-tryptophan. The Pictet-Spengler
reaction of L-tryptophan and indole-3-carbaldehyde followed by
Initially, we started the total synthesis of eudistomin I from reaction with NCS under optimized conditions produced eudistomin
Pictet-Spengler reaction of L-tryptophan ( ) and N-boc prolinal to U (10) in good yield (85%, Scheme 1).
provide the corresponding N-boc pyrrolidinyl tetrahydro-β- Additionally, to find out the scope of this protocol on the
carboline acid, which was then directly used for further tetrahydro-β-carboline esters, we have reacted various substituted
1
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followed by aromatization. Next,
a
reaction of tetrahydro-β-
Table 3 Synthesis of β-carbolines esters (4a–h) by aromatization using NCSa
carbolines (12 and 13) under optimal reaction conditionsprovided
partially dehydrogenated products (14 and 15) after 5 min, however
fully aromatized β-carbolines (2g and 2n, Figure 1) were observed
after 12 h. In addition, we saw that the tetrahydro-β-carboline
esters (3a‒h) underwent aromatization only in 30 min. From all
these results/findings, It was observed that the ester/acid
functionality accelerates the reaction and the mechanism was
proposed (Figure 1).
Entry
R
product
4a
yield (%)b
1
2
3
4
5
6
7
8
2-phenethyl
81
94
95
92
96
94
91
88
3,4,5-trimethoxy phenyl
1-napthyl
4b
Conclusions
4c
4-chlorophenyl
4d
In conclusion, we have developed an operationally simple, mild and
efficient protocol for the one-pot decarboxylative aromatization of
tetrahydro-β-carboline-3-carboxylic acids to the β-carbolines. This
protocol employs a cost effective oxidant N-chlorosuccinimide that
provides higher yields. This method could utilize an alternative to
the traditional heating methods employing harsh metal-based
reagents. Moreover, the efficacy of this reagent system was
established for the total synthesis of biologically active some of the
β-carbolines norharmane, harmane and marine β-carboline
9-phenanthryl
4e
4-fluoro-3-methoxy phenyl
4-trifluorotolyl
4f
4g
1-N-boc-2-phenethyl
4h
a3 (1 mmol) in DMF, NCS (2.1 equiv.) and TEA (2.5 equiv.) stirred for 30 min at rt.
bIsolated yield.
tetrahydro-β-carboline esters with NCS. The substrates β-carboline
esters were synthesized in two steps from commercially available L-
tryptophan methyl ester hydrochloride. Interestingly, all these
substartes successfully yielded their corresponding aromatic
alkaloids eudistomin I, N, T and U (2a, 2b, 6, 7, 9 and 10)
respectively. Additionally, aromatization of tetrahydro-β-carboline
esters to the corresponding β-carboline esters are also achieved
successfully in excellent yields.
partners (4a‒h) in excellent yields (Table 3) with out lossing ester
group.
Acknowledgements
The authors, M.S, Y.T and V.S acknowledge the Council of Scientific
and Industrial Research (CSIR), New Delhi (India) for the financial
support under the 12th Five Year Plan project “Affordable Cancer
Therapeutics (ACT)” (CSC0301). This project was also supported by
King Saud University, Deanship of Scientific Research, Research
Chair.
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This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C5RA16221A
ARTICLE
Journal Name
a.Ahmed Kamal, Manda Sathish, YellaiahTangella, VunnamSrinivasulu; Medicinal
Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India; Email: ahmedkamal@iict.res.in.
b.Ahmed Kamal, A V G Presanthi, JadalaChetna; NagulaShankaraiah; Department of
Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Hyderabad-500 037, India.
c. Ahmed Kamal, Abdullah Alarifi; Catalytic Chemistry Research Chair, Chemistry
Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
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DOI: 10.1039/C5RA16221A
An efficient oneꢀpot decarboxylative aromatization of tetrahydroꢀβꢀ
carbolines by using Nꢀchlorosuccinimide: Total synthesis of norharmane,
harmane and eudistomins
Ahmed Kamal,* Manda Sathish, A. V. G. Prasanthi, Jadala Chetna, Yellaiah Tangella,
Vunnam Srinivasulu, Nagula Shankaraiah and Abdullah Alarifi
A mild oneꢀpot synthesis of βꢀcarbolines and their natural products from their tetrahydroꢀβꢀ
carboline acids has been developed via decorboxylative aromatization using Nꢀ
chlorosuccinimide (NCS).