Application of metal free aromatization to total synthesis of perlolyrin, flazin, eudistomin U and harmane

Article abstract of DOI:10.1002/jhet.3931

Application of our recently reported metal free reaction conditions to the total synthesis of the four different and selective biologically interesting β-carboline natural products is reported. Using this simple methodology, flazin, perlolyrine, eudistomin U and harmane containing heteroaryl and alkyl substituents at C1 position were synthesized in good yields. (Figure presented.).

Full text of DOI:10.1002/jhet.3931

Received: 30 July 2019
DOI: 10.1002/jhet.3931
Revised: 7 January 2020
Accepted: 29 January 2020
A R T I C L E
Application of metal free aromatization to total synthesis of
perlolyrin, flazin, eudistomin U and harmane
Srinath Santhanam1 | Abinaya Ramu1 | Baskar Baburaj1
Balasubramanian Kalpatu Kuppusamy2
|
1Laboratory of Sustainable Chemistry,
Abstract
Department of Chemistry, SRM Institute
of Science and Technology,
Kancheepuram, India
2Department of Biotechnology, Indian
Institute of Technology Madras, Chennai,
India
Application of our recently reported metal free reaction conditions to the total
synthesis of the four different and selective biologically interesting β-carboline
natural products is reported. Using this simple methodology, flazin, per-
lolyrine, eudistomin U and harmane containing heteroaryl and alkyl substitu-
ents at C1 position were synthesized in good yields.
Correspondence
Baskar Baburaj, Laboratory of Sustainable
Chemistry, Department of Chemistry,
SRM Institute of Science and Technology,
Kattankulatur 603 203, Kancheepuram
Dt., Tamilnadu, India.
Email: bbaskar10@gmail.com
Funding information
Indian National Science Academy; SRM
Institute of Science and Technology,
Grant/Award Number: CSIR-SRF09/1045
(0024)2K18 EMR-I; Department of Science
and Technology-SERB Young Scientist
Project, Government of India, Grant/
Award Number: SB/FT/CS-082/2014
1 | INTRODUCTION
Typical
approach
involves
decarboxylative/
dehydrogenative aromatization of tetrahydro-β-carbolines.
The decarboxylative aromatization of tetrahydro-β-carbolines
is accomplished by using reagents such as K2Cr2O7,[12]
SeO2,[13] KMnO4,[14] MnO2,[15] Pd/C,[16] Pb(OAc)4.[17]
The β-carboline unit is one of the versatile indole-based
heterocycles, and this basic ring skeleton is found in a
variety of alkaloids,[1] pharmaceuticals,[2] agrochemi-
cals[3] and functional materials.[4] Particularly, there are
nearly 64 identified β-carboline alkaloids distributed
across the eight plant families. Importantly, aromatic
β-carboline natural products (Figure 1) eudistomin U,
isoeudistomin, flazin, flazinamide, perlolyrine, harmane
and harmine exhibit a wide range of biological activities
such as antimalarial,[5] antiviral,[6] neuroprotection,[7]
anti-HIV,[8] anticancer,[9] etc. Therefore, there has
been considerable interest in the synthesis of
β-carbolines.[10] Aromatiszation of the tetradhydro-
β-carboline ring constitutes a key step in all these syn-
thetic approaches.[11]
However, most of these methods require harsh
conditions. Other reagents such as chloranil,[18] DDQ,[19]
trichloroisocyanuric acid,[20] PhI(OAc)2,[21] N-chloro-
succinimide[22] (NCS) and IBX[23] have also been
employed for the aromatization but these methods have
their own drawbacks such as stoichiometric by product
generation, use of expensive reagents, low yields or lack
of general application. We had recently reported a metal
free one pot synthesis of various β-carbolines involving a
domino Pictet-Spengler reaction and aromatization using
oxygen in N-methyl-2-pyrolidone (NMP) at 140ꢀC was
efficiently established.[24] Now we demonstrate the
J Heterocyclic Chem. 2020;1–7.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
SANTHANAM ET AL.
FIGURE 1 Examples of naturally
occurring biologically active β-carbolines
SCHEME 1 Syntheses of β-carboline alkaloid natural products: flazin and perlolyrine
application of this methodology for the synthesis of a few
biologically active β-carboline natural products. Hence,
we envisioned to employ our methodology for the synthe-
sis of few β-carboline natural products viz., flazin, per-
lolyrine, eudistomin U and harmane.
of alkaloids flazin (4a) and perlolyrine (4b) using our
novel aromatization reaction of tetrahydro-β-carbolines
by oxygen in NMP at 150ꢀC as depicted in Scheme 1. The
methodology involved the one pot Pictet-Spengler reac-
tion of tryptophan methyl ester (1a) and tryptophan (1b)
with 2-furaldehyde (2a) followed by aromatization in
presence of oxygen at 150ꢀC to give the β-carbolines 3a
and 3b in 73% and 79% yields, respectively. Next, hydro-
xymethylation of compounds 3a with HCHO in AcOH
and then hydrolysis of methyl ester afforded the flazin 4a
in 65% yields whereas hydroxymethylation of compounds
3b with HCHO in AcOH afforded perlolyrine 4b in 80%
by following the procedure reported in literature.[28a]
Thus, flazin 4a was synthesized from tryptophan methyl
ester in four steps in 47.5% overall yield and perlolyrine
4b was synthesized from tryptamine in three steps in 62%
overall yield (Figure S1).
2 | RESULTS AND DISCUSSION
2.1 | Synthesis of perlolyrine and flazin
We have successfully demonstrated the substrate scope of
our novel aromatization reaction of tetrahydro-
β-carbolines by oxygen in NMP at 150ꢀC by extending to
the total syntheses of alkaloids flazin (4a) and perlolyrine
(4b) as shown in Scheme 1. These alkaloids have been
obtained from several natural sources such as plants, bac-
teria, Japanese sake and soy sauce.[25] Flazin (4a), per-
lolyrine (4b) alkaloids are found to display strong
fluorescence.[26] Recent report on fazin (4a) shows anti-
HIV activity.[27] There are a few reports[28] on total syn-
theses of alkaloids flazin (4a) and perlolyrine (4b) but
most of them involve either expensive or toxic metal cata-
lyzed aromatization reactions. Flazin and Perlolyrine
were obtained in overall yields 63% and 58%,
respectively.[28a] Herein, we describe the total syntheses
2.2 | Synthesis of eudistomin U
Eudistomin U (Figure 1) exhibits DNA-binding and anti-
microbial activities[29] and syntheses have been reported
for eudistomin U.[30] All of them use metal catalysts,
toxic, expensive reagents or involve multiple steps and
the overall yield in most of these routes is moderate.

SANTHANAM ET AL.
3
SCHEME 2 Syntheses of alkaloid natural products: edistomin U
Initially, we attempted to synthesize eudistomin U
directly from the indole aldehyde 5a and tryptamine 1c
using our domino methodology (Scheme 2). When a mix-
ture of 1c with 5a was heated in NMP at 150ꢀC under
oxygen atmosphere, the reaction did not yield the desired
product probably due to the diminished reactivity of the
aldehyde which is a vinylogous amide (5a). Under these
conditions, N-methylindole-3-aldehyde 5b also failed to
undergo any reaction with 1c. The preformed imine, 8a
prepared by heating a mixture of 1c and 5a in toluene,[31]
also was unreactive when heated in NMP at 150ꢀC under
oxygen atmosphere evidently due to the absence of any
acid in the system. However, when a mixture of 1c with
5a was heated in presence of p-toluenesulphonic acid
(PTSA) in NMP at 150ꢀC under nitrogen atmosphere, it
gave rise to the tetrahydro-β-carboline (6a) in 85% yield
3-methoxycarbonyl tetrahydro-β-carboline derivative by
IBX followed by hydrolysis of the methyl ester and decar-
boxylation. This sequence involves not only many steps
but also harsh reagents or conditions and the overall
yield is rather low. Particularly, the yield in the final
decarboxylation is also low. Further aromatization by
IBX worked out only in the case of 3-methoxycarbolyl
tetrahydro-β-carboline but not in the case of simple
tetrahydro-β-carbolines.
2.3 | Synthesis of harmane
Another β-carboline alkaloid, harmane was found to dis-
play antitumor activities via different mechanisms such
as inserting into DNA or inhibiting Topoisomerase I and
II, cyclin-dependent kinases (CDK), PLK or MAO.[32]
Though many syntheses have been reported for harmane,
most of these methods involve decarboxylation followed
by aromatization.[33] In the present work, we have suc-
cessfully synthesized harmane (10a) by the Pictet Speng-
ler reaction[34] of the reaction of tryptamine (1c) with
acetaldehyde (5c) to provide the corresponding
tetrahydro-β-carboline (9a) in 85% yield which was sub-
jected to the aromatization in presence of oxygen at
150ꢀC in NMP to obtain harmane 10a in 76% (Scheme 3;
Figure S1).
1
(Scheme 2), which was characterized by the H and 13C
NMR spectroscopic techniques (Figure S1). To our
delight and as expected, when the same reaction was car-
ried out at 170ꢀC for 36 h in oxygen atmosphere, it
furnished eudistomin U 7a in 43% yield (Scheme 2). Fur-
thermore, when 6a was heated at 150ꢀC for 24 h in NMP,
it underwent the aromatization and afforded eudistomin
U 7a in 75% yield. A similar reaction with 5b furnished
the N-methyl eudistomin U 7b in 44% yield when heated
in NMP at 170ꢀC for 36 h as outlined in Scheme 2.
Reported literature[23] method for the synthesis of 7a by
Panarese et al involves the condensation of tryptophan
methyl ester with N-acetyl-indole-3-aldehyde in benzene
under reflux to form the imine, cyclisation of the imine
to the 3-methoxycarbonyl tetrahydro-β-carboline inter-
mediate using trifluoroacetic acid and chloroform mix-
ture in 2:1 ratio and aromatization of the
3 | CONCLUSION
We have demonstrated the application of our one pot
Pictet-Spenger reaction and novel methodology for

4
SANTHANAM ET AL.
SCHEME 3 Synthesis of
alkaloid natural product:
harmane
aromatization reaction of tetrahydro-β-carbolines by oxy-
gen in NMP at 150ꢀC to the total synthesis of β-carboline
derived indole alkaloids, flazin, perlolyrine, eudistomin
U and harmane. These alkaloids were obtained in good
yields in a straight forward way under metal free reaction
conditions.
achieved from 3a by following the procedure reported in
the literature.[28a]
1
Flazin 4a: H NMR (500 MHz, DMSO-d6) δ 8.78 (s,
1H), 8.34 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),
7.62 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 2.9 Hz, 1H), 7.33 (t,
J = 7.5 Hz, 1H), 6.61 (d, J = 3.1 Hz, 1H), 4.65 (s, 2H). 13C
NMR (125 MHz, DMSO-d6) δ 167.63, 157.14, 151.79,
141.75, 132.71, 132.00, 130.27, 129.43, 129.36, 122.29,
121.20, 121.13, 116.01, 113.30, 111.50, 110.05, 56.11.
HRMS (ESI) m/z calcd for C17H12N2O4Na [M + Na]+:
331.0695, found: 331.0697.
4 | EXPERIMENTAL
General: All reactions were carried out either under an
argon or oxygen atmosphere unless otherwise noted. All
chemicals used in the reactions such as tryptophan, trypt-
amine, aliphatic aldehyde and hetero aldehyde were pur-
chased from Aldrich and used without further
purification. CDCl3 and DMSO-d6 for NMR sample prep-
aration were purchased from Aldrich. Dry solvent, NMP,
used in synthesis with minimum purity of 99.9% was pur-
chased from Aldrich. Thin-layer chromatography (TLC)
was performed using 60 mesh silica gel plates visualized
with short-wavelength UV light (254 nm). Silica gel
60 (230-400 mesh) was used for flash column chromatog-
raphy. 1H NMR and 13C NMR spectra were recorded on a
4.2 | Synthesis of natural product
perlolyrine (4b)
In a 5 mL RB flask were added a mixture of
2-furaldehyde (2a) (23 μL, 0.22 mmol, 1.2 equiv.,), trypto-
phan (1b) (45 mg, 0.20 mmol, 1 equiv.) in NMP (1 mL)
and the resulting mixture was heated at 150ꢀC under oxy-
gen atmosphere for 24 h. After the reaction was com-
plete, the reaction mixture was concentrated under
reduced pressure using rotary evaporator. The crude
product thus obtained was purified by flash column chro-
matography on silica gel using mixture of hexane-ethyl
acetate (70:30) as eluent to obtain the product 3b in 79%
yield (37 mg, 0.158 mmol). (5-(9H-pyrido[3,4-b]indol-
1-yl)furan-2-yl)methanol (perlolyrine 4b) was achieved
from compound 3b by following the procedure reported
in the literature.[28a]
1
Bruker 500 instrument (500 MHz for H and 125 MHz
for 13C NMR). Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constants J are
reported in hertz.
1
4.1 | Synthesis of natural product
flazin (4a)
Perlolyrine 4b: H NMR (500 MHz, DMSO-d6) δ 8.33
(d, J = 5.1 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.05 (d,
J = 5.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.61-7.50 (m,
1H), 7.34-7.24 (m, 1H), 7.20 (d, J = 3.3 Hz, 1H), 6.59 (d,
J = 3.3 Hz, 1H), 4.65 (s, 2H).13C NMR (125 MHz, DMSO-
d6) δ 156.72, 152.63, 141.33, 138.47, 133.28, 130.70,
130.05, 129.05, 122.08, 120.85, 120.33, 114.23, 112.85,
110.15, 109.94, 56.16. HRMS (ESI) calcd for C16H13N2O2
[M + H]+: 265.0977, found: 265.0974.
Step 1: Synthesis of methyl 1-(furan-2-yl)-9H-pyrido
[3,4-b]indole-3-carboxylate (3a): In a 5 mL RB flask
were added a mixture of 2-furaldehyde (2a) (23 μL,
0.22 mmol, 1.2 equiv.,), tryptophan methyl ester (1a)
(44 mg, 0.20 mmol, 1 equiv.) in NMP (1 mL) and the
resulting mixture was heated at 150ꢀC under oxygen
atmosphere for 24 h. After the reaction was complete,
the reaction mixture was concentrated under reduced
pressure using rotary evaporator. The crude product
thus obtained was purified by flash column chromatog-
raphy on silica gel using mixture of hexane-ethyl acetate
(70:30) as eluent to obtain the product 3a in 73% yield
(43 mg, 0.144 mmol). 1-(5-(Hydroxymethyl)furan-2-yl)-
9H-pyrido[3,4-b]indole-3-carboxylic acid (flazin 4a) was
Synthesis of natural product, eudistomin U and its N-
methylated derivative (7a and 7b):
Step 1: In a 5 mL RB flask were added a mixture of
1H-indole-3-carbaldehyde (9a) (32 mg, 0.22 mmol, 1.2
equiv.,), tryptamine (1a, 32 mg, 0.20 mmol, 1 equiv.,) and
p-toluene sulphonic acid (3.44 mg, 0.02 mmol, 0.1 equiv.,)
in NMP (1 mL) and the resulting mixture was heated at
150ꢀC under argon atmosphere for 24 h. After the reaction

SANTHANAM ET AL.
5
was complete, the reaction mixture was concentrated
under reduced pressure using rotary evaporator. The crude
product thus obtained was purified by flash column chro-
matography on silica gel using mixture of DCM-Methanol
(95:5) as eluent to obtain the product 6a in 85% yield
(48.8 mg, 0.17 mmol).
4.3 | Synthesis of natural product,
harmane[22] (10a)
Step 1: In a 5 mL sealed tube were added a mixture of
acetaldehyde (5c) (110 μL, 2 mmol, 10 equiv.,), trypt-
amine (1c, 32 mg, 0.20 mmol, 1 equiv.,) and p-toluene
sulphonic acid (3.44 mg, 0.02 mmol, 0.1 equiv.,) in NMP
(1 mL) and the resulting mixture was heated at 140ꢀC
under argon atmosphere for 24 h. After the reaction was
complete, the reaction mixture was concentrated under
reduced pressure using rotary evaporator. The crude
product thus obtained was purified by flash column chro-
matography on silica gel using mixture of Hexane: Ethyl
acetate (70:30) as eluent to obtain the product 9a in 85%
yield (31.6 mg, 0.17 mmol).
Step 2: In a 5 mL RB flask was added compound 9a
(37.2 mg, 0.20 mmol) in NMP (1 mL) and the resulting
mixture was heated at 150ꢀC under oxygen atmosphere for
24 h. After the reaction was complete, the reaction mixture
was concentrated under reduced pressure using rotary
evaporator. The crude product thus obtained was purified
by flash column chromatography on silica gel using mix-
ture of hexane: Ethyl acetate (70:30) as eluent to obtain
the product 10a in 76% yield (30.6 mg, 0.168 mmol).
Compound 6a.[21] Yield: 85% yield (48 mg); 1H
NMR (500 MHz, DMSO-d6) δ 7.46 (d, J = 7.7 Hz, 1H),
7.40 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22
(d,
J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.07 (t,
J = 7.6 Hz, 1H), 7.04-6.95 (m, 2H), 6.88 (t, J = 7.5 Hz,
1H), 5.45 (s, 1H), 3.20 (dt, J = 11.8, 4.8 Hz, 1H), 2.98
(ddd, J = 12.3, 7.4, 4.9 Hz, 1H), 2.89-2.79 (m, 1H),
2.78-2.69 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ
136.8, 136.1, 136.0, 127.3, 126.6, 124.9, 121.6, 120.9,
119.7, 119.0, 118.7, 118.0, 115.7, 111.9, 111.5, 108.0,
49.8, 42.1, 22.37.
Step 2: In a 5 mL RB flask was added compound 6a
(57.4 mg, 0.20 mmol) in NMP (1 mL) and the resulting
mixture was heated at 150ꢀC under oxygen atmosphere
for 24 h. After the reaction was complete, the reaction
mixture was concentrated under reduced pressure using
rotary evaporator. The crude product thus obtained was
purified by flash column chromatography on silica gel
using mixture of DCM-Methanol (95:5) as eluent to
obtain the product 7a in 89% yield (50.4 mg,
0.178 mmol).
1
Harmane (10a). Yield: 84% yield (30 mg); H NMR
(400 MHz, DMSO-d6) δ: 11.64 (s, 1H), 8.24 (d,
J = 5.31 Hz, 1H), 8.17 (d, J = 7.9, 1H), 7.91 (d, J = 5.3 Hz,
1H), 7.63 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H),
2.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ; 142.6,
140.9, 138.0, 135.0, 128.3, 127.4, 122.1, 121.6, 119.6, 113.1,
112.4, 20.9.
1
Eudistomin U[22] (7a). Yield: 89% yield (50 mg); H
NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.32 (s,
1H), 8.54 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 5.2 Hz, 1H),
8.29 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.97 (d,
J = 5.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.54 (dd,
J = 14.3, 7.6 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.22 (t,
J = 7.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H).13C NMR
(125 MHz, DMSO-d6) δ 141.3, 140.8, 138.3, 137.0, 132.5,
128.7, 128.2, 126.6, 126.5, 122.7, 122.5, 121.9, 121.6,
120.3, 119.9, 112.9, 112.1. High-resolution mass spec-
trum (ESI) m/z 284.1182 [M + H]+; calcd for C19H14N3:
284.1188].
ACKNOWLEDGEMENTS
B. B. thanks Department of Science and Technology-
SERB Young Scientist Project, Government of India for
financial support (SB/FT/CS-082/2014) to carry out this
work. S. S. thanks SRM Institute of Science and Technol-
ogy for Junior Research Fellowship (JRF) (CSIR-
SRF09/1045(0024)2K18 EMR-I). K. K. B. thanks the
Indian National Science Academy for the INSA Senior
Scientist position.
Synthesis of N-methyl eudistomin U was achieved by
following the procedure of Edistomin U as mentioned
above and obtained in 72% yield.
N-methyl eudistomin U (7b). Yield: 75% yield
(44 mg); 1H NMR (500 MHz, DMSO−d6) δ: 11.31 (s, 1H),
8.59 (d, J = 7.8 Hz, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.30 (s,
1H), 8.26 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.72 (d,
J = 8.2 Hz, 1H), 7.57 (m, 2H), 7.29 (m, 2H), 7.27 (m, 1H),
3.98 (m, 3H);13C NMR (100 MHz, DMSO−d6) δ; 153.8,
141.2, 140.5, 138.8, 137.4, 132.6, 130.6, 128.7, 128.3, 127.1,
122.9, 122.6, 121.9121.8, 120.5, 119.9, 116.1, 112.0, 110.3,
33.4; HRMS (ESI): calcd. for C20H15N3 [M + H]+
298.1344; found 298.1340.
ORCID
Baskar Baburaj https://orcid.org/0000-0002-4463-1627
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How to cite this article: Santhanam S, Ramu A,
Baburaj B, Kalpatu Kuppusamy B. Application of
metal free aromatization to total synthesis of
perlolyrin, flazin, eudistomin U and harmane.
J Heterocyclic Chem. 2020;1–7. https://doi.org/10.
1002/jhet.3931
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