Synthesis of Phaitanthrin E and Tryptanthrin through Amination/
Takumi Abe* and Masaru Terasaki
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293,
Japan, e-mail: email@example.com
Phaitanthrin E was biomimetically synthesized from methyl indole-3-carboxylate and methyl anthranilate or
anthranilic acid using the ester group as an activating group. The reaction proceeds through NCS-mediated
dearomatization/TFA-catalyzed protonation of indolenine/C(2) amination/Et
N-promoted aromatization and cyclization
in one-pot procedure. This method is capable of converting simple biomass materials to phaitanthrin E. The synthesis
not only allows assessment of antiproliferative activity, but also affords experimental support for the hypothetical
biosynthetic pathway of phaitanthrin E. The resulting phaitanthrin E derivatives were evaluated for in vitro
antiproliferative activity against human colorectal cancer cells (DLD-1). The biogenetic intermediate of phaitanthrin E
showed higher antiproliferative activity than the natural product, phaitanthrin E. Furthermore, a concise synthesis of
tryptanthrin is also accomplished from indole-3-carbaldehyde and methyl anthranilate using the aldehyde group as
an activating group.
Keywords: biomimetic, synthesis, alkaloids, cascade reaction, indoles.
Alkaloids with an indolo[2,1-b]quinazoline have
attracted considerable interest because of their
intriguing tetracyclic core and wide range of promis-
ing biological activities.
[1 – 3]
Phaitanthrins A (1), B (2),
C(3), D (4), and E (5aa) were isolated from the Tai-
wanese orchid Phaius mishmensi by Wu and co-work-
ers (Figure 1,a).
In these alkaloids, biological activity
of 5aa has not been systematically evaluated because
only a limited amount of sample has been obtained
from the natural source (2.0 mg of 5aa was isolated
from 3.5 kg of dried P. mishmensis plants). In 2015,
Argade and co-workers reported the ﬁrst pioneering
synthesis of 5aa through unusual rearrangement of 4
This synthesis is a milestone and useful, but
the multi-step synthesis is not adequate for supply of
sample materials with various substituents for biologi-
Recently, aromatic hydrocarbons, methyl indole-3-
carboxylate (6a), methyl anthranilate (7a), and anthrani-
lic acid (8), were also isolated from P. mishmensis with
phaitanthrins (Figure 1,b).
These reports suggested
that naturally occurring 5aa is biogenetically derived
from methyl indole-3-carboxylate and anthranilic acid.
The biosynthesis of indoloquinazoline alkaloids,
tryptanthrin (10), phaitanthrin A (1), B (2), and C (3),
starting from tryptophan and anthranilic acid have
been proposed (Scheme 1,a).
In addition, the bio-
genetic pathway of phaitanthrin D (4) starting from
anthranilic acid (8), o-aminophenylacetic acid (9), and
glycolic acid was proposed by Argade and co-workers
However, the biosynthesis of 5aa
was not proposed to date among the phaitanthrins. On
the basis of earlier studies
and our previous work
on the synthesis of tryptanthrin from simple biomass
[11 – 13]
we next set out to synthesize phaitan-
thrin E (5aa) from simple biomass materials on the basis
of the hypothetical biosynthetic pathway. In this article,
we report the full details of our approach to phaitan-
thrin E (5aa), as well as the biogenetic precursor of nat-
urally occurring phaitanthrin E (5aa)(Scheme 1,c).
Furthermore, the synthesized phaitanthrin E derivatives
were evaluated for antiproliferative effects against
human colorectal cancer cells (DLD-1), and were found
to have promising anticancer properties competitive
with the natural phaitanthrin E.
Results and Discussion
Synthesis of Phaitanthrin E Derivatives via Acid-
Catalyzed Amination/Cyclization Cascade
Anthranilate, renewable resource and simple bio-
mass, is frequently used as biomimetic synthesis
(1 of 14) e1700284
DOI: 10.1002/hlca.201700284 Helv. Chim. Acta 2018, 101, e1700284 © 2018 Wiley-VHCA AG, Zurich, Switzerland