First total synthesis of the β-carboline alkaloids trigonostemine A, trigonostemine B and a new synthesis of pityriacitrin and hyrtiosulawesine

Article abstract of DOI:10.1016/j.tetlet.2019.04.044

The total synthesis of four natural products, trigonostemine A, trigonostemine B, pityriacitrin, and hyrtiosulawesine was accomplished. The key intermediates, variously substituted 1-formyl-β-carbolines, were prepared in five steps via a novel synthetic approach using readily available starting materials. These formyl derivatives were then further transformed, providing a general route for the synthesis of the four title alkaloids. The method reported herein represents the first total synthesis of the two trigonostemines and a new pathway to pityriacitrin and hyrtiosulawesine.

Full text of DOI:10.1016/j.tetlet.2019.04.044

Accepted Manuscript
First total synthesis of the β-carboline alkaloids Trigonostemine A, Trigonos-
temine B and a new synthesis of Pityriacitrin and Hyrtiosulawesine
Tímea Szabó, Viktor Hazai, Balázs Volk, Gyula Simig, Mátyás Milen
PII:
S0040-4039(19)30392-2
https://doi.org/10.1016/j.tetlet.2019.04.044
TETL 50759
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
1 March 2019
16 April 2019
25 April 2019
Please cite this article as: Szabó, T., Hazai, V., Volk, B., Simig, G., Milen, M., First total synthesis of the β-carboline
alkaloids Trigonostemine A, Trigonostemine B and a new synthesis of Pityriacitrin and Hyrtiosulawesine,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.044
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First total synthesis of the β-carboline alkaloids Trigonostemine A,
Trigonostemine B and a new synthesis of Pityriacitrin and
Hyrtiosulawesine
Tímea Szabó, Viktor Hazai, Balázs Volk, Gyula Simig, Mátyás Milen*
Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, 1475 Budapest,
P.O.B. 100, Hungary
GRAPHICAL ABSTRACT
ABSTRACT
The total synthesis of four natural products, trigonostemine A, trigonostemine B, pityriacitrin,
and hyrtiosulawesine was accomplished. The key intermediates, variously substituted 1-
formyl-β-carbolines, were prepared in five steps via a novel synthetic approach using readily
available starting materials. These formyl derivatives were then further transformed,
providing a general route for the synthesis of the four title alkaloids. The method reported
herein represents the first total synthesis of the two trigonostemines and a new pathway to
pityriacitrin and hyrtiosulawesine.
KEYWORDS
Alkaloids, Total synthesis, β-Carbolines, Indole
1

INTRODUCTION
The β-carboline (1, 9H-pyrido[3,4-b]indole, Fig. 1) scaffold can be found in many natural
products and synthetic compounds. Moreover, several representatives of this family show
varied biological activities.15
Figure 1. Structure of β-carboline (1) and alkaloids 2a6.
Kumujian C (1-formyl-9H-β-carboline, 2a), as a natural member of this alkaloid family has
been used as a building block for the synthesis of more complex compounds. Thanks to the
synthetic potential of aldehyde 2a and its derivatives, a number of syntheses have been
described (Scheme 1).58 Many syntheses start from tryptamine or its derivatives and build the
β-carboline scaffold via a Pictet-Spengler reaction, followed by aromatization of the C-ring
with a dehydrogenation catalyst or with an oxidizing agent, and construction of the aldehyde
functional group at the C1 position in diverse overall yields.918 Other synthetic methods are
based on more complex and less available starting materials such as harmane or β-carboline
(1).19 These methods usually use difficult-to-handle or toxic reagents (e.g. OsO4,20 SeO221 or
22
H2SO4/H2O2 ) and prepare this important building block with modest yields.
2

Scheme 1. Synthesis of 1-formyl-9H-β-carboline (2).
Pityriacitrin (3), trigonostemine A (4), trigonostemine B (5), and hyrtiosulawesine (6) are β-
carboline alkaloids possessing an indol-3-carbonyl moiety at position 1 (Fig. 1) and were
isolated from various sources.
Pityriacitrin (3) was first extracted from a marine bacterium of the genus Paracoccus in
1999;23 later the same compound was isolated from the human pathogenic yeast Malassezia
furfur.24 Recently, pityriacitrin (3) was discovered as a secondary metabolite from the marine
fungus Dichotomomyces cejpii F31-1.25 Hitherto, four total syntheses of pityriacitrin (3) have
been described in the literature (Scheme 2)2629 and the compound has also been tested for
various biological activities.2830
3

Scheme 2. Total syntheses of pityriacitrin (3) and hyrtiosulawesine (4).
Hyrtiosulawesine (4) was first isolated from an Indonesian specimen of the marine sponge
Hyrtios erectus.31 Ten years later, alkaloid 4 extracted from the Asian medicinal plant
Alocasia macrorrhiza showed antiproliferative activity against human nasopharyngeal
carcinoma epithelial.32 Recently, hyrtiosulawesine (4) has been isolated from two different
sources: a marine sponge Ircinia sp.33 and from the roots of Aristolochia cordigera34 which is
a member of the birthwort family. The antimalarial activity of hyrtiosulawesine (4) was
observed against chloroquine resistant29 and 3D734 strains of the protozoan parasite
Plasmodium falciparum. In addition, compound 4 exhibited antiphospholipase A235 and
antioxidant activities.29 The first total synthesis of hyrtiosulawesine (4) in eight steps was
reported by Zhang and co-workers in 2010.36 Four years later, Liew and co-workers described
a new 9-step synthetic strategy for the preparation of compound 4 (Scheme 2).29
4

Trigonostemine A (5) and trigonostemine B (6) were isolated from plants that are members of
the spurge family. In the literature they were originally extracted from the leaves of
Trigonostemon lii along with twelve other β-carboline alkaloids.37 Recently Wang and co-
workers isolated alkaloids 5 and 6 from the ethanolic extract of the twigs of Trigonostemon
filipes.38 For comparison, compounds 5 and 6 exhibited a higher cytotoxic activity against
various human cancer cell lines than the chemotherapy medication cisplatin.36,37 To the best
of our knowledge, the total synthesis of these promising alkaloids trigonostemine A (5) and
trigonostemine B (6) have not been described.
In this paper, we report the synthesis of various β-carboline alkaloids with a remarkable
pharmacological potential using a novel and efficient synthetic approach via well-known 1-
formyl-β-carboline building blocks (2). A new and convenient synthetic route for pityriacitrin
(3) and hyrtiosulawesine (4), as well as the first total synthesis of trigonostemine A (5) and B
(6) are described below.
RESULTS AND DISCUSSION
Initially, the appropriate 1-formyl-9H-β-carboline key intermediates (2ac) were prepared via
a novel and practical synthetic route (Scheme 3). Although a number of syntheses have been
described for the preparation of 1-formyl-9H-β-carboline (2a),59 many of them use toxic or
difficult-to-handle reagents and result in low yields,1822 while others could hardly be
reproduced in our experiments.1217 Therefore, we developed an improved and efficient
method for the construction of compounds 2ac. In the first step, the Pictet–Spengler reaction
of tryptamines 7ac and glyoxylic acid monohydrate in an ethyl acetate−water biphasic
system39 gave tetrahydro-β-carboline-carboxylic acids (8ac) in excellent yields under mild
conditions (24-hour stirring at room temperature). This was followed by the esterification of
compounds 8ac using a literature method (thionyl chloride, methanol).40 During the addition
of reagents, a low temperature (−25 °C) was used then the mixture was stirred for 24 hours at
room temperature to give methyl esters 9ac. Compounds 9ac were used in the next step
without further purification and characterization. Aromatization of the C-ring was carried out
using elemental sulfur in xylene isomers41 at reflux for 5 hours. The dehydrogenated
compounds 10ac were synthesised in good yields (71100%). Afterwards the ester group of
5

10ac was reduced to give alcohols 11ac using lithium chloride-activated sodium
borohydride42 in an ethanol/tetrahydrofuran solvent system at room temperature for 24 hours.
Finally, oxidation of the hydroxyl group in alcohols 11ac was achieved using MnO2 on
Celite® prepared by Attenburrow’s method43,44 in 1,4-dioxane at reflux, and aldehydes 2ac
were isolated in excellent yields after stirring for 2 hours. The overall yield of the building
blocks was 4681%. It should be noted that compounds 2ac were obtained 1020% lower
yield when commercially available activated MnO2 was used in the oxidation step.
Scheme 3. Synthesis of 1-formyl-9H-β-carbolines (2ac).
Next, the preparation of alkaloids 36 took place from the synthesised 1-formyl-9H-β-
carbolines (2ac, Scheme 4). First, the appropriate 1-formyl-9H-β-carbolines (2ac) were
coupled with indole (12a) or substituted indole derivatives 12b,c under basic conditions.
Although the conversion was not complete with 1 equivalent of indoles, the corresponding
products were selectively obtained and the formation of disubstituted products (containing 2
indole moieties)45,46 was avoided. The isolated secondary alcohols (13ad) were obtained in
moderate yields and then oxidized to ketones using activated MnO2 under the same conditions
described for the preparation of 1-formyl-9H-β-carbolines (2ac). This gave the desired
natural products (3, 5, 6) were isolated in excellent yields (9297%). An additional double O-
demethylation step was required to obtain hyrtiosulawesine (4). The reaction with 1-
dodecanethiol47 in N-methyl-2-pyrrolidone in the presence of NaOH at 130 °C for 2 hours did
6

not result in the product, and only the starting material was detected in the reaction mixture.
O-Demethylation with iodotrimethylsilane48 in acetonitrile at 82 °C for 48 hours led to only
trace amounts of 4, and partially demethylated products were detected as well. The attempted
demethylation of 14 with boron tribromide36 in dichloromethane at room temperature for 72
hours gave partially demethylated derivatives as the main products, along with a minor
amount of the target compound hyrtiosulawesine (5). Finally, the O-demethylation of 14 with
pyridine hydrochloride49 at 145 °C led to hyrtiosulawesine (4) selectively in good yield (71%)
after 36 hours.
Scheme 4. Synthesis of β-carboline alkaloids 3−6.
The overall yield of the synthesized alkaloids, calculated from tryptamines 7a−c, was 31% for
pityriacitrin (3), 33% for trigonostemine A (5), 48% for trigonostemine B (6) and 13% for
hyrtiosulawesine (4) through a 7- or 8-step synthetic route. The NMR data of the synthesised
alkaloids pityriacitrin (3, see ESI, Table S1) and hyrtiosulawesine (4, Table S2) are identical
with the literature data. Similarly, the spectral data of trigonostemine A (5, Table S3) and
trigonostemine B (6, Table S4) are the same as those described from natural sources.37,38
CONCLUSION
1-Formyl-9H-β-carboline intermediates (2) were synthesized in five steps starting from
tryptamines 7 using simple reactions, readily available materials and easy-to-handle reactants.
These were further transformed to four β-carboline alkaloids in 2 or 3 steps. While for
trigonostemines 5 and 6, this represents the first reported total synthesis, the methodology
7

could also be applied to the preparation of pytiriacitrin (3) and hyrtiosulawesine (4),
representing a fundamentally new synthetic approach towards these two alkaloids.
ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the Tetrahedron Letters website at
DOI:
AUTHOR INFORMATION
Corresponding author
*Tel.: +36 1 8035874. E-mail: milen.matyas@egis.hu
8

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Highlights
 First reported synthesis of trigonostemine A and trigonostemine B
 New synthesis of pityriacitrin and hyrtiosulawesine
 An improved preparation of 1-formyl-β-carboline building blocks
12