Efficient 'one-pot' methodology for the synthesis of novel tetrahydro-β-carboline, tetrahydroisoquinoline and tetrahydrothienopyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.08.135

A simple and efficient 'one-pot' methodology was developed to generate a new series of tetrahydro-β-carboline (THBC), tetrahydroisoquinoline (THIQ) and tetrahydrothienopyridine (THTP) derivatives. The key step of the methodology is based on a Pictet-Spengler type cyclization of a reactive N-carbamyliminium ion. This methodology was applied to the synthesis of a library of 32 compounds with potential anti-tumoral activity.

Full text of DOI:10.1016/j.tetlet.2013.08.135

Accepted Manuscript
Efficient “one-pot” methodology for the synthesis of novel tetrahydro-β-carbo‐
line, tetrahydroisoquinoline and tetrahydrothienopyridine derivatives
Alexandra Ionescu, Damien Cornut, Sébastien Soriano, Céline Guissart, Pierre
Van Antwerpen, Ivan Jabin
PII:
S0040-4039(13)01536-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.135
TETL 43501
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 June 2013
19 August 2013
28 August 2013
Please cite this article as: Ionescu, A., Cornut, D., Soriano, S., Guissart, C., Van Antwerpen, P., Jabin, I., Efficient
“one-pot” methodology for the synthesis of novel tetrahydro-β-carboline, tetrahydroisoquinoline and
tetrahydrothienopyridine derivatives, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.08.135
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Graphical Abstract
Efficient “one-pot” methodology for the
synthesis of novel tetrahydro-β-carboline,
tetrahydroisoquinoline and
tetrahydrothienopyridine derivatives
Alexandra Ionescu, Damien Cornut, Sébastien Soriano, Céline Guissart, Pierre Van Antwerpen and Ivan Jabin*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Efficient ―one-pot‖ methodology for the synthesis of novel tetrahydro-β-carboline,
tetrahydroisoquinoline and tetrahydrothienopyridine derivatives
Alexandra Ionescua, Damien Cornut a, Sébastien Sorianoa, Céline Guissarta, Pierre Van Antwerpenb and
Ivan Jabin a,
a Laboratoire de Chimie Organique, Faculté des Sciences, Université Libre de Bruxelles (ULB), avenue F. D. Roosevelt, 50 CP160/06, B-1050 Brussels, Belgium
bPlate-Forme Analytique, Faculté de Pharmacie, ULB, boulevard du Triomphe, CP205/01, 1050 Brussels, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient ―one-pot‖ methodology was developed to generate a new series of
tetrahydro-β-carboline (THBC), tetrahydroisoquinoline (THIQ) and tetrahydrothienopyridine
(THTP) derivatives. The key step of the methodology is based on a Pictet-Spengler type
cyclization of a reactive N-carbamyliminium ion. This methodology was applied to the synthesis
of a library of 32 compounds with potential anti-tumoral activity.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydro-β-carbolines
N-carbamyliminium
Pictet-Spengler
Tetrahydroisoquinoline
Tetrahydrothienopyridine
Sub-families of natural or synthetic alkaloids with a partly
reduced β-carboline moiety are known to possess interesting
pharmacological properties.1 Among these alkaloids, several
tetrahydro-β-carbolines (THBCs) with anticancer activity have
been reported.2,3,4 Some of them display a tetracyclic core with an
additional fused heterocyclic ring, including for example
eudistomine K5 and azatoxin.6
cleavage from the resin led to THBC derivatives with a fused
imidazolidin-2-one ring. In this case, the additional ring is
formed in position 1,6 of the pyrimidine moiety.13
All in all, only a few examples of THBC derivatives with a
fused imidazolidin-2-one or tetrahydropyrimidin-2-one ring have
been reported in the literature and only solid phase or multi-step
processes have been described. The current study aims at
The synthesis of such tetracyclic THBC derivatives with a
fused imidazolone or tetrahydropyrimidin-2-one ring was
recently developed by the group of Meldal through an
intramolecular N-carbamyliminium Pictet-Spengler reaction,
using an elegant multistep solid phase methodology.7,8 However,
due to the cleavage from the resin, this methodology is limited to
the formation of compounds possessing an amino acid residue on
the main scaffold. A second inconvenience of this method is the
multi-step synthesis of the precursors.9 A multi-step method
based on the Pictet-Spengler condensation of α-Cbz protected α-
aminoaldehydes with tryptophane was also described.10 In this
case, the fused imidazolidin-2-one ring was elaborated through
removal of the Cbz group and reaction of the amino group with
1,1‘-carbonyldiimidazole. Another way to synthesize similar
tetracyclic derivatives is by reaction of 1,3-isothiocyanocarbonyl
compounds with β-arylethylamines11 or by heating α,β-
unsaturated carbonyl compounds with ureas12 but these methods
only give access to THBC scaffolds with a fused six-member
tetrahydropyrimidin-2-one or tetrahydropyrimidin-2-thione ring.
Finally, a solid-phase Pictet-Spengler reaction of a resin-bound
describing
a
general and efficient ―one-pot‖ synthetic
methodology that leads to the THBC, tetrahydroisoquinoline
(THIQ) or tetrahydrothienopyridine (THTP) skeleton in good
yields. The usefulness of this methodology was illustrated by the
synthesis of
anti-tumoral activity.
a library of 32 compounds with potential
A general one-pot methodology for the synthesis of THBC
THIQ or THTP derivatives. Our approach for the synthesis of
THBC, THIQ or THTP derivatives relies on a one-pot multi-step
reaction sequence that involves a Pictet-Spengler type cyclization
of an N-carbamyliminium ion as a key step (Scheme 1).
In the case of the THBC derivatives, isocyanates 2a-b were
first generated in situ from the known azides 1a14 and 1b15
through a domino Staudinger/aza-Wittig reaction.16 A subsequent
addition of a tryptamine derivative to the reaction mixture led to
the corresponding ureido derivatives. Acidic treatment of the
mixture produced the intermediate N-carbamyliminium ion
through an intramolecular cyclization and the elimination of
ethylene glycol. Pictet-Spengler cyclization of this highly
tryptophane derivative followed by a two-step sequence and
———
 Corresponding author. Tel.: + 32-2-650-3537; fax: + 32-2-650-2798; e-mail: ijabin@ulb.ac.be

2
Tetrahedron Letters
reactive intermediate provided the desired THBC derivatives,
imidazolone through its deprotonation at the α-position (Scheme
1). This process is reversible under acidic conditions, the
irreversible Pictet-Spengler type cyclization displacing the
equilibrium toward the formation of the cyclized products. Thus,
the conversion of these intermediates into the cyclization
products 6a-c and 8 was possible, but stronger acidic conditions
were required (i.e. pure TFA) to reduce the reaction time.
which were purified by flash chromatography (FC) (Scheme 2).
Synthesis of a small library of THBC derivatives. Among
promising kinase inhibitors appears harmine which belongs to the
large chemical family of alkaloids displaying a β-carboline
skeleton.18 Because it was reported that N-acylation and N-
benzylation of harmine provides compounds with growth
inhibitory activity and reduced neurotoxicity,19 the synthesis of a
library of THBCs bearing various alkyl and acyl groups on the
indolic and urea nitrogen atoms was achieved.
First, diversity was introduced on the THBC scaffold by
modifying the substituents R1, R2 and R3 (Scheme 3). Phenolic
compound 4h was obtained by the demethylation of compound
4b in the presence of BBr3. LiOH/THF hydrolysis of methyl ester
(+)-4d afforded acid (+)-4f which was further coupled with
benzylamine to yield amide (+)-4g.
The general N-alkylation method used in our study consisted
in the deprotonation with NaH of the indole and the urea
nitrogens, followed by reaction with at least 2 equiv. of an
alkylating agent. Hence, dialkylated products 9d-l and 9o-p were
readily obtained from either 4a-c or 4e (yields range from 36 %
to 86 %).
It is noteworthy to mention that the enantiomeric resolution of
compound 9f was performed by semi-preparative chiral HPLC in
order to test the biological activity of both enantiomers (see
Supplementary Information for details).
In the case of the reaction of (+)-4d with benzyl bromide,
besides the benzyl ester (+)-9m, a small amount of benzylated
methyl ester (+)-9n was also obtained. It was possible to purify
(+)-9m by FC, (+)-9n being accessible by the trans-esterification
of (+)-9m in MeOH. In addition, when 4a was alkylated with
only 1.5 equiv of CH3I, a mixture of mono- and dialkylated
products 9a and 9c was obtained. These two compounds were
separated by FC, and a subsequent alkylation of 9a with 1 equiv.
of benzyl bromide yielded the unsymmetrically dialkylated
product 9b.
Scheme 1. General strategy for the one-pot synthesis of the THBC,
THIQ, THTP and imidazolone derivatives. i) PPh3, CO2, THF, rt; ii)
THF, rt; iii) in situ addition of aq. HCl (2.8 M), 55 °C; iv)
evaporation of the solvent and aq. HCl (2.8 M)/MeOH or
TFA/MeOH or TFA, 55 °C.
This straightforward and efficient methodology can be
achieved in a one-pot process from compounds 1a-b, or the
ureido intermediate can be isolated by FC and subjected to the
cyclization step under acidic conditions in a second time. High
overall yields (61 – 92 %) were obtained for the pure THBC
derivatives 4a-e from amines 3a-d (Scheme 2).
When enantiopure tryptophan derivative (S)-3d or (R)-3d was
employed, the reaction proceeded with a high diastereoselectivity
(ca. 9:1), and the major diastereomer was obtained pure after FC.
It is noteworthy to mention that the protons of the
imidazolidinone ring of this major diastereomer display similar
chemical shifts and coupling constants than the corresponding
protons of a known and related Pictet–Spengler product.7 These
NMR data thus suggest that the protons of the two asymmetric
centres display
a trans relationship (see Supplementary
Information for details).
The methodology was also successfully extended to activated
phenyl ethylamines 5a-c and thiophenethylamine 7, resulting in
the formation of THIQs 6a,17 6b-c and THTP 8 in moderate to
good overall yields (37 – 60 %) (Scheme 2). In the case of
compounds 5a, 5b and 7, NMR monitoring of the acidic
cyclization reaction [i.e. aq. HCl (2.8 M)/MeOH or TFA/MeOH]
clearly showed the formation of an imidazolone as the main
product. It is noteworthy to mention that, as previously reported,8
the intermediate iminium ion can also lead to the formation of an
Scheme 2. Synthesis of THBC, THIQ and THTP derivatives. Reagents: i) 2a or 2b, THF, rt; ii) evaporation of THF then addition to the crude
ureido intermediate of either HCl (2.8 M)/MeOH for compounds 3a-c, 5a, or 25 % TFA/MeOH for 3d, or TFA for compounds 5b-c, 7; 55 °C.

3
Scheme 3. Modification of the THBC scaffold. Reagents: i) BBr3, CH2Cl2, 0 °C to rt; ii) LiOH, THF, rt; iii) BnNH2, TBTU, DIPEA,
CHCl3/DMF, rt; iv) DMF/THF, NaH, R4Br or R5Br, rt; v) CH3COCl, TEA, 4-DMAP, THF, rt; vi) NaH, PhCH2Br, DMF, rt; vii) PTSA, MeOH,
reflux; viii) TFA, CH2Cl2, rt; ix) NaH, PhCH2Br, DMF/THF (1:4), rt, then H2O.
3. Kumar, R.; Gupta, L.; Pal, P.; Khan, S.; Singh, N.; Katiyar, S. B.;
Finally, acylation of the THBC scaffold was performed in
Meena, S.; Sarkar, J.; Sinha, S.; Kanaujiya, J. K.; Lochab, S.;
Trivedi, A. K.; Chauhan, P. M. S. Eur. J. Med. Chem. 2010, 45,
2265-2276.
anhydrous THF with acetyl chloride (4.5 equiv.)/triethylamine in
the presence of catalytic amounts of 4-DMAP. Interestingly,
under these reaction conditions, only the nitrogen atom of the
urea group is acylated, leading to compound 9r. A subsequent
alkylation of the indole ring with benzylbromide followed by the
hydrolysis of the acyl moiety led to the monobenzylated product
9s. Since this compound could be further alkylated on the urea
nitogen, the selective acylation provides a convenient way for the
orthogonal introduction of substituents on the nitrogen atoms and
thus opens new paths for modulating the pharmacological
properties of the tetracyclic THBC derivatives.
4. Shen, L.; Park, E.-J.; Kondratyuk, T. P.; Guendisch, D.; Marler,
L.; Pezzuto, J. M.; Wright, A. D.; Sun, D. Bioorg. Med. Chem.
2011, 19, 6182-6195.
5. Lake, R.; Blunt, J.; Munro, M. Aust. J. Chem. 1989, 42, 1201-
1206.
6. Leteurtre, F.; Madalengoitia, J.; Orr, A.; Cuzi, T. J.; Lehnert, E.;
Macdonald, T.; Pommier, Y. Cancer Res. 1992, 52, 4478-4483.
7. Diness, F.; Beyer, J.; Meldal, M. Chem. Eur. J. 2006, 12, 8056-
8066.
8. Diness, F.; Meldal, M. Chem. Eur. J. 2009, 15, 7044-7047.
9. Diness, F.; Beyer, J.; Meldal, M. QSAR Comb. Sci. 2004, 23, 130-
144.
In conclusion, we have developed a simple, general and
efficient ―one-pot‖ methodology for the synthesis of tetracyclic
10. Pulka, K.; Feytens, D.; Misicka, A.; Tourwé, D. Mol. Divers.
2010, 14, 97-108.
11. Fisyuk, A. S.; Mukanov, A. Y.; Poendaev, N.V. Mol. Divers.
2010, 14, 455-462.
12. Fisyuk, A. S.; Mukanov, A.Y.; Novikova, E.Y. Mendeleev
Commun. 2003, 13, 278-279.
13. Klein, G.; Ostresh, J. M.; Nefzi, A. Tetrahedron Lett. 2003, 44,
2211-2215.
14. Wu, J.-P.; Emeigh, J.; Gao, D. A.; Goldberg, D. R.; Kuzmich, D.;
Miao, C.; Potocki, I.; Qian, K. C.; Sorcek, R. J.; Jeanfavre, D. D.;
Kishimoto, K.; Mainolfi, E. A.; Nabozny, G.; Peng, C.; Reilly, P.;
Rothlein, R.; Sellati, R. H.; Woska, J. R.; Chen, S.; Gunn, J. A.;
O‘Brien, D.; Norris, S. H.; Kelly, T. A. J. Med. Chem. 2004, 47,
5356-5366.
tetrahydro-β-carboline,
tetrahydrothienopyridine derivatives via a Pictet-Spengler type
intramolecular cyclization of an N-carbamyliminium
intermediate. Further functionalization at the nitrogen atoms was
also used to increase molecular diversity allowing preparation of
a library of 32 novel compounds in good yields and high
purities.20 The biological activity of these compounds against
several cancer cell lines will be reported elsewhere.
tetrahydroisoquinoline
and
Acknowledgments
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1810.
16. Kovács, J.; Pintér, I.; Messmer, A.; Tóth, G. Carbohyd. Res.
1985, 141, 57-65.
17. Liao, Z. K.; Kohn, H. J. Org. Chem. 1984, 49, 4745-4752.
18. Ionescu, A.; Dufrasne, F.; Gelbcke, M.; Jabin, I.; Kiss, R.;
Lamoral-Theys, D. Mini Rev. Med. Chem. 2012, 12, 1315-1329.
19. Cao, R.; Chen, Q.; Hou, X.; Chen, H.; Guan, H.; Ma, Y.; Peng,
W.; Xu, A. Bioorg. Med. Chem. 2004, 12, 4613-4623.
20. The purity of each compound was evaluated by NMR
spectroscopy and RP HPLC analysis and was estimated to be
satisfactory for biological testing (see Supplementary Information
for details).
A. I. is a Ph.D. student who received a grant from the Fonds
pour la formation à la Recherche dans l’Industrie et dans
l’Agriculture (FRIA-FRS, Belgium). The Analytical Platform of
the Faculty of Pharmacy is supported by grants from the ‗Fonds
National de la Recherche Scientifique’ (FNRS-FRS, Belgium).
Supplementary data
Supplementary data associated with this article can be found
in the online version.
References and notes
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2. Skouta, R.; Hayano, M.; Shimada, K.; Stockwell, B. R. Bioorg.
Med. Chem. Lett. 2012, 22, 5707-5713.