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

Reference: TETL 43501

To appear in: Tetrahedron Letters

Received Date: 20 June 2013

Revised Date: 19 August 2013

Accepted Date: 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.e lsevier .com

Efficient ―one-pot‖ methodology for the synthesis of novel tetrahydro-β-carboline,

tetrahydroisoquinoline and tetrahydrothienopyridine derivatives

Alexandra Ionescua, Damien Cornut

a, Sébastien Soriano

a, Céline Guissart

a, Pierre Van Antwerpen

b 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

———

Corresponding author. Tel.: + 32-2-650-3537; fax: + 32-2-650-2798; e-mail: ijabin@ulb.ac.be

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

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

tryptophane derivative followed by a two-step sequence and

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

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 a library of 32 compounds with potential

anti-tumoral activity.

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

ART ICLE INFO AB ST R ACT

Article history:

Received

Received in revised form

Accepted

Available online

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.

2013 Elsevier Ltd. All rights reserved.

Keywords:

Tetrahydro-β-carbolines

N-carbamyliminium

Pictet-Spengler

Tetrahydroisoquinoline

Tetrahydrothienopyridine

Tetrahedron Letters 2 reactive intermediate provided the desired THBC derivatives,

which were purified by flash chromatography (FC) (Scheme 2).

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

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.

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, R

2 and R

3 (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 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.

Finally, acylation of the THBC scaffold was performed in

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.

In conclusion, we have developed a simple, general and

efficient ―one-pot‖ methodology for the synthesis of tetracyclic

tetrahydro-β-carboline, tetrahydroisoquinoline and

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.

Acknowledgments

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

1. Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479-500.

2. Skouta, R.; Hayano, M.; Shimada, K.; Stockwell, B. R. Bioorg.

Med. Chem. Lett. 2012, 22, 5707-5713.

3. Kumar, R.; Gupta, L.; Pal, P.; Khan, S.; Singh, N.; Katiyar, S. B.;

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.

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.

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.

15. Carboni, B.; Vaultier, M.; Carrié, R. Tetrahedron 1987, 43, 1799-

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).