Malaysian Journal of Analytical Sciences, Vol 27 No 6 (2023): 1183 - 1191

 

SYNTHESIS OF 4-ARYL SUBSTITUTED CANTHIN-6-ONE WITH

β-CARBOLINE SKELETON VIA PICTET-SPENGLER CONDENSATION AND CYCLIZATION REACTION

 

(Sintesis 4-Aril Gantian Kantin-6-One dengan Rangka β-Karbolina Melalui Kondensasi Pictet-Spengler dan Tindak Balas Kitaran)

 

Noor Hidayah Pungot1,2*, Noor Hamizah Mohammad Tarmizi1,2 and Siti Zafirah Zulkifli1,2

 

 1School of Chemistry and Environment, Faculty of Applied Sciences, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor, Malaysia

2 Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA, UiTM Puncak Alam Campus,

 42300 Bandar Puncak Alam, Selangor, Malaysia

 

*Corresponding author: noorhidayah977@uitm.edu.my

 

 

Received: 17 September 2023; Accepted: 29 October 2023; Published:  29 December 2023

 

 

Abstract

This study presents a comprehensive synthesis of 4-aryl substituted canthin-6-one through a versatile Pictet-Spengler condensation and subsequent cyclization, involving the formation of 1-aroyl substituted β-carbolines as pivotal intermediates. β-Carbolines, as indole alkaloids, serve as fundamental building blocks with diverse biological activities. In particular, canthin-6-one and its derivatives exhibit a wide range of promising biological properties, which include anti-cancer, antibacterial, anti-inflammatory, and cytotoxic effects, thus making them valuable in pharmaceutical and medicinal chemistry applications. The method outlined herein involves the utilization of readily available starting materials in a direct reaction sequence, resulting in an efficient and moderate-yield access to 4-aryl substituted canthin-6-one. Synthesizing canthine was initiated by forming the intermediates, 1-aroyl substituted β-carbolines via Pictet-Spengler condensation of different substituted aromatic glyoxals with 5-hydroxy tryptophan in the presence of trifluoroacetic acid. This synthesis route avoids the formation of tetrahydro-β-carbolines. Subsequently, the series of 1-aroyl substituted β-carboline intermediates were cyclized to yield the desired 4-aryl substituted canthin-6-one derivatives. The reaction mechanism and key intermediates are discussed, providing insights into the synthesis pathway. The structure of the synthesized compounds were confirmed by using Infrared Radiation (IR) and Nuclear Magnetic Resonance (NMR) spectroscopy. This research not only contributes to the understanding of synthetic methodologies but also paves the way for the development of novel compounds with promising pharmaceutical properties.

 

Keywords: β-carboline, Pictet-Spengler condensation, cyclization, canthin-6-one

 

Abstrak

Kajian ini membentangkan sintesis komprehensif 4-aril digantikan kantin-6-satu melalui pemeluwapan Pictet-Spengler serba boleh dan kitaran seterusnya, melibatkan pembentukan 1-aroil digantikan β-karbolin sebagai perantaraan penting. β-karbolina, sebagai alkaloid indole, berfungsi sebagai blok binaan asas dengan pelbagai aktiviti biologi. Khususnya, kantin-6-satu dan derivatifnya mempamerkan pelbagai sifat biologi yang menjanjikan, termasuk kesan anti-kanser, antibakteria, anti-radang dan sitotoksik, dengan itu menjadikannya berharga dalam aplikasi kimia farmaseutikal dan perubatan. Kaedah yang digariskan di sini melibatkan penggunaan bahan permulaan yang sedia ada dalam urutan tindak balas langsung, menghasilkan akses hasil yang cekap dan sederhana kepada 4-aril digantikan kantin-6-satu. Mensintesis kantin telah dimulakan dengan membentuk perantaraan, β-karbolina yang digantikan 1-aroil melalui kondensasi Pictet-Spengler bagi glioksal aromatik tersubstitusi berbeza dengan triptofan 5-hidroksi dengan kehadiran asid trifluoroasettik. Laluan sintesis ini mengelakkan pembentukan tetrahidro-β-karbolina. Selepas itu, siri perantaraan β-karbolina yang digantikan 1-aroil telah dikitar untuk menghasilkan derivatif 4-aril digantikan kantin-6-satu yang dikehendaki. Mekanisme tindak balas dan perantaraan utama dibincangkan, memberikan pandangan tentang laluan sintesis. Struktur sebatian yang disintesis telah disahkan dengan menggunakan spektroskopi sinaran inframerah (IR) dan resonans magnetik nuklear (NMR). Penyelidikan ini bukan sahaja menyumbang kepada pemahaman metodologi sintetik tetapi juga membuka jalan untuk pembangunan sebatian baru dengan sifat farmaseutikal yang menjanjikan.

 

Kata kunci: β-karbolina, kondensasi Picter-Spengler, kitaran, kantin-6-satu

 

References

1.       Banoth, K. K., Faheem, ChandraSekhar, K. V. G., Adinarayana, N. and Murugesan, S. (2020). Recent evolution on synthesis strategies and anti-leishmanial activity of β-carboline derivatives – An update. Heliyon, 6(9): e04916.

2.       Ash’ari, N. A. N., Pungot, N. H., Shaameri, Z. and Jani, N. A. (2021). A facile synthesis of n-alkylated daibucarboline A derivative via pictet-spengler condensation of tryptamine. Malaysian Journal of Analytical Sciences, 25(5): 706-715.

3.       Kukula-Koch, W. A., and Widelski, J. (2017). Alkaloids. Pharmacognosy: Fundamentals, Applications and Strategy. Academic Press: pp. 163-198.

4.       Riggs, R. L., and Smith, D. M. (2008). Three heterocyclic rings fused (5-6-6). Comprehensive Heterocyclic Chemistry III. Elsevier: pp. 857-973.

5.       Manasa, L. K., Yadav, S. S., Nagesh, N. and Alvalaa, M. (2020). Recent insights into β-carboline alkaloids with anticancer potential. Modern Approaches in Drug Designing, 3(1): 1-24.

6.       Dighe, S. U., Samanta, S. K., Kolle, S. and Batra, S. (2017). Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles. Tetrahedron, 73(17): 2455-2467.

7.       Kuo, P. C., Li, Y. C., Hwang, T. L., Ma, G. H., Yang, M. L., Lee, E. J., and Wu, T. S. (2014). Synthesis and structural characterization of an anti-inflammatory principle purified from Lindera aggregata. Tetrahedron Letters, 55(1): 108-110.

8.       Calcaterra, A., Mangiardi, L., Delle Monache, G., Quaglio, D., Balducci, S., Berardozzi, S., ... and Ghirga, F. (2020). The Pictet-Spengler reaction updates its habits. Molecules, 25(2): 414.

9.       Samala, A. (2016). Therapeutic journey of synthetic β-carboline derivatives: A short review. International Journal of Pharmacy and Analytical Research, 5(1): 161-168.

10.    Shamsujunaidi. R., Saaidin. A. S., Abdul Aziz. M. H., Mohammat. M. F. and Pungot, N. H. (2023). Studies on the synthesis of β-carboline and its derivatives as potential antimalarial drug components. Malaysian Journal of Analytical Sciences, 27(1): 44-53.

11.    Yang, M. L., Kuo, P. C., Damu, A. G., Chang, R. J., Chiou, W. F. and Wu, T. S. (2006). A versatile route to the synthesis of 1-substituted β-carbolines by a single step Pictet-Spengler cyclization. Tetrahedron, 62(47): 10900-10906.

12.    Duggineni, S., Sawant, D., Saha, B. and Kundu, B. (2006). Application of modified Pictet–Spengler reaction for the synthesis of thiazolo-and pyrazolo-quinolines. Tetrahedron, 62(14): 3228-3241.

13.    Durham, S. D., Sierra, B., Gomez, M. J., Tran, J. K., Anderson, M. O., Whittington-Davis, N. A. and Eagon, S. (2017). Synthesis of β-carbolines via a silver-mediated oxidation of tetrahydro-β-carbolines. Tetrahedron Letters, 58(28): 2747-2750.

14.    Maresh, J. J., Giddings, L. A., Friedrich, A., Loris, E. A., Panjikar, S., Trout, B. L., ... and O'Connor, S. E. (2008). Strictosidine synthase: Mechanism of a Pictet-Spengler catalyzing enzyme. Journal of the American Chemical Society, 130(2): 710-723.

15.    Dighe, S. U., Samanta, S. K., Kolle, S. and Batra, S. (2017). Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles. Tetrahedron, 73(17): 2455-2467.