Efficient Synthesis of Novel 1-Substituted β- Carboline Derivatives via Pictet-Spengler Cyclization of 5-Hydroxy-L-Tryptophan


  • Nur Ain Nabilah Ashari Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA Puncak Alam, 43200 Bandar Puncak Alam, Selangor, Malaysia
  • Noor Hidayah Pungot Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA Puncak Alam, 43200 Bandar Puncak Alam, Selangor, Malaysia
  • Nor Akmalazura Jani Faculty of Applied Sciences, Universiti Teknologi MARA, 72000 Kuala Pilah, Negeri Sembilan, Malaysia
  • Zurina Shaameri Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA Puncak Alam, 43200 Bandar Puncak Alam, Selangor, Malaysia




Pictet-Spengler condensation, Wolff-Kishner reaction, β-carbolines, 5-hydroxy-L-tryptophan


A facile synthesis of novel 1-substituted β-carboline derivatives by using three efficient reaction steps was described. The synthetic route began with the construction of β-carboline frameworks involving the coupling of 5-hydroxy-L-tryptophan with different substituted phenylglyoxal via Pictet-Spengler condensation. Subsequent reduction of carbonyl functionality on carbon-7’ by using Wolff-Kishner reaction followed by N-alkylation afforded a practical access to a series of 1-substituted β-carboline derivatives in moderate yields. These novel derivatives were successfully synthesized without the use of expensive metal catalyst, prolonged reaction hours or critical reaction conditions. The molecular structures of all synthesized derivatives were confirmed by infrared (IR), gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy.


J. A. Lima and L. Hamerski, “Alkaloids as potential multi-target drugs to treat Alzheimer's disease,” Natural Products Chemistry, vol. 61, pp. 301-334, 2019.

N. Arshad, K. Zitterl‐Eglseer, S. Hasnain and M. Hess, “Effect of Peganum harmala or its β‐carboline alkaloids on certain antibiotic resistant strains of bacteria and protozoa from poultry,” Phytotherapy Research, vol. 22, no. 11, pp. 1533-1538, 2008.

H. R. Monsef, A. Ghobadi, M. Iranshahi and M. Abdollahi, “Antinociceptive effects of Peganum harmala L. alkaloid extract on mouse formalin test,” J. Pharm. Pharm. Sci, vol. 7, pp. 65–69, 2004.

A. M. Sobhani, S. A. Ebrahimi and M. Mahmoudian, “An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids,” J Pharm Pharm Sci, vol. 5, pp. 19–23, 2002.

A. Astulla, K. Zaima, Y. Matsuno et al., “Alkaloids from the seeds of Peganum harmala showing antiplasmodial and vasorelaxant activities,” J. Nat. Med., vol. 62, pp. 470–472, 2008.

H. Berrougui, M. Isabelle, M. Cloutier, M. Hmamouchi and A. Khalil, “Protective effects of Peganum harmala L. extract, harmine and harmaline against human low-density lipoprotein oxidation,” J. Pharm. Pharmacol., vol. 58, pp. 967–974, 2006.

A. Shahverdi, S. Ostad, S. Khodaee et al., “Antimicrobial and cytotoxicity potential of Peganum harmala smoke,” Pharmacognosy Magazine, vol. 4, no. 15, pp. 236, 2008.

R. Cao, W. Peng, Z. Wang, and A. Xu, “β-Carboline alkaloids: biochemical and pharmacological functions,” Current medicinal chemistry, vol. 14, no. 4, pp. 479-500, 2007.

S. L. Wong, H. S. Chang, G. J. Wang et al., “Secondary metabolites from the roots of Neolitsea daibuensis and their anti-inflammatory activity,” Journal of natural products, vol. 74, no. 12, pp. 2489-2496, 2011.

N. A. Jani, H. M Sirat, F. Ahmad, S. A. Abed and N. I. Aminudin, “Chemical constituents of the stems of Neolitsea kedahensis gamble,” Phytochemistry Letters, vol. 26, pp. 12-15, 2018.

E. D. Cox and J. M. Cook, “The Pictet-Spengler condensation: a new direction for an old reaction,” Chemical Reviews, vol. 95, no. 6, pp. 1797-1842, 1995.

P. C. Kuo, Y. C. Li, T. L. Hwang et al., “Synthesis and structural characterization of an anti-inflammatory principle purified from Lindera aggregate,” Tetrahedron Letters, vol. 55, no. 1, pp. 108-110, 2014.

A. Calcaterra, L. Mangiardi, G. Delle Monache et al., “The pictet-spengler reaction updates its habits,” Molecules, vol. 25, no. 2, pp. 414, 2020.

A. Samala, “Therapeutic journey of synthetic β-carboline derivatives: A short review,” International Journal of Pharmacy and Analytical Research, vol. 5, no. 1, pp. 161-168, 2016.

H. Jin, P. Zhang, K. Bijian, “Total synthesis and biological activity of marine alkaloid Eudistomins Y1–Y7 and their analogues,” Marine drugs, vol. 11, no. 5, pp. 1427-1439, 2013.

S. D. Durham, B. Sierra, M. J. Gomez et al., “Synthesis of β-carbolines via a silver-mediated oxidation of tetrahydro-β-carbolines,” Tetrahedron Letters, vol. 58 no. 28, pp. 2747-2750, 2017.

Y.Q Huang, H. J. Song, Y. X. Liu et al., “Dehydrogenation of N‐Heterocycles by Superoxide Ion Generated through Single‐Electron Transfer,” Chemistry–A European Journal, vol. 24, no. 9, pp. 2065-2069, 2018. 20.

S. Eagon and M. O. Anderson, “Microwave-Assisted Synthesis of Tetrahydro-β-carbolines and β-Carbolines,” European Journal of Organic Chemistry, vol. 8, pp. 1653-1665, 2014.

M. Cain, R. W. Weber, F. Guzman et al., “Beta-Carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 25,no. 9, pp. 1081-1091, 1982.

H. Chen, P. Gao, M. Zhang et al., “Synthesis and biological evaluation of a novel class of β-carboline derivatives,” New Journal of Chemistry, vol. 38, no. 9, pp. 4155-4166, 2014.

S. Gaikwad, D. Kamble and P. Lokhande, “Iodine-catalyzed chemoselective dehydrogenation and aromatization of tetrahydro-β-carbolines: A short synthesis of Kumujian-C, Eudistomin-U, Norharmane, Harmane Harmalan and Isoeudistomine-M,” Tetrahedron Letters, vol. 59, no. 25, pp. 2387-2392, 2018.

M. L. Yang, P. C. Kuo, A. G. Damu et al., “A versatile route to the synthesis of 1-substituted β-carbolines by a single step Pictet–Spengler cyclization,” Tetrahedron, vol. 62, no. 47, pp. 10900-10906, 2006.

J. J. Maresh, L. A. Giddings, A. Friedrich et al., “Strictosidine Synthase: Mechanism of a Pictet-Spengler Catalyzing Enzyme,” Journal of American Chemical Society, vol. 130, pp. 710-723, 2008.

T. M. Heidelbaugh, P. X. Nguyen, K. Chow et al., “Quinolynylmethylimidizoles as therapeutic agents,” U.S. Patent Application No. 12/436,837.

P. V. Reddy, S. Mishra, M. P. Tantak et al., “Design, synthesis, and in vitro cytotoxicity studies of novel β-carbolinium bromides,” Bioorganic & medicinal chemistry letters, vol. 27, no. 6, pp. 1379-1384, 2017.