molecules Review Recent Advances in the Synthesis of β-Carboline Alkaloids Tímea Szabó , Balázs Volk and Mátyás Milen *   Citation: Szabó, T.; Volk, B.; Milen, M. Recent Advances in the Synthesis of β-Carboline Alkaloids. Molecules 2021, 26, 663. https://doi.org/ 10.3390/molecules26030663 Academic Editors: György Szöllösi and Eva Frank Received: 13 November 2020 Accepted: 21 January 2021 Published: 27 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P.O. Box 100, H-1475 Budapest, Hungary; szabo.timea91@gmail.com (T.S.); volk.balazs@egis.hu (B.V.) * Correspondence: milen.matyas@egis.hu; Tel.: +36-1-8035-874 Abstract: β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex β-carboline frameworks. In this review, we describe the recent developments in the synthesis of β-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted. Keywords: β-carboline; natural products; total synthesis; bioactive molecules 1. Introduction Carbolines are a remarkable family of heterocyclic natural products, with outstanding pharmacological potential. They are determined by their tricyclic, pyridine-fused indole framework (where the rings are identified as A, B and C), and classified according to the degree of saturation (fully saturated: 1,2,3,4-tetrahydro; partially saturated: 3,4-dihydro; and unsaturated β-carbolines) and the position of the N-atom in the C-ring as α-, β-, γ- or δ-carbolines (Figure 1)[1,2]. β-Carboline alkaloids are widely distributed in nature including various plants, foodstuffs, marine creatures, insects, mammals as well as human tissues and body fluids. Numerous representatives of this family show various biological activities [3–5]. The fascinating diversity of structures and medicinal potential [6] inherent in them encourage several researchers to deal with the synthesis of β-carboline containing natural products and their synthetic derivatives [2,4,7–9]. Several commercial drugs or drug candidates such as vinpocetine, brovincamine, abecarnil, cipargamin, tadalafil, reserpine and lurbinectedin contain this unique framework (Figure 1). This review focuses on the field of β-carboline research through selected examples from the last 5 years, where the key information on natural occurrence, structural diversity and biological activities is highlighted (Table 1). The comprehensive demonstration of recent advances in the synthesis of naturally occurring β-carbolines, including both simple β-carbolines (Section 2 of this review) and fused ring systems containing this framework (see Figure 1 and Section 3 of this review), is discussed with a special emphasis on the innovative framework construction steps. Molecules 2021, 26, 663. https://doi.org/10.3390/molecules26030663 https://www.mdpi.com/journal/molecules