Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• efficiency and step-economy of natural product total synthesis. This symbiotic relationship has also helped to accelerate natural product biological evaluation and the subsequent biomedical development [1]. Lycopodium alkaloids are one of the largest families of natural products [2], from which famous

• these lycopodium alkaloids [12]. Lysine could be advanced to 4-(2-piperidyl)acetoacetate (7) and pelletierine (8), which would react with each other to deliver phlegmarine (9). Double oxidation of 9 would give 10 for a subsequent intramolecular Mannich-type cyclization to forge the C4–C13 bond and

• removal of the two Boc protecting groups completed the Sarpong total synthesis of complanadine A. Efficient access of key coupling intermediates 33 and 34 further enabled Sarpong and co-workers to successfully synthesize other lycopodium alkaloids. For example, to synthesize complanadine B with mono

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• natural product synthesis. This review summarizes the latest advancements in these reactions for constructing terpenoids, alkaloids, and antibiotics. Through Norrish–Yang cyclization, dicarbonyls (e.g., 1,2-diketones and α-keto amides) can efficiently construct sterically hindered ring structures, which

• as powerful tools for constructing complex molecular architectures. Centered on the structural diversity and synthetic relevance of target natural products, this review is divided into three main sections: terpenoids, alkaloids, and antibiotics. Each section highlights the recent application of

• congested structures in complex bicyclic systems. 2 Alkaloids 2.1 Lycoplatyrine A In 2020, Sarpong's group disclosed their progress toward a robust and broadly applicable strategy for the C–H functionalization of piperidines and related saturated N-heterocycles. This approach involves lactamization via

The application of desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds in the total synthesis of terpenoid and alkaloid natural products

• Dong-Xing Tan and
• Fu-She Han

Beilstein J. Org. Chem. 2025, 21, 2085–2102, doi:10.3762/bjoc.21.164

• complex natural products. On the other hand, terpenoids and alkaloids, with their intricate and diverse skeletal frameworks as well as the broad range of biological activities, have long been a major focus for synthetic chemists. Over the past fifteen years, significant progress has been made in the total

• synthesis of several terpenoids and alkaloids through the desymmetric enantioselective reduction of five-membered cyclic 1,3-dicarbonyl compounds. Subsequently, the utilization of six-membered cyclic 1,3-dicarbonyl compounds for the synthesis of some terpenoids natural products is described. Keywords

• : alkaloids; cyclic 1,3-dicarbonyl compounds; desymmetrization; enantioselective reduction; terpenoids; Introduction Terpenoids and alkaloids are two major classes of highly important natural products because they usually exhibit diverse and important biological activities, such as antitumor, anti

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• generation of our synthetic strategy to chaetominine-type alkaloids featuring two modifications of the last step of our 4 to 6-step approach. Firstly, by employing EDCI/HOBt as the coupling system for the last step of the one-pot O-debenzylation–lactamization reaction, the overall yield of our previous total

• reported structures of alkaloids aspera chaetominines A and B have been synthesized. Moreover, the four-step synthesis of the reported structure of aspera chaetominine B generated another diastereomer that was converted in one-pot to (–)-isochaetominine C, which turned out to be the revised structure of

• fungus Aspergillus versicolour SCSIO XWS04 F52 [32]. All these alkaloids distinguish each other only by alkyl substituent at C11 and by relative stereochemistries at C2, C3, C11, and C14. Soon after the report of the isolation, structural elucidation, and bioactivity of (–)-chaetominine by Tan and co

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• indolo[1,2-c]quinazoline derivatives was patented as anti-HCV compounds acting through selective inhibition of viral polymerase (Figure 1, top) [17]. Other notable bioactive indoloquinazoline compounds include the natural alkaloids tryptanthrin and hinckdentine A (Figure 1, bottom). Tryptanthrin (indolo

• reports that focused on natural alkaloids or limited antimicrobial studies, this study expands the pharmacological scope by demonstrating selective antiproliferative effects and identifying promising SAR trends. The originality of the research lies in linking strategic scaffold functionalization

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• , bioinspired total synthesis of three types of natural products, namely diterpenoids (chabranol, and monocerin), alkaloids (indole, hydroquinoline, and monoterpenoid−indolidinoid hybrid), and gymnothelignans are discussed. Based on these achievements on bioinspired total synthesis, we provide some information

• [8], and Corey drove it to a precise science full of chemical logics [6]. In this period, a lot of biomimetic total synthesis came out, such as Johnson’s progesterone synthesis [9][10] Heathcock’s synthesis of daphniphyllum alkaloids [11] and Nicolaou’s synthesis of endiandric acids [12][13][14][15

• biomimetic or bioinspired total synthesis. Indeed, this approach has been proved to be of great power to access molecular complexity, and it is applicable to diverse types of natural products such as terpenoids, alkaloids, polyketides and lignans. Herein, we document our adventure of bioinspired total

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• sequence comprising TBS protection, ester hydrolysis, mesylation, and hydride reduction. In 2014, Tokuyama and co-workers accomplished the total synthesis of (−)-petrosin and (+)-petrosin, two marine-derived bisquinolizidine alkaloids [45]. They first completed the synthesis of (−)-petrosin (84) (Scheme

• indole derivatives mediated by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is an efficient strategy that the Cook group utilized in the total synthesis of several indole alkaloids [75][76][77]. In 2005, they reported the synthesis of vincamajine-related indole alkaloids, among which

• position. Compound 271, prepared from 270 in eight steps, was treated with N-bromosuccinimide (NBS) in a H2O/THF solution to afford lactone 272 in 50% yield. Finally, 272 was converted to stephadiamine (273) in three steps. In 2018, the Garg group completed the total synthesis of akuammiline alkaloids

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• condensation, cyclisation, and cycloaddition as an efficient strategy for the rapid formation of complex spirocyclic products that could have value for the formation of novel, bioactive oxindoles. Keywords: cascade; cycloaddition; oxindole; spirocycle; stereochemistry; Introduction The Alstonia alkaloids are

• , sore throats, toothache, ulcers, and snake bites [1]. The medicinal qualities of these plants are ascribed to the presence of alkaloids, and they are rich in many different indole and oxindole alkaloids [2]. About 100 Alstonia alkaloids are known, with more being isolated on a regular basis [3][4

• ]. Representative examples are shown in Figure 1. The alkaloid alstonisine has antimalarial activity, with IC50 7.6 μM against Plasmodium falciparum [5]. However, the biological activities of most of the Alstonia alkaloids are currently unknown, despite the potential of spirooxindoles for drug discovery [6]. This

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• . 5%. Furthermore, the present method may also be used to prepare related compounds. Keywords: bis(aryl/heteroaryl)ketones; EDC; indole alkaloids; malassezione; Introduction Lipophilic yeasts of the genus Malassezia are commensal fungi that constitute the normal skin microbiota; however, when they

• nitrogen source followed by thin-layer chromatography and reversed-phase (RP)-HPLC to isolate and purify the compound from a complex mixture of indole alkaloids [11], (ii) prepared by aerobic incubation of indole-3-pyruvic acid at pH 7.4, 37 °C for 24 h followed by isolation and purification using RP-HPLC

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• oxindole [3][8][9], chrysenequinone [10], cycloheptatriene [11][12], thiazole [13], and matrine-type alkaloids [14]. The hybrid pharmacophore design is a frequently employed approach in the development of potential antitumor and other drugs [15][16]. This method involves the merging of two distinct

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• (HAS) and deprotonation. In 2022, Zhang’s group introduced an innovative electrochemical approach for the collective synthesis of labeled pyrroloindoline alkaloids, utilizing Freon-type methanes as functional one-carbon (C1) synthons (Scheme 49) [29]. This methodology employed an electroreductive C–X

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• -inducing properties in peptides [22][23][24]. Furthermore, derivatives of pipecolic acid are known for their bioactivity as secondary metabolites [25][26][27] and for being building blocks for piperidine alkaloids [28] with a variety of uses. Results and Discussion Addressing specific positions in the ring

Synthesis of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones by domino C–N coupling/hydroamination reactions

• Ruben Manuel Figueira de Abreu,
• Robin Tiedemann,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2025, 21, 1010–1017, doi:10.3762/bjoc.21.82

• instance, deazapurines represent heterocyclic fused pyrimidine bases which have found special attention, due to their widespread occurrence in natural alkaloids exhibiting various biological properties. For example, cadeguomycin (A), tubercidin (B), and toyocamycin (C) show antibiotic properties, while

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cyclization modes that provide entries to various N-heterocycles, some of which serve as key structural motifs in natural alkaloids. This review highlights recent advancements in enamide-based cyclization reactions, including enamide–alkyne cycloisomerization, [3 + 2] annulation, and polycyclization, with a

• have attracted considerable attention due to their promise in the total synthesis of alkaloids [16]. Notably, these valuable compounds can be employed as efficient synthons in enamide–alkyne cycloisomerization, [n + m] cycloadditions, pericyclic reactions, and radical cyclizations. A comprehensive

• review of these advancements up until 2015 has already been documented [16]. In this review, recent breakthroughs of these enamide cyclizations will be surveyed from the viewpoint of natural product synthesis. Leveraging the enamide–alkyne cycloisomerization cyclizations, Lycopodium alkaloids

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• DC is a widely distributed sedge which can be mainly found in the Central and South-Eastern European region. It contains several alkaloids, including β-carboline alkaloids (S)-brevicolline (S-(1)) and brevicarine (2, Figure 1) as the two main components [1][2][3]. Our long-standing interest in the

• chemistry of β-carbolines [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] has now focused our attention on these two alkaloids. In a recent publication we disclosed a new total synthesis of racemic brevicolline ((±)-1) (Scheme 1) [9]. A prerequisite for the synthesis was the development of a new

• silico for non-peptide malignant brain tumor (MBT) antagonist activity, showing hits on three MBT-containing proteins [35]. Although Carex brevicollis DC has been observed to have a teratogenic effect on animals [1][36], which could be linked with the presence of the two mentioned β-carboline alkaloids

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• carbon monoxide were used as starting materials, and two natural product frameworks of phenanthridone and acridone alkaloids could be selectively obtained by controlling ligands. The reaction of o-iodoaniline with in situ-generated arynes under CO atmosphere under ligand-free conditions selectively

• protoberberine and protonitidine alkaloids are characterized by an isoquinoline ring skeleton. An analysis of their molecular structures revealed that the two alkaloids share a basic structure, differing only in the junction of the B-ring. In 2021, Liu and Jiang designed new pyridyne precursors, which underwent

• , leading to the synthesis of differently substituted protonitidine alkaloids and protoberberine alkaloids (Scheme 25) [56]. Conclusion Developing streamlined and versatile approaches for the rapid assembly of structurally diverse organic molecules represents a pivotal challenge in organic synthesis

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• coupling with gold(I)-mediated 6-endo cyclization streamlines the rapid and modular assembly of the substructure of bis-tetrahydroisoquinoline (THIQ) alkaloids. The design of the key synthetic intermediate bearing a 2,3-diaminobenzofuran moiety allows both gold(I)-mediated regiocontrolled 6-endo

• involvement of a fluorescent intermediate in the cascade synthetic process. Keywords: cascade reactions; copper-catalyzed three-component coupling; gold-mediated 6-endo hydroamination; tandem cyclizations; tetrahydroisoquinoline alkaloids; Introduction The bis-tetrahydroisoquinoline (THIQ) alkaloid family

• a fluorescent intermediate 18, and subsequent ring opening allowed a streamlined one-pot access to the substructure of THIQ alkaloids 14 in a good yield of 60% from 11. The structure of the resulting 14 was elucidated through comprehensive two-dimensional NMR spectroscopy, complemented by NOE

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• -diamino derivative 37 in a good yield and an excellent enantioselectivity. Brønsted bases Cinchona alkaloids have been established as highly efficient chiral organocatalysts, capable to engage in a wide array of enantioselective processes [35]. They possess a unique structure. Firstly, the bulky

• catalysts are synthesized by joining together two fragments of cinchona alkaloids. In this manner, it is possible to obtain a symmetric catalyst, which can engage in hydrogen bonding interactions and deprotonation processes. Although they were originally used for Sharpless dihydroxylation, they have been

Ceratinadin G, a new psammaplysin derivative possessing a cyano group from a sponge of the genus Pseudoceratina

• Shin-ichiro Kurimoto,
• Kouta Inoue,
• Taito Ohno and
• Takaaki Kubota

Beilstein J. Org. Chem. 2024, 20, 3215–3220, doi:10.3762/bjoc.20.267

• belonging to the order Verongiida are known to contain a diverse array of bromotyrosine alkaloids with a broad spectrum of biological activities [1]. To date, approximately 500 bromotyrosine alkaloids have been isolated from sponges, with those featuring the 8,10-dibromo-9-methoxy-1,6-dioxa-2-azaspiro[4.6

• ]undeca-2,7,9-trien-4-ol moiety classified as psammaplysin derivatives. About 50 psammaplysin derivatives have been identified so far [2][3]. Among bromotyrosine alkaloids, the psammaplysin derivatives are particularly intriguing due to their structural complexity and biological activities. Psammaplysin

• derivatives exhibit a range of bioactivities, including antibacterial, anticancer, antimalarial, and antiviral effects. Since the discovery of the first psammaplysin derivative, psammaplysin A [4][5], these alkaloids have been recognized as challenging targets for total synthesis. The absolute configuration

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• contained mixtures of polyamine-type alkaloids, which were combined for further isolation work. The following describes the purification of these fractions. Fractions 34–35 (5.0 mg) were purified by semipreparative phenyl RP-HPLC using isocratic conditions of 70% H2O (0.1% TFA)/30% MeOH (0.1% TFA) for the

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , inspired by natural alkaloids such as deoxyvasicinone and evodiamine with promising inhibition of ChEs and antioxidant and neuroprotective effects against glutamate-induced OS in HT-22 cells [41]. In 2016, Dgachi et al. [42] applied a Knoevenagel-based multicomponent approach to further explore the

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• bioinformatic analysis. Their updated PRISM 4 pipeline outperformed antiSMASH5 and was able to predict the chemical structures of a wide variety of secondary metabolites [90]. Notably, the repertoire of PRISM 4 spans beyond NRPs and PKs and includes alkaloids, terpenoids, aminoglycosides, nucleosides, etc

• . Structure prediction of natural products other than NRPs and PKs has historically progressed slower. However, it was not due to a lack of data. Indeed, terpenoids and alkaloids are the two largest families of natural products in plants and also represent a sizable minority in microorganisms. The lagging

• information that are available for terpenoids and alkaloids biosynthesis. Data standardization (albeit a tedious and labor-intensive task) may be the final roadblock between AI and generalizable chemical structure metagenomics [91]. Conclusion and Outlook Microorganisms produce specialized metabolites to

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• of 1-fluorobis(phenylsulfonyl)methane (FBSM) to α,β-unsaturated ketones with cinchona alkaloids [9]. Fluorinated Michael acceptors usually contain one fluorine atom or a trifluoromethyl group in the structure [10][11][12]. There are also known examples of gem-difluoroalkenes being used as Michael