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

• particular emphasis on their pivotal role as a strategy in the total synthesis of natural products. Keywords: alkaloid; cyclization; enamide; natural product; total synthesis; Introduction The use of enamines as surrogates for enols in nucleophilic reactions has been well-documented for decades since their

• 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

• (−)-dihydrolycopodine, (−)-lycopodine, (+)-lycoposerramine Q, (+)-fawcettidine, (+)-fawcettimine, and (−)-phlegmariurine have been synthesized in a concise and efficient manner, while employment of the [2 + 3] cycloadditions or a polycyclization enables the elegant total synthesis of Cephalotaxus 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

• , Semmelweis University, Üllői út 26, H-1085 Budapest, Hungary 10.3762/bjoc.21.79 Abstract A new total synthesis of the β-carboline alkaloid brevicarine is disclosed. The synthesis was carried out starting from an aromatic triflate key intermediate, allowing the introduction of various substituents into

• 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

• hydrogenation of the C=C double bond in the side chain gave brevicarine (2). The first total synthesis of brevicarine is shown in Scheme 3 [2][20][21]. Condensation of indole (11) with 1-methylpiperidone (12) gave compound 13 [22]. N-Alkylation of 13 with benzyl bromide, followed by treatment of the quaternary

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• their total synthesis. Two synthetic studies were disclosed successively by Sarpong [27] and Jirgensons [28], both focusing on the construction of the unique methanoindene cage structure (A1A2B ring system). Building upon our previous syntheses of phragmalin-type limonoids [29], we herein disclose a

• contain a distinctive octahydro-1H-2,4-methanoindene cage. The fascinating architectures and remarkable biological profiles of these compounds have attracted widespread attention from the synthetic community. In 1989, Corey and Hahl made a seminal contribution [10] to the field by completing the total

• synthesis of azadiradione (1). Following this, Ley and his team successfully synthesized azadirachtin (2) in 2007, a limonoid extensively utilized in organic agriculture [11]. In recent years, remarkable progress has been made on the total syntheses of various limonoids, with notable contributions from

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• Malkov reviewed the recent progress in the organocatalytic synthesis of chiral homoallylic amines. This important structural motif is typically made by asymmetric allylation of imines, and the authors describe various catalytic approaches as well as applications of these strategies in total synthesis [25

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• reactions with various chiral cycloallylic phosphates 17, which consistently yielded the corresponding SN2' products 18 with high stereoselectivity. The synthetic utility and broad applicability of this methodology was prominently demonstrated through the total synthesis of biologically important natural

Total synthesis of (±)-simonsol C using dearomatization as key reaction under acidic conditions

• Xiao-Yang Bi,
• Xiao-Shuai Yang,
• Shan-Shan Chen,
• Jia-Jun Sui,
• Zhao-Nan Cai,
• Yong-Ming Chuan and
• Hong-Bo Qin

Beilstein J. Org. Chem. 2025, 21, 601–606, doi:10.3762/bjoc.21.47

• Xiao-Yang Bi Xiao-Shuai Yang Shan-Shan Chen Jia-Jun Sui Zhao-Nan Cai Yong-Ming Chuan Hong-Bo Qin School of Chemistry and Environment, Yunnan Minzu University, Kunming 650000, China 10.3762/bjoc.21.47 Abstract The total synthesis of (±)-simonsol C was accomplished using a dearomatization under

• route. Keywords: acidic dearomazation; benzofuran; (±)-simonsol C; total synthesis; Introduction Star anise, derived from Illicium species cultivated in southeastern China [1] possesses significant economic, culinary, and medicinal value [2]. Particularly noteworthy are its medicinal properties

• carbon center. In the first report on the total synthesis of simonsol C (Scheme 1), in 2016 Banwell’s group employed an intramolecular Heck reaction as key step to furnish the aryl-containing quaternary center and simultaneously construct the benzofuran skeleton [7]. This synthesis involved a total of 12

Synthesis of the aggregation pheromone of Tribolium castaneum

• Biyu An,
• Xueyang Wang,
• Ao Jiao,
• Qinghua Bian and
• Jiangchun Zhong

Beilstein J. Org. Chem. 2025, 21, 510–514, doi:10.3762/bjoc.21.38

• with Grignard reagent, and oxidation with RuCl3/NaIO4. Keywords: aggregation pheromone; chiral 2-methyloxirane; red flour beetle; total synthesis; Introduction The red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae), is a cosmopolitan, destructive stored product pest [1], which

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• it to obtain significant stereoselective glycosylation products in good yields. Acetyl and benzoyl protection: The total synthesis of oligosaccharides has seen numerous illustrations of the participating role of the acyl esters. Citing a few references in order to elaborate the mechanistic protocol

• could be orthogonally deprotected in the presence of a wide range of other protecting groups like acetyl, benzoyl, acetal, and methoxymethyl [131]. It has been even applied for the first total synthesis of telophiose A [132]. The stereoselectivity and yield obtained in the presence of the PhCar group

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

• cyclization to efficiently construct the pentacyclic intermediate 7, as demonstrated in our previous study [15]. Following the pioneering total synthesis of saframycin A (1) by Fukuyama and co-workers taking advantage of the compatibility of phenolic hydroxy groups with PS-type cyclization [22], other groups

• led by Corey [23], Myers [24][25], Liu [26][27], and Saito [28] also efficiently exploited PS-type reactions to accomplish the total synthesis of saframycin A (1) (Scheme 1b) [3][4][5][29][30][31][32][33][34][35][36][37][38][39][40][41]. However, PS-type reactions impose constraints due to the

• expected to facilitate the 6-endo-dig cyclization to the distant sp-carbon on the alkyne, as demonstrated by Fujii and Ohno in their total synthesis of (−)-quinocarcin [52][53]. Secondly, the 6-endo-cyclized product 12, bearing the furan-conjugated isoquinoline-type framework, is predicted to be

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• total synthesis of the fungal natural product bulgarein. Keywords: acenaphthylene-fused heteroarenes; benzo[j]fluoranthenes; C–H arylation; fluoranthenes; heterocycles; Introduction An important subclass of polycyclic aromatic hydrocarbons (PAHs) [1] is comprised of fluoranthenes, which have been the

• formal total synthesis of bulgarein (5) [54]. A careful design of the synthetic sequences enabled the syntheses of benzo[j]fluoranthenes 27 and 32 with differentially protected naphthol groups at different positions, which provides potential opportunities for further structural diversification. Examples

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

• 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

• , the first asymmetric total synthesis of psammaplysin A was accomplished by Smith and Morrow, and the absolute configuration of compound 1 was also confirmed through organic synthesis [7]. In our ongoing research focused on uncovering new bioactive secondary metabolites from Okinawan marine sponges, we

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

• . Ianthelliformisamine D (4) contains a rare N-(3-aminopropyl)-2-pyrrolidone moiety only found in <30 natural products. Owing to the novelty of compound 4, we undertook the first total synthesis of this natural product, which was achieved in three steps. Keywords: ianthelliformisamine; marine sponge; natural products

• ; Pseudomonas; Suberea; total synthesis; Introduction The marine environment covers over two thirds of the earth’s surface and it encompasses a wide range of complex ecosystems that are highly variable in their physical attributes including pressure, salinity, temperature, and light availability. Both flora

• activity against both Pseudomonas aeruginosa and Staphylococcus aureus, has contributed to a surge in the interest of polyamines as new antibacterial leads [6]. To date the total synthesis of ianthelliformisamines A–C (1–3) has been described [7] and numerous synthetically related analogues have been

Structure and thermal stability of phosphorus-iodonium ylids

• Andrew Greener,
• Stephen P. Argent,
• Coby J. Clarke and
• Miriam L. O’Duill

Beilstein J. Org. Chem. 2024, 20, 2931–2939, doi:10.3762/bjoc.20.245

• synthetic organic chemistry, becoming indispensable tools in total synthesis, late-stage functionalisation and radiolabelling [1][2][3][4][5][6][7][8][9]. Due to their great mechanistic flexibility, including reactivity as oxidants, electrophiles, radical precursors and transmetalating agents, they often

Young investigators in natural products chemistry, biosynthesis, and enzymology

• Jeffrey D. Rudolf,
• Lena Barra and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 2720–2721, doi:10.3762/bjoc.20.229

• clusters, and enzymes, development of chemical probes, biocatalysis and chemoenzymatic total synthesis, enzymatic mechanisms, and computational investigations of chemical structures and reactions. All of the major classes of natural products are represented here: nonribosomal peptides, ribosomally

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• , encompassing cutting-edge advances in hydrogen-bond catalysis and non-classical approaches. Furthermore, practical examples showcasing the application of these innovative methodologies in total synthesis are presented. Keywords: asymmetric catalysis; asymmetric synthesis; chiral amines; organicatalysis

• almost exclusively produced anti-homoallylamine 7, with (E)-6 being slightly more efficient. This was explained by the reaction switching from the chair-like TS in (E)-crotylation to the boat-like TS in (Z)-crotylation. The developed methodology was successfully applied for the total synthesis of

• , that the 2-aminophenol functionality in the substrates is a prerequisite for attaining high enantioselectivity in the allylation. Interestingly, the aldimines synthesised from 2-hydroxy-4-methylaniline produced inferior yields. While the N-aryl homoallylic amines 66 can be useful intermediates in total

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• interesting biological activities. Keywords: biosynthesis; fungal metabolites; polyketides; resorcylic lactones; total synthesis; Introduction Alternariol and some of its derivatives are ubiquitous as fungal metabolites present in infested plants and in food and feed, but similarly in soil, in wallpapers

• intermediates [34] (e.g., G) or side products [35] (e.g., H) during their total synthesis, are neither systematically covered in this review. A number of wrongly assigned structures have been proposed over the decades (Figure 3). These are mentioned here in summary, where further details will be given in the

• : Total synthesis and comparison of the NMR spectra revealed that this natural product is identical with altertenuol [41], whose structure was correctly given previously [42]. Furthermore, the originally proposed structures [43] of graphislactones E and F were corrected after total synthesis and

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• as pivotal element during the total synthesis of natural products. Therefore, the development of mild and efficient methods to access this motif from readily available starting materials is a never-ending quest. With the aim to propose an alternative to the classical olefination of carbonyls through

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• biosynthetic enzymatic transformations with chemical conversions. This review focuses on the total synthesis of natural products and classifies the enzymatic reactions into three categories. The total synthesis of five natural products: cotylenol, trichodimerol, chalcomoracin, tylactone, and saframycin A, as

• -enzymatic synthesis, featuring the late-stage enzymatic oxidation of chemically synthesized intricate scaffolds are attracting increasing attention. A collaboration between Stoltz and Arnold led to the pioneering accomplishment in the total synthesis of nigelladine A by exploiting P450 enzymes engineered

• through directed evolution [11]. P450 catalysis during the oxidation phase enabled the total synthesis of mitrephorone A [12], chevalone A [13], polysin [14], excolide B [15], and gedunin [16]. Fe(II)/2OG-dependent dioxygenases, such as FtmOx1, were employed as versatile catalysts in the synthesis of 13

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• intramolecular Cannizzaro reaction was demonstrated by the group of Schmalz in the total synthesis of the marine antibiotic pestalone [86]. They observed a facile isomerization of the pestalone derivatives 55/57 into the intramolecular lactone derivatives rac-56a,b which features a Cannizzaro–Tishchenko-type

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• anhydride. This is a useful approach for the total synthesis of complex natural compounds, epoxyisoindole skeleton-based precursors for various polycyclic compounds, and bio-based homo- and copolymers [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• was determined by total synthesis. The biological activities of these maniwamycins were also evaluated, and they showed antiviral activity against influenza (H1N1) virus and the causative agent of COVID-19, SARS-CoV-2. This was the first report of such activity for a natural product having an azoxy

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• cell suspension culture, heterologous biosynthesis, and total synthesis [16][17]. Crocins can be obtained from plant cell culture, but the production is prone to epigenetic silencing and toxic intermediates. The chemical synthesis of crocins is challenging due to the presence of numerous chiral centers

• clearance in vivo. Only a few plants can produce crocins, and the content of crocins in these plants is very low. Due to the numerous chiral centers, the total synthesis of crocins is challenging. Therefore, heterologous biosynthesis of crocins utilizing the synthetic biology strategy holds great potential

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• , and their hybrids, thioesterase (TE) domains play a significant role in late-stage macrocyclization. These domains can accept mimics of native substrates in vitro and exhibit potential for use in total synthesis. This review summarizes the recent advances of TE domains in the chemoenzymatic synthesis

• method to produce analog libraries is critical for structure–activity relationship studies to enhance its specificity. Since the first total synthesis by Ohno and Izumiya in 1966 [31], tyrocidine A and its analogs have been synthesized by several groups employing viable strategies over the past half

• sequential NRPS genes. However, none of them contain the thioesterase domain, which is essential for late-stage cyclization [59]. In 2018, Wakimoto, Kuranaga and co-workers reported the first total synthesis of surugamide B (16) in 34% overall yield through the general SPPS process and the macrocyclization

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• ]. Two decades later, in 2012 the Overman group demonstrated the utility of this transformation in the total synthesis of (–)-aplyviolene, involving the diastereoselective coupling of a tertiary radical and an enone acceptor [38]. Further developments of this chemistry resulted in the general use of NHPI

• -derived NHPI esters has found application in the total synthesis of natural products, including the plant metabolite denobilone A and the highly oxidized dibenzocyclooctadiene lignans heteroclitin J and kadsulignan E [55]. Activation via charge-transfer complex formation Under conditions where oxidative

• of chemoselectivity can benefit from the multitude of mechanisms for their activation. Particularly, the use of RAEs in natural product total synthesis enables the assembly of strategic C–C bonds through radical coupling reactions that can draw from a wide range of reaction conditions (Scheme 37

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• analogues through the incorporation of alternative building blocks at different stages of synthesis. Keywords: chemical glycosylation; lipid II; peptidoglycan; polyprenyls; total synthesis; Introduction Lipid II (Figure 1) is an essential bacterial glycolipid involved in peptidoglycan biosynthesis [1]. It

• provides a practical avenue for producing substantial amounts of lipid II analogues. Consequently, this approach offers a more feasible means of addressing the demands associated with biophysical screening pursuits. Prior research in the field of total synthesis of lipid II has elucidated that specific