Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• -carbonyl reduction by dissolved lithium metal in liquid NH3 solution, and the C11 α-hydroxylated intermediate 13 was obtained as a single diastereoisomer in 54% yield. Lastly, as expected, a Co(acac)2-catalyzed Mukaiyama hydration of 13 afforded the desired natural product sarmentogenin (2) in 69% yield

• final natural product rhodexin A in one step. Just as expected, when directly subjecting 16 to the abovementioned conditions, rhodexin A was indeed afforded albeit in only 10% yield. The required longer reaction time and elevated temperature to achieve deprotection of the sugar motif resulted in an over

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• Juan Huang Ming Yang State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, Gansu Province 730000, China 10.3762/bjoc.21.199 Abstract Illicium sesquiterpenes are a large class of highly oxygenated and

• rearrangement of 28 enabled the rearrangement of cis-pentalene to trans-pentalene, delivering intermediate 29, which possesses the same carbon skeleton as the natural product. Further oxidation of the primary alcohol to a carboxylic acid, accompanied by TBS deprotection, afforded hemiketal 30. Finally, a White

• product. They resolved racemic intermediate 27 by derivatization with (S)-1-(1-naphthyl)ethyl isocyanate, followed by separation of the resulting diastereomers via silica gel chromatography (Scheme 3). By converting diastereomer 32 to (−)-illisimonin A, the absolute configuration of the natural product

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• were ultimately elucidated in 1968 by Wiesner and co-workers using a combination of chemical degradation and X-ray crystallography [14]. Notably, in 2016, Inoue’s group at the University of Tokyo reconciled discrepancies through comparative analysis of experimental and natural product data, confirming

• constructed the ABC tricyclic core skeleton of the target molecule. This achievement transformed a simple monocyclic precursor into a complex fused-ring skeleton, vividly demonstrating the application value of the multi-reaction synergistic strategy in natural product synthesis. The specific synthetic route

• product’s core structure. Finally, multisite functional group modifications and oxidation state adjustments enabled the total synthesis of ryanodol (4) in 35 steps. Ryanodine (1), a prominent member of the Ryanoid diterpene natural product family, exhibits remarkable insecticidal and pharmacological

Ni-promoted reductive cyclization cascade enables a total synthesis of (+)-aglacin B

• Si-Chen Yao,
• Jing-Si Cao,
• Jian Xiao,
• Ya-Wen Wang and
• Yu Peng

Beilstein J. Org. Chem. 2025, 21, 2548–2552, doi:10.3762/bjoc.21.197

• aryltetralin[2,3-c]furan skeleton embedded in this natural product. Keywords: aryltetralin; conjugate addition; cyclolignan; nickel; reductive coupling; Introduction Proksch and co-workers isolated aglacins A, B, C, and E (1–4, Figure 1) from the methanolic extract of stem bark of Aglaia cordata Hiern from

• and Et3SiH as the hydrogen source [22], affording this natural product in 58% isolated yield. NMR data of the synthetic sample were found to be in agreement with those of previous literature (Tables S1 and S2, Supporting Information File 1). Moreover, the newly synthesized (+)-aglacin B (2) formed

• of (+)-aglacin B, a typical aryltetralin natural product [23][24], was completed from 2,6-dimethoxyphenol. The key Ni-promoted reductive cyclization cascade of a β-bromo acetal with an allyl tether, smoothly established the tetrahydronaphtho[2,3-c]furan core of this molecule in a new fashion. The

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• considerable attention in recent decades. Numerous approaches to natural product synthesis have been reported in which a photochemical transformation represents a key step [1][2][3]. In this context, the photochemical [2 + 2] cycloaddition and subsequent fragmentation of the resulting cyclobutane provides a

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• single diastereomer with a yield of 72%. A subsequent series of synthetic transformations on acid 140 resulted in the target (−)-pavidolide B (134) (Scheme 24). Hu and Snyder [71] carried out the first enantioselective synthesis of the highly strained natural product (−)-presilphiperfolan-8-ol (141) in

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• ), a marine natural product isolated by Fenical and co-workers [12], also acts as a proteasome inhibitor and displays more potent in vitro cytotoxicity than omuralide (2). Anisatin (4), which contains a characteristic spiro β-lactone has been identified as a noncompetitive antagonist of GABA-gated ion

• several potent pancreatic lipase inhibitors with nanomolar IC50 values [24], further supporting vibralactone as a promising lead compound warranting further investigation. Although vibralactone (6) is a relatively small natural product, its molecular structure features a unique 4/5-fused bicyclic β

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

• strategies and creative tactics, reflecting how emerging synthetic capabilities and concepts can positively impact natural product total synthesis. Keywords: biomimetic synthesis; C–H functionalization; complanadine; lycopodium alkaloid; skeletal editing; total synthesis; transition metal catalysis

• 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

• approaches. Overall, their synthesis highlights the impact of enabling transition metal catalysis on natural product total synthesis. The Siegel synthesis starts with chiral pool molecule (+)-pulegone (14), which encodes the first stereocenter of the entire sequence. (+)-Pulegone was converted to compound 15

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

• review, drawing on examples from recently reported natural product syntheses, elaborates on reaction mechanisms, factors governing regioselectivity and stereoselectivity, and the impact of substrate structures on reaction pathways. These reactions not only serve as robust tools for the streamlined

• synthesis of natural products but also establish a solid foundation for subsequent pharmaceutical investigations. Keywords: dicarbonyls; natural product; Norrish–Yang cyclization; photoredox; total synthesis; Introduction In the 1930s, Norrish documented the photodecomposition of aldehydes and ketones [1

A chiral LC–MS strategy for stereochemical assignment of natural products sharing a 3-methylpent-4-en-2-ol moiety in their terminal structures

• Rei Suo,
• Raku Irie,
• Hinako Nakayama,
• Yuta Ishimaru,
• Yuya Akama,
• Masato Oikawa and
• Shiro Itoi

Beilstein J. Org. Chem. 2025, 21, 2243–2249, doi:10.3762/bjoc.21.171

• obtained suffered from co-evaporation during solvent removal under reduced pressure, which led us to consider that degradation of the natural product to obtain the corresponding fragment would be challenging. Accordingly, esterification of the hydroxy group at C3 in 3, and suitable acyl groups were then

• to the natural product capsulactone (1), an α-pyrone polyketide first isolated in 2021 from the endophytic fungus Penicillium capsulatum [17], and re-isolated in 2023 from the endophytic fungus Neurospora dictyophora WZ-497 [18], whose absolute configuration had been determined by computational

• stereoisomers. Additionally, the reversed-phase HPLC conditions without TFA in the mobile phase are compatible with LC–MS, enabling highly sensitive detection, and facilitating reliable stereochemical assignment using only a minimal amount (less than a microgram) of a natural product derivative. Conclusion In

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• ), phenylamide (30u) as well as natural product-derived and pharmaceutical skeletons: fenchol (30v), ᴅ-ribofuranoside (30w), diacetone galactose (30x), and epiandrosterone (30y). Based on the experimental results, a possible reaction mechanism was disclosed. Initially, the anodic oxidation of I− formed I+ or I2

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

• shortage of natural product sources. Nevertheless, the asymmetric total synthesis of terpenoid and alkaloid natural products presents significant challenges due to their complex and diverse ring systems and the presence of multiple stereocenters, including all-carbon quaternary stereocenters. Consequently

• . We hope this review can stimulate the methodology development and application of this strategy toward further improving the synthetic efficiency of natural product synthesis. Review Total synthesis of terpenoid and alkaloid natural products through the desymmetric enantioselective reduction of five

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

• . The former was demonstrated by the synthesis of alkaloid 14-epi-isochaetominine C that was used to determine the enantiomeric excess of the synthesized natural product (98.7% ee), while the latter was illustrated by the synthesis of both enantiomers of the alkaloid isochaetominine. Additionally, the

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

• Zhengyi Qin Yuting Yang Nuran Yan Xinyu Liang Zhiyu Zhang Yaxuan Duan Huilin Li Xuegong She State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China State Key Laboratory of Green Pesticide, Guizhou University

• natural products. Recently, we have achieved an array of bioinspired total syntheses, which showed the great power of this approach in natural product synthesis. Documented herein is a review of these achievements which include the detailed process of how we develop these strategies. Specifically

• on how to use this important strategy in natural product synthesis. Keywords: bioinspired total synthesis; chabranol; gymnothelignans; monocerin; sarglamides; taberginggine; Introduction Natural products are chemical substances generated within living organisms in nature. They are products of

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

• biologically active molecules. Based on the reaction types, three strategies are discussed: enzymatic acylation, transition-metal-catalyzed acylation, and local desymmetrization. Keywords: asymmetric synthesis; desymmetrization; 1,3-diols; natural product; total synthesis; Introduction Natural products

• desymmetrization strategies for diols, including enzymatic desymmetrization and organocatalytic approaches, have been published in the past decade, most of which focus on the methodological development. Although there are reviews on desymmetrization in natural product synthesis [19][20][21], none of these have put

• completed the total synthesis of salinosporamide A, a marine-derived natural product with anticancer activity, featuring an enzymatic desymmetrization (Scheme 17) [49]. To establish the C4 chiral center, prochiral diol 118 (prepared from known compound 117) was treated with lipase from Pseudomonas sp. (WAKO

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

• advisable to stockpile the penultimate synthetic intermediate 23 and subsequently conduct the deprotection on the smaller scale. Conclusion Overall, we have developed a facile synthesis of the natural product malassezione, utilizing an EDC-mediated coupling of N-Boc-protected indole-3-acetic acid. The use

N-Salicyl-amino acid derivatives with antiparasitic activity from Pseudomonas sp. UIAU-6B

• Joy E. Rajakulendran,
• Emmanuel Tope Oluwabusola,
• Michela Cerone,
• Terry K. Smith,
• Olusoji O. Adebisi,
• Adefolalu Adedotun,
• Gagan Preet,
• Sylvia Soldatou,
• Hai Deng,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2025, 21, 1388–1396, doi:10.3762/bjoc.21.103

• extract. The chemical dereplication of the crude extract by high-resolution electrospray ionisation mass spectrometry (HRMS) analysis and online natural product databases (Reaxys [19], AntiBase 2017 [20] and Natural Product Atlas [21]) revealed the presence of unknown molecular ions in addition to the

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• Mannich reactions [20], lipase-catalyzed esterification [21], nitro-aldol [22], Michael [23], and aza-Michael reactions [24][25], Diels–Alder reactions [26][27] and Friedel–Crafts alkylation of indoles [28]. Many high pressure reactions were applied in natural product synthesis [29]. The high pressure

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• by yields of 69% and 54% for products 85, and 86, respectively. Notably, the natural product sclareolide underwent chlorination with an impressive selectivity, achieving an 82% yield for the product 87. Amidyl radical from amide anion In 2024, Ooi and colleagues established a pivotal advancement in

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• precursor 88. Minnaard’s strategy for constructing Ōmura’s C1–C11 and C12–C23 fragments Minnaard and Madduri in 2010 [37] developed a novel strategy to prepare the C1–C11 and C12–C23 fragments of borrelidin, representing the upper and lower parts of this natural product as classified by Ōmura [27][29

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• been successfully done for this method. Similarly, Hou and co-workers (2022) also used CO2 to carry out an auto-tandem Cu-catalyzed carboxylation of styrenes via β-hydride elimination (208) (Scheme 60B) [104]. Impressively, several natural product-like compounds (e.g., 207) were successfully prepared

• -Markovnikov selectivity catalyzed by Au(III) in the presence of dimethylaminopyridine N-oxide (DMAPO) as oxidant. The reaction proceeds via Au–allenylidene species 307 (Scheme 73) [124]. Various cinnamic esters and amides with natural product-based alkoxy groups 301–304 and sulfoximines 305 and 306, a

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

• Chun-Yu Mi Jia-Yuan Zhai Xiao-Ming Zhang State Key Laboratory of Natural Product Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China 10.3762/bjoc.21.81 Abstract Enamides are distinctive amphiphilic synthons that can be strategically

• 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

• 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

• group with methylhydrazine afforded butynylamine derivative 6. Cyclization of the latter to dihydropyrrole 7 and subsequent reduction resulted in compound 8, which was N-methylated to give racemic brevicolline ((±)-1). The natural product (S)-brevicolline ((S)-1) was finally obtained by chiral

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