Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• Mannich reaction between a 2-sulfonylpyridine protected imine and a malonate (Scheme 1). The pyridine-containing protecting group was chosen considering our catalyst design. We envisioned that halogen bond (XB) will complement hydrogen bonds to activate an imine towards the nucleophilic attack of the

• the halogen bond is not essential for the stereoselectivity of the reaction, but the halogen atom has a beneficial effect on both reactivity and stereoselectivity. A comparative experiment using an imine with a para-toluenesulfonyl protecting group afforded the product in lower selectivity (Table 1

• , entry 17), further highlighting the importance of the pyridine ring containing protecting group. The interaction between catalyst E and the imine was further investigated by 19F NMR studies (see Supporting Information File 1). To further elucidate the role of noncovalent interactions, we conducted

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• contain complex three-dimensional structures, make total synthesis challenging. The retrosynthetic analysis [9], alongside the evolution of methodologies such as “two-phase synthesis” [10], “biomimetic synthesis” [11], or “protecting-group-free synthesis” [12], has progressively streamlined synthetic

• chloride. Finally, through a sequence of removal of the Cbz protecting group, alcohol chlorination, proximal nucleophilic substitution, and deprotection of the secondary alcohol, the first total synthesis of nominine was completed. Although the synthetic route seemed to be lengthy, this challenging total

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• % yield. No epimerization at the β-position was observed, and 57 was obtained as a single product. Subsequent removal of the silyl protecting group under PivOH buffer/TBAF conditions, followed by PPTS treatment, enabled spiroketal formation. Finally, epimerization at C38 with TMSOTf completed the total

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• via methylation of a dianionic intermediate, proved unsuitable due to competing overalkylation and the necessity of sub-zero temperatures. In contrast, a transient protecting group approach enabled selective methylation under mild conditions. This culminated in a scalable, operationally simple one-pot

• explore a modified and more selective approach with milder reaction parameters. In our revised strategy, we planned to introduce a transient protecting group for the free hydroxy group, thereby avoiding the necessity of dianion formation with the aim of improving solubility and stability (Table 2). We

• sub-zero temperatures rendered the strategy undesirable. Subsequent exploration of a transient protecting group strategy culminated in a one-pot procedure affording ethylmaltol (1) at a multigram-scale at ≥0 °C with a markedly improved purity profile. A key advantage of the presented approach to

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• 68% yield without cleavage of the acetonide protecting group. Note that compound 2f is not accessible using the known approach (see Scheme 1a), because the dioxane ring is opened during the nitration step. Surprisingly, nitro-NNO-azoxylation products 2g and 2h were obtained from methyl and ethyl 2

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• , treatment of N-acetyl-5-prenyl-1H-indole (22) as a test substrate with HCl in dioxane or TFA in dichloromethane led to Markovnikov hydrochlorination and hydrotrifluoroacetylation of the prenyl group, respectively (Scheme 4) [57][58]. This result required the use of an N-protecting group in the iodozinc

• (6) and ent-asperdinone E, now using an N-Boc protecting group (Scheme 8). Treatment of 3-iodoindole 39 with the iodozinc reagent prepared from N-Boc-ʟ-alanine methyl ester ((R)-35) under Negishi coupling conditions afforded 40 in excellent yield. Cleavage of the N-Boc group and amide formation with

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• of green for strategic connections, yellow for neutral, e.g., functional group interconversion and isomerization, orange for non-strategic reactions, and red for protecting group (PG) manipulations (Scheme 3). Protecting group manipulations refer to any protection or deprotection of a functional

• installed another exo-methylene (in the future F-ring), which would later be reduced to the methyl group at C25. Staudinger reduction and two protecting group manipulations set the stage for the formation of the piperidine (F-ring) through a Mitsunobu reaction. Hydrogenation employing Wilkinson’s catalyst

• metathesis for closing the D-ring (Scheme 7). For the left-hand fragment including the A-, B-, and C-ring, the synthesis started from commercially available (S)-Wieland–Miescher ketone (34), which can also be synthesized via a three-step sequence (Scheme 8). To access 35, several protecting group

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

• Sciences and Biotechnology, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 200240, China 10.3762/bjoc.21.204 Abstract Herein, we report a concise chemoenzymatic synthesis of the cardenolide rhodexin A in 9 steps and the first protecting-group-free synthesis of its

• ; C–H hydroxylation; chemoenzymatic synthesis; Mukaiyama hydration; protecting-group-free synthesis; Introduction Cardiac glycosides (CGs) are widely distributed natural products, generated by plants and amphibians [1]. Structurally, they are composed of an aglycone-steroidal moiety, an unsaturated

• -electron demand Diels–Alder (IEDDA) reaction was utilized to successfully construct the BCD tricyclic structure with the correct configuration of the four contiguous stereocenters in just one step. However, the requirement of a series of protecting group manipulations undermined the step-economy and

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• by the removal of the PMP protecting group using 2 equivalents of CAN and pyridine, affording 2,3-dihydrofurans 12a in 58% (Scheme 4) [54]. In 2022, Sumida, Ohmiya, and co-workers developed a dual NHC/4CzIPN-organocatalyzed, versatile, light-driven silyl radical generation strategy from substituted

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

• reported the first total synthesis of ryanodine from ryanodol [47] (Scheme 5). Their strategy utilized a novel boronate protecting group to mask the four syn-oriented hydroxy groups. A critical step was the in-situ generation of the pyrrole-2-carboxylate unit from a glycine ester and 1,3-bis(dimethylamino

• to “climbing a staircase” – where each successive step involves functional group interconversions and protecting group manipulations, culminating in low overall efficiency. In contrast, Baran’s “two-phase” synthesis strategy emulates nature’s “cyclization–functionalization” logic [53][54]. This

• transesterification sequence produced mono-enone 106, whose hydration installed the C6 stereocenter to yield 107. Further protecting group and oxidation state adjustments afforded lactone 108, which was transformed via an intramolecular SN2′ reaction (single-electron reduction), m-CPBA epoxidation, acid-promoted

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• inaccessible (Scheme 5) [41]. We assumed the steric hinderance of the Boc protecting group might have a great impact to the reactivity of ketone. Investigation along this line is currently on the way. Conclusion In summary, we have streamlined the rapid construction of the core perhydrofuropyran skeleton of

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

• % (Table 1, entry 10) compared with that in entry 9 (42%). These results indicate that Cbz is a more effective protecting group than Boc under the profiled conditions. The effects of the reaction temperature on the outcome of the PET reaction of 9a were investigated. Among the conditions screened (Table 1

• , which indicates that steric hindrance at C2 has a limited effect on the reactivity. However, when the steric hindrance of the protecting group was increased by replacing –Cbz with –Boc, the activity of the PET reaction decreased, which resulted in a lower yield of 10f (45%). In the case of substrate 9g

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

• completed by converting the exocyclic methyl ester 144 to an aldehyde145 using a one-pot DIBAL-H/Dess–Martin procedure followed by the removal of TMS protecting group using a stoichiometric Wilkinson’s catalyst (Scheme 25). The authors noted that, in the final stages of reduction and oxidation, yields were

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

• deprotection followed by C–H insertion. However, when attempting to remove the ketal protecting group, only decomposition of the starting material was observed. A plausible explanation for this outcome is that the β-lactone ring, located at the β-position of the methyl ketone, may undergo facile β-elimination

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

• reinstallation of a single TMS on the alkyne provided pyridyl-alkyne 22 for the second [2 + 2 + 2] cycloaddition reaction which proved nontrivial, with the protecting group on the secondary amine of the alkyne-nitrile moiety and the choice of ligand playing crucial roles. Specifically, when using 19 as the

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

• blue LEDs at room temperature constructed a single diastereoisomer 23 in 90% yield. From 23, the ABCDE pentacyclic skeleton of phainanoids (27) was ultimately established via a Mitsunobu reaction, intramolecular nucleophilic substitution with in situ-generated aryllithium, and protecting group

• stereoretentive coupling at C2 with aryl bromide 86, yielding 88 as a single diastereomer. Manipulation of the protecting group of 88 arrived at lycoplatyrine A (89). Notably, 87 and related α-hydroxy-β-lactams were obtained via Norrish–Yang cyclization of the corresponding neat α-keto amides in the solid state

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

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

• the presence of Fe(dpm)3/Ph(iPrO)SiH2 proceeded smoothly to furnish the tetracyclic product 39 in 56% yield with 2.5:1 ratio. Finally, removal of the acetonide and the Bn protecting group completed the total synthesis of (+)-aplysiasecosterol A (6). Total synthesis of (+)-cyrneine A, (−)-cyrneine B

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

• as the activating agent under standard peptide coupling conditions. Cleavage of the Boc-protecting group with TFA afforded the target 6-oxoindolo[1,2-c]quinazoline-12-carboxamides 7a–c (Scheme 2). 3-Aminomethylindole derivatives represent a well-established class of compounds with diverse biological

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

• using chiral compound 40 with an acid-sensitive protecting group MEM on the alcohol as the precursor, the simple Brønsted acid TsOH successfully promoted the deprotection and dehydration to generate oxa-carbenium 41, which subsequently proceeded the Friedel–Crafts cyclization to furnish

• sarglamides A, C, D and E were established through a concise and protecting group-free approach, which was definitely inspired and utilized by the analysis of the biogenetic pathway of these natural products. Through this approach, a notable amount of natural products were made in one batch. The synthesis

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• bromide 47, followed by Fmoc protection of 56, Boc deprotection of 57, reduction of the NO2 group to NO and intramolecular Mills coupling to form 35h. Removal of the Fmoc protecting group under basic conditions affords the unsubstituted product 35d which, after N-alkylation or acylation affords the

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• attempted (Scheme 2). For this purpose, tert-butyl N-[(1R,2R)-2-amino-1,2-diphenylethyl]carbamate (2h) with an acid-sensitive Boc (tert-butoxycarbonyl) protecting group was prepared in 70% yield from C2-symmetric (1R,2R)-1,2-diphenylethane-1,2-diamine (1) and Boc2O. Compound 2h was then converted to (1S,2S

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• ][24] (Scheme 1). The proposed strategy relied on the N-deprotection of the intermediate ester 3d inducing O-to-N rearrangement to form amide 5 as a precursor of vinyloxazoline 6. For this purpose, Alloc (allyloxycarbonyl) turned out to be a suitable N-protecting group as it was compatible with the

• analogously from ester R-3d. Thus, Alloc was validated as non-expensive and relatively small N-protecting group, removal of which is compatible with double bond and acetal function of amides S-5 and R-5. The removal of the Pd catalyst at laboratory scale was done by chromatography. For large scale synthesis

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

• conducted on the gram-scale starting from indole-3-acetic acid with consistently good yields up to and including the EDC-mediated coupling step. However, the subsequent removal of the Boc protecting group proved more challenging. We observed lower yields during this step, despite screening a range of acids

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• exploiting the participation effect of the neighboring protecting group [43][44], employing anomeric lactols as acceptors is more complex as lactols with the desired configuration are frequently difficult to obtain (e.g., through anomerization). In addition to the nature of the leaving group and promoter

• of the 2N-protecting group on GlcN- and GalN-derived lactol acceptors proved crucial for the success of borinic acid-promoted glycosylation, as the 2N-Troc-protected acceptor 41 failed to participate in the reaction. In contrast, the 2N-naphthalenesulfonyl (NapSO₂)-protected glucosamine-derived

• /β = 1:1.3), leading to a loss of stereoselectivity and affording the α/β-linked product 59 in 32% yield [40]. The stereodirecting effect of the O-picoloyl protecting group at remote position on the pyranose ring (C3–OH, C4–OH, or C6–OH) in glycosyl donors has been known to induce high facial