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

• transforming it into the pivotal C14 β-hydroxylated steroidal intermediate. As shown in Scheme 2, a BF3·Et2O-promoted elimination afforded the 14-olefinated intermediate 3 in a moderate yield. However, the following Mukaiyama hydration to introduce the C14 β-hydroxy group was unsuccessful. Owing to the

• typical Mukaiyama hydration conditions [30][31][32] to install the C14 β-hydroxy group. However, only a trace amount of the undesired C14α-hydroxylated product 10 was obtained. Additional optimizations regarding the transition-metal catalyst, hydrogen source and solvent all failed to improve the results

• hand, we first tried the synthesis of rhodexin A through direct glycosylation of 2 by the ʟ-rhamnose donor 2,3,4-tri-O-benzoyl-α-ʟ-rhamnopyranosyl trichloroacetimidate (14). However, the selective glycosylation at the C3-hydroxy group of 2 was a formidable challenge since competitive glycosylations of

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• ortho-position such as a hydroxy group generated compound 3f in good yield (87%). A broad scope was observed for para-substituted aldehydes, where both weak (3g, 3h) and strong (3i, 3j) electron-withdrawing groups gave good to excellent yields (83–95%). Similarly, aldehydes with electron-donating groups

• , such as –Me (3k), –OH (3l) or –NR2 (3m, 3n), also resulted in good to excellent yields (82–94%) of products. However, disubstituted aldehydes containing a hydroxy group in the ortho-position resulted in significantly lower yields (26%) for the corresponding product (3o), a fact not observed for the

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

• , deprotonation, and intramolecular addition to ketone. Treatment of the silacycle with MeMgCl cleaved the Si–O bond and subsequent intramolecular nucleophilic substitution of the chloride with the adjacent hydroxy group yielded TMS-epoxide 41. Protonic acid-mediated opening of the TMS-epoxide, accompanied by TES

• ]dec-5-ene)-catalyzed intramolecular aldol reaction connected C6 and C8, assembling the trans-pentalene ring and affording the core carbon framework of illisimonin A. The C1 hydroxy group was initially introduced by a Mukaiyama hydration reaction using O2 as the stoichiometric oxidant; however

• hydroxy group could be responsible for this reversal in selectivity. Dai’s asymmetric synthesis of (−)-illisimonin A In 2025, Dai and co-workers accomplished an asymmetric total synthesis of (−)-illisimonin A in 16 steps from (S)-carvone (67) using a pattern-recognition strategy and five sequential olefin

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

• core, successfully completing the first asymmetric total synthesis of ryanodol (4) in 41 steps. To elucidate the role of the C15 hemiacetal hydroxy group in ryanodine (1)-type diterpenoid natural products in binding to ryanodine receptors, the authors initially proposed reducing the lactone moiety in

• secondary hydroxy group, successfully achieving the conversion of ryanodol (4) to 3-epi-ryanodol (5) and 3-epi-ryanodine (30) [45]. The specific synthetic route is as follows (Scheme 3): Beginning with ryanodol (4), an acid-promoted fragmentation yields anhydroryanodol (10). Subjecting compound 10 to Li/NH3

• ryanodine (1) from ryanodol (4) – had long eluded chemists. The primary challenge involved the selective installation of the bulky pyrrole unit onto the sterically congested C3 secondary hydroxy group within a polyfunctionalized, polyhydroxylated framework. In 2016, building upon prior work, the Inoue group

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• -dicarboxylates by its one-pot reduction–alkylation using NaBH4 in DMF followed by an alkylating agent. Base-promoted cyclization of electron-deficient 3-alkylthio derivatives furnished 2-aryl-, 2-aroyl-, and 2-cyano-substituted thieno[3,2-b]thiophenes, bearing a 3-hydroxy group. This protocol broadens access to

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

• approach to the synthesis of taiwaniaquinoids was applied by Gademann et al. [13][42] for the transition from an abietane structure to a five-membered system using a rearrangement of benzilic acid. The strong base promoted the intramolecular attack of the α-hydroxy group in compound 59 on the keto group at

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

• ][21]. Additionally, a series of vibralactone homodimers and oxime esters 10–12 were reported by the groups of Liu and Zhang, respectively [22][23]. Through modification of the primary hydroxy group, a structure-based optimization of vibralactone (6) was carried out by Liu and co-workers and yielded

• isolated via a formal [4 + 1] annulation pathway [46] (Scheme 4). Since the hydroxy group interrupted the C–H insertion, it was protected as the TES ether 23 and subjected to the same conditions. However, the reaction only afforded the C–Si insertion product 24 [47]. Based on the above results, although

• the β-lactone was converted into the linear methyl ester 19 to decrease the potential steric hinderance associated with the fused bicyclic skeleton, substrates containing a free hydroxy group or the corresponding TES ether still failed to close the cyclopentene ring. In this scenario, it was necessary

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

• a thermal Diels–Alder cycloaddition, which afforded a mixture of stereo- (endo/exo) and regioisomers, among which the desired product 46 was obtained in 45% yield as a racemic mixture. After triflation of the free hydroxy group of 46 to provide 47, an intramolecular Heck reaction was employed to

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

• configurations of the adjacent hydroxy group and methyl group (Figure 1) [24]. Therefore, a general and reliable chemical approach for the stereochemical determination of the terminal MPO-containing compounds is required. Herein, we report the development of a method for determining the absolute configuration of

• Discussion Our degradation strategy of natural products bearing an MPO moiety includes (1) acylation of hydroxy group, (2) oxidative cleavage of olefin to generate 3-acyloxy-2-methylbutanoic acid, and (3) its methyl esterification (Scheme 1A). We initially investigated derivatization strategies to enable LC

• 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

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

• hydroxy group at the α-position of the carboxyl group (Scheme 10) [38]. Yang and his team reported a metal-free catalytic system for the conversion of LA to PA (Scheme 10a). The use of NaI as catalyst and PA itself as solvent allowed to simplify the product separation process, giving yields up to 99

•  12) [43]. Many other studies have concerned lactic acid (LA) because of its low cost and versatile reactivity owing to the presence of one hydroxy group and one carboxylic group. Zhou et al. [44] summarized the selective catalytic (chemical or biological) pathways for the conversion of lactic acid

• hydroxy group on the carbonyl group of the ozonide triggers the formation of HFO in high yields (>90%) (Scheme 34) [113][114][115]. Kailasam and co-workers reported a heterogeneous photocatalytic oxidation of furfural towards HFO and maleic anhydride (MAN) [116]. This conversion is performed under

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

• catalytic asymmetric methods [26], we intended to probe this biomimetic oxidative cyclization transformation [27][28]. In 2013, we first used monocerin as a model target molecule to initiate our study (Scheme 3a). Starting from benzaldehyde 11 with an isopropyl group on the hydroxy group in 4-position

Switchable pathways of multicomponent heterocyclizations of 5-amino-1,2,4-triazoles with salicylaldehydes and pyruvic acid

• Yana I. Sakhno,
• Oleksander V. Buravov,
• Kostyantyn Yu. Yurkov,
• Anastasia Yu. Andryushchenko,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2030–2035, doi:10.3762/bjoc.21.158

• substituted salicylaldehydes are particularly interesting because of the possibility of additional reactions and post-cyclizations involving the o-hydroxy group. It was demonstrated [10][11][12] that the multicomponent reaction of substituted 3-amino-1,2,4-triazoles, various salicylaldehydes, and acetone

• NMR spectra of heterocyclic acids 5a–c exhibited a broad singlet of proton of the carboxyl group at 11.88–14.02 ppm, a singlet of proton of the hydroxy group at 9.41–9.86 ppm, a singlet of proton of the pyrimidine NH group at 7.72–7.91 ppm, a singlet of proton of the triazolylamine NH group at 7.44

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• afforded the corresponding alcohol 18 in 89% yield with excellent enantioselectivity (98% ee) [25]. The hydroxy group in 18 was then protected via treatment with TBSCl in the presence of Et3N in CH2Cl2, yielding β-keto ester 15 in 52% yield. With diketone 15 in hand, we subsequently investigated the

• intermediate 22 (see Supporting Information File 1 for the details). Reasoning that the preferential coordination of the palladium catalyst with the hydroxy group at C15 and the carbonyl group at C18 in compound 22 may have deactivated the palladium catalyst [34], we protected the hydroxy group. Compound 22

• controlled by the stereoelectronic effect of the axial hydroxy group at C11 (Scheme 4) [28]. First, β-keto ester 21 was synthesized (Scheme 5). Cross-metathesis of allylic alcohol 18 and olefin 28 with the assistance of the Hoveyda–Grubbs second-generation catalyst delivered the desired product 27 in 68

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

• functionalization of one hydroxy group, offers beneficial procedures for accessing diverse structural motifs. In this review, we highlight a curated compilation of publications, focusing on the applications of enantioselective desymmetrization of prochiral 1,3-diols in the synthesis of natural products and

• intramolecular cyclization of 16 generated benzofuran 17 in 83% yield. After protecting the phenolic hydroxy group of 17, cross-metathesis (CM) with allylic alcohol 18 catalyzed by 13 furnished intermediate 19. Desilylation of 19 produced heliannuol G (20) and heliannuol H (21), with the structure of 21

• enantioenriched monoester 53 in hand, the synthesis proceeded toward fredericamycin A (60) (Scheme 9). Dione 55, which was prepared from 53 in six steps, underwent addition with alkyne 56 followed by acylation of the resulting hydroxy group with compound 57 to yield ketone 58. A subsequent seven-step

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• planarly chiral paracyclophanes [39]. Commenced with a macrocyclization precursor 36 featuring both a hydroxy group and an allenamide moiety, the CPA-catalyzed asymmetric intramolecular addition led to the successful construction of planarly chiral macrocycles 37 (Scheme 10). This method demonstrated broad

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• the amine group would function as the catalytic unit for the Knoevenagel reaction, while the hydroxy group would serve as a handle through which we would tune the lipophilicity of the catalyst. Recently, we found that isopropyl isocyanate reacts preferentially at the DPG hydroxy groups of KSU-1 [46

• with isopropyl isocyanate and tert-butyl isocyanate required 3 and 4 hours respectively to achieve complete conversion at the hydroxy group without any amine reaction. With n-hexyl isocyanate and tetradecyl isocyanate, reaction at the amine was observed after just one hour, before complete conversion

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

• , Pd scavengers have to be considered at the work-up. Unsaturated amides trans-S-5 and trans-R-5 were transformed to oxazolines S-6 and R-6 in good yields by mesylation of the hydroxy group (Scheme 5). Having both enantiomers in hand, the enantiomeric excess of oxazolines S-6 and R-6 was determined by

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

• system, a variety of other factors commonly influences both the reaction rate and the stereochemical outcome of the glycosylation reaction, including the reactivity of the acceptor hydroxy group, the effect of remote protecting groups and a balance between the nucleophilicity of the acceptor and the

• anomeric configuration of the lactol acceptor is particularly challenging when the desired form is not thermodynamically favored, as is the case with β-mannose derivatives. A refined strategy employing cyclic stannanes to lock the anomeric hydroxy group of a mannose-derived lactol in the equatorial

• ]. Diarylborinic acids have been shown to provide exclusive catalytic performance in the site-selective monofunctionalization of various 1,2- and 1,3-diols [60], as well as in the regioselective glycosylation of polyhydroxyglycosyl acceptors via base-promoted deprotonation of a specific hydroxy group involved in

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• % yield with a cyclopropyl group. Then reducing the carboxylate group in 4 with DIBAL-H afforded alcohol 5 in 67% yield. Next, Sonogashira coupling reaction between 5 and trimethylsilylacetylene generated 6 with an alkyne moiety quantitatively. After that, the hydroxy group in 6 was oxidized into a

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• Nozaki–Hiyama–Kishi reaction and a one-pot Prins cyclization/transannular hydride transfer to construct the 5-8-5 tricyclic scaffold. Enzymatic oxidations were used to install the hydroxy group at the C-3 position. Ten fusicoccanes were synthesized in 8–13 steps each. Despite these efforts, a strategy

• cotylenin A and cotylenol (Figure 3a). Oxidation of brassicicene I with Dess–Martin reagent afforded intermediate 9 in 92% yield. The tertiary hydroxy group of compound 9 was further protected with a TMS group to provide compound 10 in 90% yield, a key intermediate in the synthesis of cotylenol and

• cotylenin A by Nakada and co-workers [21]. However, installing the C9 hydroxy group requires the use of stoichiometric MoOPH [39], which raises toxicity and safety issues. Therefore, we sought an enzymatic method to selectively oxidize 5 at the C9 position. Dairi and co-workers reported that Orf7 oxidizes

Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• )quinolin-7-ol (2) Diazotization of pentafluoroaniline has been recommended to be carried out in nonaqueous media or concentrated mineral acid, otherwise the coupling product always contains a hydroxy group on the perfluorophenyl ring at the position para to the azo group. It appears that when solutions of

• the diazonium salts are made alkaline the para-fluorine atom is so readily replaced by a hydroxy group, and that the 4-hydroxy-2,3,5,6-tetrafluorobenzene cation is the entity formed first [90][91]. A 50 mL round-bottomed flask equipped with a mini magnet was charged with pentafluoroaniline (0.64 g

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

• condensation product, compound 2. Compound 1 is proposed to further undergo a dehydration reaction by the elimination of the α-proton and β-hydroxy group of the threonine residue to form compound 3. Compound 4 is a product of methylation of 3 carboxyl functionality (see Figure 4). These compounds are possibly

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

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

• epoxidation and regioselective reduction to install the hydroxy group at the C3 position [39]. In their retrosynthetic analysis, the target molecule 61 was envisioned to be obtained from epoxide 63 through regioselective opening of the epoxide ring, oxidation of the resulting primary alcohol to a carboxylic

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

• the reduction of amide-generated ketone 12 after a subsequent Dess–Martin oxidation. Upon treatment of 12 with Co(acac)2 and PhSiH3 in iPrOH at 80 °C, the Mukaiyama hydration of enamide delivered hemiaminal 13. Despite the incorrect configuration of the newly formed hydroxy group, it is considered

• a fragmentation process for the total synthesis of (−)-phlegmariurine B. A one-pot epoxidation/nucleophilic epoxide opening introduced both a hydroxy group and a chloride across the cyclopentene, producing 14 in 57% yield. After oxidation of alcohol 14 to ketone 15, the Mukaiyama hydration then

• photocyclization. This transformation was carried out using a high-pressure mercury vapor lamp to afford benzazepine 22, completing the construction of the pentacyclic framework of the natural product. Subsequent functional group manipulations, including the Chugaev elimination of the hydroxy group on the