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

• -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

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

• and structurally established [16][17][18]. Structurally, ryanodine (1) and related diterpenoid natural products feature a 6-5-5-5-6 pentacyclic core skeleton containing 11 stereocenters, eight of which are quaternary carbons. A key structural feature is the assembly of a polycyclic cage-like framework

• -alkoxy bridgehead radical addition then installed an allyl fragment, and ring-closing metathesis (RCM) smoothly formed the C ring to complete the core skeleton. The total synthesis was finalized by installing the four remaining stereocenters (C2, C3, C9, and C10). The specific synthetic route is as

• stereocenters characteristic of the target molecule, the authors strategically implemented this methodology. This approach efficiently established two carbon–carbon and four carbon–oxygen bonds while introducing four contiguous stereocenters, successfully assembling the highly functionalized AB ring system

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

• a sterically compact [6-5-5] tricyclic skeleton, as well as a highly strained trans-fused bicyclo[3.3.0]octane ring system and seven contiguous stereocenters. A structurally interesting diol 52 was diastereoselectively obtained using a linear sequence of 14 steps starting from the readily available

• multiple stereocenters, including contiguous quaternary carbons. As a result, the carboborative ring contraction reaction is conveniently used for structural modification of natural products containing a cyclohexene ring and in the synthesis of new compounds to increase their activity, metabolic stability

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

• Terpenoids 1.1 (+)-Cyclobutastellettolide B (+)-Cyclobutastellettolide B (13), featuring an unusual 6/6/4-fused tricyclic core with six stereocenters – including three contiguous quaternary stereocenters – was first isolated by Stonik et al. in 2019 from a Stelletta sp. sponge collected in Vietnamese waters

• ingeniously leverages the high selectivity of photochemical reactions and the strain-release property of rearrangement reactions, enabling the precise construction of multiple stereocenters in one step and overcoming the synthetic challenges posed by contiguous quaternary carbon centers and sterically

• -obscurine (83) as a late-stage common intermediate. Compound 83 was readily accessible via previously reported protocols [40], which featured a diastereoselective formal [3 + 3] cycloaddition between 76 and 81 as the key step. This cycloaddition constructs the three contiguous stereocenters and two C–C

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• [22][23]. In these studies, alkyl radicals underwent conjugate addition to N-enoyloxazolidinones. Sibi later described enantioselective tandem radical conjugate addition–trapping reactions that formed two carbon–carbon bonds and created two vicinal stereocenters in a single transformation (Scheme 1

• single process that established five new carbon–carbon bonds and nine contiguous stereocenters, including four all-carbon quaternary centers (Scheme 3). Transition-metal-catalyzed radical reactions Recent advances in enantioselective radical reactions catalyzed by base metals (e.g., Fe, Co, Ni, Mn

• decatungstate (TBADT) and chiral amine 33 was able to catalyze the reaction between benzodioxoles 32 and cyclic β,β-disubstituted enones 31. Cyclic ketones 34 bearing all-carbon quaternary stereocenters at the β-position were obtained in good yields and high enantioselectivity. Enzyme-catalyzed radical

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 desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds is a powerful tool for the construction of ring systems bearing multiple stereocenters including all-carbon quaternary stereocenters, which are widely useful chiral building blocks for the total synthesis of structurally

• 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

• , (−)-glaucopine C, and (+)-allocyathin B2 The cyrneine diterpenoids represent an important subfamily of cyathane diterpenoids which possess a common 5-6-7 fused tricarbocyclic core with two all-carbon quaternary stereocenters. Many impressive syntheses have been reported to date [18][19][20][21][22][23][24][25

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

• available has prevented its practical use, and synthesis methods for tricyclic-PGDM methyl ester are required. Based on the utilization of oxidative radical cyclization for the stereoselective construction of the cyclopentanol subunit with three consecutive stereocenters, we describe an asymmetric total

• -selective cross-metathesis, respectively [9]. In general, racemic cyclopentanol precursors (A ring system, prepared in 6–9 steps) have been used to form the polyfunctionalized tricyclic frameworks incorporating contiguous stereocenters. In previous syntheses, the efficient construction of the cyclopentanol

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

• -worker described the asymmetric synthesis of (−)-rasfonin, harnessing an enantioselective enzymatic desymmetrization with lipase AK and an enzymatic oxidative kinetic resolution to install stereocenters [47]. The synthesis commenced with the preparation of fragment 100 from ethylene glycol (97) (Scheme

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• thiohydantoin 7, on the contrary, have a trans configuration of two vicinal stereocenters (Scheme 3 and Figure 1). Thus, in all cases we have obtained, probably, the most thermodynamically favorable isomers. This result allows us to assume a stepwise mechanism of the ylide addition to the double bond of

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

• the correct stereochemistry of the newly formed three stereocenters. Additionally, replacing cesium carbonate with triethylamine proved crucial for achieving efficient asymmetric hydrogenation in this case. Subsequently, the carboxylic acid group of 57 was reduced with LiAlH4 in THF to produce primary

• ]. Their method was based on the concept of “catalytic total synthesis”, wherein all stereocenters were installed under the control of catalysts. Minnaard and Madduri proposed the synthesis of the C1–C11 fragment from unsaturated thioester 92 through iterative, previously developed asymmetric 1,4-addition

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• , obtaining a separable mixture of the major cis and minor trans diastereomers of the sp3-enriched pyrazolodiazepine 17. The relative configuration of the stereocenters in the major cis isomer of 17 was established via scXRD analysis. Both diastereomers of 17 were found to be amenable to chemoselective amide

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• quaternary centers that contain functional groups is challenging mainly because of their sterically demanding property [9][10][11]. In this context, the incorporation of cyano groups at the quaternary carbon centers is promising for the development of versatile acyclic all-carbon quaternary stereocenters

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• azetidinones, enabling the efficient and enantioselective synthesis of tetrahydroquinoline-fused azetidines with three contiguous stereocenters in a single step [23]. Later, Tanaka, Nagashima, and their co-workers established a chemo-, regio-, and diastereoselective dearomative transformation of quinolines

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• ; chiral halonium salt; contiguous stereocenters; halogen bonding; Mannich reaction; Introduction Halogen bonding (XB) has attracted intense research attention for its unique interaction between halogen atoms and electron-rich substituents [1]. XB has been applied to various fields of chemistry, such as

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• standard conditions. Subsequently, radical-polar coupling between electrophilic Ni-bound α-carbonyl radical intermediate 45 and remaining nucleophilic Cu-enolate 44 provides a chiral product 42 containing vicinal quaternary stereocenters with high stereoselectivity, and all three possible stereoisomers of

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

• bifunctional squaramide-catalyzed asymmetric domino Mannich/formal [4 + 2] cyclization of 2-benzothiazolimines 21 with azlactones 15 [30]. Using cinchona-derived squaramide VII it was possible to obtain 25 different chiral benzothiazolopyrimidines 22 bearing adjacent tertiary and quaternary stereocenters in up

• isocyanide carbon, behaves a C3 synthon affording benzo[d]isothiazole 1,1-dioxide-dihydropyrroles 27 bearing two adjacent stereocenters in high yields (27–98%) and with moderate to excellent stereoselectivities (54–97% ee) when using thiourea IX (Scheme 10). The cyclization was observed with all derivatives

• methodology to synthesize interesting benzofuran-fused 2-piperidinol derivatives 29 and 31 bearing three adjacent stereocenters using squaramide X as organocatalyst (Scheme 11). Firstly, the reaction between azadiene 11 and trimethylsilyl dienolate 28 was explored obtaining 16 different derivatives in

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• , halogen bonding is an important interaction in biological systems [12][13][14][15][16][17] and the beneficial effect of the chloro substituent has been reviewed recently [18]. As a result, there is a lack of efficient synthetic strategies to access multivicinal inter-halide stereocenters (i.e., contiguous

• chiral halides: F, Cl, Br, I) [19]. Only a handful of natural product syntheses have been reported [20][21], despite the promising biological activity of these unique inter-halides [22]. For our part, we recently reported the synthesis of contiguous inter-halide-bearing stereocenters using a Chiron

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• medicines such as erythromycin and rapamycin. They are often rich in stereocenters biosynthesized by the ketoreductase (KR) domain within the polyketide synthase (PKS) assembly line. Previous studies have identified conserved motifs in KR sequences that enable the bioinformatic prediction of product

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• diols by addition of water. For each of these intermediates, simple deprotonation or nucleophilic attack by water are possible. Also, hydride shifts can occur first, which widens the chemical space of possible products. Additionally, the presence of multiple stereocenters adds to the rich

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• stereoselective process to form complex terpene skeletons, normally with multiple stereocenters. In this context, the 3D-defined cyclization products retain the rich information of the complex cyclization process. Thus, assignment of the stereochemistry of the terpene skeleton with high confidence is crucial for

• stereocenters was elucidated on the basis of their NOESY spectra. Thus, the key NOE correlations of H-1/H-6, H-1/H3-19, and H-2/H3-20 of 9 allowed to assign the 1-OH to be α-oriented, while correlations of H-9/H-14 of 10, and H-9/H-3 of 11, supported the assignment of 9α- and 9β-oriented hydroxy groups

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• chemical shifts of allylic carbons [19]. Unfortunately, we were unable to determine the absolute configurations of Hya and three stereocenters in 4-amino-7-guanidino-3-hydroxy-2-methylheptanoic acid. ʟ-threo-Hya is reportedly present in 1, based on the elution order of FDAA (Nα-(5-fluoro-2,4-dinitrophenyl

• )-ʟ-alaninamide) derivatives [5]. In addition, a combination of NOESY and bioinformatics analyses proposed all three stereocenters of 4-amino-7-guanidino-3-hydroxy-2-methylheptanoic acid as S configured [5]. The stereochemistry of these moieties in 3–5 are discussed in the next section, regarding the

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• bicyclic cinmethylin (1) and methiozolin (2), substituted 1,8-naphthyridine 4 does not contain any stereocenters but still displays promising efficacy against grass weeds. Further considering the rather low molecular weight (220 g/mol) and structural simplicity, compound 4 is a highly attractive initial

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

• ). Pioneering work by Schnermann and Overman demonstrated the early potential of photocatalytic Giese-type additions, successfully coupling two complex ring fragments and creating adjacent stereocenters, which effectively solved major challenges in the synthesis of (–)-aplyviolene [38] (Scheme 37A). Brown and

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• stereocenters [7]. In the Review paper by Kisszékelyi and Šebesta, the diverse variety of chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents and the possibilities to engage metal enolates in tandem reactions with new electrophiles are presented [8]. A Perspective from X

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• surface of carbon allotropes can increase diastereo- and enantioselectivity of Diels–Alder reactions. The direct formation of 1,3-nonadjacent stereocenters is a topic of concern in asymmetric catalysis [67]. To explore compatibility with anion–π catalysis, the addition of ethyl 2-cyano-2-phenylacetate (28

• selectivity generally increases with the polarizability of the carbon allotrope. Other reactions like asymmetric anion Diels-Alder reactions, the construction of 1,3-nonadjacent stereocenters and bioinspired ether cyclizations have been realized as well. The emerging combination with oriented external