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

• 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

• , achieved the total synthesis of anhydroryanodol (10) and a formal synthesis of ryanodol (4) through a key low-valent titanium-mediated intramolecular stereoselective coupling of alkynes with 1,3-dicarbonyl compounds [52] (Scheme 9). To construct the oxygenated fused-ring system with contiguous

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

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

• -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

• 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

• photoenzymatic transformation developed by the Hyster group, α-chloroamides were converted to enantioenriched 5-, 6-, 7-, and 8-membered lactams through an enantioselective radical cyclization followed by a diastereoselective HAT, producing contiguous stereocenters [75]. In the subsequent year, the same group

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

• sesquiterpenoids, toxicodenanes A–C and E (see representative structure 16 in Scheme 7) were isolated from Toxicodendron vernicifluum in 2013 to 2015 [63][64], whose structures feature the all-carbon bicyclic skeleton and four to seven contiguous stereocenters, posing significant challenges to their synthesis

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

• -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

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

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• using acyclic enones 14 [27]. Their tandem conjugate addition/Mannich reaction methodology offers access to various non-cyclic β-aminoketones 16 with multiple contiguous stereocenters in high diastereo- and enantioselectivity (Scheme 5a). Additionally, chiral isoindolinones 18 and 2,3,4-trisubstituted

• enantioselective tandem borylation/intramolecular aldol cyclization procedure (Scheme 37) [78]. The desymmetrization process of cyclic diones 147 gave the densely functionalized bicyclic products 148 with four contiguous stereocenters usually in a highly diastereoselective fashion. Presumably, the difference in

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• ), where the eight-membered ring was accessed through a SmI2-mediated cyclization cascade reaction of a dialdehyde [69]. In this approach, an original way was proposed to form in a single step the tricyclic core of pleuromutilin (1) with a stereocontrol at the four contiguous stereocenters [69][70]. The

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• White’s oxidation method as the final step in the first total synthesis of gracilioether F (75) [157], a natural polyketide with an unusual tricyclic core and five contiguous stereocenters, part of the family of gracilioethers 71–74 (Scheme 26A) extracted from the marine sponge Plakinastrella mamillaris

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• region on chromosome 6 [172]. Chemically, pyripyropene (PP) analogs are meroterpenoids containing a fused pyridyl α-pyrone moiety and eight contiguous stereocenters [170]. Metabolically, PPPA non-covalently binds within the fifth transmembrane domain of acyl-coenzyme A (CoA):cholesterol acyltransferase

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• three contiguous stereocenters in one single operation [59]. The utility of this approach is showcased in the enantioselective total synthesis of (+)-prelactones B, C, and V, as shown in Scheme 25. Yadav’s group reported the synthesis of 4-iodotetrahydropyrans (dr = 7.5:2.5) from aromatic aldehyde 111

• addition to construct a homoallylic alcohol, followed by Prins cyclization to furnish 2,3,4,5,6-pentasubstituted tetrahydropyrans 137 using β,γ-unsaturated N-acyloxazolidin-2-ones 134 as a key precursor [67]. In this Evans aldol−Prins (EAP) protocol, four new σ-bonds and five contiguous stereocenters were

• 302 and substituted aromatic aldehydes 303 to form hexahydro-1H-benzo[f]isochromenes 305 with three new contiguous stereocenters in high enantio- and diastereoselectivity [112]. The three new contiguous stereogenic centers formed resulted from an attack of the alkene to the Si-face of the oxocarbenium

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• (inclusive). Keywords: all-carbon; cyclization; [3 + 2] cycloaddition; natural product synthesis; stereocenters; Introduction The highly-substituted, stereo-congested, five-membered carbocycle containing contiguous stereocenters is one of the most common structural features in many structurally complicated

• % yield, which possesses three contiguous stereocenters with vicinal all-carbon quaternary centers. (Scheme 11A). According to the proposed mechanism, coordination of the triple bond of 142 to the electrophilic platinum complex A followed by intramolecular nucleophilic attack by the methoxy group gives

• ) catalyst and subsequent base-promoted epimerization produced meloscine (158) in 83% yield. In 2017, Yang and co-workers disclosed the synthesis of (−)-pavidolide B (166) by using a thiyl-radical-mediated [3 + 2] annulation reaction to create four contiguous stereocenters on tricycle 162 in one step [71][72

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• University, Leninskie Gory, 1, 119991, Mosсow, Russian Federation 10.3762/bjoc.16.174 Abstract A new synthetic strategy toward nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes with three and five contiguous stereocenters is presented. Readily available β-keto phosphonates react with

• diastereoselectively, such has been previously described [45]. These considerations prompted us to explore further applications of 4-nitro-2-oxophosphonates containing two contiguous stereocenters for the synthesis of the target compounds. Initially, 4-nitro-2-oxophosphonates 6a–f (Figure 2) were synthesized similar

• assumed by analogy. Dehydration of compound 13b in the presence of p-toluenesulfonic acid gives dihydropyran 14 as a single stereoisomer (Scheme 4). Conclusion In summary, a convenient protocol for the synthesis of phosphoryl-substituted pyrrolidines with three contiguous stereocenters via asymmetric

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• to access functionalized alkylidenecyclopropanes, with creation of a new carbon–carbon bond on the three-membered ring with the control of two contiguous stereocenters. Ireland–Claisen rearrangement of cyclopropenylcarbinyl esters The Ireland–Claisen rearrangement of silyl ketene acetals generated

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• spirocyclopentaneoxindoles containing multiple contiguous stereocenters remains challenging [23][24][25][26]. The medicinal properties of these frameworks mean that fast enrichment of spirooxindoles bearing diverse functional groups is of considerable importance. Recently, an increasing number of asymmetric catalysis

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

• Sara Meninno,
• Chiara Volpe,
• Giorgio Della Sala,
• Amedeo Capobianco and
• Alessandra Lattanzi

Beilstein J. Org. Chem. 2016, 12, 643–647, doi:10.3762/bjoc.12.63

• giving four diastereoisomers instead [21]. Finally, the sulfa-Michael/nitroaldol cascade reaction was applied to other trans-β-methyl-β-nitrostyrenes under the optimized conditions (Table 3). Tetrahydrothiophenes, bearing three contiguous stereocenters, were isolated in good to high yield, moderate

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• first tested in the reaction of trans-nitrostyrene (1a) with diethyl malonate (2a), leading to the enantioenriched addition product 4aa with a single stereocenter. In order to the creation of two tertiary-quaternary contiguous stereocenters (5aa) we also used ethyl 2-oxocyclopentanecarboxylate (3a) as

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• 64 in good yield. The substrate scope of this reaction was thoroughly studied and the products of the transformation were exploited to generate a variety of γ-amino acids, including examples containing three contiguous stereocenters. In 2010, Yan and co-workers described the Michael addition of

• multiple contiguous stereocenters, including one quaternary center [35]. The reaction proceeded smoothly and a wide range of products 75 were obtained in good yields and moderate to excellent stereoselectivity (Scheme 26). The authors proposed that the organocatalyst deprotonates substrate 73 to produce a

• , Enders and co-workers described the three-component domino Michael–Michael aldol reaction between β-ketoesters 153, nitroalkenes 77 and α,β-unsaturated aldehydes 154, producing heavily substituted cyclohexanes 155 containing six contiguous stereocenters with excellent stereocontrol (Scheme 49) [70]. In

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of

• clinical application of 1, as well as the development of more active derivatives. Due to the unique tricyclic core of 1, which bears four contiguous stereocenters, various approaches for the synthesis of key intermediate 2 (Scheme 1) have been reported [14][15][16][17][18][19][20][21][22][23], including a

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• rearrangements and cyclizations experimentally. The structure elucidation of terpenoids can be challenging because of the multicyclic carbon skeletons with several contiguous stereocenters. The assistance of 13C labels can in such cases be especially helpful, and if completely 13C-labeled carbon backbones can be

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• member of the Aspidosperma alkaloid family, but it also holds particular significance as a valuable precursor to pharmaceutically important vincamine, vincamone, and cavinton [94][95][96][97]. The molecule has a fused pentacyclic framework with three contiguous stereocenters, two of which are all-carbon