Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• ] cycloaddition reaction with the nitroalkene produces the pyrrolidine XXVII, which then aromatizes by extrusion of HNO2 (Scheme 21) [38]. Substituted pyrrolidines 30 were achieved in an enantioselective form starting from amino acid esters, electron-poor olefins and 4-substituted-2-picolinaldehydes or 4

• -dihydroquinazolin-4(1H)-one derivatives 26. Synthesis of polysubstituted pyrroles 27. Enantioselective synthesis of polysubstituted pyrrolidines 30 directed by the copper complex 29. Synthesis of 4,5-dihydropyrazoles 31. Synthesis of 2 arylisoindolinones 32. Synthesis of imidazo[1,2-a]pyridines 33. Synthesis of

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• are of interest and have been recently investigated by Jørgensen and co-workers. The authors employed an enantioselective aminocatalytic cycloaddition between 5H-benzo[a]pyrrolizine-3-carbaldehydes 22 and naphthyl-substituted nitroalkenes, α,β-unsaturated ketoesters, or α,β-unsaturated aldehydes 23

• reaction pathway was proposed [56]. The first step is a CPA C27-catalyzed condensation giving rise to the imine intermediate followed by isomerization to the enamine stabilized by CPA. An enantioselective intramolecular cyclization followed by dehydration then afford the aromatic ring and desired product

• and stereoselectivities (85%, 90% ee, >95:5 E/Z). A biological activity investigation led to promising results in the case of one substrate displaying cytotoxicity towards several cancer cell lines. Organocatalytic enantioselective construction of axially chiral styrenes 175 and 177 was done utilizing

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

• -heterocycles using various catalytic systems such as chiral metal catalysts, chiral Lewis acids or chiral organocatalysts. This review presents an overview of the recent advances in enantioselective cyclization reactions of 1-azadienes catalyzed by non-covalent organocatalysts. Keywords: α,β-unsaturated

• dienophile, and therefore it proceeds through the reaction of electron-poor dienes and electron-rich dienophiles (Figure 2b). α,β-Unsaturated imines can undergo inverse electron demand aza-Diels–Alder reactions (IEDADA) to produce N-heterocyclic compounds. The search for an enantioselective pathway to carry

• out IEDADA reactions has been a glowing field in recent years [11][12]. In particular, organocatalysis can provide different activation modes to promote enantioselective IEDADA reactions [13][14], based on three strategies (Figure 3): i) LUMO-lowering activation (Brønsted acid catalysis), ii) HOMO

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• formed. The use of a chiral aryl iodide was tested, which gave products with low enantiomeric excess. However, these preliminary trials represent the first example of a catalytic, enantioselective HVI-mediated fluorocyclisation. The authors proposed a mechanism (Scheme 4) for this reaction that involved

• fluoroacetate as an internal standard). Electrochemical synthesis of fluorinated oxazolines. Electrochemical synthesis of chromanes. Synthesis of fluorinated oxazepanes. Enantioselective oxy-fluorination with a chiral aryliodide catayst. Catalytic synthesis of 5‑fluoro-2-aryloxazolines using BF3·Et2O as a

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• , the enantioselectivity consistently decreased as the chiral pocket became narrower while the reactivity remained the same. As such, we reduced the size of the substituents that craft the chiral pocket (7) and found that unsubstituted catalyst 8 was the most enantioselective. This observed catalyst

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• formation of peroxide 9. The enantioselective peroxidation of alkenes 10 with TBHP with the formation of the optically active products 11 was carried out in good yields and low ee by the use of in situ-generated chiral bisoxazoline–copper(I) complexes (Scheme 7) [43]. Studying the oxidation of α-pinene (12

• . The oxidation of benzyl alcohol 62 with TBHP results in aldehyde C, HAT from which by tert-butoxy radical A leads to the C-centered radical D. Subsequent recombination of radicals D and B provides the target product 63. An enantioselective peroxidation method of alkylaromatics with TBHP using chiral

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• advancements have broadened the scope of Michael donors and acceptors to encompass fluorine-containing compounds, enhancing the reaction's utility in synthesizing fluorinated derivatives [7][8]. Shibata and colleagues pioneered the use of fluorinated Michael donors, notably achieving enantioselective addition

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• reports on the preparation of chiral molecules possessing a tetrafluoroethylene unit on an asymmetric carbon center in a high optical purity, and to the best of our knowledge, only the following have been published so far (Scheme 1). As a highly enantioselective synthesis, there has been a pioneering work

• high enantiomeric excess (90% ee for (S)-23d and (S)-23e). Furthermore, it was found that the substituent position on the aromatic ring did not significantly influence the reaction efficiency as well as optical purity and the reaction proceeded in a highly enantioselective manner (91% ee for (S)-23f

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• et al. [63][64] reported the first amine-mediated highly enantioselective copper-catalyzed asymmetric yne-allylic substitution, affording 1,4-enynes with up to 98% ee and >20:1 rr. A series of secondary amines can react smoothly and achieve good enantioselectivities and regioselectivities (Scheme 7

• vinyl allenylidene is the key intermediate during the process (Scheme 14). Recently, Fang et al. [67] used electron-rich arenes as the nucleophiles to achieve remote enantioselective control of yne-allylic substitutions. It is worth noting that when indoles or indolizines were used, the reactions

• confirmed that a copper–ligand monomer complex exists in the mechanism through nonlinear relationship experiments and kinetic studies (Scheme 17). He et al. [68] developed the regio- and enantioselective monofluoroalkylation of yne-allylic esters using fluorinated malonates as the starting materials, giving

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen”, an interesting approach to recycling the very useful cinchona squaramide organocatalysts was described. This approach involved functionalization of the organocatalyst with a lipophilic linker (octadecyl side chains), resulting in a

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• product (Scheme 34). To date, only a few enantioselective reactions using metal catalysis and electrochemistry have been reported. Very recently, Ackermann and coworkers employed Co(OAc)2 as a catalyst and a salicyloxazoline derivative as a chiral ligand to achieve the electrochemical atroposelective C–H

• ). In 2023, the Guo group reported the enantioselective cross-dehydrogenative amination via electrochemical oxidation of C–H and N–H bonds, successfully achieved the LSF of several bioactive molecules and natural products with good yields and high stereoselectivities [50]. The plausible catalytic

• applications of electrochemical methods in organic synthesis. In this context the Meggers group developed an asymmetric Rh catalyst-promoted alkylation [56]. The Rh complex was used as a chiral catalyst and Cp2Fe as an anodic oxidation catalyst to achieve the enantioselective C(sp3)–H alkenylation of 2

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• are applicable to various substrates within the same reaction type [211][212][213][214][215]. For instance, the generality of chiral catalysts for asymmetric or enantioselective catalysis has been a longstanding interest in synthetic chemistry [216]. Angello et al. [53] applied uncertainty-minimizing

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• important area of study as this ring system is prevalent in many useful molecules. Typical literature procedures include multistep derivations of proline itself, e.g., the destruction of the stereocenter and then its reinstallation by an enantioselective conjugate addition [9]. Other methods include the

• enantioselective conjugate addition to α,β-unsaturated pyroglutamic acid derivatives followed by deoxygenation [10], and the enantioselective organocatalytic reaction between 2-acylaminomalonates and α,β-unsaturated aldehydes [11][12]. The development of new synthetic methods using hypervalent iodine reagents has

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• highly enantioselective nucleophilic addition of primary (10), secondary, and even tertiary allylboronates, as well as allenylboronates to a broad set of imines, bearing the N-phosphinoyl group. The new approach allowed the activation of both the substrate and the reagent using aminophenol organocatalyst

• organocatalytic enantioselective Hosomi–Sakurai reaction of imines using allyltrimethylsilane was reported by List and co-worker [32]. In this approach, the direct synthesis of Fmoc-protected homoallylic amines 47 was achieved by a three-component coupling of allyltrimethylsilane (46) with the in situ-formed N

• securing the enantioselectivity of the reaction by locking the catalyst in the more active and enantioselective Z-configuration (Figure 2). Further, the authors found that H-bond donors featuring urea, thiourea, and guanidine motifs were either inactive or provided racemic mixtures. Among 3,5-dichloro

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• Research (NCCR) Catalysis, ETH Zurich, Zurich CH-8093, Switzerland 10.3762/bjoc.20.196 Abstract Organocatalysis has established itself as a third pillar of homogeneous catalysis, besides transition metal catalysis and biocatalysis, as its use for enantioselective reactions has gathered significant

• catalysts [3]. In particular, enantioselective organocatalysis has shown an impressive rise in the last decades, owing to the tunability of catalysts and different modes of activation, enabling a manifold of different transformations [4][5]. The development of the field, driven by many researchers, led to

• , Chen and Pollice proposed Pint as a descriptor of the London dispersion potential that is universal and can be calculated without a probe system [94]. Although Pint has not been utilised for organocatalysis, the authors applied it to a Pd-metal-catalysed enantioselective 1,1-diarylation of benzyl

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• methods, such as the application of immobilised organocatalysts [14][15] and heterogeneous organocatalysis [16][17][18], could be a potential driver for the introduction of, for example, enantioselective organocatalysis in the pharmaceutical industry [19]. Knowledge of the factors that influence catalyst

• organocatalyst also depend on the density of catalytic sites on the support surface, as well as the nature and length of the linker [8]. Additionally, the linker itself could serve as a competitive active site. In the case of enantioselective catalysis, the linker could promote the formation of racemic products

• cases, the support surface can even impede unwanted side reactions. Pericàs and co-workers immobilised a thiourea organocatalyst on PS (28) and applied it in the enantioselective α-amination of 1,3-dicarbonyl compounds [36]. Unlike homogeneous thioureas, catalyst 28 is not irreversibly deactivated by

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• –acceptor with nitroalkenes, resulting in multi-substituted cyclohexanones through a cascade inter–intramolecular double Michael addition process with high diastereoselectivity [26][27]. Subsequently, the enantioselective versions of the above reaction and a similar diastereoselective cascade Michael

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• ][28]. However, the selectivity of these photoredox reactions is driven by the structural properties of the heteroaromatic ring. During the preparation of this article, the Meggers group published an outstanding enantioselective iron-catalyzed α-amination pathway (Scheme 1b) [29]. The method is widely

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• Sao Sumida Ken Okuno Taiki Mori Yasuaki Furuya Seiji Shirakawa Institute of Integrated Science and Technology, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan 10.3762/bjoc.20.158 Abstract Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates

• required to achieve highly enantioselective halolactonizations (Scheme 1a) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates without substituents on the carbon–carbon double bond have

• -substituted 4-pentenoic acids without additional substituents on the carbon–carbon double bond (Scheme 1c) [26][27]. Chiral α-substituted γ-butyrolactone products as important building blocks for pharmaceutical development were obtained in a highly enantioselective manner in our catalytic system using

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• dearomatization of 33 via enantioselective hydroxylation using molecular oxygen and generates cyclohexadienone 34. As demonstrated by Corey [36] and Nicolaou [37], highly reactive intermediate 34 likely dimerizes non-enzymatically through stepwise reactions involving (1) an initial intermolecular Michael addition

• diversity, the research group achieved the synthesis of various dearomatized compounds, and the total synthesis of a member of the sorbicillinoid family. Enantioselective intermolecular Diels–Alder reaction to assemble core scaffolds: chalcomoracin and kuwanons Chalcomoracin (3) and kuwanons bearing a

• the Diels–Alder reactions (Scheme 6B). Notably, MaDA-3 exhibited high exo-selectivity (original MaDA: endo-selective) and enabled the enantioselective rapid total synthesis of guangsangon J (60) and mongolicin F (61), which are epimers of 58 and 3, respectively. Comparative analysis of the X-ray

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• different functional groups at the 5-position. The Shi group reported the use of Pd(II) and Selectfluor to enable the enantioselective β-fluorination of α-amino acids (Figure 6) [40]. The presence of 2-(pyridin-2-yl)isopropylamine (PIP) as directing group was essential for the formation of a four-coordinate

• from 61–75% across a series of nine benzylic substrates with various substitution patterns on the aromatic ring. In 2018, Yu and co-workers reported a palladium-catalysed enantioselective fluorination of benzylic C(sp3)–H bonds with the use of a transient chiral directing group 6 [43]. This approach

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• 10.3762/bjoc.20.136 Abstract The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine–Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent

• -covalent catalysis via bifunctional hydrogen-bonding organocatalysts. The C-4 nucleophilicity of pyrazolin-5-ones was also explored in enantioselective reactions with α,β-unsaturated carbonyl compounds through covalent catalysis with chiral amine-based catalysts; however, it has achieved limited success

• [10][11][12][13][14][15][16][17][18][19][20][21]. Among the developed organocatalyzed enantioselective 1,4-addition reactions of pyrazolin-5-ones, the catalytic asymmetric reactions of pyrazolin-5-ones with α,β-unsaturated ketones are comparatively less studied. In 2009, Zhao’s group were the first

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• easily available and cheapest nucleophilic N3 source (for other remarkable approaches using alternative catalysts and oxidants see references [24][25][26]). In addition to the racemic approach, they also showed that this reaction can be rendered enantioselective by using advanced Maruoka-type quaternary

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• studies we also realized that the masked β-AA derivatives 2 undergo enantioselective β-addition to allenoates 3 under chiral ammonium salt catalysis (Scheme 1B) [18]. Interestingly, hereby we also found that the use of alternative catalyst systems (i.e., tertiary phosphines) allows for a γ-selective