New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• contributions in stereoselective organocatalytic transformations. The collection contains nine articles featuring various aspects of asymmetric organocatalysis. In the first contribution, Waser et al. examined how chiral phase-transfer catalysts promote β-selective additions of azlactones to allenoates. Maruoka

• Malkov reviewed the recent progress in the organocatalytic synthesis of chiral homoallylic amines. This important structural motif is typically made by asymmetric allylation of imines, and the authors describe various catalytic approaches as well as applications of these strategies in total synthesis [25

• organocatalytic cycloaddition reactions of unsaturated imines. A broad variety of activation modes, as well as catalyst structures, was covered and found to be useful in affording a diverse array of chiral N-heterocycles [27]. In my group, we recently became interested in atroposelective catalytic syntheses

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• in elucidating the mechanism by which these bifunctional compounds act as powerful catalysts [21][22][23][24][25][26][27][28][29]. Since Ishihara disclosed the crucial role of calcium in many purportedly purely organocatalytic BINOL phosphate-catalyzed reactions [30][31], several asymmetric synthesis

• [40][41][42][43][44]. However, this catalytic system has not yet been employed explicitly in the hydrocyanation of hydrazones. In 2010, our group reported the first organocatalytic enantioselective hydrocyanation of hydrazones catalyzed by BINOL phosphate [45], giving valuable and potentially

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• organocatalytic synthesis of 2-cyclohexen-1-ones via a Michael/Michael/retro-Michael cascade reaction [31]. Our research has shown that the Jørgensen–Hayashi catalyst [32][33] is a highly promising organocatalyst, facilitating enantioselective Michael addition reactions with high yields and excellent levels of

• enantiocontrol [34][35][36][37][38][39]. In our studies on the organocatalytic enantioselective synthesis of 1,5-ketoaldehydes [40], we found that the prolinol derivative A is an outstanding catalyst for the enantioselective preparation of these adducts (Scheme 2). We are currently investigating whether this

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• organocatalysts [222][234] all suffer from the same limitation: they all fail to rigidly organize sufficient bifunctional groups to obtain clear transition-state binding – a hallmark of enzymes and organocatalysts [107][180]. Strategy towards organocatalytic organic cages: My laboratory has levied the following

• design criteria in the pursuit of organocatalytic organic cages: (i) efficient synthesis, ideally by self-assembly; (ii) soluble and stable in organic solvent and in the presence of reactive reagents; (iii) extreme preorganization of functionality in a cavity; (iv) the lowest possible symmetry. We

• : When we entered the field, it quickly became apparent that one reason functional organocatalytic cages had not been reported is the synthetic challenge: our chosen cage frameworks [300][302], at least, were poorly soluble [297], and required development to exploit them in the solution state (Figure 8A

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

• organocatalytic reactions are discussed according to the dominant catalyst activation mode. For covalent organocatalysis, the typical enamine and iminium modes are presented, followed by N-heterocyclic carbene-catalyzed reactions. The bulk of the review is devoted to non-covalent activation, where chiral Brønsted

• organocatalyzed, methods [7][8][9][10][11]. Asymmetric organocatalysis offers efficient and environmentally benign access to numerous chiral compounds [12]. Therefore, an increasing number of researchers are now investigating the organocatalytic formation of compounds with axial stereogenic axes across various

• advances in organocatalytic atroposelective syntheses. Review Atroposelective reactions via enamine and iminium activation Iminium activation was utilized in the synthesis of axially chiral styrenes. Tan and co-workers developed an atroposelective strategy toward axially chiral alkenylarenes 3 based on an

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

• ]. Although quite important in all organocatalytic processes, there are specific organocatalysts which activate reactants through non-covalent interactions such as hydrogen bonding. These interactions are crucial to obtain high enantioselectivity in the reaction. The 1-azadienes possess an electronegative

• utilized for a wide variety of organocatalytic processes. In this section, different cyclizations of α,β-unsaturated imines involving Brønsted base organocatalysts such as (DHQD)2-based catalysts will be described. In 2015, Jiang, Chen and co-worker published a modified cinchona alkaloid-catalyzed [4 + 2

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• -defined binding pockets, offer a preorganized arrangement of functional groups as a suitable microenvironment for organocatalysis. In 2008, Kohnke, Soriente and co-workers first reported [37] the H-bonding organocatalytic activity of calix[4]pyrrole derivatives 3 and 4 and acyclic dipyrromethane 5 for the

• due to the sp3-linkage between the pyrrole units that allows their inversion through the plane of the macrocycle and could inhibit the organocatalytic activity. 1.2 Porphyrin macrocycles as organocatalysts Porphyrins can coordinate almost any metal from the periodic table [42][43], they offer high

• factors on the organocatalytic performance in the same reaction as before (Table 2) [62]. Among the tested compounds, the highly nonplanar macrocycle 26 with a good accessibility of both pyrrolic –N/N–H moieties turned out to be the best candidate, giving an 80% conversion yield, whereas the other

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• , it is worth mentioning the work of Li and co-workers (2011) [20], who described a single example of the formation of such structures by carrying out an organocatalytic domino aza-Michael–Mannich reaction between benzylidene-1H-imidazol-2-amine and cinnamaldehyde. Although the imidazo[1,2-a

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• -hydroxybenzophenones are conventionally prepared via Fries rearrangement of a phenyl ester [10]. Organocatalytic methods have also been reported for the synthesis of 2-hydroxybenzophenones [11]. In addition, several metal-mediated methods for their synthesis have been reported. For example, the Rh-catalyzed

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

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

• 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

• equimolar chiral controller. However, recent years have witnessed the rise of asymmetric transition-metal catalysts and, importantly, organocatalytic allylation, reshaping the landscape of modern synthetic chemistry. This review explores the latest developments in the asymmetric allylation of imines

• ][18][19][20][21][22][23], none have focused specifically on organocatalytic approaches, which are particularly important for medicinal chemistry due to their greener credentials. Given the wide range of organocatalytic methods for synthesising homoallylic amines developed in the past decade, it is

• essential to provide a comprehensive overview of this significant topic. Review Asymmetric allylation with boron-based reagents The research on the metal-free, asymmetric organocatalytic allylation of acylimines was pioneered in 2007 by Schaus and co-workers [24]. In their elegant approach, high

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• [15][16] or iminium-ion catalysis [17] under ball-mill conditions are scarce, in contrast to the abundance of transformations catalyzed by such covalent catalysis. Among the numerous organocatalytic reactions facilitated by primary amine-based iminium ions, Michael-type additions deserve special

• low conversions and stereoselectivities when applied to benzylidene acetones or cyclic enones (vide infra). In our latest research in establishing a mild organocatalytic protocol for incorporating benzyl malonates and bisthiomalonates into cyclic enones and benzylidene acetones, we have developed a

• product with 93% ee after 24 h, while the bifunctional primary amine-thiourea catalysts (system B) required 4 days to provide an adduct with similar enantioselectivity. Prolonged reaction time is in general the innate nature of organocatalytic reactions employing iminium activation approaches. With the

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

• decades have showed an increased interest from the community. This review gives an overview of the work in the field of ML in organocatalysis. The review starts by giving a short primer on ML for experimental chemists, before discussing its application for predicting the selectivity of organocatalytic

• the award of the Nobel Prize to List and MacMillan in 2021 ‘for the development of asymmetric organocatalysis’. Organocatalytic transformations have also seen the transition to industrial processes for the production of a variety of pesticides and medicinal compounds, as recently reviewed [6][7][8][9

• ]. Despite the prominence of organocatalytic reactions, catalyst development has so far mostly been conducted guided by intuition of skilled organic chemists. Given that organocatalytic reactions are governed by different competing interactions, the influence of a change in molecular structure is often non

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

• MacMillan were awarded the Nobel Prize in 2021 for the development of asymmetric organocatalysis [6]. To date, industrial companies have used a number of asymmetric organocatalytic processes to synthesise pharmaceuticals and fine chemicals on large scales [7]. Catalyst recycling is key from both an economic

• supported organocatalyst whose catalytic efficiency can be reproduced over a sufficient number of reaction cycles. Despite the difficulty of the challenge, the design of heterogeneous, recyclable organocatalytic systems is of high interest [8]. The continued development of efficient catalytic recovery

• controllability of surface, geometry, and pore size makes silica-based materials sustainable and functionalisable supports for organocatalytic reactions [44]. The particle morphology of mesoporous silica can be tuned to various shapes, including spheres, tubes, and rods of various dimensions [45], by using a co

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

• synthesize functionalized pyrimidobenzothiazoles [37]. An in situ generated conjugated α-cyanoester/malononitrile has been successfully employed as substrate in the double Michael reaction with curcumins by Lalitha et al. [38]. An organocatalytic cascade double Michael reaction between curcumins and 2

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

• organocatalyzed asymmetric Michael addition reaction of 4-monosubstituted pyrazol-5-ones to simple enones for the synthesis of pyrazolone derivatives [25]. Despite these progresses, arylidene/heteroarylideneacetones have remained untapped by 4-unsubstituted pyrazolin-5-ones under asymmetric organocatalytic or

• acetylation of the ent-3ba' using acetic anhydride and DABCO, furnishes the desired product ent-3ba. Conclusion In summary, we have realized the Michael addition reaction of 4-unsubstituted pyrazolin-5-ones to α,β-unsaturated ketones under organocatalytic conditions. The developed protocol was efficiently

• ). Representative examples of asymmetric organocatalytic conjugate addition of pyrazolin-5-ones to α,β-unsaturated ketones and present study. Scope of substrates. Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), 15 mol % of catalyst I, 30 mol % A5 (for 3) or 15 mol % catalyst II, 30 mol % A5 (for ent-3) in 1.0 mL

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

• , Iran 10.3762/bjoc.20.134 Abstract We herein report the asymmetric organocatalytic addition of azlactones to allenoates. Upon using chiral quaternary ammonium salt catalysts, i.e., Maruoka’s binaphthyl-based spirocyclic ammonium salts, the addition of various azlactones to allenoates proceeds in a β

• synthesis approaches. Our group has a longstanding focus on the development of asymmetric organocatalytic methods to access non-natural chiral α- and β-AA [14][15][16][17][18][19]. Hereby we are especially interested in utilizing simple (prochiral) starting materials and carry out stereoselective α

• in a straightforward manner. Conclusion The development of novel catalytic methods for the asymmetric synthesis of non-natural amino acid derivatives is a contemporary task and we herein introduce an organocatalytic protocol for the β-selective addition of various azlactones 1 to allenoates 3. Upon

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• -proline-modified magnetic nanoparticles (LPMNPs) that combine organocatalytic protocols with nanocatalysis, which enhances the surface-to-volume ratio of the catalyst opening up new possibilities [107]. The ʟ-proline molecules were anchored on a Fe3O4@SiO2 nanoparticle, which was already known for its

• facile recyclability, with the silica layer preventing the Fe3O4 from aggregation. The LPMNPs managed to provide impressive yields, while employing an amount of 2.5 mol % in water, with the help of conventional heating at 50 °C, which facilitated the organocatalytic process that required 1 to 1.5 hours

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

• there might be more to win before the electrons jump. Being general and easy to use, the introduced supramolecular organocatalytic systems promise to lift all involved topics to a new level of significance. Essentially every reaction consists of the movement of electrons, from nucleophile to

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen

• Gyula Dargó,
• Dóra Erdélyi,
• Balázs Molnár,
• Péter Kisszékelyi,
• Zsófia Garádi and
• József Kupai

Beilstein J. Org. Chem. 2023, 19, 1811–1824, doi:10.3762/bjoc.19.133

• Budapest, Hungary 10.3762/bjoc.19.133 Abstract Synthesizing organocatalysts is often a long and cost-intensive process, therefore, the recovery and reuse of the catalysts are particularly important to establish sustainable organocatalytic transformations. In this work, we demonstrate the synthesis

• time was increased to 5 hours to achieve full conversion. After the organocatalytic reaction in toluene, the volatile components were evaporated, and acetonitrile was added to precipitate the catalyst. In contrast to the small-scale recycling, in this case, we used filtration instead of centrifugation

• to recover the catalyst without significant loss (<5%). This demonstrates that we developed an organocatalytic reaction that can be easily scaled-up and the novel lipophilic catalyst can be recovered not only by centrifugation but also by filtration. From the baclofen precursor (S)-17, baclofen can

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• pairs and provides a good basis and scope for further extensions and explorations [39] (Scheme 3). Based on the work by Wu et al. and extending their previous work, Rueping and co-workers explored the effects of fluorine in organocatalytic reactions. They developed an asymmetric Brønsted acid–Lewis base

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• and Cheng et al. developed a convenient approach for the thiolation of β-keto phosphonates 89 by using N-(arylthio)phthalimides 14 under α,α-diaryl-ʟ-prolinols B organocatalytic system (Scheme 37) [71]. Sulfenylation of 3-aryloxindoles 91 with N-(arylsulfenyl)phthalimides 14 as the electrophilic

• thiophosphates, thiophosphinates and selenophosphates by reaction with the P(O)H moieties of H-phosphonates [105]. Conclusion To date, both metal-catalyzed and organocatalyzed C–S bond formations have been widely expanded. In particular, organocatalytic methodologies are effective for direct construction of

• conjugate Lewis base Brønsted acid catalyst. Sulfenylation of deconjugated butyrolactams. Intramolecular sulfenofunctionalization of alkenes with phenols. Organocatalytic 1,3-difunctionalizations of Morita–Baylis–Hillman carbonates. Organocatalytic sulfenylation of β‑naphthols. Acid-promoted

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• single operation and from readily available substrates. Their combination with asymmetric aminocatalysis [4][6][7][8] has recently led to innovative approaches for the one-step enantioselective preparation of stereochemically dense molecules. Nowadays, organocatalytic cascade processes provide a powerful

• organocatalytic cascade reaction developed by Enders. Acetaldehyde dimethyl acetal (6) as an acetaldehyde surrogate to effect a triple organocatalytic cascade reaction. Enders reaction with acetaldehyde.a Selected optimization reaction conditions.a Supporting Information Supporting Information File 34

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• simultaneous organocatalytic activation of the ester on the other hand. Following a previously established synthetic pathway [49], we have found that transmetallation via silver(I)/NHC complex 4 was the only viable synthetic entry point to this sophisticated bifunctional catalyst (Scheme 2) [10][12][14][50