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

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• invention of cooperative catalysis with electrochemical transition metal catalysis, which generally has mild oxidation potential for the generation of persistent radicals in the form of nucleophile-bound metal complexes. We and other groups have successfully applied this reaction design to enantioselective

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• enantioselective intramolecular Cannizzaro reaction of aryl and alkyl glyoxals 1a–h and alcohol 2 using trisoxazoline (TOX) ligand (4)/copper catalysts to furnish the requisite mandelic esters 3a–h in good yields (greater than 90%) and high enantioselectivity. This was observed in the wide substrate scope as

• )3 (Scheme 3). They also extended the approach to study enantioselective Cannizzaro reactions of similar substrates using a Cu bisoxazoline (A) [Cu(OTf)2-PhBox] complex as the chiral catalyst, producing the desired enantiomeric compounds in modest yields and up to 33% ee (Scheme 4). The mechanistic

• . developed an asymmetric iron catalyst with the aim of expanding the platform of metal catalysis. Catalysts 14 and 15 proved to be effective in the transformation of glyoxal monohydrates 1a and alcohol 2, to deliver mandelate esters 3a in good yields and enantioselectivities via an enantioselective

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• herein an enantioselective palladium-catalyzed Heck–Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation

• followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the

• commercial drug baclofen as hydrochloride. Keywords: desymmetrization; enantioselective Heck–Matsuda reaction; lactam synthesis; N,N-ligands; palladium; Introduction Desymmetrization reactions consist in the modification of a molecule with the loss of one or more symmetry elements, such as those which

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• ]. It is important to note that we are not aware of any catalytic enantioselective hydrochlorination reactions of alkenes. Conjugate additions of HCl to a complex of α,β-unsaturated acids, incorporated in an α-cyclodextrin, which corresponds to a formal hydrochlorination was reported by Tanaka and co

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained. Keywords: asymmetric aldol reaction; asymmetric Henry reaction; chiral ligands; enantioselective catalysis; imidazolidine derivatives

• ; Introduction The application of chiral metal complexes as enantioselective catalysts is among the fundamental strategies for preparing compounds in non-racemic forms [1][2][3][4]. These complexes typically comprise a chelating chiral ligand capable of coordinating with a metal ion; otherwise, a metal atom

• -(pyridin-2-yl)imidazolidin-4-one, differentiated by various substitutions at the imidazolidine ring [5][6][7]. Their copper(II) complexes were evaluated as efficient enantioselective catalysts, particularly in asymmetric Henry reactions (Scheme 1). Subsequent research has led to the development of various

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• substrate is the most active. In 2012, Kojima and Mikami utilized bimetallic tropos BIPHEP [bis(phosphino)biphenyl]–digold complexes for enantioselective intramolecular hydroamination of N-alkenylureas [9], and they hypothesized that N-alkenylureas could be activated through bimetallic coordination not only

• mechanism in Scheme 2). Solvent effects: Michon and co-workers reported the beneficial assistance of water on enantioselective hydroamination, with the perchlorate being the best performing counterion. They propose that the anion is acting as a salting-in agent to contribute to better solvation of catalyst

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

• . With this mechanistic blueprint as a backdrop, Phipps and co-workers developed an enantioselective Minisci-type addition, under dual photoredox and chiral Brønsted acid catalysis [44] (Scheme 5A). In their proposed mechanism, the activation of the NHPI ester radical precursor was proposed to occur via

• the phthalimidyl anion within the chiral pocket of the phosphate catalyst to form complex 55, before enantioselective addition to the iminium ion affords product 56. NHPI esters can also engage in π–π interactions with electron-rich species to generate charge-transfer complexes that can absorb light

• enantioselective cross-electrophile coupling between NHPI esters and alkenyl bromides [100] (Scheme 26A). In addition, Jolit and Molander disclosed the decarboxylative arylation of NHPI esters derived from bicyclo[1.1.1]pentanes (BCPs) by combining Ni-catalysis and photoinduced EDA complex activation [101] (Scheme