Novel macrocycles: from synthesis to supramolecular function

• Veronica Iuliano,
• Carmen Talotta,
• Margherita De Rosa,
• Paolo Della Sala,
• Konrad Tiefenbacher,
• Pablo Ballester and
• Carmine Gaeta

Beilstein J. Org. Chem. 2026, 22, 982–985, doi:10.3762/bjoc.22.76

• designed protection and functionalization sequences, the authors introduced orthogonal reactive groups at opposite rims of the macrocycle. The synthetic versatility of these systems was demonstrated by copper-catalyzed “click” reactions and amine-based transformations, yielding highly functionalized

Electrochemical reduction of unsaturated carbon–carbon bonds via 3d transition-metal catalysis

• Geon Kang,
• Minki Jeon,
• Pooja Kumari Jat,
• Cheoljae Kim and
• Isaac Choi

Beilstein J. Org. Chem. 2026, 22, 955–981, doi:10.3762/bjoc.22.75

• configurations [75][76][77][78] have recently emerged as promising platforms for scalable electrochemical hydrogenation reactions. These advanced architectures offer enhanced mass transport, significantly reduced ohmic resistance, and the capability to operate at industrially relevant current densities, thereby

• reductive chemical transformations [110]. In 2022, Peters and co-workers demonstrated that a nickel-based electrocatalyst for hydrogen evolution reactions (HER) can be repurposed as a hydride-delivery agent through incorporation of a cobalt-based PCET mediator under constant potential electrolysis with a

• suppressing undesired side reactions, most notably hydrogen evolution reactions (HER) (Scheme 12A) [126]. This catalytic platform enabled selective semihydrogenation of both internal and terminal alkynes, including unactivated substrates, with broad tolerance toward heterocycles and alcohol functionalities

Synthesis of sterically shielded piperidine nitroxides via acid-catalyzed heterocyclization of β-aminoketone derivatives with ketones

• Mark M. Gulman,
• Yurii I. Glazachev and
• Sergey A. Dobrynin

Beilstein J. Org. Chem. 2026, 22, 948–954, doi:10.3762/bjoc.22.74

• reactions of cyclic nitrones with organometallic compounds is a fruitful approach for the synthesis of sterically shielded radicals of the pyrrolidine, imidazoline, and imidazolidine series [23], including those with functional groups in the side chains [24]. Here we applied this strategy for the synthesis

Recent advances in copper-catalyzed direct hydroamination of alkenes with (hetero)aromatic amines

• Hyejeong Lee and
• Yunmi Lee

Beilstein J. Org. Chem. 2026, 22, 925–947, doi:10.3762/bjoc.22.73

• Cu as a catalytic platform for C–N bond construction. Unlike earlier review articles that broadly covered copper-catalyzed C–N bond-forming reactions or hydroamination chemistry across diverse nitrogen sources [24][25][26][27], this review places a clear and specific emphasis on recent advances in

• β-amino nitrile motifs, which are commonly found in biologically active molecules. However, the relatively low nucleophilicity of aromatic amines and N-heteroaromatic substrates often limits their reactivity in conjugate addition reactions. To overcome this limitation, transition metal catalysis has

• nucleophilicity, facilitating conjugate addition to electron-deficient alkenes. The formation of such well-defined copper–amido complexes provides valuable mechanistic insights into copper-catalyzed hydroamination and conjugate addition reactions. Pioneering studies by Gunnoe et al. describe the synthesis and

A practical CO₂-mediated synthesis of 5,6-carboxylated silicon-rhodamines for targeted probe development

• Dongjie Hou,
• Shaowei Wu,
• Ning Xu,
• Pengjun Bao,
• Wenhao Jia,
• Qinglong Qiao and
• Zhaochao Xu

Beilstein J. Org. Chem. 2026, 22, 915–924, doi:10.3762/bjoc.22.72

• derivatives can be directly used in subsequent amidation reactions with targeting ligands without column chromatography, facilitating the rapid construction of high-performance targeted fluorescent probes. Overall, this strategy provides a straightforward, efficient, and practical synthetic route for the

• . Importantly, these species lack a carboxy group and therefore cannot participate in subsequent amide coupling reactions. Moreover, although small amounts of these byproducts were formed, they did not significantly interfere with the subsequent reactions. Thus, the reaction mixtures could be extracted with

Palladium-catalyzed benzocyclization reactions of quinoline-2-carboxamides via sequential C–H/N–H functionalization

• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2026, 22, 905–914, doi:10.3762/bjoc.22.71

• metal affinity [9][10]. It is therefore expected that annulation of the amide moiety in quinoline-2-carboxamides would extend their functionality as biologically active structures, ligands, and extractants. Transition-metal-catalyzed coupling reactions are crucial for constructing carbon–carbon and

• carbon–heteroatom bonds. The classical coupling reactions, such as Kumada–Tamao–Corriu coupling [11][12][13], Sonogashira coupling [14][15], Negishi coupling [16][17], Migita–Kosugi–Stille coupling [18][19][20], Suzuki–Miyaura coupling [21][22], and Hiyama coupling [23][24] involve carbon–halogen and

• carbon–metal species (Scheme 1a). Fagnou and co-workers reported direct arylation reactions with palladium(II) acetate to synthesize biaryl compounds via concerted metalation–deprotonation (CMD; Scheme 1b) [25][26][27]. Buchwald, Hartwig, and co-workers explored carbon–nitrogen coupling reactions that

Cascade transformation of 2-(diazoacetyl)-2H-azirines to 2-aroyl-3-hydroxy-1H-pyrroles via condensation with aromatic aldehydes

• Timur O. Zanakhov,
• Ekaterina E. Galenko,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2026, 22, 897–904, doi:10.3762/bjoc.22.70

• azirine 1. Alkylation and triflation reactions of pyrrole 5a. Optimization of the synthesis of pyrrole 5a.a Supporting Information Deposition number CCDC 2536266 (compound 5a) contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge

Chiral cyclopropenimine-catalyzed enantioselective Michael reactions of phenol and benzofuran-derived α,β-unsaturated pyrazolamides with benzophenone-imine of glycine esters

• Ya Bai,
• Xue-Ying Wang,
• Si-Kai Zhu,
• Yan-Ting Shen,
• Sheng-Yong Zhang and
• Ping-An Wang

Beilstein J. Org. Chem. 2026, 22, 888–896, doi:10.3762/bjoc.22.69

• , 710032, China School of Pharmacy, Lanzhou University, Lanzhou, 730000, China 10.3762/bjoc.22.69 Abstract The enantioselective Michael reactions of benzophenone-imine of glycine esters with phenol- and benzofuran-derived α,β-unsaturated pyrazolamides have been realized by using a chiral cyclopropenimine

• reactions of phenol- and benzofuran-derived α,β-unsaturated pyrazolamides with benzophenone-imine of glycine esters by a chiral cyclopropenimine (CSB-1) to give 3-substituted glutamic and pyroglutamic acid esters in up to 98% ee and 20:1 diastereomeric ratio. In this reaction, a phenoxymethyl or benzofuryl

• asymmetric Michael reactions between β-substituted α,β-unsaturated ester 1a and benzophenone-imine of glycine tert-butyl ester 2a in the presence of 20 mol % of CSB-1 and other chiral tertiary amine catalysts including quinine, levamisole, (+)-sparteine (Scheme 1). To our disappointment, the results showed

Diastereodivergent electrophilic trapping of α-boryl lithium derivatives

• Tereza Pavlíčková,
• Noam Orbach and
• Ilan Marek

Beilstein J. Org. Chem. 2026, 22, 882–887, doi:10.3762/bjoc.22.68

• their stereoselective reactions remains challenging. Here, we examine the diastereoselective generation and trapping of α-boryl lithium species formed by ring opening of substituted iodomethylcyclopropanes. After lithium–iodine exchange and selective C–C bond cleavage, these intermediates react with a

• engaging in diverse bond-forming processes, including C–C, C–O and C–N bond formations [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Despite their growing utility, controlling the stereoselectivity in substitution reactions of α-boryl carbanions remains a formidable

• diverse catalytic and stereoselective transformations [28][29][30][31][32][33]. In this context, we have recently demonstrated that a broad range of arylated (iodomethyl)cyclopropylboronic ester 2 [34] undergo ring-opening reactions, followed by electrophilic trapping of the resulting α-boryl carbanion

Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• research to commercial applications: site-specificity, usability and scalability. Site-specificity. The ideal modification chemistry targets a single, well-defined site without stochastic off-site reactions. Product homogeneity enhances safety by mitigating toxic by-products that require excessive

• (19) was later adapted for modification of an asparagine (Asn) residue in the Fc domain of trastuzumab [61]. Rhodium has also been used in visible-light-triggered single-electron transfer (SET) reactions, enabling labelling under mild conditions with spatiotemporal control. Another strategy employs a

• binder to its target protein [52][53][54][55], whereas incorporation of DAP requires photodeprotection [47]. Furthermore, all current proximity-directed reagents, including catalytic systems such as the reactions mediated by DMAP and PyOx (Scheme 7d and 7e), still require extensive screening and

The trans-influence in gold chemistry from a catalytic perspective

• Manfred Bochmann

Beilstein J. Org. Chem. 2026, 22, 838–856, doi:10.3762/bjoc.22.66

• also controls the nature of the gold frontier orbitals. This Perspective highlights recent insights into the origins and consequences of the ligand trans-influence and its importance for the energetics of gold-catalysed reactions, with special emphasis on the trans-influence in gold(III) hydrides and

• and reactivity in catalytic reactions [11][12][13][14][15][16][17][18][19]. There is however one important aspect of gold chemistry that is often under-appreciated: the strong control of reactions by the influence of a given ligand on another ligand in trans position, known as the trans-influence

• electronic aspects such as photoluminescence and the spectroscopic and reactivity properties of gold(III) hydrides, before moving on to trans-influence enabled insertion reactions and catalytic applications. Perspective General considerations “Trans-influence” is a term applied to the weakening or

Unsymmetrical sulfoxides with sterically hindered catechol fragment: synthesis, structure, electrochemical properties, and antiradical activity

• Daria A. Burmistrova,
• Vasiliy A. Fokin,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Maxim V. Arsenyev,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2026, 22, 828–837, doi:10.3762/bjoc.22.65

• , and antibacterial agents [6][7][8]. However, the practical utility of such type of compounds extends beyond biomedical applications. For instance, Michael addition reactions between dithiols and phenolic compounds yield cross-linked, colorless polymer films with universal adhesion and high stability

Synthesis and structural elucidation of a novel bis-spirooxindole from isatin and ethylenediamine

• Irene Moreno-Gutiérrez,
• Josefa L. López-Martínez,
• Sonia Berenguel-Gómez,
• Irene Torres-García,
• Duane Choquesillo-Lazarte,
• Manuel Muñoz-Dorado,
• Miriam Álvarez-Corral and
• Ignacio Rodríguez-García

Beilstein J. Org. Chem. 2026, 22, 813–820, doi:10.3762/bjoc.22.63

• complexity and, in some cases, unexpected reaction outcomes. In reactions involving amino acids or diamines, the coexistence of multiple nucleophilic and electrophilic sites can give rise to competing pathways and polycyclic architectures. A well-documented example is the condensation of isatin (1) with ʟ

• may proceed beyond simple imine formation and generate highly condensed frameworks. A related behavior has been observed in reactions of isatin with diamines. Whereas condensation with propan-1,3-diamine (10) under controlled stoichiometry affords the corresponding diiminoisatin 11 (Scheme 2) [18

• ], reactions involving N-methylated ethylenediamines like 12 or 13 lead to spirocyclic products (14 and 15) [19]. These outcomes were rationalized through the involvement of imine and dipolarophilic intermediates (16 and 17), highlighting the sensitivity of the system to substitution at nitrogen. Furthermore

Knoevenagel condensation of 4,5- and 1,8-diazafluorenes

• Darya S. Cheshkina,
• Christina S. Becker,
• Alina A. Sonina and
• Maxim S. Kazantsev

Beilstein J. Org. Chem. 2026, 22, 803–812, doi:10.3762/bjoc.22.62

• for their synthesis involves coupling reactions of diazafluoren-9-one [4][6][7] or diazafluoren-9-diazomethane [17][18] with thiones yielding the products in moderate yields (20–70%). However, these routes require the preliminary synthesis of malodorous thiones and diazomethane derivatives from the

• malononitrile or acetonitrile derivatives [14][19][20]. However, the use of diazafluorenes as the methylene component in condensation reactions remains underexplored. These reactions can be carried out under basic [13][21], acidic [3][5] or Lewis acid catalysis [15][22], but the corresponding literature

• iminium cation. Additionally, we performed the condensation of diazafluorenes with ketones yielding unique di(pyridin-2-yl)methylene)-9H-diazafluorenes. Results and Discussion Basic conditions Following the typical protocol of the Knoevenagel condensation, the reactions of 4,5- and 1,8-diazafluorenes with

Synthetic study of vic-bromination of diarylacetylenes, easy purification and separation

• Akane Togo,
• Hiyono Suzuki,
• Yuto Akai,
• Makoto Matsumoto,
• Yoshinori Suzuma,
• Hidehiko Kodama and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2026, 22, 795–802, doi:10.3762/bjoc.22.61

• ; Introduction The addition reaction of bromine to diphenylacetylene is one of basic reactions and is recognized as important, because resulting 1,2-dibromo-1,2-diphenylethylene can serve as a precursor for various molecular transformations in organic synthesis [1][2]. This reaction seems to be simple, but some

Preparation of 3-(alkylamino)imidazo[1,2-a]pyridine-2-carbaldehydes via Kornblum oxidation and unexpected ring-opening reactions of the corresponding alcohols under oxidative conditions

• Sandile J. Mkhize,
• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2026, 22, 763–770, doi:10.3762/bjoc.22.58

• oxidation conditions, reaction in the presence of DMSO and NaHCO3 under conventional or microwave heating to ≈100 °C, were applied to the bromides derived from these alcohols by treatment with PBr3, resulting in the desired aldehydes which successfully underwent reductive amination reactions with 2

• derivatives have been found to be of interest in the development of organic materials with interesting properties [11][12]. The importance of imidazo[1,2-a]pyridines is evidenced by the plethora of recent review articles covering methods for their preparation [13][14][15][16] and functionalisation reactions

• similar reactions on alcohols 17b–d led to the corresponding ring-opened products 18b–d (Scheme 4). The ring-opened products were isolated in yields of 26–36%, with loss of one carbon atom occurring (-CH2OH). To test whether C-2 decarboxylation could have immediately preceded ring-opening, decarboxylated

Rongalite addition to dienones: diastereoselectivity in cyclic sulfone synthesis; stereochemical rationalization and prospects as a general conjugate nucleophile

• Melina Goga,
• Hao Zong,
• James Franco,
• Jazmine Prana,
• Rudolph Michel,
• Antonia Muro,
• Elana Rubin,
• Janet Brenya,
• Henk Eshuis and
• Magnus W. P. Bebbington

Beilstein J. Org. Chem. 2026, 22, 742–752, doi:10.3762/bjoc.22.56

• over the last two decades [5][6]. Modified reagents in which the Rongalite hydroxy group has been protected have allowed for consecutive and different reactions at sulfur, giving access to a range of unsymmetrical sulfones [18][19]. Although sulfur nucleophiles often participate in conjugate additions

• (indicated). There is nothing to suggest from the calculations that an inherent reactivity problem prevents the initial addition of Rongalite to the enone, especially given that the singly electrophilic 2,6-dimethylbenzalacetone is known to participate in reactions with conjugate nucleophiles [25]. It is

• work, by which we were able to locate transition states for reactions to give trans-12a and the unobserved cis-12b (Figure 4). The activation energy difference to reach TS-12a, leading to 12a and TS-12b, leading to 12b was found to be a significant 4.7 kcal/mol in favor of TS-12a (see Supporting

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• derivatives with multiple chiral centers under high regio- and stereocontrol. Currently, strategies using azomethine ylides based on imino esters or α-amino acids with a variety of cyclic and acyclic carbonyl compounds dominate. Enantioselective (3 + 2) cycloaddition reactions of azomethine ylides obtained

• from imino esters, catalyzed by chiral Cu(I,II) and Ag(I) complexes, are widely used. Reactions using α-amino acids proceed, in most cases, without the use of catalysts, with high yields and high stereoselectivity. Electrophilic alkenes of various structures, (hetero)aromatic olefins and benzofulvenes

• compounds; catalysis; (3 + 2) cycloaddition; decarboxylation; dipolarophiles; iminoesters; polycyclic compounds; spirocyclic compounds; stereoselectivity; Introduction The 1,3-dipolar cycloaddition is one of the most popular pericyclic reactions in organic synthesis, in which a dipole molecule interacts

Anti-invasive and cytotoxic evaluation of a (+)-pinoresinol-based semisynthetic library against glioblastoma

• Chen Zhang,
• Kah Yean Lum,
• Jonathan M. White,
• Paul I. Forster,
• Nicholas Booth,
• Sunita A. Ramesh and
• Rohan A. Davis

Beilstein J. Org. Chem. 2026, 22, 691–704, doi:10.3762/bjoc.22.54

• vitro cytotoxicity and anti-invasive properties using two glioblastoma cancer cell lines [23][24]. During our semisynthetic studies, several reactions including methylations, halogenations, and acylations were performed, leading to the generation of five analogues in varying yield (10−81%) and high

Harnessing light energy with molecules

• Grace G. D. Han,
• Mogens Brøndsted Nielsen and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2026, 22, 680–682, doi:10.3762/bjoc.22.52

• singlet-state photoredox catalyst in the sulfonylation/arylation of styrenes and as a triplet sensitizer in energy transfer catalysis. In addition to the photoredox contribution mentioned above, this thematic issue contains two publications on photochemical reactions beyond photoisomerizations. In the

• article by Wahl and co-workers [21], ring-opening of photogenerated azetidinols was used as a strategy for the convenient synthesis of aminodioxolanes. Photochemical denitrogenation reactions of bicyclic azoalkanes present a way to prepare strained bicyclic compounds. Further, Gomes and Lopez [22] report

Photoorganocatalytic trifluoromethylation of (het)arenes in green conditions

• Egor N. Boronin,
• Svetlana E. Kaurkina,
• Milena M. Svetlakova,
• Anton S. Bolshakov,
• Maxim V. Arsenyev,
• Vasilii F. Otvagin,
• Alexey Yu. Fedorov,
• Timothy Noël and
• Alexander V. Nyuchev

Beilstein J. Org. Chem. 2026, 22, 662–671, doi:10.3762/bjoc.22.50

• -catalyzed [8], organic photocatalyst-mediated, or electrochemical transformations [9], and also include continuous-flow processes [6][10][11][12][13]. Given that photocatalytic reactions align with the principles of green chemistry, particularly energy efficiency and the use of catalytic pathways, such

• solvent. Results and Discussion To identify reaction conditions consistent with the principles of green chemistry, we carried out an optimization study using different organic photocatalysts and solvents. The reactions were performed under an argon atmosphere in anhydrous solvents, employing 1,3,5

• trifluoromethylated product was high (74% for 13), whereas the para-substituted analogue provided only 18% yield (14). To further investigate the influence of substituent position on substrate reactivity, reactions with dialkylanisoles were examined. For meta-methylanisoles bearing an additional methyl group at the

Hydrogen production from formic acid catalyzed by NHC–Cu complexes

• Orlando Santoro and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2026, 22, 620–627, doi:10.3762/bjoc.22.48

• ]. Finally, a Cu(I)–formato complex able to promote FA dehydrogenation in the absence of any additive was very recently reported by Berthet, Cantat and co-workers [48]. During the past decades, NHC–Cu complexes have shown to be efficient catalysts in a plethora of reactions. Indeed, they guarantee better

• ), almost 2 equivalents of gas were produced from 1 equivalent of formic acid within 3 hours. It has to be noted that, since all reactions were conducted in solution, all copper complexes must be considered as monomeric. In fact, dimeric Cu–H and Cu–formato are generally observed only in the solid state [53

• silicon compounds was observed in all reactions (see Supporting Information File 1, Figure S3). Noteworthy, by replacing formic acid with acetic acid only 1 equivalent of hydrogen was released. The different reactivity towards the dehydrogenative coupling of the silyl carboxylate species can be due to

Computational prediction of C–H hydricities and their use in predicting the regioselectivity of electron-rich C–H functionalisation reactions

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2026, 22, 603–610, doi:10.3762/bjoc.22.46

• regioselectivity of electron-rich C–H functionalisation reactions. The workflow was benchmarked against 35 experimentally determined C–H hydricities in DMSO, yielding a mean absolute error (MAE) of 4.43 kcal/mol and a root mean squared error (RMSE) of 5.45 kcal/mol. Leveraging this approach, we generated a dataset

• of 3278 C–H sites across 740 molecules to train a machine learning (ML) model based on CM5 atomic charge descriptors, achieving an MAE of 2.30 kcal/mol and an RMSE of 3.74 kcal/mol relative to QM-computed hydricities. The method was further applied to 250 hydride transfer-like reactions, including C

• ten representative reactions, surpassing BDEs in most cases. These findings highlight hydricity as a complementary and, in some cases, superior descriptor for guiding regioselectivity predictions in electron-rich C–H functionalisation. The model is made available at regioselect.org, together with a

Regioselective approach to 5-arylsulfonylisoxazoles and their antimicrobial activity

• Artem S. Sazonov,
• Dmitry A. Vasilenko,
• Denis V. Porfiriev,
• Yuri K. Grishin,
• Rimma A. Gazzaeva,
• Alisa P. Chernyshova,
• Maxim A. Kryakvin,
• Anna A. Baranova,
• Vera A. Alferova and
• Elena B. Averina

Beilstein J. Org. Chem. 2026, 22, 592–602, doi:10.3762/bjoc.22.45

• nucleophilic aromatic substitution with thiophenols followed by oxidation with m-chloroperbenzoic acid (mCPBA). The scope of the reactions was explored, demonstrating high yields across a variety of functional groups and substituents. Optimized conditions enabled selective oxidation of thioaryl groups to

• nitrile oxides in cycloaddition reactions, complete control of regioselectivity without metal catalysis is not always achievable. Another problem with this method is the tendency of nitrile oxides to form dimers (furoxanes), which entails a decrease in the yield of isoxazoles. Due to dimerization, nitrile

• the SNAr reactions with 3-nitro- and 3-methoxycarbonyl-substituted 5-nitroisoxazoles 1a and 1g. The obtained results revealed that the nature of the substituents in the isoxazole cycle as well as in the aromatic ring of thiophenols does not have a noticeable influence on the reaction yields. The SNAr

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• growth factor receptor 2 (FGFR2) to overcome the issues of drug resistance and adverse reactions associated with traditional inhibitors in the treatment of FGFR2-driven tumors. Erdafitinib was employed as the targeting ligand, and its aliphatic amine site was conjugated with a CRBN E3 ligase ligand to