Pd-catalyzed dehydrogenative arylation of arylhydrazines to access non-symmetric azobenzenes, including tetra-ortho derivatives

• Loris Geminiani,
• Kathrin Junge,
• Matthias Beller and
• Jean-François Soulé

Beilstein J. Org. Chem. 2025, 21, 2234–2242, doi:10.3762/bjoc.21.170

• and co-workers developed a Chan–Evans–Lam-type oxidative cross-coupling reaction between N-arylphthalic hydrazides and arylboronic acids using copper catalysis [41]. Similarly, in 2003, Lee and co-workers introduced a desymmetrization approach employing simpler N=N precursors, specifically N-protected

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

• : alkaloids; cyclic 1,3-dicarbonyl compounds; desymmetrization; enantioselective reduction; terpenoids; Introduction Terpenoids and alkaloids are two major classes of highly important natural products because they usually exhibit diverse and important biological activities, such as antitumor, anti

• cyclic prochiral dicarbonyl substrates. In addition, various approaches could be used for the desymmetrization reactions such as enzyme catalytic-, organocatalyst-, and transition-metal-catalyzed reductions [5][6][7]. Advance about the synthesis of several terpenoid and alkaloid natural products (1–5

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• reaction to two prochiral faces of a planar substrate, where the prostereogenic carbon is part of the reaction site. However, this is not always the case, particularly in remote desymmetrization reactions [2][3][4][5][6][7][8]. For instance, the catalytic desymmetrization of phosphine oxides [9] will be

• are assigned following the 3-step procedure for all types of strategies including cyclization, biaryl coupling, and desymmetrization, irrespective of the chemical identity of the newly established chiral axis including C–C [10][11] (Scheme 3C and 3D), C–N [12] (Scheme 3B), N–N [13] (Scheme 3A), and C

• same procedure as in Scheme 5C. In analogy to Scheme 5B, the direct cyclization forging the planar chirality [24] in Scheme 6B is regarded as [31 10], in which two stereogenic arenes are proximate and the two distal arenes are considered diastereomeric. The desymmetrization cross-coupling of cavitands

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• Technology, Guangzhou 510006, P. R. China 10.3762/bjoc.21.151 Abstract Enantioselective desymmetrization is employed as a powerful tool for the creation of chiral centers. Within this scope, the enantioselective desymmetrization of prochiral 1,3-diols, which generates chiral centers by enantioselective

• functionalization of one hydroxy group, offers beneficial procedures for accessing diverse structural motifs. In this review, we highlight a curated compilation of publications, focusing on the applications of enantioselective desymmetrization of prochiral 1,3-diols in the synthesis of natural products and

• biologically active molecules. Based on the reaction types, three strategies are discussed: enzymatic acylation, transition-metal-catalyzed acylation, and local desymmetrization. Keywords: asymmetric synthesis; desymmetrization; 1,3-diols; natural product; total synthesis; Introduction Natural products

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• -meta- (48f,g) and pseudo-para-substituted ones (see 48h,i). Furthermore, this method could also be utilized for the enantioselective desymmetrization of achiral diamido-substituted [2.2]paracyclophane substrate 50, delivering the C–H amination product 51 with excellent enantioselectivity (99% ee

• [49] and the Liu group [50] independently reported the asymmetric synthesis of inherently chiral calix[4]arenes through an enantioselective desymmetrization strategy. Starting from the achiral aniline-containing calix[4]arenes 52, we employed the CPA 11-catalyzed asymmetric Povarov reaction [51] with

• enantioselective desymmetrization strategy [52]. Commencing with phenol-containing prochiral calix[4]arenes 55, the CPA 3-catalyzed asymmetric ortho-C–H amination with electrophilic azo reagents 56 effectively broke the symmetry of the substrate, leading to the formation of inherently chiral calix[4]arenes 57 with

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• achieve a full desymmetrization of both pyranose moieties by additionally differentiating the protecting groups at C6–OH and C4–OH of each monosaccharide component, the cyclic 4,6-O-di-tert-butylsilylene (DTBS) group was installed as seen in the orthogonally protected lactol acceptor 94 (Scheme 8) [95

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• of structurally novel atropisomeric N-arylindoles 56 bearing an eight-membered lactam in 51–85% yield with 54–92% ee. Of note, these scaffolds exhibited remarkably large Stokes shifts, showing great potential in the development of fluorescent dyes. Desymmetrization of prochiral compounds Beyond DKR

• of bridged biaryls, our group has successfully applied α-acidic isocyanides in the catalytic asymmetric desymmetrization of substrates featuring a prochiral axis, realizing the preparation of structurally complex scaffolds possessing both axial and central chirality. Notably, in these cases, both

• Groebke–Blackburn–Bienaymé reaction. Construction of axially chiral 3-arylpyrroles via de novo pyrrole formation. Synthesis of atropoisomeric 3-arylpyrroles via central-to-axial chirality transfer. Dynamic kinetic resolution of bridged biaryls with α-acidic isocyanides. Desymmetrization of prochiral

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• . Intermediate 25 was prepared through TBDMS protection and desulfonylation of 24, itself derived from the condensation of epoxide 23b and sulfone 27. The precursor 27 was synthesized from Roche ester 29 via a sequence of steps, including reduction, three-carbon homologation, and enzymatic desymmetrization. An

• diol desymmetrization of ent-28 was best achieved with Amano lipase PS (PSL), yielding monoacetate ent-37 (de 99.6%, 93% yield) without the formation of diacetate ent-39. Compound 37 was tosylated using tosyl chloride in pyridine with the addition of DMAP and the resulting product was treated with

• alcohol as a THP ether. Yadav and Yadav commenced their synthesis with the enzymatic desymmetrization of meso-diol 67 to monoacetate 66, achieving a 47% yield with an enantiomeric excess greater than 95%, using porcine pancreatic lipase (PPL) and vinyl acetate in THF (Scheme 10). The remaining primary

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• -controlled regio- and enantioselective hydroalkylation reaction, enabling the divergent synthesis of chiral C2- and C3-alkylated pyrrolidines through desymmetrization of readily available 3-pyrrolines (Scheme 8) [31]. The cobalt catalytic system (CoBr₂ with modified bisoxazoline ligands) achieved asymmetric

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

• followed by lactonization to Int-21 and Int-22 (Scheme 11c). Chi and co-workers showed that desymmetrization of urazoles can lead to axially chiral derivatives [31]. The NHC-catalyzed (3 + 2) annulation between α,β-unsaturated aldehydes 36 and urazoles 37 generates atropoisomers 38 with a C–N stereogenic

• benzofuran-3-carbaldehydes 50 (Scheme 16). Another demonstration of the atroposelective formation of compounds with a C–N stereogenic axis was developed by Jindal, Mukherjee, Biju, and co-workers [36]. The authors developed an NHC-catalyzed desymmetrization of N-aryl maleimides 53, which afforded a range of

• -Breslow-type intermediates with the chiral NHC-catalyst and subsequent deprotonation toward the nitrile product. Zhang, Wang, Ye, and co-workers utilized NHC-catalysis for the atroposelective synthesis of axially chiral diaryl ethers 59 and 61 [38]. This transformation was realized via desymmetrization of

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

• , Ballester and co-workers reported on the preparation of an octapyridinium-based water-soluble superaryl-extended calix[4]pyrrole molecular container and used it as a capsule for desymmetrization reactions [41], where the reported compound acts both as sequestering and supramolecular protecting group. All of

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• observed (Table 3, entries 9 and 10). 4-Pyridylboronic acid pinacol ester (25) was also attempted; however, no product was formed. Vinylboronic acid ester 22, was also explored as a substrate, with multiple porphyrin products being observed by TLC and by 1H NMR. Desymmetrization of the porphyrin was also

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

• terazosin and prazosin were successfully synthesized. Oliveira Jr. et al. developed a new methodology for the asymmetric synthesis of β-aryl-γ-lactam derivatives with very good yield and enantioselectivity [16]. This was achieved through a palladium-catalyzed Heck–Matsuda desymmetrization of N-protected 2,5

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• was shown that subsequent ring opening can be triggered by the addition of electron-deficient ketones or boronic acids, which resembles a novel strategy for azetidinol desymmetrization. The nature of the protecting group was found to be critical for the two-step process to be effective, which resulted

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

• potentially useful molecules. Keywords: Cannizzaro reaction; crossed-Cannizzaro; desymmetrization; Lewis acid catalyst; natural products; Introduction The synthesis of functionalized molecules with structural complexity has always been a challenge to synthetic chemists. The Cannizzaro reaction, in its

• -transfer catalyst in the presence of KOH as the base. Canipelle et al. [28] put forward an improved Cannizzaro disproportionation of 4-biphenylcarboxaldehyde into the corresponding alcohol and carboxylic acid products employing cyclodextrins as the phase-transfer agent. A Cannizzaro desymmetrization

• methodologies, such as Lewis acid catalysis, desymmetrization of symmetrical dialdehydes, synthesis of natural products, and building blocks. These modifications constitute the main highlight of this review. The use of modern technology and newer strategies aiming towards industrial benefit is the goal for the

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

• 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

• complexity in a synthetic route. The palladium-catalyzed coupling of arenediazonium salts with olefins, the Heck–Matsuda reaction, has been instrumental in this strategy involving the desymmetrization of cyclic systems [3], especially five-membered substrates [4][5][6][7]. As we have demonstrated previously

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

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

• . presented their work on the asymmetric desymmetrization of cyclopentene-1,3-diones 5 (Scheme 3) [23]. Following the Cu(OTf)2-catalyzed conjugate addition of R2Zn, the enolate 6 was trapped by several aromatic aldehydes 7. These complex chiral cyclopentane derivatives 8 bearing all-carbon quaternary

• 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

• desymmetrization step during which the chiral enolate attacks (Si-face) the prochiral cyclohexadienone ring via a chair-like transition state. The reaction requires an excess amount of base, resulting in the formation of a more favorable lithium enolate. Subsequent oxidation of the boronates gave the corresponding

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• Morgan Cormier Florian Hernvann Michael De Paolis COBRA, Normandie University, 76000 Rouen, France 10.3762/bjoc.18.183 Abstract A convergent approach to the skeleton of tridachiapyrone B is described taking advantage of the desymmetrization of α,α’-dimethoxy-γ-pyrone leading to α-crotyl-α

• -pyrone by desymmetrization of α,α’-dimethoxy-γ-pyrone 2 through the addition of hindered nucleophiles to construct the vicinal quaternary carbon. In a subsequent and potentially enantioselective desymmetrization step, compound 5 would be converted into trichiachiapyrone B by 1,4-addition of the side

• yield was actually noted with (PhSe)2 as electrophile, 5 being obtained in 62% yield, enabling thus an evaluation of the next desymmetrization step. An overview of the scientific literature revealed that, while the asymmetric desymmetrization of prochiral 2,5-cyclohexadienones is a rich topic of

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• desymmetrization of the molecule caused by a partial and reversible self-inclusion of the triazole moiety into the CD cavity, as was previously studied in detail for the CD dimers prepared by CuAAC reaction [15]. Although such self-inclusion was not prominent for dimers based on the short propargyl ether linker

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• thread also leads to a desymmetrization of the BINOL-based macrocycle (loss of C2 symmetry), as seen by 13C NMR spectroscopy. Stoddart and co-workers also used their π–π-recognition approach for the synthesis of BINOL-containing cationic catenanes [47][48]. They employed BINOL-based macrocycles

• desymmetrization of meso-1,2-diols [58]. The [2]rotaxane (R)-42 was synthesized by interaction of the ammonium salt 41 with the BINOL-based macrocycle (R)-12 and end-capping with 3,5-di-tert-butylbenzoic acid (see Figure 10). In the asymmetric desymmetrization reaction of meso-hydrobenzoin, rotaxane (R)-42 gave

• desymmetrization reaction of meso-1,2-diols with rotaxane (R)-42. Synthesis of Niemeyer´s axially chiral [2]catenane (S,S)-47. Results for the enantioselective transfer hydrogenation of 2-phenylquinoline with catalysts (S,S)-47, (S)-48, and (S)-49. Synthesis of Niemeyer´s chiral [2]rotaxanes (S)-56/57. Results for

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• greatly differ, as described by Allen and co-workers in their 2007 report on rhodium-catalyzed cyclodimerization reactions [59]. Moreover, desymmetrization of OBD produces more unique sites of reactivity allowing for the production of regioisomeric products. In 2019, Deng et al. described syn

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• central chirality information to the axial chirality to give the chiral biaryldiols (Scheme 3) [14]. In 2013, Akiyama and co-workers described the enantioselective preparation of multisubstituted biaryls by the desymmetrization strategy, which was further enhanced by the subsequent asymmetric reaction

• (kinetic resolution) in the presence of chiral phosphoric acid CPA 3. In this work, various EWG- and EDG-containing substrates were incorporated, and chiral biaryls 10 were obtained with good to excellent selectivities of 81–93% ee by desymmetrization and 63–96% ee by kinetic resolution. The subsequent

• discovered in 2019 a highly effective approach using organocatalytic atroposelective desymmetrization and kinetic resolution to obtain enantioenriched axially chiral arylpyrroles. The axially chiral arylpyrroles 73 were prepared in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• , desymmetrization of 86 was achieved under Sharpless epoxidation conditions employing a t-BuOOH/(+)-DIPT/Ti(O-iPr)4 system to give epoxide 85 (63%), which was subsequently protected as PMB ether 84 in 86% yield (Scheme 10). In parallel, the same precursor 86 was subjected to another Sharpless epoxidation using

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• example utilizing this strategy was provided by Jacobsen and co-workers for the desymmetrization of meso-aziridines 29. In their work, the bifunctional phosphinothiourea catalyst 31 promoted the C–N bond cleavage by hydrochloric acid upon initial protonation (Scheme 7) [55]. Subsequently, the catalyst

• -bound chloride anion performs a SN2-type attack on the coordinated benzoyl-protected aziridine, which leads to a formal addition of HCl. This concept was further developed and successfully employed by Ooi in the desymmetrization of meso-aziridines 32 with TMSX as chloride and bromide with similar

• performances as nucleophile precursors using a triazolium-amide chiral catalyst 34 [21] (Scheme 8a), as well as by Jacobsen in the desymmetrization of oxetanes 35 using TMSBr and squaramide 37 as catalyst [56] (Scheme 8b). For the latter, a more detailed mechanistic study was recently provided [57]. The