New advances in asymmetric organocatalysis II
Comenius University Bratislava
Asymmetric organocatalysis is among the most prominent approaches for the catalytic synthesis of chiral compounds. This thematic issue of the Beilstein Journal of Organic Chemistry builds upon the success of the previous thematic issue devoted to advances in asymmetric organocatalysis. It highlights new developments across all branches of enantioselective organocatalysis as well as applications and cooperation with other research areas. This timely collection of articles deals with methodological advances, new catalysts and activation modes, mechanistic and computational studies, and synthetic applications of covalent and noncovalent organocatalytic activations.
Moreover, sustainable synthetic approaches are an important aspect of organocatalytic transformations. Therefore, submissions covering the green chemistry of asymmetric organocatalysis, such as green solvents, photocatalysis, flow, and mechanochemical activation are also encouraged.
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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
Graphical Abstract
Scheme 1: General use of azlactones 1 to access more advanced α-AA derivatives (A), our recently reported amm...
Scheme 2: Application scope (conditions as detailed in Table 1, entry 13).
Scheme 3: Azlactone opening reactions.
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
Graphical Abstract
Figure 1: Selected examples of drugs and bioactive molecules bearing a pyrazole core.
Scheme 1: Representative examples of asymmetric organocatalytic conjugate addition of pyrazolin-5-ones to α,β...
Scheme 2: Scope of substrates. Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), 15 mol % of catalyst I, 30 mo...
Scheme 3: Synthesis of pyrazole-benzofuran and pyrazole–indole hybrid molecules. Reaction conditions: 1m or 1n...
Scheme 4: Synthesis of 3aa on preparative scale.
Figure 2: Single crystal X-ray structure of ent-3ba (CCDC 2234286).
Scheme 5: Proposed reaction mechanism.
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
Graphical Abstract
Scheme 1: Catalytic asymmetric halolactonizations of alkenoic acids.
Scheme 2: Effects of chiral sulfide catalysts.
Scheme 3: Effects of brominating reagents and solvents.
Scheme 4: Substrate scope.
Scheme 5: Larger-scale synthesis and transformations of bromolactonization product 3a.
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
Graphical Abstract
Scheme 1: Two examples of base-catalyzed addition of thiomalonates to enones and the scope of the work.
Scheme 2: Tested reactions of cyclohexanone with dibenzyl thiomalonate 1.
Scheme 3: Impact of the bisthiomalonate on the yield and the stereoselectivity of the products.
Scheme 4: Plausible stereochemical model of the addition to cyclohexenone.
Scheme 5: Addition of bisthiomalonates 1–3 to cyclopentenone.
Scheme 6: Acyclic enone in reactions with thiomalonates 1–4.
Scheme 7: Reaction of β-ketothioesters with acceptor E1.
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
Graphical Abstract
Scheme 1: The position of homoallylic amines in the landscape of alkaloid and nitrogen compounds syntheses.
Scheme 2: 3,3’-Diaryl-BINOL-catalysed asymmetric organocatalytic allylation of acylimines [24].
Scheme 3: Aminophenol-catalysed reaction between N-phosphinoylimines and pinacol allylboronic ester. Imine sc...
Scheme 4: Asymmetric geranylation and prenylation of indoles catalysed by (R)- or (S)-3,3’-dibromo-BINOL [25]. aA...
Scheme 5: (R)-3,3’-Di(3,5-di(trifluoromethyl)phenyl-BINOL-catalysed asymmetric geranylation and prenylation o...
Scheme 6: Microwave-induced one-pot asymmetric allylation of in situ-formed arylimines, catalysed by (R)-3,3’...
Scheme 7: Microwave-induced one-pot asymmetric allylation of in situ-formed arylimines, catalysed by (R)-3,3’...
Scheme 8: Kinetic resolution of chiral secondary allylboronates [15,30].
Scheme 9: (E)-Stereospecific asymmetric α-trifluoromethylallylation of cyclic imines and hydrazones [31].
Scheme 10: Hosomi–Sakurai-type allylation of in situ-formed N-Fmoc aldimines [32].
Figure 1: Two different pathways for the Hosomi–Sakurai reaction of allyltrimethylsilane with N-Fmoc aldimine...
Scheme 11: Chiral squaramide-catalysed hydrogen bond-assisted chloride abstraction–allylation of N-carbamoyl α...
Figure 2: The pyrrolidine unit gem-methyl group conformational control in the squaramide-based catalyst [34].
Figure 3: The energetic difference between the transition states of the two proposed modes of the reaction (SN...
Scheme 12: One-pot preparation procedure for oxazaborolidinium ion (COBI) 63 [37].
Scheme 13: Chiral oxazaborolidinium ion (COBI)-catalysed allylation of N-(2-hydroxy)phenylimines with allyltri...
Scheme 14: The two-step N-(2-hydroxy)phenyl group deprotection procedure [37].
Scheme 15: Low-temperature (−40 °C) NMR experiments evidencing the reversible formation of the active COBI–imi...
Figure 4: Two computed reaction pathways for the COBI-catalysed Strecker reaction (TS1 identical to allylatio...
Scheme 16: Highly chemoselective and stereospecific synthesis of γ- and γ,δ-substituted homoallylic amines by ...
Scheme 17: Catalytic cycle for the three-component allylation with HBD/πAr–Ar catalyst [39].
Scheme 18: Reactivity of model electrophiles [39].
Scheme 19: HBD/πAr–Ar catalyst rational design and optimisation [39].
Scheme 20: Scope of the three-component HBD/πAr–Ar-catalysed reaction [39].
Scheme 21: Limitations of the HBD/πAr–Ar-catalysed reaction [39].
Scheme 22: Asymmetric chloride-directed dearomative allylation of in situ-generated N-acylquinolinium ions, ca...
Scheme 23: Chiral phosphoric acid-catalysed aza-Cope rearrangement of in situ-formed N-α,α’-diphenyl-(α’’-ally...
Scheme 24: Tandem (R)-VANOL-triborate-catalysed asymmetric aza-Cope rearrangement of in situ-formed aldimines ...
Scheme 25: (S)-TRIP-catalysed enantioconvergent aza-Cope rearrangement of β-formyl amides, substrate scope [43]. a...
Scheme 26: (S)-TRIP-catalysed enantioconvergent aza-Cope rearrangement of β-formyl amides 16–19, amide and all...
Scheme 27: Synthetic applications of homoallylic N-benzophenone imine products 131 [43].
Scheme 28: Chiral organocatalysed addition of 2,2,2-trifluoroethyl ketimines to isatin-derived Morita–Baylis–H...
Scheme 29: Chiral chinchona-derived amine-catalysed reaction between isatin-based Morita–Baylis–Hilman carbona...
Scheme 30: (R)-VAPOL-catalysed hydrogen atom transfer deracemisation [45].
Scheme 31: Chiral PA-catalysed [1,3]-rearrangement of ene-aldimines [46].
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
Graphical Abstract
Scheme 1: Metallotropic rearrangement and regioselectivity issues.
Scheme 2: Asymmetric catalytic allenylation of aldehydes.
Scheme 3: Selective preparation of propargyltrichlorosilane.
Scheme 4: Evaluation of C2-symmetric catalysts with benzaldehyde (1a) as a model aldehyde. Reaction condition...
Scheme 5: Evaluation of the extent to which (S)-8 catalyzed the allenylation reaction. Reaction conditions: a...
Figure 1: A potential energy surface (PES) for the proposed mechanism for (a) isomerization of propargyltrich...
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
Graphical Abstract
Figure 1: Reactivity of α,β-unsaturated imines and variety of structures.
Figure 2: The hetero-Diels–Alder and inverse electron demand hetero-Diels–Alder reactions.
Figure 3: Different strategies to promote the activation of dienes and dienophiles in IEDADA reactions.
Figure 4: Examples of non-covalent interactions in organocatalysis.
Scheme 1: Enantioselective bifunctional thiourea-catalyzed inverse electron demand Diels–Alder reaction of N-...
Scheme 2: Cinchona-derived thiourea-catalyzed stereoselective (3 + 2) reaction of α,β-unsaturated imines and ...
Scheme 3: Cinchona-derived thiourea-catalyzed stereoselective (3 + 2)/(4 + 2) cascade reaction of α,β-unsatur...
Scheme 4: Enantioselective bifunctional squaramide-catalyzed formal [4 + 2] cycloaddition of malononitrile wi...
Scheme 5: Bifunctional squaramide-catalyzed IEDADA reaction of saccharin-derived 1-azadienes and azlactones.
Scheme 6: Chiral guanidine-catalyzed enantioselective (4+1) cyclization of benzofuran-derived azadienes with ...
Scheme 7: Bifunctional squaramide-catalyzed [4 + 2] cyclization of benzofuran-derived azadienes and azlactone...
Scheme 8: Chiral bifunctional squaramide-catalyzed domino Mannich/formal [4 + 2] cyclization of 2-benzothiazo...
Scheme 9: Chiral bifunctional thiourea-catalyzed formal IEDADA reaction of β,γ-unsaturated ketones and benzof...
Scheme 10: Dihydroquinine-derived squaramide-catalyzed (3 + 2) cycloaddition reaction of isocyanoacetates and ...
Scheme 11: Enantioselective squaramide-catalyzed asymmetric IEDADA reaction of benzofuran-derived azadienes an...
Scheme 12: Scale up and derivatizations of benzofuran-fused 2-piperidinol derivatives.
Scheme 13: Dihydroquinine-derived squaramide-catalyzed Mannich-type reaction of isocyanoacetates with N-(2-ben...
Figure 5: Structure of a cinchona alkaloid and (DHQD)2PHAL.
Scheme 14: Enantioselective modified cinchona alkaloid-catalyzed [4 + 2] annulation of γ-butenolides and sacch...
Scheme 15: Chiral tertiary amine-catalyzed [2 + 4] annulation of cyclic 1-azadiene with γ-nitro ketones.
Scheme 16: Inverse electron demand aza-Diels–Alder reaction (IEDADA) of 1-azadienes with enecarbamates catalyz...
Scheme 17: Phosphoric acid-catalyzed enantioselective [4 + 2] cycloaddition of benzothiazolimines and enecarba...
Scheme 18: Phosphoric acid-catalyzed enantioselective inverse electron demand aza-Diels–Alder reaction of in s...
Scheme 19: Proposed reaction mechanism for the phosphoric acid-catalyzed enantioselective inverse electron dem...
Scheme 20: Enantioselective dearomatization of indoles by a (3 + 2) cyclization with azoalkenes catalyzed by a...
Scheme 21: Synthetic applicability of the pyrroloindoline derivatives.
Scheme 22: Chiral phosphoric acid-catalyzed (2 + 3) dearomative cycloaddition of 3-alkyl-2-vinylindoles with a...
Scheme 23: Chiral phosphoric acid-catalyzed asymmetric [4 + 2] cycloaddition of aurone-derived 1-azadienes and...
Scheme 24: Phosphoric acid-catalyzed enantioselective formal [4 + 2] cycloaddition of dienecarbamates and 2-be...
Scheme 25: Chiral phosphoric acid-catalyzed asymmetric inverse electron demand aza-Diels–Alder reaction of 1,3...
Scheme 26: Chiral phosphoric acid-catalyzed asymmetric Attanasi reaction between 1,3-dicarbonyl compounds and ...
Scheme 27: Synthetic applicability of the NPNOL derivatives.
Scheme 28: Chiral phosphoric acid-catalyzed asymmetric intermolecular formal (3 + 2) cycloaddition of azoalken...
Scheme 29: Enantioselective [4 + 2] cyclization of α,β-unsaturated imines and azlactones.
Scheme 30: Catalytic cycle for the chiral phosphoric acid-catalyzed enantioselective [4 + 2] cyclization of α,...
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
Graphical Abstract
Scheme 1: Formation of axially chiral styrenes 3 via iminium activation.
Scheme 2: Synthesis of axially chiral 2-arylquinolines 6.
Scheme 3: Atroposelective intramolecular (4 + 2) annulation leading to aryl-substituted indolines.
Scheme 4: Atroposelective formation of biaryl via twofold aldol condensation.
Scheme 5: Strategy towards diastereodivergent formation of axially chiral oligonaphthylenes.
Scheme 6: Atroposelective formation of chiral biaryls based on a Michael/Henry domino reaction.
Scheme 7: Organocatalytic Michael/aldol cascade followed by oxidative aromatization.
Scheme 8: Atroposelective formation of C(sp2)–C(sp3) axially chiral compounds.
Scheme 9: NHC-catalyzed synthesis of axially chiral styrenes 26.
Scheme 10: NHC-catalyzed synthesis of biaxial chiral pyranones.
Scheme 11: Formation of bridged biaryls with eight-membered lactones.
Scheme 12: The NHC-catalyzed (3 + 2) annulation of urazoles 37 and ynals 36.
Scheme 13: NHC-catalyzed synthesis of axially chiral 4‑aryl α‑carbolines 41.
Scheme 14: NHC-catalyzed construction of N–N-axially chiral pyrroles and indoles.
Scheme 15: NHC-catalyzed oxidative Michael–aldol cascade.
Scheme 16: NHC-catalyzed (4 + 2) annulation for the synthesis of benzothiophene-fused biaryls.
Scheme 17: NHC-catalyzed desymmetrization of N-aryl maleimides.
Scheme 18: NHC-catalyzed deracemization of biaryl hydroxy aldehydes 55a–k into axially chiral benzonitriles 56a...
Scheme 19: NHC-catalyzed desymmetrization of 2-aryloxyisophthalaldehydes.
Scheme 20: NHC-catalyzed DKR of 2-arylbenzaldehydes 62.
Scheme 21: Atroposelective biaryl amination.
Scheme 22: CPA-catalyzed atroposelective amination of 2-anilinonaphthalenes.
Scheme 23: Atroposelective DKR of naphthylindoles.
Scheme 24: CPA-catalyzed kinetic resolution of binaphthylamines.
Scheme 25: Atroposelective amination of aromatic amines with diazodicarboxylates.
Scheme 26: Atroposelective Friedländer heteroannulation.
Scheme 27: CPA-catalyzed formation of axially chiral 4-arylquinolines.
Scheme 28: CPA-catalyzed Friedländer reaction of arylketones with cyclohexanones.
Scheme 29: CPA-catalyzed atroposelective Povarov reaction.
Scheme 30: Atroposelective CPA-catalyzed Povarov reaction.
Scheme 31: Paal–Knorr formation of axially chiral N-pyrrolylindoles and N-pyrrolylpyrroles.
Scheme 32: Atroposelective Paal–Knorr reaction leading to N-pyrrolylpyrroles.
Scheme 33: Atroposelective Pictet–Spengler reaction of N-arylindoles with aldehydes.
Scheme 34: Atroposelective Pictet–Spengler reaction leading to tetrahydroisoquinolin-8-ylanilines.
Scheme 35: Atroposelective formation of arylindoles.
Scheme 36: CPA-catalyzed arylation of naphthoquinones with indolizines.
Scheme 37: Atroposelective reaction of o-naphthoquinones.
Scheme 38: CPA-catalyzed formation of axially chiral arylquinones.
Scheme 39: CPA-catalyzed axially chiral N-arylquinones.
Scheme 40: Atroposelective additions of bisindoles to isatin-based 3-indolylmethanols.
Scheme 41: CPA-catalyzed synthesis of axially chiral arylindolylindolinones.
Scheme 42: CPA-catalyzed reaction between bisindoles and ninhydrin-derived 3-indoylmethanols.
Scheme 43: Atroposelective reaction of bisindoles and isatin-derived imines.
Scheme 44: CPA-catalyzed formation of axially chiral bisindoles.
Scheme 45: Atroposelective reaction of 2-naphthols with alkynylhydroxyisoindolinones.
Scheme 46: CPA-catalyzed reaction of indolylnaphthols with propargylic alcohols.
Scheme 47: Atroposelective formation of indolylpyrroloindoles.
Scheme 48: Atroposelective reaction of indolylnaphthalenes with alkynylnaphthols.
Scheme 49: CPA-catalyzed addition of naphthols to alkynyl-2-naphthols and 2-naphthylamines.
Scheme 50: CPA-catalyzed formation of axially chiral aryl-alkene-indoles.
Scheme 51: CPA-catalyzed formation of axially chiral styrenes.
Scheme 52: Atroposelective formation of alkenylindoles.
Scheme 53: Atroposelective formation of axially chiral arylquinolines.
Scheme 54: Atroposelective (3 + 2) cycloaddition of alkynylindoles with azonaphthalenes.
Scheme 55: CPA-catalyzed formation of axially chiral 3-(1H-benzo[d]imidazol-2-yl)quinolines.
Scheme 56: Atroposelective cyclization of 3-(arylethynyl)-1H-indoles.
Scheme 57: Atroposelective three-component heteroannulation.
Scheme 58: CPA-catalyzed formation of arylbenzimidazols.
Scheme 59: CPA-catalyzed reaction of N-naphthylglycine esters with nitrosobenzenes.
Scheme 60: CPA-catalyzed formation of axially chiral N-arylbenzimidazoles.
Scheme 61: CPA-catalyzed formation of axially chiral arylbenzoindoles.
Scheme 62: CPA-catalyzed formation of pyrrolylnaphthalenes.
Scheme 63: CPA-catalyzed addition of naphthols and indoles to nitronaphthalenes.
Scheme 64: Atroposelective reaction of heterobiaryl aldehydes and aminobenzamides.
Scheme 65: Atroposelective cyclization forming N-arylquinolones.
Scheme 66: Atroposelective formation of 9H-carbazol-9-ylnaphthalenes and 1H-indol-1-ylnaphthalene.
Scheme 67: CPA-catalyzed formation of pyrazolylnaphthalenes.
Scheme 68: Atroposelective addition of diazodicarboxamides to azaborinephenols.
Scheme 69: Catalytic formation of axially chiral arylpyrroles.
Scheme 70: Atroposelective coupling of 1-azonaphthalenes with 2-naphthols.
Scheme 71: CPA-catalyzed formation of axially chiral oxindole-based styrenes.
Scheme 72: Atroposelective electrophilic bromination of aminonaphthoquinones.
Scheme 73: Atroposelective bromination of dienes.
Scheme 74: CPA-catalyzed formation of axially chiral 5-arylpyrimidines.
Scheme 75: Atroposelective hydrolysis of biaryloxazepines.
Scheme 76: Atroposelective opening of dinaphthosiloles.
Scheme 77: Atroposelective reduction of naphthylenals.
Scheme 78: Atroposelective allylic substitution with 2-naphthols.
Scheme 79: Atroposelective allylic alkylation with phosphinamides.
Scheme 80: Atroposelective allylic substitution with aminopyrroles.
Scheme 81: Atroposelective allylic substitution with aromatic sulfinamides.
Scheme 82: Atroposelective sulfonylation of naphthylynones.
Scheme 83: Squaramide-catalyzed reaction of alkynyl-2-naphthols with 5H-oxazolones.
Scheme 84: Formation of axially chiral styrenes via sulfonylative opening of cyclopropanols.
Scheme 85: Atroposelective organo-photocatalyzed sulfonylation of alkynyl-2-naphthols.
Scheme 86: Thiourea-catalyzed atroposelective cyclization of alkynylnaphthols.
Scheme 87: Squaramide-catalyzed formation of axially chiral naphthylisothiazoles.
Scheme 88: Atroposelective iodo-cyclization catalyzed by squaramide C69.
Scheme 89: Squaramide-catalyzed formation of axially chiral oligoarenes.
Scheme 90: Atroposelective ring-opening of cyclic N-sulfonylamides.
Scheme 91: Thiourea-catalyzed kinetic resolution of naphthylpyrroles.
Scheme 92: Atroposelective ring-opening of arylindole lactams.
Scheme 93: Atroposelective reaction of 1-naphthyl-2-tetralones and diarylphosphine oxides.
Scheme 94: Atroposelective reaction of iminoquinones with indoles.
Scheme 95: Kinetic resolution of binaphthylalcohols.
Scheme 96: DKR of hydroxynaphthylamides.
Scheme 97: Atroposelective N-alkylation with phase-transfer catalyst C75.
Scheme 98: Atroposelective allylic substitution via kinetic resolution of biarylsulfonamides.
Scheme 99: Atroposelective bromo-functionalization of alkynylarenes.
Scheme 100: Sulfenylation-induced atroposelective cyclization.
Scheme 101: Atroposelective O-sulfonylation of isochromenone-indoles.
Scheme 102: NHC-catalyzed atroposelective N-acylation of anilines.
Scheme 103: Peptide-catalyzed atroposelective ring-opening of lactones.
Scheme 104: Peptide-catalyzed coupling of 2-naphthols with quinones.
Scheme 105: Atroposelective nucleophilic aromatic substitution of fluoroarenes.
