Asymmetric Synthesis Research Articles

Brønsted Acid Catalyzed Asymmetric Synthesis of Cyclopentenones with C4-Quaternary Centers Starting from Vinyl Sulfoxides and Allenyl Ketones or Allenoates.

Starting with chiral vinyl sulfoxides and allenyl ketones or allenoates, a triflic acid-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfoniums is reported to have a direct access to highly functionalized C4-chiral cyclopentenones (19 examples, up to 85% yield and >95% enantiomeric excesses). In addition to the use of these chiral compounds as key building blocks in organic synthesis, the antiproliferative activities of sulfoxide substrates and the corresponding cyclopentenones were evaluated, and promising cytotoxicity against the HL-60 human tumor cell line was found.

Chromium- and Metal-Reductant-Free Asymmetric Nozaki-Hiyama-Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis.

Chiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki-Hiyama-Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox-catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements.

Enantioselective synthesis of γ-chiral amides via copper-catalyzed reductive relay hydroaminocarbonylation

Chiral amides are common and effective structural motifs found in many pharmaceuticals and biologically active molecules. Despite their importance, existing synthetic methods are predominantly employed for the synthesis of α-amides and β-amides. The synthesis of remote chiral amides, characterized by distal stereocenters, typically requires intricate synthetic steps conducted under demanding conditions. Here, we present a general procedure for the copper-catalyzed enantioselective synthesis of γ-chiral amides, employing a reductive relay hydroaminocarbonylation strategy with trisubstituted allylic benzoates and hydroxylamine electrophiles. This approach demonstrates a wide substrate scope with excellent enantioselectivity and regioselectivity, thus providing access to challenging enantioenriched γ-chiral amides.

Recent Advances on Catalytic Atroposelective Synthesis of Planar‐Chiral Macrocycles

Planar chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of central or axial chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar chiral [2,2]‐paracyclophanes and metallocenes. This Minireview describes the recent advancements on asymmetric catalytic synthesis of planar chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar chiral skeletons.

Recent Advances on Catalytic Atroposelective Synthesis of Planar-Chiral Macrocycles.

Planar chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of central or axial chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar chiral [2,2]-paracyclophanes and metallocenes. This Minireview describes the recent advancements on asymmetric catalytic synthesis of planar chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar chiral skeletons.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides

Despite recent advancements in catalytic synthesis of axial chirality, reports on non‐biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho‐aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Pd-Catalyzed Asymmetric Allylic Substitution Cascade via Desymmetrization for the Construction of Chiral Polyheterocycles

Chiral polyheterocycles represent an important class of compounds because of their prevalence in bioactive natural products and chiral drugs. Pd-catalyzed allylic substitution is a powerful synthetic tool for forming C–C and C–X bonds (X = N, O, S, etc.). Naturally, asymmetric cascade reactions that utilize allylic substitution are undoubtedly efficient pathways to construct heterocycles. In this article, we reviewed the Pd-catalyzed asymmetric allylic substitution cascade via the desymmetrization of meso-diol diesters of cycloolefins, for the construction of chiral polyheterocycles and their derivatives.

Synthesis and Application of Planar Chiral NHC/Rh Complexes Bearing CoC4Ph4 Group.

Sandwich compound-based planar chiral N-heterocyclic carbene (NHC) ligands having a bulky η5-cyclopentadienyl-cobalt-η4-tetraphenylcyclobutadiene core were developed, and their donor strengths were evaluated by determining the Tolman electronic parameter (TEP) of the Rh dicarbonyl complex. The TEP was high at 2048 cm-1, as expected for an NHC ligand. The utility of the carbenes as chiral ligands was examined in the Rh-catalyzed asymmetric ring-opening reaction of oxabenzonorbornadienes with benzylamine, and the corresponding products were obtained with moderate enantioselectivities (up to 66% ee).

Electromagnetic Enantiomer: Chiral Nanophotonic Cavities for Inducing Chemical Asymmetry.

Chiral molecules, a cornerstone of chemical sciences with applications ranging from pharmaceuticals to molecular electronics, come in mirror-image pairs called enantiomers. However, their synthesis often requires complex control of their molecular geometry. We propose a strategy called "electromagnetic enantiomers" for inducing chirality in molecules located within engineered nanocavities using light, eliminating the need for intricate molecular design. This approach works by exploiting the strong coupling between a nonchiral molecule and a chiral mode within a nanocavity. We provide evidence for this strong coupling through angular emission patterns verified by numerical simulations and with complementary evidence provided by luminescence lifetime measurements. In simpler terms, our hypothesis suggests that chiral properties can be conveyed on to a molecule with a suitable chromophore by placing it within a specially designed chiral nanocavity that is significantly larger (hundreds of nanometers) than the molecule itself. To demonstrate this concept, we showcase an application in display technology, achieving efficient emission of circularly polarized light from a nonchiral molecule. The electromagnetic enantiomer concept offers a simpler approach to chiral control, potentially opening doors for asymmetric synthesis.

Catalytic enantioselective intramolecular hydroamination of alkenes using chiral aprotic cyclic urea ligand on manganese (II)

Asymmetric catalysis for enantioselective intramolecular hydroamination of alkenes is a critical method in the construction of enantioenriched nitrogen-containing rings, often prevalent in biologically active compounds and natural products. Herein, we demonstrate a facile enantioselective intramolecular hydroamination of alkenes for the synthesis of chiral pyrrolidine, piperidine, and indoline moieties, using a manganese (II) chiral aprotic cyclic urea catalyst. The cyclic ligand hinders the inversion of the N atom of the urea and effectively discriminate between the enantiomers of substrates. High-resolution mass spectrometry, deuterium labeling experiments, and molecular orbital energy analysis clearly reveal the intermediates and mechanism of the transformation. As a key step, oxygen coordination by chiral aprotic urea presents a robust control over the asymmetric intra-HA reaction through the involvement of a convergent assembly of two vital intermediates (Mn-N and C-Mn-Br), providing access to chiral cyclic amine systems in high yields with excellent enantioselectivity.

Stereoconvergent and Enantioselective Synthesis of Z-Homoallylic Alcohols via Nickel-Catalyzed Reductive Coupling of Z/E-1,3-Dienes with Aldehydes.

Stereoconvergent reactions enable the transformation of mixed stereoisomers into well-defined, chiral products─a crucial strategy for handling Z/E-mixed olefins, which are common but challenging substrates in organic synthesis. Herein, we report a stereoconvergent and highly enantioselective method for synthesizing Z-homoallylic alcohols via the nickel-catalyzed reductive coupling of Z/E-mixed 1,3-dienes with aldehydes. This process is enabled by an N-heterocyclic carbene ligand characterized by C2-symmetric backbone chirality and bulky 2,6-diisopropyl N-aryl substituents. Our method achieves excellent stereocontrol over both enantioselectivity and Z-selectivity in a single step, producing chiral Z-homoallylic alcohols that are valuable in natural products and pharmaceuticals.

Stereoselective Syntheses of Polyunsaturated Fatty Acids, 13-(S)-HODE and 15-(S)-HETE.

Polyunsaturated fatty acids and their metabolites have been reported in which their pathway has potential for the modulation of cancer cell growth. 13-(S)-HODE and 15-(S)-HETE, both of which are main metabolites of 15-LOXs, play an important role as endogenous ligands in biological systems. However, the modification of 13-(S)-HODE and 15-(S)-HETE in pharmaceutical applications has not been explored widely. Herein, we report the stereoselective syntheses of 13-(S)-HODE, 15-(S)-HETE, and its derivatives to enable the synthesis of bioactive fatty acid analogues.

Cascade Oxypalladation/1,3-Palladium Shift to Access Cyclopentene-Fused Isocoumarins.

Fused isocoumarins are frequently found in several natural products and pharmaceuticals. Herein, a cascade annulation of 2-alkynylbenzoate-tethered cyclic 1,3-diones via sequential trans-oxypalladation, carbonyl insertion, 1,3-Pd shift, and β-hydride elimination is reported. This method provides efficient access to highly diastereoselective tetracyclic cyclopentene-fused isocoumarins containing two contiguous quaternary stereocenters. A plausible reaction mechanism is proposed on the basis of mechanistic studies, including deuterium labeling experiments. Studies toward enantioselective synthesis using a chiral Bpy ligand gave encouraging initial results.

Construction of central and axial chirality via Pd(II)/Bim-catalyzed asymmetric dearomative Michael reaction of polycyclic tropones.

A highly enantioselective Pd/Bim-catalyzed dearomative Michael reaction applying polycyclic tropones as non-benzenoid aromatic Michael acceptors and arylboronic acids as aryl pronucleophiles has been developed. The bridged biaryls bearing central and axial chirality, including pentacyclic cyclohepta[b]indoles and 6,7-dihydrodibenzo[a,c][7]annulen-5-ones, are generally generated in good to high yields and excellent enantioselectivities and can be readily transformed into useful derivatives.

Biocatalytic Stereoselective Synthesis of Chiral Precursors for Liposoluble β1 Receptor Blocker Nebivolol.

Asymmetric reduction of 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (NEB-7) into 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (NEB-8) is the crucial step for synthesis of liposoluble β1 receptor blocker nebivolol. Four efficient and stereoselective alcohol dehydrogenases were identified, enabling the stereoselective synthesis of all enantiomers of NEB-8 at a substrate loading of 137 g·L-1 with ee values of >99% and high space-time yields. This study provides novel biocatalysts for the efficient synthesis of nebivolol precursors and uncovers the molecular basis for enantioselectivity manipulation by parametrization of Prelog's rule.

Asymmetric Construction of Ethenyl-Substituted Acyclic Quaternary Stereocenters at the α-Position of Carbonyl Surrogates via Stereoselective Sulfonylvinylation-Reductive Desulfonylation.

N-Sulfinyl metalloenamines, derived from geometry-defined β,β-disubstituted enesulfinamides, undergo conjugate addition-elimination reaction with β-tosyl nitroolefin to afford α-sulfonylvinylated ketimines with high stereocontrol. Further desulfonylation using sodium naphthalenide gives carbonyl surrogates bearing a less-accessible acyclic quaternary α-stereocenters substituted with an ethenyl group and two sterically and electronically similar groups (e.g., methyl and ethyl). Synthetic application of the described protocol was demonstrated by enantioselective synthesis of (S)-bakuchiol.

Asymmetric Synthesis of α-Arylcyclohexenones Catalyzed by Diphenylprolinol Silyl Ether.

A general methodology for the asymmetric synthesis of α-arylcyclohexeneones from arylacetones and α,β-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether followed by p-TSA-mediated cyclization is developed. A variety of arylacetones and α,β-unsaturated aldehydes were successfully converted to α-arylcyclohexeneones in 34-67% yield, 10:1-100:0 dr, and 81-99% ee. The scalability of this methodology by a gram-scale synthesis and their utility by converting the product to the corresponding epoxide, alcohol, and diol are demonstrated.

Organocatalyzed Synthesis of γ-Alkenyl Butenolides via Asymmetric Direct Vinylogous Conjugate Addition-Elimination of Substituted Furanone Derivatives to β-Phenylsulfonylenones.

A diaminomethylenemalononitrile organocatalyst efficiently promoted the asymmetric direct vinylogous conjugate addition of α-angelica lactone derivatives to β-phenylsulfonylenones, affording the corresponding γ-alkenyl γ-butenolides in high yields with excellent enantioselectivities (up to 97% ee) after the elimination of the phenylsulfonyl group. This study reports the first successful example of a stereoselective reaction using β-phenylsulfonylenone as the direct alkenyl donor.