Excellent Enantioselectivities Research Articles

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis

AbstractThe isolation and catalytic enantioselective synthesis of configurationally stable S‐stereogenic sulfonium ylides have been significant challenges in the field of asymmetric synthesis. These reactive intermediates are crucial for a variety of synthetic transformations, yet their inherent tendency towards rapid inversion at the sulfur stereocenter has hindered their practical utilization. Conventional approaches have focused on strategies that incorporate a C=S bond‐containing cyclic framework to help mitigate this stereochemical lability. In this work, we present an alternative tactic that leverages the stabilizing influence of an adjacent N‐atom and cyclic sulfide moiety. Exploiting a copper catalyzed enantioselective intermolecular carbene transfer reaction, structurally diverse S‐stereogenic aminosulfonium ylides have been achieved in excellent yields and enantioselectivities. Experimental results indicate that the careful selection of 2‐diazo‐1,3‐diketone precursors is crucial for achieving optimal stereoinduction in this transformation. The resulting highly enantioenriched aminosulfonium ylides allow for further stereospecific elaborations to furnish aminosulfonium ylide oxides and sulfinamide. This work expands the boundaries of chiral sulfonium ylide chemistry, providing access to a broad range of previously elusive S‐stereogenic aminosulfonium ylide scaffolds.

Construction of Dihydropyrano[2,3‐c]pyrazolone via Photo‐induced Wolff Rearrangement/Chiral Isothiourea Catalyzed [4+2] Cyclization Reaction

AbstractA photoinduced Wolff rearrangement/chiral isothiourea catalyzed [4+2] cycloaddition reaction of pyrazolone derivatives and α‐diazoketones was developed, affording the corresponding dihydropyrano[2,3‐c]pyrazolone derivatives in moderate to good yields (50–94 %) with satisfactory to excellent diastereoselectivities (>20 : 1 dr, in almost all cases) and enantioselectivities of 31–99 %. This protocol features readily available substrates, mild reaction conditions, and effective construction of vicinal tertiary and quaternary carbon stereocenters.

Enantioselective Synthesis of Axially Chiral Allylic Nitriles via Nickel-Catalyzed Desymmetric Cyanation of Biaryl Diallylic Alcohols.

Axially chiral nitriles are common motifs in organic photoelectric materials, biological compounds, and agrochemicals. Unfortunately, the limited synthetic approaches to axially chiral nitriles have impeded their availability. Herein, we report the first nickel-catalyzed desymmetric allylic cyanation of biaryl allylic alcohols for the synthesis of axially chiral nitrile structures in high yields with excellent enantioselectivities (up to 90% yield and >99% ee). This process enables the synthesis of a diverse range of axially chiral allylic nitriles bearing β,γ-unsaturated alcohol moieties. Leveraging the allylic alcohol and cyano groups as versatile functionalization handles allow for further derivatization of these axially chiral frameworks. Density functional theory (DFT) calculations suggest that both steric and electronic interactions play crucial roles in determining the enantioselectivity of this transformation. Moreover, this mild and facile protocol is also applicable for gram-scale preparation of the chiral nitriles.

Enantioselective Synthesis of Axially Chiral Allylic Nitriles via Nickel‐Catalyzed Desymmetric Cyanation of Biaryl Diallylic Alcohols

Axially chiral nitriles are common motifs in organic photoelectric materials, biological compounds, and agrochemicals. Unfortunately, the limited synthetic approaches to axially chiral nitriles have impeded their availability. Herein, we report the first nickel‐catalyzed desymmetric allylic cyanation of biaryl allylic alcohols for the synthesis of axially chiral nitrile structures in high yields with excellent enantioselectivities (up to 90% yield and >99% ee). This process enables the synthesis of a diverse range of axially chiral allylic nitriles bearing β,γ‐unsaturated alcohol moieties. Leveraging the allylic alcohol and cyano groups as versatile functionalization handles allow for further derivatization of these axially chiral frameworks. Density functional theory (DFT) calculations suggest that both steric and electronic interactions play crucial roles in determining the enantioselectivity of this transformation. Moreover, this mild and facile protocol is also applicable for gram‐scale preparation of the chiral nitriles.

Enantioselective Synthesis of Chiral 1,5-Benzodiazepin-2-ones by Pd-Catalyzed Asymmetric Hydrogenation and Reductive Amination.

The enantioselective synthesis of chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones via asymmetric hydrogenation catalyzed by the Pd/f-spiroPhos complex in the presence of hydrochloric acid as an additive has been developed, achieving excellent enantioselectivities and high turnover numbers, up to 99% ee and TON = 4600. More significantly, the asymmetric reductive amination of β-keto esters with 1,2-phenylenediamine has also been successfully realized to afford chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones with comparable enantioselectivities of up to 99% ee.

Halogen-Bond-Assisted NHC-Catalyzed (Dynamic) Kinetic Resolution for the Atroposelective Synthesis of Heterobiaryls.

We report a novel halogen-bond-assisted NHC-catalyzed (dynamic) kinetic resolution strategy for the synthesis of axially chiral heterobiaryls. A class of axially chiral quinolines are prepared efficiently in excellent enantioselectivities (≤98% ee) employing 3-5 mol % NHC catalyst. Mechanistic studies reveal the indispensability of 5-bromo-2-iodobenzaldehyde in this reaction, in which a pivotal halogen bonding interaction plays a crucial role in the process.

Enantioselective Synthesis of 3-Hydroxy-2-Oxindoles via Ni-Catalyzed Asymmetric Addition of Aromatic Bromides to α-Ketoamides.

Nickel-catalyzed asymmetric intramolecular addition of aryl halides to α-ketoamides has been achieved to afford chiral 3-substituted-3-hydroxy-2-oxindoles in excellent yields and high enantioselectivities (up to 99% yield and 98% ee), which provides efficient access to valuable molecules containing 3-hydroxy-2-oxindole core. The gram-scale reaction proved the potential utility of the methodology.

N-Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P-Stereogenicity.

P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96 % ee, and good diastereoselectivity, with up to 14 : 1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.

Pd(II)-Catalyzed Chemo-, Diastereo-, and Enantioselective C(sp3)-H Arylation to Construct Contiguous Phosphorus and Carbon Stereocenters.

Chiral phosphorus compounds with contiguous P,C-stereogenic centers are widely found in chiral ligands. The synthesis of these skeletons has been scarcely reported. Herein, we developed a Pd(II)-catalyzed chemo-, diastereo-, and enantioselective arylation of diisopropyl phosphinamide enabled by 2-pyridinylisopropyl (PIP) auxiliary and (S)-6,6'-(CN)2-SPINOL. A range of chiral phosphinamides containing contiguous P,C-stereocenters were obtained in good yields (up to 85%) with excellent enantioselectivities (up to >99% ee).

Organocatalyzed Asymmetric Conjugate Addition of Cyclic β-Keto Esters to (E)-β-Nitroacrylate Derivatives.

A diaminomethylenemalononitrile organocatalyst efficiently promoted the asymmetric conjugate addition of cyclic β-keto esters to (E)-β-nitroacrylate derivatives, yielding the corresponding β-nitro esters derivatives with excellent enantioselectivities (up to >99% ee). This is the first successful example of highly stereoselective conjugate addition of cyclic β-keto esters to (E)-β-nitroacrylate derivatives to obtain anti-isomers.

Asymmetric one-carbon ring expansion of diverse N-heterocycles via copper-catalyzed diyne cyclization.

One-carbon ring expansion reaction of N-heterocycles has gained particular attention in the past decade because this method allows for the conversion of readily available N-heterocycles into potentially useful complex ring-expanded N-heterocycles, which are inaccessible by traditional methods. However, the catalytic asymmetric variant of this reaction has been rarely reported to date. Herein, we disclose an enantioselective one-carbon ring expansion reaction through chiral copper-catalyzed diyne cyclization, leading to the practical, atom-economic and divergent assembly of an array of valuable chiral N-heterocycles bearing a quaternary stereocenter in generally good to excellent yields with excellent enantioselectivities (up to >99% ee). This protocol represents the first example of asymmetric one-carbon ring expansion reaction of N-heterocycles based on alkynes.

Asymmetric Allylic Amination of Alkyl-Substituted Allylic Carbonates with Pyridones Catalyzed by the Krische Iridium Complex.

An efficient Ir-catalyzed asymmetric allylic amination reaction of alkyl-substituted allylic carbonates is disclosed. With the Krische iridium complex as the catalyst, asymmetric allylic amination of alkyl-substituted allylic carbonates with pyridones proceeds effectively, affording pyridone derivatives containing a stereocenter α to the nitrogen atom in excellent yields and enantioselectivity (up to 99% yield, 95% ee). This catalytic system broadens the substrate scope of the reaction compared with that of the known catalytic systems. This reaction can also be conducted on a gram scale, further enhancing its potential for synthetic application.

Asymmetric Aza Friedel-Crafts Reaction of 3,4-Dihydroisoquinolines with 1-Naphthols Catalyzed by Chiral Phosphoric Acids.

An efficient chiral phosphoric acid-catalyzed asymmetric aza Friedel-Crafts reaction of 3,4-dihydroisoquinolines and 1-naphthols is described. The reaction provides a general method for the synthesis of diverse chiral tetrahydroisoquinoline with 1-naphthol substituents at the C1-position in excellent yields and enantioselectivities. Based on the conducted mechanistic experiments, a plausible catalytic mechanism was proposed. Moreover, the practicability of the reaction is successfully demonstrated by its application on a gram scale.

Nickel/Photoredox-Catalyzed Asymmetric Three-Component Cross-Coupling To Access Enantioenriched 1,1-Diaryl(heteroaryl)alkanes.

An enantioselective 1,2-dicarbofunctionalization of vinyl (hetero)arenes with alkyl bromides and aryl bromides through nickel/photoredox catalysis is described. This three-component enantioselective domino alkyl arylation of vinyl (hetero)arenes could generate a diverse array of enantioenriched 1,1-diaryl(heteroaryl)alkanes with good to excellent yields (up to 88%) and high enantioselectivities (up to 99% ee). This transformation could proceed well under mild conditions with excellent chemo- and regioselectivity due to the avoidance of the use of air- and moisture-sensitive organometallic reagents and stoichiometric metal reductants. Mechanistic studies suggested that the alkyl radical is generated via NiI species or photocatalyst.

De Novo Enantioselective Synthesis of Hexafluorinated d-Glucose.

We report a de novo enantioselective synthesis of 2,3,4-trideoxy-2,2,3,3,4,4-hexafluoro-d-glycero-hexopyranose (hexafluorinated d-glucose), an iconic polar hydrophobic glycomimetic. The 12-step synthesis features robust and reproducible chemistry and was achieved by incorporating an asymmetric dihydroxylation step to install the stereogenic center with excellent enantioselectivity (95:5 er). Virtual enantiopurity (>99.5% ee) was further reached using a simple crystallization procedure and the absolute confirmation was ascertained by X-ray analysis. The synthetic route also allowed access to the novel hexafluorinated heptose derivative 2,3,4-trideoxy-2,2,3,3,4,4-hexafluoro-l-threo-heptopyranose.

Substrate-Controlled Regioselective Cascade Reactions of Deconjugated Butenolides and Cinnamaldehydes: Access to Structurally Diverse Spirobutenolides.

Two different cascade pathways to access spirobutenolides were achieved based on the substrate-controlled regioselectivity of deconjugated butenolides. A new class of functional deconjugated butenolides was designed and exhibited superior γ-regioselectivity in the vinylogous Michael/Michael cascade reactions with cinnamaldehydes. The aryl-substituted deconjugated butenolides and cinnamaldehydes underwent a Michael/Michael/aldol/dehydration cascade process induced by double α-regioselectivities. Both conjugated and deconjugated spirobutenolides could be obtained in good yields with excellent enantioselectivities.

Diastereoselective Stereo-Divergent Synthesis of Spiroindolines via Ligand-Controlled Silver(I)-Catalyzed Asymmetric [3 + 2] cycloadditions

A series of spirocyclic pyrrolidine derivatives with quaternary stereocenters was constructed via asymmetric [3 + 2] cycloaddition reactions between imino esters and 2-oxindole. By ingenious use of ligands on the silver catalyst allows stereoselectivity to either endo-isomers (ee up to 98 %, yields up to 96 %) with (R, Rp)-Ph-Phosferrox or exo-isomers (ee up to 99 %, yields up to 87 %) with (R)-BINAP. This work is notable for its high yields, broad substrate adaptability and excellent enantioselectivity.

Synergistic Homogeneous Asymmetric Cu Catalysis with Pd Nanoparticle Catalysis in Stereoselective Coupling of Alkynes with Aldimine Esters.

Understanding the nature of a transition-metal-catalyzed process, including catalyst evolution and the real active species, is rather challenging yet of great importance for the rational design and development of novel catalysts, and this is even more difficult for a bimetallic catalytic system. Pd(0)/carboxylic acid combined system-catalyzed allylic alkylation reaction of alkynes has been used as an atom-economical protocol for the synthesis of allylic products. However, the asymmetric version of this reaction is still rather limited, and the in-depth understanding of the nature of active Pd species is still elusive. Herein we report an enantioselective coupling between readily available aldimine esters and alkynes using a synergistic Cu/Pd catalyst system, affording a diverse set of α-quaternary allyl amino ester derivatives in good yields with excellent enantioselectivities. Mechanistic studies indicated that it is most likely a synergistic asymmetric molecular Cu catalysis with Pd nanoparticle catalysis. The Pd catalyst precursor is transformed to soluble Pd nanoparticles in situ, which are responsible for activating the alkyne to an electrophilic allylic Pd intermediate, while the chiral Cu complex of the aldimine ester enolate provides chiral induction and works in synergy with the Pd nanoparticles.

Preparation of two new chiral metal-organic frameworks for lipase immobilization and their use as biocatalysis in the enantioselective hydrolysis of racemic naproxen methyl ester

Considering the selective pharmacological activity of chiral drugs, it is important to develop new chiral materials to synthesize them. In this work, two new chiral MOFs (UiO-66@Np and UiO-66@Ib) were prepared by the covalent attachment of the chiral compounds (S-naproxen and S-ibuprofen) to the amine-functionalized Zr-MOF (UiO-66-NH2). Then, Candida rugosa lipase (CRL) was immobilized on these chiral MOFs to fabricate two new biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) as effective biocatalysts, which enable significant enhancement in the catalytic activity and enantioselectivity of lipase. The FTIR, SEM, EDX, TGA, and PXRD analyses were carried out to confirm the formation of the biocomposites. The catalytic performances of the biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) were evaluated in the typical hydrolysis of p-nitro-phenyl palmitate (p-NPP) and the catalytic enantioselective hydrolysis of (R,S)-naproxen methyl ester. Under optimal conditions, UiO-66@Np@CRL showed a higher enantiomeric excess of the substrate (ees) value and a 98 % and 50 % conversion rate, respectively, than that of UiO-66@Ib@CRL. Besides, an excellent enantioselectivity (E) value of 458 was obtained in the presence of the biocomposite (UiO-66@Np@CRL). In addition, it was observed that the catalytic activity, conversion rate and ees value of this composite (UiO-66@Np@CRL) remained almost unchanged in reuse after 6 months. The results showed that in enantioselective reactions, the highest conversion and enantioselectivity could be achieved when the chiral compound bound to the MOF and the model compound used are the same.

Nickel-Catalyzed Enantioconvergent Allenylic Amination of Allenols Activated by Hydrogen-Bonding Interaction with Methanol.

The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.