Asymmetric Synthesis Research Articles

Base-Promoted Coupling of HFIP in Cu-Catalyzed Asymmetric Ring Opening of Cyclic Diaryliodoniums.

We report a Cu-catalyzed asymmetric ring-opening reaction of cyclic diaryliodoniums with 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), enabling the construction of axially chiral biaryl compounds containing HFIP ether. HFIP is highly polar and exceptionally stable; thus, it is commonly used as a solvent due to its poor nucleophilicity. However, its use as a nucleophilic reagent has been rare. In this study, we successfully employed HFIP as a nucleophilic coupling partner in a Cu-catalyzed asymmetric ring-opening experiment of cyclic diaryliodoniums.

Chiral SPINOL‐Derived Borophosphate‐Catalyzed Asymmetric 1,4‐Reduction of Exocyclic α,β‐Unsaturated Ketones

AbstractAn asymmetric 1,4‐reduction of exocyclic α,β‐unsaturated ketones, yielding diverse optically active α‐substituted tetralones, has been achieved using a chiral SPINOL‐derived borophosphate catalyst. The enantioselectivity‐determining step of the reaction involves the protonation of a highly active boron enolates intermediate. This catalytic reduction system, comprising chiral SPINOL‐derived borophosphate and pinacolborane, has potential for broader application in other asymmetric reduction reactions.

Asymmetric Synthesis of Polycyclic Heterocyclic Compounds via Friedel-Crafts Reaction/Cyclization Reaction Catalyzed by Nickel Catalyst.

The first highly enantioselective asymmetric Friedel-Crafts reaction/cyclization reaction of 5-aminopyrazoles with 3-alkenyloxindoles to afford polycyclic heterocyclic compounds bearing an all-carbon quaternary stereocenter catalyzed by a complex of NiII with the C2-symmetric bipyridine-N,N'-dioxide ligand L12 has been developed. The relevant products with a wide range of substrates and good functional tolerance were obtained in 89-98% yield with 56-99% ee in the presence of 10 mol % Ni(OTf)2 and 11 mol % L12 in DCM at 25 °C. Moreover, an experiment on scaling up the process along with the transformations of the cycloadducts further emphasized the practical application of the synthesis.

Asymmetric Construction of Chiral 2‐Azetines and Axially Chiral Tetrasubstituted Allenes via Phosphine Catalysis

Chiral 2‐azetines and allenes are highly valuable structural units in natural products and useful chemicals. However, enantioselective synthesis of both 2‐azetines and allenes has been extremely challenging. Herein, we present asymmetric construction of chiral 2‐azetines (70–98% yields and up to 96% ee) through chiral phosphine‐catalyzed [2+2] annulation of yne‐enones with sulfamate‐derived cyclic imines. These 2‐azetines were easily transformed into chiral allenes upon treatment with Et3SiH, BF3•Et2O and water at rt for 2 minutes. Based on the above transformations, a concise one‐pot synthetic procedure combining [2+2] annulation of yne‐enones and sulfamate‐derived cyclic imines under phosphine catalysis and sequential reduction/isomerization/ring‐opening reaction through Et3SiH, BF3•Et2O and water was thus set up, providing axially chiral tetrasubstituted allenes in satisfactory yields and enantioselectivities (56–90% yields and up to 91% ee).

Asymmetric Construction of Chiral 2-Azetines and Axially Chiral Tetrasubstituted Allenes via Phosphine Catalysis.

Chiral 2-azetines and allenes are highly valuable structural units in natural products and useful chemicals. However, enantioselective synthesis of both 2-azetines and allenes has been extremely challenging. Herein, we present asymmetric construction of chiral 2-azetines (70-98% yields and up to 96% ee) through chiral phosphine-catalyzed [2+2] annulation of yne-enones with sulfamate-derived cyclic imines. These 2-azetines were easily transformed into chiral allenes upon treatment with Et3SiH, BF3•Et2O and water at rt for 2 minutes. Based on the above transformations, a concise one-pot synthetic procedure combining [2+2] annulation of yne-enones and sulfamate-derived cyclic imines under phosphine catalysis and sequential reduction/isomerization/ring-opening reaction through Et3SiH, BF3•Et2O and water was thus set up, providing axially chiral tetrasubstituted allenes in satisfactory yields and enantioselectivities (56-90% yields and up to 91% ee).

Organocatalytic Asymmetric Synthesis of C-N Atropisomers with Pyrrole, Oxindole and Succinimide Scaffold.

An asymmetric synthesis of C-N atropisomers with pyrrole, oxindole and succinimide moities was developed via organocatalytic desymmetric Michael addition of 3-pyrrolyloxindole with prochiral N-aryl maleimides. The C-N atropisomers were obtained in acceptable yields with high diastero- and enantioselectivities (>20:1 dr, up to >99% ee). C-N Rotational energy barrier has also been determined.

Chiral Polar Bifunctional Polyimide Enantiomers for Asymmetric Photo- and Piezo-Catalysis.

Chiral catalysts for asymmetric catalysis represent a crucial research focus in chemistry and materials science. However, a few cases about chiral-dependent photocatalysts primarily focus on plasmonic noble metals. Particularly, developing chiral nano-catalysts that can be driven by mechanical energy remains in the blank stage. Herein, organic polymer-based enantiomers, chiral polar polyimide (PI) microspheric nano-assembly are synthesized as novel bifunctional catalysts for asymmetric photocatalysis and piezocatalysis. The PI catalyst enantiomers present enantioselectivity towards left- and right-circularly polarized light, demonstrating chiral-dependent H2O2 photoproduction. Interestingly, enantioselectivity of the catalyst reverses under irradiation of different bands, presenting tunability in the interaction between chiral catalysts and circularly polarized light. For the first time, enantioselective piezocatalytic behavior is demonstrated by the chiral polar PI catalysts. They show remarkable chiral preference for asymmetric Diels-Alder reaction and enantioselective conversion of tyrosine substrates under ultrasonic vibration. The findings provide a new perspective into exploring metal-free chiral catalysts and their asymmetric catalysis applications across multiple energy forms.

Multicomponent Cyanation of 2‐Amino‐3‐cyano‐4H‐chromenes in Aqueous Media

AbstractChromenes represent a pivotal molecular structure found in a diverse range of biologically active compounds. Specifically, derivatives of 2‐amino‐3‐cyano‐4H‐chromene have demonstrated pharmacological applications, displaying potential antioxidant and anticancer activities. This has heightened interest in the exploration of new and more efficient methods for their synthesis. In recent years, few examples have emerged, focusing on the organocatalytic and enantioselective synthesis of 2‐amino‐3‐cyano‐4H‐chromene derivatives, although the overall number of works to date is limited. In this study, we present the results of the synthesis of 2‐amino‐4H‐chromen‐3,4‐dicarbonitriles through a Michael addition of cyanide to 2‐iminochromenes. To achieve this, we utilized a mild source of cyanide (acetone cyanohydrin), green solvents and catalytic conditions at room temperature, via a multicomponent approach. Furthermore, we initiated the enantioselective study of this process using chiral organocatalysts obtaining promising preliminary results.

Access to Alkenyl Cyclobutanols by Ni-Catalyzed Regio- and Enantio-Selective syn-Hydrometalative 4-exo-trig Cyclization of Alkynones.

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

Stereoselective Ring-Opening Reaction of α-Fluorinated Oxetanes: A Practical and Theoretical Investigation.

The ring-opening reaction of fluorinated oxetanes by halides, including alkylidene oxetanes and spirocyclic oxetanes, was highly stereoselective and directed by the presence of a fluorine atom. This reaction allowed a stereoselective preparation of tetrasubstituted alkenes and substituted pyrrolidines containing all-carbon quaternary centers. Theoretical calculations were performed to shed light on experimentally observed regioselectivity in the opening of oxetane derivatives. Transition state calculations were carried out to compare the energy of transition states responsible for forming different diastereoisomers. These calculations were performed using several DFT functionals and benchmarked to DLPNO-CCSD(T)/def2-TZVP calculations. Intrinsic reaction coordinated (IRC) calculations were run to confirm if the found transition states connect reactants and products. The IRC paths were then decomposed into the electrostatic, steric hyperconjugative contributions to reaction barriers by using the natural bond orbital (NBO) analysis. The destabilizing Fδ-···Br- electrostatic interaction directs the reaction pathway.

Mechanistic Investigations of Chiral Lithium Binaphtholate Catalysis for Asymmetric Aldol-Tishchenko Reaction of α-Fluoroarylketones.

In this study, we analyzed the asymmetric aldol-Tishchenko reaction of α-fluoroarylketones with aldehydes in the presence of chiral lithium binaphtholate, which was readily prepared from a chiral BINOL derivative and lithium tert-butoxide. This tandem reaction afforded enantiomerically enriched 2-fluoro-1,3-diols with three contiguous stereogenic centers in high yield and with high diastereo- and enantioselectivities. Moreover, mechanistic investigations of the lithium binaphtholate-catalyzed enantioselective aldol-Tishchenko reaction were performed based on the kinetic isotope effect and computational analyses.

Dual-Enzyme Catalyzed Stereoselective Synthesis of Chiral Aromatic Polysubstituted γ-Butyrolactones

Dual-Enzyme Catalyzed Stereoselective Synthesis of Chiral Aromatic Polysubstituted γ-Butyrolactones

Catalytic Asymmetric Reactions of Ketimines and Alkenes via [2 + 2] Cycloaddition: Chemical Reactivity Controlled by Switching a Heteroatom.

Azetidine units are commonly found in natural products and biologically active drugs. The [2 + 2] cycloaddition of imines and alkenes has been extensively used in the synthesis of such structures, while enantioselective approaches remain elusive. Herein, an efficient B(C6F5)3/chiral phosphoric acid-catalyzed asymmetric [2 + 2] cycloaddition of ketimines and aryl vinyl selenides was presented, delivering valuable chiral azetidines with excellent stereoselectivities (>20:1 dr and up to 96:4 er). What's even more interesting was that when a "Se" atom was switched to an "S" atom, the reaction proceeded through a [2 + 2] cycloaddition/ring-opening cascade process, affording a range of chiral thioacetals with high enantioselectivities (up to 98:2 er), which were also important organic sulfur compounds. Mechanistic experiments, coupled with density functional theory (DFT) calculations, shed light on a mechanism involving stepwise [2 + 2] cycloaddition and ring-opening processes, with the initial alkenylation step identified as crucial for achieving stereoselective control.

Electrooxidative C(sp3)-H Cyanation of Sparteine and Lupanine in Undivided Batch and Continuous-Flow Cells.

Sparteine is widely used as a chiral ligand in asymmetric synthesis, but methods for providing efficient access to functionalized sparteine derivatives are still limited. Herein, we describe an electrochemical α-cyanation of sparteine-type bis-quinolizidine alkaloids. This method features commercially available setups for batch and single-pass continuous flow conditions, enabling easy gram scale synthesis of valuable racemic and enantiopure products. Moreover, insights into the selectivity of the reaction and overoxidation mechanisms are disclosed. This allows for the development of divergent oxidation pathways depending on the electrolysis conditions.

TMSOTf‐Mediated Aminocyclization/[1,3]‐Sulfonyl Migration of N‐Homopropargyl Hydroxylamines for the Stereoselective Synthesis of 3‐Sulfonyl Cyclic Nitrones

AbstractTMSOTf‐mediated 5‐endo‐dig aminocyclization followed by N‐ to C‐[1,3]‐sulfonyl migration on N‐homopropargyl hydroxylamines gave diastereoselective access to trisubstituted 3‐sulfonyl cyclic nitrone (3‐sulfonyl pyrroline N‐oxide) derivatives. The synthetic utility of the 3‐sulfonyl cyclic nitrone products was demonstrated through the diastereoselective synthesis of the sulfonyl‐substituted nonaromatic N‐heterocycles such as N‐hydroxypyrrolidine, pyrrolidine‐fused isoxazoline, and isoxazolidine derivatives.

Visible‐Light‐Induced Stereoselective C(sp3)−C(sp3)−H Glycosylation for the Synthesis of C‐Glycoamino Acid Derivatives

AbstractChiral C‐Glycosyl amino acids are prevalent structural motifs found in pharmaceuticals and natural products, making them a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the current synthesis methods for these compounds face numerous environmental and practical challenges, highlighting the critical need to establish more sustainable approaches. Herein, we report a simple and powerful strategy for the stereoselective synthesis of C‐glycoamino acids derivatives. This method features the design and use of (−)/(+)‐camphorsultam as an ideal chiral auxiliary, shielding one prochiral face of the glycine α‐carbon efficiently and imposing a high kinetic barrier for the epimerization of thus‐generated chiral α‐carbon that two configuration products of R and S could be achieved independently. It proceeds under mild conditions, shows broad scope, and allows for the direct stereoselective glycosylation without metal and chiral ligand.

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides.

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.

A Multiresponsive Ferrocene‐Based Chiral Overcrowded Alkene Twisting Liquid Crystals

AbstractThe reversible modulation of chirality has gained significant attention not only for fundamental stereochemical studies but also for numerous applications ranging from liquid crystals (LCs) to molecular motors and machines. This requires the construction of switchable molecules with (multiple) chiral elements in a highly enantioselective manner, which is often a significant synthetic challenge. Here, we show that the dimerization of an easily accessible enantiopure planar chiral ferrocene‐indanone building block affords a multi‐stimuli‐responsive dimer (FcD) with pre‐determined double bond geometry, helical chirality, and relative orientation of the two ferrocene motifs in high yield. This intrinsically planar chiral switch can not only undergo thermal or photochemical E/Z isomerization but can also be reversibly and quantitatively oxidized to both a monocationic and a dicationic state which is associated with significant changes in its (chir)optical properties. Specifically, FcD acts as a chiral dopant for cholesteric LCs with a helical twisting power (HTP) of 13 μm−1 which, upon oxidation, drops to near zero, resulting in an unprecedently large redox‐tuning of the LC reflection color by up to 84 nm. Due to the straightforward stereoselective synthesis, FcD, and related chiral switches, are envisioned to be powerful building blocks for multi‐stimuli‐responsive molecular machines and in LC‐based materials.

Direct Experimental Characterization of a Sialyl Cation.

Sialic acids are monosaccharide residues involved in several biological processes. Controlling the stereoselectivity of sialylation reactions is challenging and mechanistic studies on the structure of its intermediate, the sialyl cation, are scarce. Here it is shown that a sialyl cation can be generated and isolated from an ionized sialic acid precursor. This short-lived species is structurally characterized for the first time using cryogenic infrared spectroscopy. In combination with quantum chemical calculations, the results reveal that the positive charge at the anomeric carbon of the sialyl cation is stabilized by remote participation of the C5-NHAc group leading to the formation of a bridged structure. In this structure, the β-side is shielded from nucleophilic attack, potentially explaining the α-selectivity of this building block in SN1-type sialylation reactions. Other modes of participation are energetically unfavored and cannot be observed experimentally.

Mechanochemical Organocatalysis: Simple Chiral Primary Diamine‐TfOH‐catalysed Asymmetric Aldol and Robinson Annulation Reactions

AbstractMechanochemical organocatalysis, which integrates mechanochemistry and organocatalysis to provide a metal‐and solvent‐free synthetic method for synthesizing chiral products, has garnered significant interest recently due to its importance in green chemistry. In this study, simple, unmodified commercially available chiral primary diamines with TfOH were employed as catalysts in mechanochemical direct asymmetric aldol and Robinson annulation reactions. This protocol demonstrated high efficiency, atom economy and high stereoselectivity. Notably, direct asymmetric aldol reactions involving unreactive aromatic methyl ketones, which still is a challenge for mechanochemical organocatalysis, proceeded smoothly. Additionally, chiral 3,5‐diaryl‐cyclohexenones were efficiently synthesized using this mechanochemical asymmetric catalytic protocol and afforded high‐to‐excellent enantioselectivities. These findings highlight the potential of mechanochemical organocatalysis for asymmetric catalysis.