Asymmetric Synthesis Research Articles

Synthesis of C-N bonds by nicotinamide-dependent oxidoreductase: an overview.

Compounds containing chiral C-N bonds play a vital role in the composition of biologically active natural products and small pharmaceutical molecules. Therefore, the development of efficient and convenient methods for synthesizing compounds containing chiral C-N bonds is a crucial area of research. Nicotinamide-dependent oxidoreductases (NDOs) emerge as promising biocatalysts for asymmetric synthesis of chiral C-N bonds due to their mild reaction conditions, exceptional stereoselectivity, high atom economy, and environmentally friendly nature. This review aims to present the structural characteristics and catalytic mechanisms of various NDOs, including imine reductases/ketimine reductases, reductive aminases, EneIRED, and amino acid dehydrogenases. Additionally, the review highlights protein engineering strategies employed to modify the stereoselectivity, substrate specificity, and cofactor preference of NDOs. Furthermore, the applications of NDOs in synthesizing essential medicinal chemicals, such as noncanonical amino acids and chiral amine compounds, are extensively examined. Finally, the review outlines future perspectives by addressing challenges and discussing the potential of utilizing NDOs to establish efficient biosynthesis platforms for C-N bond synthesis. In conclusion, NDOs provide an economical, efficient, and environmentally friendly toolbox for asymmetric synthesis of C-N bonds, thus contributing significantly to the field of pharmaceutical chemical development.

Polymerization-induced Chiral Self-assembly for the In-situ Construction, Modulation, Amplification and Applications of Asymmetric Suprastructures.

In the polymerization-induced chiral self-assembly (PICSA) process, chiral functional monomers undergo spontaneous supramolecular self-assembly and asymmetric stacking during living polymerization, leading to the in-situ generation of chiroptical polymer assemblies characterized by diverse morphologies. The PICSA strategy facilitates precise control and manipulation of both non-covalent supramolecular helices and covalent macromolecular helices within aggregated cores, thereby driving significant advancements in fields such as chiral recognition materials, asymmetric catalysts, nonlinear optical materials, and ferroelectric liquid crystals (LC). This minireview summarizes recent developments in the in-situ chiroptical construction and modulation associated with the PICSA methodology. Furthermore, it seeks to elucidate emerging PICSA systems founded on various living polymerization mechanisms, exploring hierarchical chirality transfer processes and the pathway complexities in both equilibrium and non-equilibrium conditions. This minireview also presents several illustrative examples that demonstrate the practical applications of chiral polymer materials synthesized through the PICSA approach, thereby illuminating future opportunities in this innovative field.

Polymerization‐induced Chiral Self‐assembly for the In‐situ Construction, Modulation, Amplification and Applications of Asymmetric Suprastructures

In the polymerization‐induced chiral self‐assembly (PICSA) process, chiral functional monomers undergo spontaneous supramolecular self‐assembly and asymmetric stacking during living polymerization, leading to the in‐situ generation of chiroptical polymer assemblies characterized by diverse morphologies. The PICSA strategy facilitates precise control and manipulation of both non‐covalent supramolecular helices and covalent macromolecular helices within aggregated cores, thereby driving significant advancements in fields such as chiral recognition materials, asymmetric catalysts, nonlinear optical materials, and ferroelectric liquid crystals (LC). This minireview summarizes recent developments in the in‐situ chiroptical construction and modulation associated with the PICSA methodology. Furthermore, it seeks to elucidate emerging PICSA systems founded on various living polymerization mechanisms, exploring hierarchical chirality transfer processes and the pathway complexities in both equilibrium and non‐equilibrium conditions. This minireview also presents several illustrative examples that demonstrate the practical applications of chiral polymer materials synthesized through the PICSA approach, thereby illuminating future opportunities in this innovative field.

Triplet Energy Transfer (EnT)-Promoted 1,3-Dipolar Cycloaddition Reactions of N-(Trimethylsilyl)methylphthalimide with Electron-Deficient Alkynes and Alkenes.

Triplet energy transfer (EnT)-promoted photochemical pathways, arisen by visible light and its photosensitizers, have gained significant attention as a complementary strategy for initiating organic transformations in photochemical reactions that are unlikely to occur through a single electron transfer (SET) process. In the present study, we investigated the triplet EnT-promoted 1,3-dipolar cycloaddition reactions of N-(trimethylsilyl)methylphthalimide with electron-deficient alkynyl and alkenyl dipolarophiles. The triplet excited state of N-(trimethylsilyl)methylphthalimide, promoted by the triplet EnT from thioxanthone (TXA) photosensitizer, underwent sequential intramolecular SET and carbon-to-oxygen migration of the silyl group to form azomethine ylide. This generated ylide cycloadded to alkynes or alkenes to regioselectively and stereospecifically produce a nitrogen-containing benzopyrrolizidine scaffold with multiple stereogenic centers. Crucially, the stereoselectivity of these cycloaddition reactions (i.e., endo versus exo addition) was influenced by the nature of the dipolarophiles.

Asymmetric Catalytic Synthesis of Allylic Sulfenamides from Vinyl α-Diazo Compounds by a Rearrangement Route.

The asymmetric rearrangement of allylic sulfilimines is an effective route to synthetic attractive targets such as allylic sulfenamides and others. The current methods are limited to chirality transfer from chiral allylic sulfilimine precursors. Herein, we report a general and fundamentally new rearrangement route accessing optically enriched allylic sulfenamides and their derivatives. The process involves a S-alkylation and an unusual S-to-N rearrangement step. The chiral nickel complex enables the transformation of a broad scope of sulfenamides and vinyl α-diazo pyrazoleamides under mild conditions. Various allylic sulfenamides have been synthesized with excellent γ-regioselectivity and enantioselectivity, which can be efficiently converted to sulfinamide and 4-aminobutenoic acid derivatives. In addition, DFT calculations demonstrate the connection between the spin state and conformation of nickel vinyl carbenoid, as well as an unknown rearrangement process.

Asymmetric Catalytic Synthesis of Allylic Sulfenamides from Vinyl α‐Diazo Compounds by a Rearrangement Route

The asymmetric rearrangement of allylic sulfilimines is an effective route to synthetic attractive targets such as allylic sulfenamides and others. The current methods are limited to chirality transfer from chiral allylic sulfilimine precursors. Herein, we report a general and fundamentally new rearrangement route accessing optically enriched allylic sulfenamides and their derivatives. The process involves a S‐alkylation and an unusual S‐to‐N rearrangement step. The chiral nickel complex enables the transformation of a broad scope of sulfenamides and vinyl α‐diazo pyrazoleamides under mild conditions. Various allylic sulfenamides have been synthesized with excellent γ‐regioselectivity and enantioselectivity, which can be efficiently converted to sulfinamide and 4‐aminobutenoic acid derivatives. In addition, DFT calculations demonstrate the connection between the spin state and conformation of nickel vinyl carbenoid, as well as an unknown rearrangement process.

Chiral Brønsted Acid-Catalyzed Intramolecular Asymmetric Dearomatization Reaction of Indoles with Cyclobutanones via Cascade Friedel-Crafts/Semipinacol Rearrangement.

The highly efficient synthesis of chiral indolines fused with an azabicyclo[2.2.1]heptanone moiety is achieved by an asymmetric dearomatization reaction of indoles with cyclobutanones. A new chiral imidodiphosphorimidate (IDPi) catalyst is synthesized and exhibits extraordinary activity in promoting a cascade Friedel-Crafts/semipinacol rearrangement. Target molecules are prepared in good yields (up to 95%) with excellent enantioselectivity (up to 98% ee) with operational convenience. Combined experimental and computational studies provide detailed mechanistic insights into the energy landscape and origin of the stereochemical induction of the reaction.

Enantioselective Construction of Planar‐Chiral Molecules by Catalytic Asymmetric Late‐Stage Functionalizations

Planar chirality, as one of the most important manifestations of chirality, is frequently employed to constrain three‐dimensional chiral configurations. Recent advancements in the study of planar chirality by chemists have opened up innovative possibilities for designing new catalysts, developing novel drugs, and creating new optical materials. However, the flexible ansa chains present a challenge during the synthesis process of these unique planar‐chiral macrocycles, hindering chemists from achieving high enantioselectivity. In this mini review, we primarily introduce the catalytic asymmetric synthesis methods that have been reported for late‐stage functionalization of planar macrocycles to generate planar chirality. Additionally, we present several recent examples of catalytic enantioselective synthesis of mechanically planar‐chiral rotaxanes through late‐stage functionalization methods. The sources of stereoselectivity are also discussed in this mini review. We aim to inform more researchers about this field and attract chemists to engage in this important and scientifically significant area of research.

A Concise, Stereoselective and Scalable Synthesis of Optically Pure (3R,4R)-1-Benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines

A Concise, Stereoselective and Scalable Synthesis of Optically Pure (3R,4R)-1-Benzyl- and (3R,4R)-1-Boc-3-methyl-4-aminopiperidines

Chiral-induced covalent organic framework as novel chiral stationary phase for chiral separation using open-tubular capillary electrochromatography

As a novel class of chiral stationary phase (CPS) material, chiral covalent organic frameworks (CCOFs) have already shown great promise in open-tubular capillary electrochromatography (OT-CEC) for chiral separation. The synthesis methods of CCOFs used in OT-CEC mainly include bottom-up, post modification and chiral induction. The CCOFs synthesized by bottom-up and post modification strategies already have lots of applications in capillary electrochromatography, however, the chiral-induced synthesized via an asymmetric catalytic strategy has not yet been reported for using as the chiral stationary phase (CPS) in OT-CEC or even in chromatographic separation. Herein, the chiral-induced COF (Λ)-TpPa-1 was synthesized by asymmetric catalytic synthesis and coated on the inner surface of a capillary by an in-situ growth strategy as the CPS for chiral drug separation. The baseline separation of six enantiomers was achieved within 14 minutes, with a high-resolution (Rs) range from 1.85 to 6.75. Moreover, the resolution and migration time of the capillary keep stable within 160 runs, showing its superior stability and repeatability. This research provides a new idea for the development and application of novel CPS materials in the field of capillary electrochromatography separation, also shows the new application of chiral induced COFs. Furthermore, the chiral-induced CCOFs can be easily applied to other chromatographic separation fields, exhibiting its extensive application value in chiral analysis separation.

Catalyst Control over S(IV)-stereogenicity via Carbene-derived Sulfinyl Azolium Intermediates.

Stereoselective synthesis utilizing small-molecule catalysts, particularly N-heterocyclic carbene (NHC), has facilitated swift access to enantioenriched molecules through diverse activation modes and NHC-bound reactive intermediates. While carbonyl derivatives, imines, and "activated" alkenes have been extensively investigated, the exploration of heteroatom-centered analogues of NHC-bound intermediates has long been neglected, despite the significant potential for novel chemical transformations they offer once recognized. Herein, we disclose a carbene-catalyzed new activation mode by generating unique sulfinyl azolium intermediates from carbene nucleophilic addition to in situ-generated mixed sulfinic anhydride intermediates. Combined experimental and computational mechanistic investigations pinpoint the chiral NHC-catalyzed formation of sulfinyl azolium intermediate as the enantio-determining step. The novel "S"-based carbene reactive intermediate imparts high efficiency for the catalytic construction of sulfur-stereogenic compounds, giving rise to sulfinate esters with high yields and enantioselectivities under mild conditions. Notably, distinct from most of the NHC-catalyzed enantioselective transformations focusing on the "C" central chiral products, our study realizes a unique carbene-catalyst control over chiral "S" stereocenters via direct asymmetric S-O bond formation for the first time. Furthermore, these sulfinyl-containing products could serve as versatile synthetic platforms for enantioenriched S-stereogenic functional molecules and exhibit remarkable antibacterial activities against rice plant pathogens, which is valuable for the development of novel agrochemical agents.

Ru-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams.

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a C2-symmetric ruthenocenyl phosphine-oxazoline as the chiral ligand. This method achieves the enantioselective synthesis of chiral β-substituted γ-lactams in high yields and with excellent enantioselectivities (up to 99% yield with 99% ee). Mechanistic studies based on detailed control experiments and computational investigation revealed that the cationic Ru-complex acts as the active catalytic species; the protonation process of the oxa-π-allyl-Ru complex, which is formed by the migratory insertion of the C=C double bond to the Ru-H bond (the stereocontrolling step) followed by an isomerization process, is the rate-determining step, and the existence of PPh3 is crucial for the highly efficient catalytic behavior. The protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs and bioactive compounds, particularly for the 150 kg-scale industrial production of Brivaracetam, an antiepileptic drug that shows 13-fold more potent binding to the synaptic vesicle protein 2A compared with the well-known Levetiracetam.

Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.

Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs.

Asymmetric Formal Total Syntheses of (+)- and (-)-Limaspermidine from Chirally Resolved 2-Pyrone Diels-Alder Cycloadducts via Aromatic C-H Amidation and Imino-Diels-Alder Reaction.

A new asymmetric synthetic route to (+)- and (-)-limaspermidine was devised, starting with chirally resolved enantiomerically pure 2-pyrone Diels-Alder cycloadducts. This route utilizes intramolecular Pd-catalyzed aromatic C-H amidation and imino-Diels-Alder reactions to construct the key indoline and indolizidine subunits onto the central cyclohexane core, allowing the straightforward formal total syntheses of both (+)- and (-)-limaspermidine.

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis.

The isolation and catalytic enantioselective synthesis of configurationally stable S-stereogenic sulfonium ylides has been a significant challenge 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.

Cu-Catalyzed Asymmetric Synthesis of γ-Amino Alcohols Featuring Tertiary Carbon Stereocenters.

Alkyne-functionalized oxetanes are presented as versatile substrates that in combination with amine reagents can be transformed into structurally diverse, chiral γ-amino alcohols featuring a tetrasubstituted tertiary stereocenter under Cu catalysis. Control experiments demonstrate the privileged nature of these oxetane precursors in terms of yield and asymmetric induction levels in the developed protocol, and postsynthetic modifications offer an easy way to access more advanced synthons.

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis

Synthesis of Bridged Five-Membered Ring Systems by Type II [3 + 2] Annulation of Allenylsilane-ene.

The first type II intramolecular [3 + 2] annulation of allenylsilane-ene has been achieved, enabling diastereoselective and efficient construction of synthetically challenging bridged five-membered ring systems such as bicyclo[3.2.1]. This mild and direct process shows a broad substrate scope and is highly stereospecific. Particularly, this work represents the first stereoselective method for the direct synthesis of bicyclo[3.2.1] ring systems from acyclic precursors. Additionally, the first asymmetric total syntheses of (+)- and (-)-strepsesquitriol, and the efficient formation of the synthetically challenging tetracyclic core of pierisjaponol D are achieved by this type II [3 + 2] annulation reaction.

Asymmetric Coupled Binuclear-Site Catalysts for Low-Temperature Selective Acetylene Semi-hydrogenation.

Heterogeneous metal catalysts with bifunctional active sites are widely used in chemical industries. Although their improvement process is typically based on trial-and-error, it is hindered by the lack of model catalysts. Herein, we report an effective vacancy-pair capturing strategy to fabricate 12 heterogeneous binuclear-site catalysts (HBSCs) comprising combinations of transition metals on titania. During the synthesis of these HBSCs, proton-passivation treatment and step-by-step electrostatic anchorage enabled the suppression of single-atom formation and the successive capture of two target metal cations on the titanium-oxygen vacancy-pair site. Additionally, during acetylene hydrogenation at 20 °C, the HBSCs (e.g., Pt1Pd1-TiO2) consistently generated more than two times the ethylene produced by their single-atom counterparts (e.g., Pd1-TiO2). Furthermore, the Pt1Pd1 binuclear sites in Pt1Pd1-TiO2 were demonstrated to catalyze C2H2 hydrogenation via a bifunctional active-site mechanism: initially C2H2 chemisorb on the Pt1 site, then H2 dissociates and migrates from Pd1 to Pt1, and finally hydrogenation occurs at the Pt1-Pd1 interface.