Stereogenic Research Articles

Total Synthesis of Berkeleyone A and Preaustinoid A through Epoxypolyene Cyclization

AbstractA bioinspired Lewis acid‐catalyzed epoxypolyene cyclization was developed to construct the tetracyclic framework containing a bicyclo[3.3.1]nonane core and seven chiral centers. The usage of this approach for assembling these natural products of 6/6/6/6 tetracyclic skeleton with bicyclo[3.3.1]nonane core is demonstrated by the total synthesis of highly oxidized berkeleyone A and preaustinoid A.

Controlled Helical Organization in Supramolecular Polymers of Pseudo‐Macrocyclic Tetrakisporphyrins

AbstractTetrakisporphyrin monomers with amino acid side chains at each end form intramolecular antiparallel hydrogen‐bonds to adopt chirally twisted pseudo‐macrocyclic structures that result in right‐handed and left‐handed (P)‐ and (M)‐conformations. The pseudo‐macrocyclic tetrakisporphyrin monomers self‐assembled to form supramolecular helical pseudo‐polycatenane polymers via head‐to‐head complementary dimerization of the bisporphyrin cleft units in an isodesmic manner. The formation of one‐handed supramolecular helical pseudo‐polycatenane polymers was confirmed by circular dichroism (CD) spectroscopy. The methyl and iso‐propyl groups at the stereogenic center greatly enhanced the induced circular dichroism in the Soret bands of the supramolecular helical pseudo‐polycatenane polymers. The induced CDs were reduced upon the introduction of large iso‐butyl and tert‐butyl groups. Atomic force microscopy revealed well‐grown and long supramolecular helical pseudo‐polycatenane polymer chains with chain lengths in the range of 361 to 13.6 nm. The right‐handed helical chains were established by the self‐assembly of the right‐handed (P)‐conformation of the pseudo‐macrocyclic monomer.

Asymmetric Vinylogous Michael/Oxa-Michael Tandem Reaction between β,γ-Unsaturated Amides and Isatin-Derived β,γ-Unsaturated α-Ketoesters.

An organocatalytic asymmetric vinylogous Michael/oxa-Michael tandem reaction between β,γ-unsaturated pyrazoleamides and isatin-derived β,γ-unsaturated ketoesters has been developed with excellent regio-, diastereo-, and enantioselectivities. The methodology provides an effective approach to construct enantiomerically pure 3,4'-pyranyl spirooxindole derivatives containing three contiguous chiral centers. Moreover, the transformations of the chiral products, including the removal and reduction of the pyrazole group, have been investigated.

Observation of Ferroelectricity in Carbapenem Intermediates Enables Reactive Oxygen Species Generation by Ultrasound.

Organic ferroelectrics show great applications in the fields of biomedicine, including disease treatment, biosensors, and tissue engineering. Organosilicon pharmaceutical intermediates generally include chiral centers and have satisfying biosafety, biocompatibility, or even biodegradability, which provide versatile platforms for the design of ferroelectricity. However, their academic values in ferroelectricity have long been long overlooked. Here, we demonstrated the ferroelectric properties of 4-acetoxy-azacyclic butanone (4-AA), a key synthetic organosilicon-based intermediate of carbapenem drugs. This compound undergoes a 222F2-type ferroelectric-ferroelastic phase transition at 326 K. As an organic piezoelectric material, 4-AA can produce reactive oxygen species when subjected to ultrasonic vibrations. Combined with its desirable biocompatibility, this material may contribute to antimicrobial and wound healing, tumor treatment, etc. This work will provide inspiration for the discovery of multifunctional biomedical ferroelectric materials as well as their related application prospects.

Remote Enantioselective ϵ-Alkylation of Copper Ethynylallenylidenes: Precise Control of Central and Axial Chirality.

Chiral tetrasubstituted allenes have emerged as important architectures for engineering biologically active compounds. The construction of unique tetrasubstituted allene scaffolds with precise control of continuous central and axial chirality remains yet to be developed. Here, we report a remote enantioselective ϵ-alkylation of yne-propargylic acetates with enals enabled by NHC and copper cooperative catalysis, leading to a series of tetrasubstituted allenes with excellent enantioselectivities (up to >99 % ee) and diastereoselectivities (up to >95 : 5 dr). This method features high regioselectivity and simultaneous control of axial and central chirality. Mechanistic studies suggest a cooperative activation mode and synergistic control of distal chirality created from the copper ethynylallenylidenes.

Remote Enantioselective ϵ‐Alkylation of Copper Ethynylallenylidenes: Precise Control of Central and Axial Chirality

AbstractChiral tetrasubstituted allenes have emerged as important architectures for engineering biologically active compounds. The construction of unique tetrasubstituted allene scaffolds with precise control of continuous central and axial chirality remains yet to be developed. Here, we report a remote enantioselective ϵ‐alkylation of yne‐propargylic acetates with enals enabled by NHC and copper cooperative catalysis, leading to a series of tetrasubstituted allenes with excellent enantioselectivities (up to >99 % ee) and diastereoselectivities (up to >95 : 5 dr). This method features high regioselectivity and simultaneous control of axial and central chirality. Mechanistic studies suggest a cooperative activation mode and synergistic control of distal chirality created from the copper ethynylallenylidenes.

Switch of Five Contiguous Chiral Centers in the Synthesis of Both Enantiomers of Hajos-Parrish Ketone Analogs via Diphenylprolinol Silyl Ether-Mediated Domino Reaction.

Both enantiomers of functionalized Hajos-Parrish ketone (HPK) analogs were prepared with excellent diastereoselectivities and enantioselectivities using the same chiral catalyst under two slightly different conditions. In condition A, dioxane was used as the solvent with 3 equivalents of water. In condition B, acetonitrile was used as the solvent with 30 equivalents of water, followed by epimerization with a base in a one-pot. The reaction consisted of a domino reaction including a diphenylprolinol silyl ether-mediated asymmetric Michael reaction and an intramolecular Henry reaction. In the Michael reaction, depending on the solvent and water amounts, syn- and anti-isomers were selectively synthesized with excellent enantioselectivity, in which the absolute configuration at C5 (indanone numbering) was opposite. The subsequent Henry reaction was diastereoselective, in which the C5 substituent controlled the three chiral centers in a highly diastereoselective manner. The final base treatment in condition B caused epimerization, changing the stereochemistry at C6. Switching more than two chiral centers with high enantioselectivity is extremely difficult using the same chiral catalyst; the present reaction is a very rare enantiodivergent reaction that switches five continuous chiral centers with high enantioselectivity.

Strong Electrochemiluminescence Response Derived from Ionic Chiral Covalent Organic Frameworks for Enantioselective Discrimination of Amino Acid Enantiomers via an Electrostatic Attraction Effect.

Porous chiral materials accompanied by electrochemiluminescence (ECL) activity are rarely reported for enantioselective discrimination because of the big challenges to integrate the stereogenic center and ECL-active unit in the backbone. In the present study, ionic chiral covalent organic frameworks (iCCOFs) consisting of the pyridinium unit as the ECL-active species were prepared by a facile strategy. We were amazed that such iCCOFs could display strong cathodic ECL responses. Meanwhile, the as-prepared ECL-active iCCOFs performed enantioselective ECL quenching toward amino acid enantiomers, attributed to the enhanced photoinduced electron transfer process derived from the formed complex between the iCCOFs and amino acids via an electrostatic attraction effect. The iCCOF with an (S)-configuration was prone to interact with l-amino acids, producing a lower ECL intensity. The maximum intensity ratio between the d- and l-enantiomers was 33.0. Finally, the enantiomeric compositions of the measured amino acids presented a good linear relation with the obtained ECL intensity, which was fit for the determination of samples with unknown enantiomeric purity. In brief, the obtained results convince us that this study advances a new generation of ECL-active iCCOFs and displays great potential in enantioselective sensing.

Construction of Spiro[pyrrolidine-azlactone] via [2 + 3] Cycloaddition of Alkylidene Azlactone with Trifluoromethylated Imine.

A Ag-catalyzed [2 + 3] cycloaddition of alkylidene azlactones with trifluoromethylated imines has been documented, providing spiro[pyrrolidine-azlactones] bearing four adjacent stereogenic centers with good yields and excellent diastereoselectivities. Catalytic asymmetric cycloaddition has also been developed with good yields and excellent enantioselectivities. Further gram-scale preparation and synthetic transformation to pyrrolidine derivative showed the good practicality and applicability of this reaction.

Vibrational Mode-Dependent Circular Dichroism of Jet-Cooled Styrene Oxide.

Vibrational mode-dependent circular dichroism (CD) effects in vibrational CD spectra are often used to determine the handedness of molecules with multiple chiral centers. Here, we investigate vibrational mode-dependent CD effects in the electronic CD spectra of jet-cooled (R)-(+)- and (S)-(-)-styrene oxide obtained by using resonant two-photon ionization CD (R2PICD) spectroscopy. Although most fundamental vibronic bands demonstrated CD signatures consistent with that of the origin band, the overtone and combination bands exhibited opposite CD signatures. Theoretical calculations suggest that CD in fundamental bands are primarily governed by Franck-Condon contributions, whereas Herzberg-Teller contributions, which reflect the influences of vibrational modes on CD values, become more significant in overtone and combination bands. These results underscore the potential of mode-dependent vibronic CD signals in R2PICD spectra for determining the absolute configurations of molecules with multiple chiral centers.

Concise Synthesis of Norzoanthamine Enabled by a Set of Photochemical Transformations.

Norzoanthamine is a structurally complex polycyclic natural product that expresses a broad range of biological activities, rendering facile access to it and its analogs of considerable importance in drug discovery and development. However, strategies for efficient access to this class of marine alkaloids remain lacking. Here, we report a strategy, characterized by three key photochemical reactions, that we used to synthesize norzoanthamine in 16 steps. A photoinduced dearomative-6π-desymmetrization was developed for facile access to the ABC-tricyclic core of the alkaloid. This was supplemented by a [2 + 2]-photocycloaddition, a visible-light-induced decarboxylative borylation, and a retro-aldol process, constituting an effective solution to the challenging problem of establishing the C9-C22 vicinal all-carbon quaternary stereogenic centers. Finally, a one-pot cascade transformation, involving global deprotection, cyclization, and epimerization reaction, was designed for efficient and stereocontrolled assembly of the core framework of norzoanthamine.

Podophyllotoxin and Aryltetralin Lignans: Methods for the Synthesis of Rings A, B, C, D

Podophyllotoxin, its derivatives and structural analogues are an extensive group of aryl-tetralin-lignans of interest in pharmacology due to their promising anticancer and antitumor activity. The synthesis methods that have been proposed to date seek to resolve synthetic, stereochemical, pharmacodynamic and environmental aspects. In this review we have updated and brought together different classifications of lignan and podophyllotoxin synthesis. Transformation methods focus on the strategies used to form or functionalize rings A, B, C and D, as well as the configuration of the system of four stereogenic centers that fuse rings C and D.

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.

Crystal structures and circular dichroism of {2,2′-[(1S,2S)-1,2-diphenylethane-1,2-diylbis(nitrilophenylmethanylylidene)]diphenolato}nickel(II) and its ethanol solvate

The title compound, [Ni(C40H30N2O2)] (1), with an optically active Schiff base ligand derived from 2-hydroxybenzophenone and (1S,2S)-1,2-diphenylethylenediamine, was crystallized as the solvent-free and ethanol solvate forms (1 and 1·2C2H5OH). In both structures, the two phenyl groups on the stereogenic centers of the O,N,N,O-tetradentate ligand are axially oriented, and the conformation of the central diamine chelate ring is λ. The circular dichroism (CD) spectra of 1 and the analogous nickel(II) complex [Ni(C30H26N2O2)] (2) in solution show partially similar patterns in the 350–450 nm range, but are mirror images in the longer wavelength region (450–650 nm). In the latter region, the sign of CD for these complexes is sensitive to the substituents on the C=N carbon atoms (phenyl for 1 and methyl for 2) rather than the diamine chelate ring conformation.

Modular Synthesis of α-Quaternary Chiral β-Lactams via Three-Component Asymmetric Kinugasa/Aldol or Kinugasa/Mannich Cascade Reactions.

The β-lactam scaffolds are the prevalent structural units in antibiotics and natural products. Herein, three-component asymmetric Kinugasa/aldol and Kinugasa/Mannich cascade reactions have been developed for constructing α-quaternary chiral β-lactams. This strategy enables sequential assembly of alkynes, nitrones and aldehydes (or imines) and creates three contiguous stereogenic centers, controlled by copper(I) catalysts and chiral bis(oxazolidine) ligands. The developed protocol features high enantioselectivity, good reaction efficiency, and mild operational conditions representing a practical and sustainable synthetic tool for the construction of functionalized chiral β-lactams.

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.

Hydrophobic deep eutectic solvent-ferrofluid microextraction followed by liquid chromatography-mass spectrometry for the enantioselective determination of chiral agrochemicals in natural waters.

The increasing use of chiral agrochemicals sold as racemic formulations raises concern for the negative impacts that inactive enantiomers can have on aquatic life and human health. The present work just focuses on the determination of ten chiral pesticides in river water samples by applying a ferrofluid-based microextraction followed by their stereoselective liquid chromatography analysis. To develop the ferrofluid, magnetite nanoparticles were prepared and coated with oleic acid and then dispersed in a hydrophobic natural deep eutectic solvent (NaDES), composed ofL-menthol and thymol (1:1). The stable colloidal dispersion was characterised by scanning electron microscopy, thermogravimetric analysis, energy-dispersive X-ray spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy. The analyte microextraction from 5ml river samples was performed using 50µl of ferrofluid, while acidified acetonitrile (150µl) was used to break down the ferrofluid and solubilise the NaDES containing the analytes. All the extracts were analysed by high-performance liquid chromatography-tandem mass spectrometry. For each analyte, the baseline separation of isomers was achieved on a Lux i-Amylose-3 column (amylose tris(3-chloro-5-methylphenylcarbamate) working in reversed-phase mode; the combination with mass spectrometry detection allows the overall separation of 24 isomers (ten chiral analytes among which eight containing a single (one) chiral centre, one with two chiral centres and the last one existing in four stereoisomeric forms, due to the presence of two regioisomers with a chiral carbon) within 37min. The method showed very good figures of merit in terms of recoveries (77.7-97.5%), intra-day and inter-day precision (2.7-7.7% and 6.9-14.9%, respectively), limit of detection (0.01-0.35µg/L), limit of quantitation (0.03-1.20µg/L), linear dynamic range, and intra-day and inter-day accuracy (1.2-14.8% and 1.8-15.0%, respectively). The presented method was able to detect 14 out of 24 isomers at the preventive limit established by the Italian legislation for single pesticide (that for a chiral pesticide is the sum of all its isomers) in surface waters, set at 0.1µg/l. Finally, the method was evaluated using AGREEprep and ComplexGAPI metrics, compared with other ferrofluid-based methods, and applied to the analysis of water samples from two Italian rivers (the Nera River and the Tiber River), providing to be sustainable and reliable for the application to real river matrices.

Enantioselective Synthesis of Azatricycles via Post-Ugi Cyclizations.

We report a new method to create enantioenriched azatricycles using chiral α-amino acids in a two-step process after an Ugi reaction. Amino acids are great building blocks for making pure chiral molecules. Using chiral natural molecules in multicomponent reactions (MCRs) helps increase their variety by adding new chiral centers. The Ugi reaction, discovered by Ivar Karl Ugi in 1959, is a versatile MCR that helps create complex molecular structures and natural products through additional transformations called post-Ugi modifications. Designing these modifications requires selecting the right amine, acid, aldehyde/ketone, and isocyanide. Amino acids, with their primary amine and carboxylic acid groups and a pre-existing chiral center, are ideal for making diverse and selective post-Ugi modifications. Our method uses ipso-cyclization and aza-Michael cyclization with hypervalent iodine to create various azaspirotricyclic structures with high stereocontrol. This approach works well with different substrates and shows promise for further development in drug discovery.

Enantioselective Borylative Functionalization of Internal Alkenes: A Platform for Constructing Vicinal Stereocenters†

Comprehensive SummaryVicinal stereogenic centers are ubiquitous structural scaffolds in both natural products and synthetic compounds, yet their enantioselective construction remains a significant challenge in organic synthesis. Organoboron compounds are of paramount importance in synthetic chemistry due to their ability to undergo facile transformations, yielding diverse essential chemical bonds such as carbon‐carbon, carbon‐oxygen, carbon‐nitrogen, and carbon‐halogen bonds. Transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes offer a promising strategy for the enantioselective installation of two adjacent chiral centers across carbon‐carbon bonds. By leveraging the versatile transformations of the newly introduced boryl unit, this approach holds great potential for expanding the structural diversity of vicinal stereogenic scaffolds. In this concise review, we aim to highlight recent advancements in transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes, underscore their utility as a versatile approach for constructing vicinal stereogenic centers, and discuss unsolved challenges and future directions in this field. Key Scientists

Asymmetric Carbene Insertion into Se-S Bonds by Synergistic Rh(II)/Guanidine Catalysis Involving Chalcogen-Bond Assistance.

The efficient construction of chalcogen-atom-based chiral compounds remains a challenge, despite the importance of organoselenium and organosulfur compounds in life and materials science. Chalcogen atoms can form net attractive interactions called chalcogen bonds, but it is an undeveloped tool to assist asymmetric catalysis. Herein, we report an enantioselective insertion platform to install a stereogenic center bearing selanyl and thiocyano functional groups. Our method operates by synergistic catalysis by a chiral guanidine and an achiral dirhodium complex in a three-component or four-component reaction, through Se-S bond insertion into carbene species, competing successfully with the spontaneous racemic process and showing high regioselectivity. As elucidated by spectroscopic experiments and computational studies, a unique mechanism involving chalcogen as well as hydrogen bonding was established to account for the enantiocontrol. The high stereoselectivity holds for a broad array of selanylthiocyanatopropanoates, which showed excellent anti-inflammatory toward IL-1β and low cytotoxicity.