Stereogenic Research Articles

Gold‐Zinc Co‐Catalyzed Alkynoate Hydrocarboxylation with N‐Protected Amino Acids for Preparation of Storable Acylating Reagents and Racemization‐Free Peptide Synthesis

AbstractHydrocarboxylation of methyl 2‐octynoate, a chemical commercially available at a low cost, with N‐protected amino acids was developed with a gold‐zinc cooperative catalyst constructed with a 5‐[(2,2′‐bipyridin)‐5‐yl]imidazo[1,5‐a]pyridin‐3‐ylidene to prepare α‐methoxycarbonyl enol esters as acylating reagents. The α‐methoxycarbonyl enol esters were isolable through silica‐gel column chromatography and storable without precautions regarding moisture. Acylation of free amines with the α‐methoxycarbonyl enol esters proceeded without epimerization of the stereogenic center derived from the enol esters, affording analytically pure dipeptide compounds through filtration and hexane‐washing.

Enantioselective Construction of Polycyclic Chromanes through Organocatalytic Sequential Quintuple Reaction via One‐Pot Step‐Wise Procedure

Comprehensive SummaryAn efficient and highly stereoselective synthetic method to access polycyclic chromanes has been achieved through organocatalyzed one‐pot step‐wise reactions involving 2‐hydroxycinnamaldehydes, 2‐aminochalcones, and malononitrile as substrates. The reactions underwent a quintuple process by aza‐Michael/Michael/Knoevenagel/oxa‐Michael/aldol‐type reaction in sequence to give products bearing 3 new generated rings and 5 chiral centers in moderate to quantitative yields with excellent stereoselectivities. A novel retro‐reaction mechanism was discovered in the synthetic transformations of products.

Facile Asymmetric Syntheses of Non-Natural Amino Acid (S)-Cyclopropylglycine by the Developed NADH-Driven Biocatalytic System

A self-sufficient bifunctional enzyme integrating reductive amination and coenzyme regeneration activities was developed and successfully employed to synthesize (S)-cyclopropylglycine with an improved reaction rate 2.1-fold over the native enzymes and a short bioconversion period of 6 h at a high substrate concentration of 120 g·L−1 and space–time yield of (S)-cyclopropylglycine up to 377.3 g·L−1·d−1, higher than that of any previously reported data. Additionally, (S)-cyclopropylglycine could be continuously synthesized for 90 h with the enzymes packed in a dialysis tube, providing 634.6 g of (S)-cyclopropylglycine with >99.5% ee and over 95% conversion yield up to 12 changes. These results confirmed that the newly developed NADH-driven biocatalytic system could be utilized as a self-sufficient biocatalyst for industrial application in the synthesis of (S)-cyclopropylglycine, which provides a chiral center and cyclopropyl fragment for the frequent synthesis of preclinical/clinical drug molecules.

Exploring a Non-Comfort Zone: Central Chirality-Generating Macrocyclizations.

Macrocyclization reactions that are capable of stereoselectively co-creating one or more stereogenic centers have become useful strategies for the effective syntheses of structurally and functionally diverse organic molecules. This JOCSynopsis summarizes the recent progress in the field of natural product and analogue syntheses, including both bioinspired and non-bioinspired macrocyclic disconnections. Selected examples are organized on the basis of the sources of the asymmetric inductions.

Simultaneous Stereoinvertive and Stereoselective C(sp3)-C(sp3) Cross-Coupling of Boronic Esters and Allylic Carbonates.

With increasing interest in constructing more three-dimensional entities, there has been growing interest in cross-coupling reactions that forge C(sp3)-C(sp3) bonds, which leads to additional challenges as it is not just a more difficult bond to construct but issues of stereocontrol also arise. Herein, we report the stereocontrolled cross-coupling of enantioenriched boronic esters with racemic allylic carbonates enabled by iridium catalysis, leading to the formation of C(sp3)-C(sp3) bonds with single or vicinal stereogenic centers. The method shows broad substrate scope, enabling primary, secondary, and even tertiary boronic esters to be employed, and can be used to prepare any of the four possible stereoisomers of a coupled product with vicinal chiral centers. The new method, which combines the simultaneous enantiospecific reaction of a chiral nucleophile with the enantioselective reaction of a chiral electrophile in a single process, offers a solution for stereodivergent cross-coupling of two C(sp3) fragments.

Analysis of <i>cis</i>-isomer-enriched dihydroquercetin sample by 1D and 2D NMR spectroscopy

Introduction. The structure of dihydroquercetin (DHQ) is characterized by two chiral centers at positions 2 and 3 of the benzopyran cycle, resulting in possible diastereomers: trans- and cis-isomers. Therefore, the development of methods for qualitative and quantitative control of DHQ diastereomers in analyzed samples is essential for patient safety management. Nuclear magnetic resonance (NMR) spectroscopy is one of the physicochemical methods that can be used for this purpose.Aim. The study objective was to accumulate the analytical and structural characteristics of cis-DHQ by NMR spectroscopy of the spheroidal form of this flavonoid (DHQs).Materials and Methods. 1D 1H, 1H,1H-COSY, 1H,1H-NOESY, and 1H,13C-HSQC NMR spectra were acquired at 298 K on an 800 MHz NMR spectrometer equipped with a TXI triple resonance probe. The number of scans was 32. The mixing time in the NOESY experiment was 400 ms. The 1H and 13C were analyzed using CcpNmr software. The dihedral angles were calculated by applying the Karplus equation.Results and discussion. In trans-DHQ, the chemical shift values for H2 and H3 are 4.93 ppm and 4.52 ppm, respectively, and in cis-DHQ they are 5.31 ppm and 4.20 ppm, respectively. The spin-spin coupling constants between H2 and H3 of trans- and cis-DHQ are 12.00 Hz and 2.40 Hz, respectively. Thus, the dihedral angles for the trans- and cis-isomers are 154° and 64°, respectively. We found that DHQs contains 12.5 % of the cis-isomer.Conclusion. Our experiments confirmed that NMR spectroscopy can discriminate between trans- and cis-DHQ based on the chemical shift values for the cross-peaks of H2 and H3. The second major finding was that this method can be considered as a more selective quantitative analysis than HPLC with UV detection without reference. One of the most important results of this study for drug development is the updated information on the structural parameters of DHQ diastereomers in the liquid phase.

Chiral Janus emulsions with gold nanocomposite for enantioselective catalysis

Chiral emulsions, with the chiral center of chiral-surfactant as the emulsifier, provide opportunities for selective catalysis and inorganic material synthesis. Janus emulsion draws researcher’s attention due to excellent multiple chambers, advanced structures and diverse interfaces. Chiral Janus emulsions are prepared with two immiscible oils of vegetable oil (VO)/dimethyl phthalate (DMP) and 2-(Perfluorooctyl)ethyl methacrylate (PFOEMA)/Ethoxylated trimethylolpropane triacrylate (ETPTA) as inner phases, by emulsified by chiral-surfactant [H-G-C16]FeCl4, in batch-scale by traditional vortex mixing. AuNPs as functional nanomaterials with peroxidase activity are then applied as active centers, adsorbing at the oil/water interface due to the electrostatic interactions between the positive charge of [H-G-C16]FeCl4 at Janus emulsion interfaces and the negative charge of AuNPs modified by SDS. Chiral Janus emulsion is endowed with catalytic activity and enantioselectivity. Catalytic results show two AuNPs@ Janus emulsions show better affinity to catalyze the oxidation of L-DOPA than D-DOPA. By investigating two AuNPs@ Janus emulsions with different inner phases, chiral Janus emulsion of AuNPs@ETPTA/PFOEMA/[H-G-C16]FeCl4(aq) has better catalytic activity and enantioselectivity than AuNPs@DMP/VO/[H-G-C16]FeCl4 (aq) because of the smaller droplets have larger interface areas could adsorb more [H-G-C16]FeCl4 molecules and AuNPs. The findings open an avenue in the production of chiral Janus emulsions with catalytic effect and enantioselectivity, which would push forward future applications in selective catalysis and inorganic material synthesis.

Synthesis of chiral Cu(II) complexes from pro-chiral Schiff base ligand and investigation of their catalytic activity in the asymmetric synthesis of 1,2,3-triazoles

A pro-chiral Schiff base ligand (HL) was synthesized by the reaction of 2-amino-2-ethyl-1,3-propanediol and pyridine-2-carbaldehyde in methanol. The reaction of HL with CuCl2·2H2O and CuBr2 in methanol gave neutral mononuclear Cu(II) complexes with general formula of [Cu(HL)Cl2] (1) and [Cu(HL)Br2] (2), respectively. By slow evaporation of the methanolic solutions of 1 and 2, their enantiomers were isolated in crystalline format. The formation of pure chiral crystals in the racemic mixture was amply authenticated by single crystal X-ray analysis, which indicated that S-[Cu(HL)Cl2], R-[Cu(HL)Cl2], and S-[Cu(HL)Br2] are crystallized in chiral P212121 space group of orthorhombic system. Preferential crystallization was used to isolate the R and S enantiomers as single crystals and the isolated compounds were also studied by CD analysis. Structural studies indicated that the origin of the chirality in these compounds is related to the coordination mode of the employed pro-chiral ligand (HL) because one of its carbon atoms has been converted to a chiral center in the synthesized complexes. Subsequently, these complexes were used in click synthesis of a β-hydroxy-1,2,3-triazole and the results of catalytic studies indicated that 1 and 2 can act as enantioselective catalysts for the asymmetric synthesis of β-hydroxy-1,2,3-triazole product under mild condition. This study illustrates the significant capacity of the use of pro-chiral ligands in preparing chiral catalysts based on complexes which can also be considered as an effective approach to cheap chiral catalysts from achiral reagents.

Construction of stereogenic center beta to the N-Pyrrolidinyl moiety via diastereoselective reactions of tricyclic lactones and the synthesis of (−)-Indolizidine 195G

The Enolates of hexahydro-3,4-dioxa-8a-aza-as-indacen-2-ones can react with electrophiles in a substrate-controlled fashion to create a new stereogenic center positioned beta to the N-pyrrolidinyl moiety. Preferential diastereoselective reactions predominantly proceeded from the convex face of the enolates, yielding stereospecific alkylated or halo-substituted products with high yields and exceptional diastereoselectivities. Di-substituted compounds were obtained by the alkylation or halogenation of the enolates of the corresponding mono-substituted compounds. Total synthesis of (−)-indolizidine 195G was also accomplished. © 2024 Elsevier Science. All rights reserved.

Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp 3 -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme's remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst's compatibility with diverse functional groups and tertiary C-H bonds. Mechanistic studies elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

Supertwisted Chiral Gyroid Mesophase in Chiral Rod‐Like Compounds

AbstractAmong the intriguing bicontinuous self‐assembled structures, the gyroid cubic is the most ubiquitous. It is found in block and star polymers, surfactants with or without solvent, in thermotropic liquid crystals with end‐ or side‐chains, and in biosystems providing structural color and modelling cell mitosis. It contains two interpenetrating networks of opposite chirality and is thus achiral if, as usual, the content of the two nets is the same. However, we now find that this is not the case for strongly chiral compounds. While achiral molecules follow the opposite twists of nets 1 and 2, molecules with a chiral center in their rod‐like core fail to follow the 70° twist between junctions in net 2 and instead wind against it by −110° to still match the junction orientation. The metastable chiral gyroid is a high‐entropy high‐heat‐capacity mesophase. The homochirality of its nets makes the CD signal of the thienofluorenone compounds close to that in the stable I23 phase with 3 isochiral nets.

Supertwisted Chiral Gyroid Mesophase in Chiral Rod-Like Compounds.

Among the intriguing bicontinuous self-assembled structures, the gyroid cubic is the most ubiquitous. It is found in block and star polymers, surfactants with or without solvent, in thermotropic liquid crystals with end- or side-chains, and in biosystems providing structural color and modelling cell mitosis. It contains two interpenetrating networks of opposite chirality and is thus achiral if, as usual, the content of the two nets is the same. However, we now find that this is not the case for strongly chiral compounds. While achiral molecules follow the opposite twists of nets 1 and 2, molecules with a chiral center in their rod-like core fail to follow the 70° twist between junctions in net 2 and instead wind against it by -110° to still match the junction orientation. The metastable chiral gyroid is a high-entropy high-heat-capacity mesophase. The homochirality of its nets makes the CD signal of the thienofluorenone compounds close to that in the stable I23 phase with 3 isochiral nets.

One-Carbon Homologation of Knoevenagel Adducts: Enantioselective Access to Benzhydryl Derivatives.

A one-carbon homologation of Knoevenagel adducts enabling the insertion of a CHAr fragment is reported. The strategy involves a sulfur ylide mediated cyclopropanation followed by the rearrangement of cyclopropanes and enables the synthesis of a series of benzhydryl derivatives. Mechanistic studies reveal that the cyclopropane rearrangement involves a Lewis acid catalyzed ring-opening followed by the 1,2-migration of an aryl group. The possibility of controlling the absolute stereochemistry of the generated stereogenic allylic carbon center using a chiral sulfonium ylide is demonstrated.

Effect of Hydrogen Bonding and Chirality in Star-Shaped Molecules with Peripheral Triphenylamines: Liquid Crystal Semiconductors and Gels.

Organic semiconductors with well-defined architectures pose a suitable alternative to amorphous silicon-based inorganic semiconductors. Encouraged by the development of organic semiconductors based on columnar liquid crystals, herein, we report on a family of C3-symmetric star-shaped mesogens based on triphenylamine (TPA), a functional unit with strong electron donor character. Highly stable columnar phases with high hole mobility values were obtained out of this nonplanar functional unit, and this was achieved by using flexible amide spacers to join the TPA units to a tris(triazolyl)triazine (T) star-shaped core, allowing the formation of intermolecular hydrogen bonds. The presence of hydrogen bonds results in a stabilization of the columnar architectures either in bulk or in the presence of solvents by reinforcing π-stacking and van der Waals interactions, as deduced by Fourier-transform infrared (FTIR) and X-ray diffraction (XRD) studies. Furthermore, the introduction of a stereogenic center in the flexible spacer prompts the formation of chiral aggregates in the liquid crystal state and in the organogel formed in 1-octanol, as demonstrated by circular dichroism spectroscopy.

Asymmetric synthesis of allylic sulfonamides with axially and central chirality via palladium-catalyzed of atroposelective N-allylic alkylation

Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts, biologically active scaffolds and functional materials. Compared to the C–C axially chiral molecules, the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers. Herein, the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported. A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities (up to 92 ​% yield and 99 ​% ee). In addition, the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction.

Hindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.

Chiral analysis of ostarine in commercially available products and doping control urine samples

Various substances classified as prohibited in sport by the World Anti-Doping Agency (WADA) comprise one or more chiral centers. One such substance is enobosarm ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2‑hydroxy-2-methylpropanamide, S-ostarine, S-22, MK-2866, GTx-024, VERU-024). Although ostarine is not an approved drug, it has been readily available via Internet-based suppliers, and to date it is unknown to what extent R-ostarine, S-ostarine, or a mixture of both is used in these products. Likewise, such information is not available with regards to urine samples that returned an adverse analytical finding in the context of sports drug testing programs and, hence, this pilot-study aimed at establishing a test method to provide first insights into the presence of R- and S-ostarine in commercially available products and in authentic doping control urine samples.Here, a chiral liquid chromatographic - mass spectrometric method, employing a teicoplanin-containing (chiral) stationary phase that allows the differentiation of R- and S-enantiomers of ostarine, is presented. Ostarine products were extracted and diluted prior to analysis, while urine samples were prepared for analysis by enzymatic hydrolysis followed by liquid-liquid extraction.Seven products declaring to contain ostarine were investigated, five of which were ordered via the Internet and two were confiscated and made available by a customs authority. Only 2 of the 5 purchased products contained ostarine. In these two products and the confiscated products, only the ostarine S-enantiomer was found. Further, five authentic doping control urine samples containing the target analyte were subjected to chiral analysis, also confirming the sole presence of the S-ostarine enantiomer.The developed approach proved suitable for the separation of ostarine enantiomers, which adds further information e.g. in the context of illicit drug production, trafficking, and doping controls, especially when additional details are desirable that might assist in determining the origin of a drug or drug residue.

Enantioselective Synthesis of Axially and Centrally Chiral Styrenes via Nickel-Catalyzed Desymmetric Hydrocyanation of Biaryl Dienes.

Herein, a highly regio-, enantio-, and diastereoselective nickel-catalyzed desymmetric hydrocyanation of biaryl dienes for the simultaneous construction of axial and central chiralities is presented, which offers a convenient approach to a variety of tirenes containing the union of an axially chiral biaryl and a centrally α-chiral nitrile under mild conditions using a commercially available catalyst. The synthetic utility is highlighted by the development of a novel axially chiral phosphine ligand and biphenyl-based chiral diene ligand and their potential applications in the field of asymmetric catalytic reactions.

Advances and Strategies towards Synthesis of Aspidosperma Indole Alkaloids Goniomitine.

Goniomitine is of the aspidosperma alkaloid family, with an angularly fused tetracyclic skeleton housing an all-carbon quaternary carbon chiral center alongside an aminal functional group. This natural product has garnered attention as a synthetic target due to its intriguing molecular architecture and anti-proliferative activity in recent years. Following the first synthesis of (-)-goniomitine by Takano in 1991, synthetic chemists have developed various methods. This review provides an overview of the methodologies used in the synthesis of goniomitine in racemic and enantiopure forms via divergent construction indole framework, indole functionalization, and the integrated oxidation/reduction/cyclization (iORC) sequence from 1991 to 2023.

Controlling Chirogenic Effects in Porphyrin Based Supramolecular Systems: Theoretical Analysis Versus Experimental Observations.

Electronic circular dichroism (ECD) spectroscopy is a widely employed method for studying chiral analysis, requiring the presence of a chromophore close to a chiral centre. Porphyrinoids are found to be one of the best chromophoric systems serving for this purpose and enabling the application of ECD spectroscopy for chirality determination across diverse classes of organic compounds. Consequently, it is crucial to understand the induction mechanisms of ECD in the porphyrin-based complexes. The present study explores systematically the influence of secondary chromophores, bonded to an achiral zinc porphyrin or to chiral guest molecules, on the B-region of ECD spectra using the time-dependent density functional theory (TD-DFT) calculations. The study analyses the impact of change in both the conformation of achiral porphyrin (host) and change in position and conformation of chiral organic molecule (guest) on the B-band of ECD spectra (energy, intensity, sign of Cotton effect). Finally, conclusions made on model complexes are applied to published experimental data, contributing to a deeper understanding of various factors influencing ECD spectra in chiral systems. In addition, a computer program aimed to help rationalise ECD spectra by visualizing corresponding orbital energies, rotatory strengths, electric and magnetic transition moments, and angles between them, is presented.