Enantioselective Research Articles

Defluorinative Hydroxylation Promoted by Silica to Access Optically Pure Hexahydrofuranocarbazole via [4+2] Addition Reaction

AbstractCrafting an efficient strategy for the synthesis of biologically active and functionally rich hexahydrofuranocarbazole is a highly desirable but demanding pursuit. This research elucidates a groundbreaking strategy involving an unanticipated defluorinative hydroxylation reaction facilitated by silica gel, yielding highly enantio‐ and diastereoselective hexahydrofuranocarbazole frameworks. This method results in the formation of five consecutive chiral centers, including three quaternary stereocenters and an all‐carbon spiro center, via an aminocatalytic asymmetric remote [4+2] addition process. The developed methodology allows for the construction of a diverse array of products (24 examples, up to >99 % ee and 17 : 1 dr), reflecting its notable substrate scope. Furthermore, we demonstrate the feasibility of gram‐scale synthesis and control experiments that underscore the methodological advancements and provide insights into the underlying mechanism.

DACH-Based Chiral Sensing Platforms as Tunable Benzamide-Chiral Solvating Agents for NMR Enantioselective Discrimination.

Chiral discrimination is an indispensable tool that has pivotal importance in the assignment of absolute configuration and determination of enantiomeric excess in chiral compounds. A series of enantiomerically pure trans-1,2-diaminocyclohexane (trans-DACH)-derived benzamides were first synthesized by simple chemical steps, and 14 variated derivatives 6a-6n have been assessed as NMR chiral solvating agents (CSAs) for discrimination of the signals of mandelic acid (MA) in 1H NMR analysis. The highly efficient chiral recognition of CSA 6e on different substrates, including MAs, carboxylic acids, amino acid derivatives, and phosphoric acids (32 examples), was expanded via 1H, 19F, and 31P NMR spectroscopy. The quality of enantiodiscrimination was evaluated by means of the enantioresolution parameter Rs. Single-crystal X-ray analysis of three derivatives 6c, 6e, and 6h helped to understand enantiomeric recognition for the promising NMR analysis. Interestingly, the NMR signals of nonequivalent protons between the R and S configurations were completely opposite in the presence of CSA 6e and its stereoisomer, which can be utilized to establish a straightforward method for the configuration assignment of diverse hydroxy acid substrates.

Dual Photoredox and Copper-Catalyzed Asymmetric Remote C(sp3)-H Alkylation of Hydroxamic Acid Derivatives with Glycine Derivatives.

Dual photoredox and copper-catalyzed remote asymmetric C(sp)3-H alkylation of hydroxamic acid derivatives with glycine derivatives via a 1,5-hydrogen transfer (1,5-HAT) process has been realized. The reaction was characterized by redox-neutral and mild conditions, good yields, excellent enantioselectivity, and broad substrate scope. This protocol provides a straightforward and efficient strategy to prepare highly valuable enantioenriched noncanonical α-amino acids. Moreover, the potential synthetic value of this reaction was demonstrated in late-stage asymmetric alkylation of dipeptides with a high diastereomeric ratio.

Tropos Diphenylmethane-Based Phosphine-Phosphoramidite Ligands: Design, Synthesis, and Application in Catalytic Asymmetric Hydrogenation.

A series of chiral hybrid diphosphorus ligands incorporating a conformationally flexible tropos diphenylmethane-based phosphoramidite unit have been developed and evaluated in the Rh-catalyzed asymmetric hydrogenation of 2-(1-arylvinyl)anilides and α-enamides, leading to up to >99% yield and 99% enantiomeric excess. Preliminary results from comparative studies showcased the extraordinary catalytic performance of these chiral tropos phosphine-phosphoramidite ligands, with a competency essentially superior to those of well-established ligands with a regular rigid backbone.

Cobalt-Catalyzed Enantioselective Reductive Coupling of Imines and Internal Alkynes.

Chiral allylamines are important structural components in natural products, pharmaceuticals, and chiral catalysts. Herein, we report a cobalt-catalyzed enantioselective reductive coupling of imines with internal alkynes to synthesize chiral allyl amines. The reaction is catalyzed by a cobalt complex derived from commercially available bisphosphine ligand utilizing zinc as the electron donor.The substrate scope is extensive. Symmetric and asymmetric alkyl and aryl alkynes have been successfully coupled with various imines derived from aryl and alkyl aldehydes. Tri- and tetra-substituted allyl amines were isolated in high yields exceeding 89%, with enantiomeric excess surpassing >99.9% and regioselectivities exceeding >20:1. These chiral allylamines can serve as versatile platformsfor subsequent transformations while preserving their stereochemical integrity. Extensive experimental and computational mechanistic studies were performed to elucidate the mechanism. These investigations have indicated that an in situ cobalt(I) catalyst enables the oxidative cyclization of alkynes and imines, and a spin crossover occurs during the enantio-determining step. Zinc plays a pivotal role in facilitating the transmetallation of the resulting azacobaltacycle. The observed enantioselectivity was interpreted by the stabilization of the transition state through higher stabilization interaction energy from high negative polarization, dispersion, and C-H•••π interactions.

Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes.

Chiral heterocyclic alcohols and amines are frequently used building blocks in the synthesis of fine chemicals and pharmaceuticals. Herein, we report a one-pot photoenzymatic synthesis route for N-Boc-3-amino/hydroxy-pyrrolidine and N-Boc-4-amino/hydroxy-azepane with up to 90% conversions and >99% enantiomeric excess. The transformation combines a photochemical oxyfunctionalization favored for distal C-H positions with a stereoselective enzymatic transamination or carbonyl reduction step. Our study demonstrates a mild and operationally simple asymmetric synthesis workflow from easily available starting materials.

Intramolecular Cascade Cyclization of Cyclobutanone: Asymmetric Construction of Cyclobutanone Fused Oxa-Spirocycles.

The successful implementation of a cascade reaction involving a cyclobutyl unit has posed a significant challenge in achieving ring-retentive functionalization because of the ring's sacrificial tendency. Herein, we have accomplished a cinchona-derived squaramide-catalyzed cascade reaction sequence, encompassing the desymmetrization of cyclobutanone, followed by an aldol reaction and, subsequently, a 1,4-addition step. This overall process offers a viable strategy to access architecturally fascinating oxa-spirocycles fused with cyclobutanone motifs in good yields with high optical purity.

Impact of Structural Subtleties on Chirality Induction and Amplification in Trizinc(II)Porphyrin Trimers.

Herein, we report the precise control of molecular to supramolecular chirality induction at the single-molecule level just upon subtle modification in an achiral 'nano-size' trizinc(II) porphyrin trimer. A slight variation in the projection of the substituent at the periphery of the central porphyrin unit in a porphyrin trimer (host) resulted in pronounced changes in the interchromophoric arrangement, leading to distinct 'open' and 'closed' conformations. While 'open' form generates 'monomeric' complex with low CD amplitude, 'closed' form produces exclusive 'polymer' with large, amplified CD signal with opposite sign due to stronger intermolecular excitonic coupling. Also, the sign of the CD couplets is just opposite between R and S substrates for both polymer and monomer which suggest that the chirality is predominantly governed by the stereogenic projection of the chiral center. X-ray structures of the host and polymer have been reported here. Crystallographic characterization offers a detailed perspective on the structural and geometrical transformations in the polymer, enabling a systematic understanding of its optical properties. DFT and TD-DFT calculations strongly corroborate with the experimental findings.

Mechanochemical Deracemization: A Sustainable Approach to Enantiopurity.

We introduce mechanochemical deracemization (MCDR) as a novel strategy for obtaining enantiopure compounds. This study demonstrates the successful transposition of six archetypical deracemization reactions from a solvent-based to a solvent-minimized ball milling environment. The scope includes a ketone, isoindolinones, imines, an ester, and an inorganic compound, all of which deracemized successfully. Key parameters such as milling material, ball number and size, the use of a bulk material and liquid-assisted grinding (LAG) were systematically investigated, revealing their crucial role. Quantitative enantiomeric excesses (ee) were achieved, while reaction times were reduced by up to 97 % and solvent consumption by as much as 100 %. This work establishes MCDR as a versatile, sustainable pathway to enantiopure compounds. By highlighting the generalizability of this approach and its huge potential for minimizing waste, this study provides the foundation for future advancements in mechanochemical deracemization.

A Helically-Twisted Stereodynamic Probe for Chiroptical Sensing of Chiral Amines through Point-to-Helical Chirality Transmission.

Chiral amines and amino alcohols form an important category of molecules employed in the designing of new drugs and catalyst. Herein, we present a helically-twisted stereodynamic dialdehyde probe 1 for the determining of absolute configuration, and enantiomeric excess of chiral amine and amino alcohols. Probe 1 is based on the pyridine-2,6-dicarboxamide (PDC) core and undergoes rapid interconversion between the P- and M- conformers. However, upon imine formation with chiral amines, probe 1 gets locked it in a single conformer majorly. This induces a strong CD signal in addition to changes in the UV-vis and fluorescence signals. The CD spectral change allowed for quantitative enantiomeric excess determination of chiral amines. Circular polarized luminescence (CPL) spectra having the glum of 1×10-3 was obtained upon imine formation between probe 1 and diamine 2. Single crystal X-ray diffraction studies (SCXRD) confirmed the twisted conformation in 1@(R)-4 and 1@(S)-4, stabilized by intramolecular hydrogen bonding between bound imine nitrogen and proximate amide group.

Integrating continuous flow reaction and work-up: chiral amine resolution, separation and purification using a novel coalescing filter system.

To maximize the benefits of a continuous flow reaction, a continuous work-up is also needed. Herein, we present a process design and novel equipment for a continuous amine resolution reaction, integrated with liquid-liquid (L-L) extraction, back-extraction into a different solvent, and crystallisation purification for product isolation. The reaction, in iso-propyl acetate, flows through a heated fixed-bed reactor with solid supported Candida antarctica lipase which catalyses the resolution of (rac)-1-phenylethylamine to give the (R)-amide in 50% conversion and 96% enantiomeric excess (ee). This is separated from the unreacted (S)-amine co-product by mixing with an acidic aqueous stream and separating the phases using our recently reported coalescence filter separator. The aqueous stream is neutralised by mixing with base and back-extracted into methyl-THF solvent before separating the phases using a membrane separator. Finally, a solid amine salt is isolated by filtration, achieved by mixing the free base with an organic acid to cause crystallisation to give the (S)-1-phenylethylamine in 43% yield and >99% ee from racemate. The work illustrates how typical reactions, work-up and purification steps that involve multiple phases can be telescoped together using both new and commercially available laboratory equipment. This continuous system uses mild reaction conditions, green solvents and minimises their use for reduced waste.

Hierarchical amplification of chirality in anion-coordinated tetrahedral cages

Upon the self-assembly and subsequent host-guest chemistry, a hierarchical chiral system at the supramolecular level was established, featuring controllable chiral transfer and amplification.

Fluoride binding-modulated supramolecular chirality of urea-containing triarylamine and its photo-manifestation.

In recent years, the regulation of anion-mediated chiral assemblies has gained significant interest. This study investigated the modulation of supramolecular chiroptical signals and chiral assembled structures in a triarylamine system containing a urea moiety through fluoride ion-urea bond interactions, aiming to understand the chiral sense amplification in supramolecular assemblies. Chiral triarylamine derivatives containing urea or amide units were synthesized and the self-assemblies were examined in the absence and presence of fluoride ions. The results revealed that the addition of F- led to an increase in the circular dichroism (CD) intensity for the triarylamine compounds containing urea, accompanied by a transformation of the nanofiber structure into chiral twists. Comparative studies with other anions confirmed the selective specificity for F-. Additionally, the combination of photo-induced triarylamine anion radicals allowed the F- in the system to be visualized through photoirradiation, resulting in distinct colour changes that were detectable by the naked eye. The research demonstrates that F- can selectively amplify supramolecular chirality through urea-F- interactions, which may have promising applications in the fields of sensing and chiroptical devices.

Enantioselective interactions of aminonitrile dimers.

Enantioenrichment of amino acids is essential during the early chemical evolution leading to the origin of life. However, the detailed molecular mechanisms remain unsolved. Dimerization of enantiomers is the first molecular process in the nucleation of deposition and crystallization, which are both essential for enantioenrichment. Here, we report the enantioselective interactions of dimers of chiral intermediates, i.e., aminonitriles, in both gas and water environments based on density functional theory (DFT) and more accurate coupled-cluster (CC) calculations. We show that all the aminonitriles stabilize the homochiral dimer preferentially to the heterochiral dimer in the gas phase, while this trend was not observed in water. The energies of the enantioselective interactions in aminonitriles are substantially lower compared to those in amino acids, especially isovaline. These results suggest that prebiotic enhancements of enantiomeric excess are more likely to occur in amino acids than in the aminonitrile intermediates.

Advances and prospects for lactic acid production from lignocellulose.

Lactic acid is a versatile building block that can be produced via microbial fermentation. Owing to the high optical purity, approximately 90 % of lactic acid is produced by microbes. Recently, the biosynthesis of lactic acid from lignocellulose has concerned much attentions. However, the cost-effective process faces several obstacles because of the complex structure of lignocellulose. This review will comprehensively summarize the state-of-the-art lactic acid production from lignocellulose, including the commonly used lactate-producing microorganisms, the co-utilization of glucose and xylose for the lactic acid production, as well as the lactic acid production from lignocellulose hydrolysate. Furthermore, the strategies regarding the lignocellulosic lactic acid production via consolidated bioprocessing will be also discussed, which can greatly reduce the complexity of the fermentation process.

Optimized separation of astaxanthin stereoisomers from microbial sources using chiral HPLC.

Astaxanthin (AST) is a high-value antioxidant, and its efficient isolation and utilization are challenging owing to the presence of different stereoisomers from various sources. In the present study, a semi-preparative HPLC method for the efficient separation of AST stereoisomers using a Chiralpak IC chiral column with good loading capacity and chiral recognition ability was successfully developed. The mobile phase was methanol-methyl tert-butyl ether (90 : 10, v/v), with a flow rate of 3.06 mL min-1 and a maximum injection volume of 0.32 mg. The results indicated that the purity of all-trans AST was 97.9% for Haematococcus pluvialis and 97.5% for Phaffia rhodozyma. Additionally, molecular weights and fragmentation patterns analyzed using mass spectrometry were consistent with those of all-trans AST. Linearity validation and reproducibility experiments revealed that all calibration curves had coefficients of determination (R2) greater than 0.999 and a relative standard deviation (RSD) of <3.8%. This is because all-trans AST stereoisomers could undergo specific rotations or spins due to π-π interactions, hydrogen bonding, and inclusion interactions. This process allowed the successful separation of the three all-trans AST optical isomers and provides a theoretical basis for large-scale preparation of all-trans AST stereoisomers from different sources.

Palladium-Catalyzed Enantioselective Synthesis of P(V)-Stereogenic Compounds via Desymmetric Annulation of Prochiral Phosphinamides and Aryl Iodides.

The enantioselective synthesis of P(V)-stereogenic compounds has emerged as an interesting research topic primarily due to their significant biological activity and broad application prospects. Herein, we disclose a method for the construction of P(V)-stereogenic compounds from prochiral phosphinamides and aryl iodides via palladium- and chiral norbornene-catalyzed desymmetric annulation. The P(V)-stereogenic compounds were formed with a broad scope with excellent enantiomeric excesses. It is noteworthy that the synthetic value of this procedure was proven by a variety of transition metal-catalyzed cross-coupling reactions using the C-Br bond on the product as a versatile linchpin electrophile.

Dynamic Covalent Bonds‐Mediated Color‐Switchable Circularly Polarized Luminescence in Helical Assemblies of Achiral Liquid Crystal Block Copolymer Films

Circularly polarized luminescence (CPL) film attracted considerable attention in information storage and encryption, three‐dimensional display, and chiral recognition. However, due to the limited molecular mobility within thin film, achieving a high asymmetry factor and non‐contact modulation of CPL remain challenging. In this work, color‐switchable homochiral CPL films with high luminescence asymmetry factor (glum~0.11) were constructed based on the co‐assembly of a liquid crystal block copolymer (poly (ethylene oxide)‐b‐poly (methyl methacrylate) bearing cyanostilbene group) with axial chiral dinaphthalene diamine derivatives (R/S‐DINBPA). Mechanistic investigation revealed that the efficient stacking of R/S‐DINBPA with cyanostilbene groups and the liquid crystal field provide the driving force for chiral transfer and amplification. The dynamic covalent bonds of the cyanostilbene groups endow the film with chiral fixation ability and enable precise modulation of CPL luminescence bands under UV light irradiation, making it suitable for chiral patterned anti‐counterfeit encryption. This facile strategy provides a general platform for designing intelligent chiroptical materials.

Dynamic Covalent Bonds-Mediated Color-Switchable Circularly Polarized Luminescence in Helical Assemblies of Achiral Liquid Crystal Block Copolymer Films.

Circularly polarized luminescence (CPL) film attracted considerable attention in information storage and encryption, three-dimensional display, and chiral recognition. However, due to the limited molecular mobility within thin film, achieving a high asymmetry factor and non-contact modulation of CPL remain challenging. In this work, color-switchable homochiral CPL films with high luminescence asymmetry factor (glum~0.11) were constructed based on the co-assembly of a liquid crystal block copolymer (poly (ethylene oxide)-b-poly (methyl methacrylate) bearing cyanostilbene group) with axial chiral dinaphthalene diamine derivatives (R/S-DINBPA). Mechanistic investigation revealed that the efficient stacking of R/S-DINBPA with cyanostilbene groups and the liquid crystal field provide the driving force for chiral transfer and amplification. The dynamic covalent bonds of the cyanostilbene groups endow the film with chiral fixation ability and enable precise modulation of CPL luminescence bands under UV light irradiation, making it suitable for chiral patterned anti-counterfeit encryption. This facile strategy provides a general platform for designing intelligent chiroptical materials.

Total Synthesis of (+)- and (-)-Calycanthidine and Formal Synthesis of (-)-Idiospermuline via Key Pd(0)-Catalyzed Asymmetric Allylations.

We envisioned a novel asymmetric strategy to access unsymmetrically substituted dimeric 2-oxindoles [(S,S)-8 and (R,R)-8] for the total synthesis of calycanthidine (4a). The key to success is the development of efficient Pd(0)-catalyzed asymmetric sequential allylations [via a highly enantioselective [up to 94% enantiomeric excess (ee)] and diastereoselective (up to ∼13:1) process] of unsymmetrically protected dimeric 2-oxindoles at the 3,3' position [such as (S,S)-8 and (R,R)-8]. Gratifyingly, a mixture of bis-ester (±)-10a, ester-carbonates (±)-10b and (±)-10c, and bis-carbonate 10d could afford (S,S)-8 and (R,R)-8 in highly stereoselective fashion, thereby culminating in the total synthesis of (+)-calycanthidine [ent-(4a)] and (-)-calycanthidine (4a). This effort also culminated in the formal total synthesis of idiospermuline (5).