Asymmetric Synthesis Research Articles

Synthesis of Polycyclic Olefinic Monomers from Norbornadiene for Inverse Vulcanization: Structural and Mechanistic Consequences.

The preparation of high-sulfur content organosulfur polymers has generated considerable interest as an emerging area in polymer science that has been driven by advances in the inverse vulcanization polymerization of elemental sulfur with organic comonomers. While numerous new inverse vulcanized polysulfides have been made over the past decade, insights into the mechanism of inverse vulcanization and structural characterization of the high-sulfur-content copolymers remain limited in scope. Furthermore, the exploration of new molecular architectures for organic comonomer synthesis remains an important frontier to enhance the properties of these new polymeric materials. In the current report, the first detailed study on the synthesis and inverse vulcanization of polycyclic rigid comonomers derived from norbornadiene was conducted, affording a quantitative assessment of polymer microstructure for these organopolysulfides and insights into the inverse vulcanization polymerization mechanism for this class of monomers. In particular, a stereoselective synthesis of the endo-exo norbornadiene cyclopentadiene adduct (Stillene) was achieved, which enabled direct comparison with the known exo-exo norbornadiene dimer (NBD2) previously used for inverse vulcanization. Reductive degradation of these sulfur copolymers and detailed structural analysis of the recovered sulfurated organic fragments revealed that remarkable exo-stereospecificity was achieved in the inverse vulcanization of elemental sulfur with both these polycyclic dienyl comonomers, which correlated to the robust thermomechanical properties associated with organopolysulfides made from NBD2 previously. Melt processing and molding of these sulfur copolymers were conducted to fabricate free-standing plastic lenses for long-wave infrared thermal imaging.

Asymmetric Cycloaddition of N-2,2,2-Trifluoroethylisatin Ketimines and Unsymmetrical Dicarbonyl-Activated Alkenes: Construction of 5'-Trifluoromethylated 3,2'-Pyrrolidinyl Spirooxindoles with Three Carbonyl Groups.

The asymmetric cycloaddition between N-2,2,2-trifluoroethylisatin ketimines and unsymmetrical dicarbonyl-activated alkenes catalyzed by a bifunctional squaramide has been discovered. The present study demonstrates an efficient approach for the regio-, diastereo-, and enantioselective synthesis of densely functionalized 5'-trifluoromethylated 3,2'-pyrrolidinyl spirooxindoles featuring three different types of carbonyl groups.

One-pot enantioselective synthesis of chiral phenyllactic acids by combining stereocomplementary d- and l-lactate dehydrogenases with multi-enzyme expression fine-tuning

Chiral phenyllactic acid (PLA) is a new type of antiseptic agent and a valuable precursor for active ingredients in pharmaceuticals and agrochemicals. In this study, we designed a multi-enzyme cascade that combined stereocomplementary d- and l-lactate dehydrogenases with threonine aldolase, phenylserine dehydratase, and formate dehydrogenase for the one-pot conversion of achiral glycine and benzaldehyde to synthesize d-PLA and l-PLA. To overcome the imbalance of multi-enzymes in a single cell, two enzyme modules, overexpressing four enzymes, were assembled in Escherichia coli cells to construct whole-cell catalysis systems (WCCSs). Furthermore, by optimizing reaction conditions and components, recombinant E. coli (WCCS 26) was able to produce 100 mM d-PLA with >99 % ee using a fed-batch strategy, while E. coli (WCCS 60) produced 47.2 mM l-PLA with >99 % ee. This study presents a sustainable and efficient method for synthesizing chiral PLAs from food-grade achiral starting materials.

Catalytic Enantioselective Macrocyclization for the Synthesis of Planar‐Chiral Cyclophanes: Recent Updates

The planar chirality of macrocycles is a fascinating research topic. Locking the configurational flip between the benzene ring and macrocycle leads to planar chirality, which can significantly enhance the biological activity of cyclophanes. Planar‐chiral cyclophanes are widely used in pharmaceuticals, chiral catalysts, and functional materials. However, accessing planar‐chiral cyclophanes via asymmetric catalysis has remained challenging. Among the various strategies, asymmetric macrocyclization provides a powerful tool for accessing planar‐chiral cyclophanes. This method allows for control of the planar chirality when constructing the macrocycle and greatly improves the efficiency. There are three types of macrocyclization reactions: transition metal‐catalyzed, organocatalyzed, and biocatalyzed. In addition, the chiral confinement strategy breaks through conservative synthetic approaches. This review summarizes these achievements, aiming to highlight the catalytic asymmetric synthesis of cyclophanes and inspire interested researchers.

Chemical Methods for the Construction of Spirocyclic β-Lactams and Their Biological Importance

AbstractSpirocyclic β-lactams are a family of natural and synthetic chemicals with different biological activities, including antibacterial properties, and interact with critical physiological targets such as T-type calcium channels and acetyl-CoA cholesterol acyltransferase. Their unique chemical structure, combining a spiro ring system with a β-lactam group, offers promising opportunities for the targeted discovery of medications in medicinal chemistry. Spirocyclic β-lactams have the potential to be adaptable frameworks for developing novel therapeutic medicines with particular three-dimensional pharmacophoric characteristics and increased biological efficacy. Numerous methods are employed for the synthesis of spirocyclic β-lactams, such as cyclization, functional group modifications, asymmetric synthesis utilizing chiral catalysts and biomimetic approaches. In this short review, two distinct approaches describing recent syntheses of spirocyclic β-lactams (from 2021 to 2024) are discussed. The first is based on constructing the β-lactam ring, while the other entails transforming monocyclic β-lactams into spirocyclic structures. These methods include detailed reaction processes and descriptions of the biological functions of the target spirocycles. The applications of spirocyclic β-lactams in medicinal chemistry highlight their role in the synthesis of structurally diverse compounds with significant therapeutic potential, demonstrating creative chemical methods for building complex molecular structures.1 Introduction2 β-Lactam Ring Synthesis3 Non-β-Lactam Ring Synthesis4 Miscellaneous Examples5 Conclusion and Outlook

One-Pot Multienzyme Cascades for Stereodivergent Synthesis of Tetrahydroquinolines.

The tetrahydroquinoline (THQ) framework is commonly found in natural products and pharmaceutically relevant molecules. Apart from the use of transition metal catalysts and chiral phosphoric acids, the chiral 2-substituted 1,2,3,4-THQs are synthesized using amine oxidase biocatalysts. However, the use of imine reductases (IREDs) in their asymmetric synthesis remained unexplored. In the current work, IREDs are employed in telescopic multienzyme cascades to catalyze the intramolecular reductive amination leading to chiral 2-alkyl and 2-aryl substituted-1,2,3,4-tetrahydroquinolines starting from inexpensive nitroalkenones. The cascades containing NtDBR (an ene reductase), NfsB (a nitro reductase) with either Na2S2O4 or V2O5, various IREDs, and glucose dehydrogenase (for NADPH regeneration) are used to synthesize a broad range of (R)/(S)-2-alkyl-substituted (THQs) (26 examples) with high yield (up to 93%) and excellent ee (up to 99%) in one-pot. The method further facilitates the one-pot biocatalytic synthesis of chiral 2-aryl substituted THQs (26 examples) from amino chalcones. Lastly, the asymmetric synthesis of several (R)- and (S)-THQ based intermediates of Hancock alkaloids showed the practical application of the newly developed biocatalytic cascades.

Catalytic Asymmetric Synthesis of Chiral Fluorenes: Recent Developments and Future Perspectives

The chiral fluorene fragment constitutes one of the most important scaffolds frequently found in numerous bioactive molecules, ligands, and advanced functional materials due to its unique physical properties. In this context, various transition metal‐ and organo‐catalyzed asymmetric reactions have been developed to prepare chiral fluorenes with high optical purity. In the present mini‐review, we summarize fifteen years of achievements in the catalytic asymmetric synthesis of chiral fluorenes and their derivatives. Particular attention is given to the strategies used and mechanistic aspects of some significant reactions. Moreover, the cutting‐edge developments in the catalytic asymmetric synthesis of silafluorenes are also highlighted.

Chemoenzymatic Synthesis of Plant‐Derived Kavalactone Natural Products by Dynamic Resolution Using a Biosynthetic O‐Methyltransferase Tailoring Enzyme

Biosynthetic enzymes have enormous potential for the chemoenzymatic synthesis of natural products and other bioactive compounds. Methyltransferases are promising tools for the selective enzymatic modification of complex structures. This paper describes the production, purification and biochemical characterization of the O‐methyltransferase JerF, which catalyzes unique 4‐methoxy‐5,6‐dihydropyranone formation in jerangolid A biosynthesis. Isolation problems had hitherto prevented detailed studies on JerF and were solved by the production of the maltose‐binding protein fusion protein. The differentiation of JerF between styryl‐substituted dihydropyrandion enantiomers was investigated. In combination with a spontaneous racemization occurring with this type of substrates, a new enzymatic dynamic kinetic resolution was observed, which was used for the enantioselective chemoenzymatic synthesis of kavalactone natural products and new derivatives. In combination with an HMT‐based SAM regeneration system, (+)‐kavain, (+)‐11,12‐dimethoxykavain and (+)‐12‐fluorokavain were prepared in 3‐4 steps on the 100 µmol scale with overall yields of 37‐57% and ees of 70‐86%. A mutational study based on an AlphaFold 2 model provided indications for active site residues with an influence on the performance of the enzyme that could be targets for engineering. This example illustrates how the exceptional enzymatic activities and specificities of biosynthetic enzymes can be exploited for the development of new synthesis approaches.

Probing the Mechanism of Ni-Catalyzed Asymmetric Reppe Carbonylation of Cyclopropenes with CO and ROH.

There is ongoing intense interest in catalysis with the Earth-abundant metal nickel. This DFT study reveals a plausible mechanism for the first Ni-catalyzed asymmetric Reppe carbonylation of cyclopropenes with carbon monoxide and phenols/alcohols. The RO-H bond undergoes a distinct heterolytic cleavage rather than the proposed oxidative addition, transferring a proton to a nickel-bound anionic carbon atom in a stereoselective manner. This and other novel insights gained can have implications for developing new asymmetric Reppe reactions.

Silver/Segphos‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition for the Enantioselective Synthesis of Pyrrolidine Spirooxindoles

Enantioselective synthesis of chiral heterocyclic derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, a silver‐catalyzed asymmetric 1,3‐dipolar cycloaddition of glycine iminoesters with 3‐isopropylidene‐2‐oxindoles was developed. The DTBM‐Segphos‐induced spirooxindole cycloaddition reaction was used to synthesize a range of stereodivergent alkyl‐substituted 3‐methylene‐2‐oxindoles, achieving excellent enantioselectivities (up to 99% ee), good diastereoselectivities (up to 20:1 dr), and high yields under mild reaction conditions. Computational insights from DFT calculations indicate that the Michael addition step is crucial in determining the reaction rate and enantioselectivity.

Highly Stereoselective Biocatalytic One-Pot Synthesis of Chiral Saturated Oxygen Heterocycles by Integration of a Biosynthetic Heterocyclase into Multiple-Enzyme Cascades

Highly Stereoselective Biocatalytic One-Pot Synthesis of Chiral Saturated Oxygen Heterocycles by Integration of a Biosynthetic Heterocyclase into Multiple-Enzyme Cascades

Dipeptidic Proline‐Derived Thiourea Organocatalysts for Asymmetric Michael addition Reactions between Aldehydes and Nitroolefins

AbstractThe enantiodivergent synthesis of syn‐Michael adducts can be easily achieved by switching the terminal proline in dipeptidic proline‐thiourea catalysts. In this study, a dipeptidic proline‐derived thiourea organocatalyst was rationally designed and facilely prepared from dipeptidic proline, a chiral diamine as a linker, and isothiocyanate. This asymmetric bifunctional catalyst for Michael addition between aldehydes and nitroolefins provided chiral 4‐nitro aldehyde adducts with yields of up to 99 %, 92 : 8 syn‐diastereoselectivity, and 97 % enantiomeric excess at room temperature.

Pd‐Monothiosquaramides: Efficient Catalysts for the Enantioselective Imine Reduction of Dihydro‐β‐Carbolines

AbstractAn efficient enantioselective synthesis of tetrahydro‐β‐carbolines (THBCs) using chiral metal‐monothiosquaramides (M–MTSQs) was planned. The in situ generated Pd/Fe‐monothiosquaramides (Pd/Fe‐MTSQs) catalysed imine reduction of dihydro‐β‐carbolines exceptionally to afford chiral THBCs with an excellent enantiomeric excess (up to 98% ee). In a catalysis study, Pd‐MTSQ 12 a (10 mol%) was found to be more efficient than Pd‐MTSQ 12 b and Fe‐MTSQs (13 a and 13 b) for enantioselective imine reduction of DHBCs 14 a–e. All the major chiral alkyl‐THBC isomers 15 a–c (90% ee, 98% ee and 95% ee, respectively) were observed with R configuration which was explained by Si face hydride attack on alkyl DHBC imines (14 a–c). Surprisingly, S configuration was perceived for the major isomers of chiral aryl‐THBCs 15 d and 15 e (95% ee and 96% ee, respectively) which was rationalized by Re face hydride attack on aryl DHBC imines (14 d and 14 e).

Construction of axially chiral 2-arylpyrroles using catalytic asymmetric Suzuki-Miyaura cross-coupling: an efficient approach to esaxerenone.

A general and efficient method has been developed to access axially chiral 2-arylpyrroles using catalytic asymmetric Suzuki-Miyaura cross-coupling. A wide range of axially chiral arylpyrroles were obtained in high yields with good to excellent enantioselectivities. The key to success is the use of a combined catalytic system involving a palladium catalyst and chiral ferrocene diphosphine ligand for achieving effective enantiocontrol. More importantly, this axially chiral CF3-substituted 2-arylpyrrole serves as a key intermediate in the preparation of the anti-hypertensive and diabetic nephropathy drug esaxerenone. It was directly asymmetrically synthesized with high enantioselectivity (92% ee). Thus, a new strategy is provided for the catalytic asymmetric synthesis of esaxerenone.

Elucidating Chiral Resolution of Aromatic Amino Acids Using Glycopeptide Selectors: A Combined Molecular Docking and Chromatographic Study.

An asymmetric synthesis is a favorable approach for obtaining enantiomerically pure substances, but racemic resolution remains an efficient strategy. This study aims to elucidate the chiral resolution of aromatic amino acids and their elution order using glycopeptides as chiral selectors through molecular docking analysis. Chiral separation experiments were conducted using Vancomycin as a chiral additive in the mobile phase (CMPA) at various concentrations, coupled with an achiral amino column as the stationary phase. The Autodock Vina 1.1.2 software was employed to perform molecular docking simulations between each enantiomer (ligand) and Vancomycin (receptor) to evaluate binding affinities, demonstrate enantiomeric resolution feasibility, and elucidate chiral recognition mechanisms. Utilizing Vancomycin as CMPA at a concentration of 1.5 mM enabled the separation of tryptophan enantiomers with a resolution of 3.98 and tyrosine enantiomers with a resolution of 2.97. However, a poor chiral resolution was observed for phenylalanine and phenylglycine. Molecular docking analysis was employed to elucidate the lack of separation and elution order for tryptophan and tyrosine enantiomers. By calculating the binding energy, docking results were found to be in good agreement with experimental findings, providing insights into the underlying mechanisms governing chiral recognition in this system and the interaction sites. This comprehensive approach clarifies the complex relationship between chiral discrimination and molecular architecture, offering valuable information for creating and improving chiral separation protocols.

Identification of efficient amine transaminase and applicability in dual transaminases cascade for synthesis of L-phosphinothricin

L-phosphinothricin (L-PPT) is the most popular broad-spectrum and highly effective herbicide. Transaminases (TAs) play a pivotal role in asymmetric synthesis of L-PPT, yet encounter the challenge of unfavorable reaction equilibrium. In this study, the novel dual transaminases cascade system (DTCS) was introduced to facilitate the synthesis of L-PPT. The specific amine transaminase BdATA, originating from Bradyrhizobium diazoefficiens ZJY088, was screened and identified. It exhibited remarkable activity, good stability, and required only 2.5 equivalents of isopropylamine to transform pyruvate effectively. By coupling BdATA with previously reported SeTA to construct the DTCS for pyruvate removal in situ, the L-PPT yield escalated from 37.37 % to 85.35 %. Three advantages of the DTCS were presented: the removal of pyruvate alleviated by-product inhibition, the use of isopropylamine reduced reliance on excess L-alanine, and no demand for expensive cofactors like NAD(P)H. It demonstrated an innovative idea for addressing the challenges associated with transaminase-mediated synthesis of L-PPT.

Green and Enantioselective Synthesis via Cascade Biotransformations: From Simple Racemic Substrates to High-Value Chiral Chemicals.

Asymmetric synthesis of chiral chemicals in high enantiomeric excess (ee) is pivotal to the pharmaceutical industry, but classic chemistry usually requires multi-step reactions, harsh conditions, and expensive chiral ligands, and sometimes suffers from unsatisfactory enantioselectivity. Enzymatic catalysis is a much greener and more enantioselective alternative, and cascade biotransformations with multi-step reactions can be performed in one pot to avoid costly intermediate isolation and minimise waste generation. One of the most attractive applications of enzymatic cascade transformations is to convert easily available simple racemic substrates into valuable functionalised chiral chemicals in high yields and ee. Here, we review the three general strategies to build up such cascade biotransformations, including enantioconvergent reaction, dynamic kinetic resolution, and destruction-and-reinstallation of chirality. Examples of cascade transformations using racemic substrates such as racemic epoxides, alcohols, hydroxy acids, etc. to produce the chiral amino alcohols, hydroxy acids, amines, and amino acids are given. The product concentration, ee, and yield, scalability, and substrate scope of these enzymatic cascades are critically reviewed. To further improve the efficiency and practical applicability of the cascades, enzyme engineering to enhance catalytic activities of the key enzymes using the latest microfluidics-based ultrahigh-throughput screening and artificial intelligence-guided directed evolution could be a useful approach.

Total Synthesis of (+)-Dixiamycin C via a Late-Stage Ni(II)-Photoredox N-Arylation of Carbazoles.

We report the asymmetric total synthesis of dixiamycin C (1) through the shrewd alliance of the naturally occurring monomer xiamycin A methyl ester (5) and its bromo derivative (31) following a late-stage Buchwald-Macmillan's C-N bond formation via a photoredox electron transfer approach with a less reactive carbazole nitrogen. The key step in the synthesis of monomer xiamycin A methyl ester (5) involves Buchwald's Pd(II)-mediated aerobic dehydrogenative C-N bond formation, Beckmann rearrangement, and ipso-acetylation of an electron-rich aromatic ring of an abietane core.

Catalytic asymmetric synthesis of meta benzene isosteres.

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents.

Preparation of a chiral hyperbranched polymer based on cinchona alkaloids and investigation of its catalytic activity in asymmetric reactions.

Cinchona alkaloid-derived sulfonamides and ester dimers containing chiral hyperbranched polymers have been successfully synthesized and applied as catalysts in asymmetric reactions. Several hyperbranched polymers derived from cinchona alkaloids, incorporating sulfonamides and esters, were synthesized through Mizoroki-Heck coupling polymerization. These polymers were subsequently applied in enantioselective Michael addition reactions. As the prepared polymers are not soluble in frequently used organic solvents, they act as efficient catalysts in the enantioselective reaction of β-ketoesters to nitroolefins, achieving up to 99% enantioselectivity with good yields. The insoluble property allows them to better satisfy "green chemistry" requirements and be used several times without losing the enantioselectivity.