Cationic Foldamer-Catalyzed Asymmetric Synthesis of Inherently Chiral Cages.

The stereochemistry of shape-persistent molecular cages, particularly those resembling prisms, exerts significant influence on their application-specific functionalities. Although methods exist for fabricating inherently chiral prism-like cages, strategies for catalytic asymmetric synthesis of these structures in a diversity-oriented fashion remain unexplored. Herein, we introduce an unprecedented organocatalytic desymmetrization approach for the generation of inherently chiral prism-like cages via phosphonium-containing foldamer-catalyzed SNAr reactions. This methodology establishes a topological connection, enabling the facile assembly of a wide range of versatile stereogenic-at-cage building blocks possessing two highly modifiable groups. Furthermore, subsequent stereospecific transformations of the remaining chlorides and/or ethers afford convenient access to numerous functionally relevant chiral-at-cage molecules.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers.

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

Asymmetric Synthesis and Applications of Chiral Organoselenium Compounds: A Review.

The synthesis and application of organoselenium compounds have developed rapidly, and chiral organoselenium compounds have become an important intermediate in the field of medicine, materials, organic synthesis. The strategy of developing a green economy is still a challenge in the synthesis of chiral organoselenium compounds with enantioselective properties. This review covers in detail the synthesis of chiral organoselenium compounds from 1979 to 2024 and their application in the fields of asymmetric synthesis and catalysis.

A Single Enzyme in Enantiocomplementary Synthesis of ß-Nitroalcohols: Bidirectional Catalysis by Hydroxynitrile Lyase.

A single enzyme, Baliospermum montanum hydroxynitrile lyase (BmHNL), without alteration, enabled bidirectional catalysis in enantiocomplementary synthesis of chiral ß-nitroalcohols. BmHNL catalyzed promiscuous Henry (24 examples) and retro-Henry reaction (22 examples) provided up to >99% and 50% conversion to (S)- and (R)-ß-nitroalcohols respectively, while both cases displayed up to >99% ee. The broad substrate scope and high stereoselectivity of BmHNL represents its synthetic applications in sustainable production of diverse chiral ß-nitroalcohols. Kinetic parameters of BmHNL was determined for Henry and retro-Henry reaction, which reveals poor catalytic efficiency for both the promiscuous transformations, however, the former has better efficiency than the latter. Practical applicability of the biocatalyst and transformation was illustrated by preparative scale synthesis of chiral intermediates of (S)-Tembamide, and (S)-Micanozole.

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 useful approaches.

Combining binding pocket mutagenesis and substrate tunnel engineering to improve an (R)-selective transaminase for the efficient synthesis of (R)-3-aminobutanol.

(R)-selective transaminases have the potential to act as efficient biocatalysts for the synthesis of important pharmaceutical intermediates. However, their low catalytic efficiency and unfavorable equilibrium limit their industrial application. Seven (R)-selective transaminases were identified using homologous sequence mining. Beginning with the optimal candidate from Mycolicibacterium hippocampi, virtual mutagenesis and substrate tunnel engineering were performed to improve catalytic efficiency. The obtained variant, T282S/Q137E, exhibited 3.68-fold greater catalytic efficiency (kcat/Km) than the wild-type enzyme. Using substrate fed-batch and air sweeping processes, effective conversion of 100 mM 4-hydroxy-2-butanone was achieved with a conversion rate of 93 % and an ee value > 99.9 %. This study provides a basis for mutation of (R)-selective transaminases and offers an efficient biocatalytic process for the asymmetric synthesis of (R)-3-aminobutanol.

Chemodivergent Parallel Kinetic Resolution of Paracyclophanes: Enantiomer Fishing with Different Substrates.

An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N-heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio- and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.

Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C-H bond activation.

The development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of C(sp 3)-H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon-carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity. The compatibility with bioactive motifs and expedient synthesis of pharmaceutically relevant molecules highlight the synthetic potential of this protocol.

Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions.

The Petasis reaction is a multicomponent reaction of aldehydes, amines and organoboron reagents and is a useful method for the construction of substituted amines. Despite the significant advancement of the Petasis reaction since its invention in 1993, strategies for asymmetric and non-directed Petasis reactions remain limited. To date, there are very few catalytic asymmetric Petasis reactions and almost all asymmetric reports employ a chiral auxiliary. Likewise, the aldehyde component often requires a directing group, ultimately limiting the reaction's scope. In this Concept, key methods for asymmetric and non-directed Petasis reactions are discussed, focusing on how these conceptual advances can be applied to solve long-standing gaps in the Petasis literature.

Enantioselective Arylation of Sulfenamides to Access Sulfilimines Enabled by Palladium Catalysis.

Sulfur-containing functional groups have garnered considerable attention due to their common occurrence in ligands, pharmaceuticals, and insecticides. Nevertheless, enantioselective synthesis of sulfilimines, particularly diaryl sulfilimines remains a challenging and persistent goal. Herein we report a highly enantio- and chemoselective cross-coupling of sulfenamides with aryl diazonium salt to construct diverse S(IV) stereocenters by Pd catalysis. Bisphosphine ligands bearing sulfinamide groups play a crucial role in achieving high reactivity and selectivity. This approach provides a general, modular and divergent framework for quickly synthesizing chiral sulfilimines and sulfoximines that are otherwise challenging to access. In addition, the origins of the high chemoselectivity and enantioselectivity were extensively investigated using density functional theory calculations.

Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1H-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.

A new series of chiral 4,5-dihydro-1H-[1,2,4]-triazoline molecules, featuring a ß-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (8a-j) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative 8b provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the (S)-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative 8c showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.

Sequence-Guided Redesign of an Omega-Transaminase from Bacillus megaterium for the Asymmetric Synthesis of Chiral Amines.

ω-Transaminases (ω-TAs) are attractive biocatalysts asymmetrically catalyzing ketones to chiral amines. However, poor non-native catalytic activity and substrate promiscuity severely hamper its wide application in industrial production. Protein engineering efforts have generally focused on reshaping the substrate-binding pockets of ω-TAs. However, hotspots around the substrate tunnel as well as distant sites outside the pockets may also affect its activity. In this study, the ω-TA from Bacillus megaterium (BmeTA) was selected for engineering. The tunnel mutation Y164F synergy with distant mutation A245T which was acquired through a multiple sequence alignment showed improved soluble expression, a 3.7-fold higher specific activity and a 19.9-fold longer half-life at 45 °C. Molecule Dynamics simulation explains the mechanism of improved catalytic activity, enhanced thermostability and improved soluble expression of BmeTAY164F/A245T(2 M). Finally, the resting cells of 2 M were used for biocatalytic processes. 450 mM of S-methoxyisopropylamine (S-MOIPA) was obtained with an ee value of 97.3 % and a conversion rate of 90 %, laying the foundation for its industrial production. Mutant 2 M was also found to be more advantageous in catalyzing the transamination of various ketones. These results demonstrated that sites that are far away from the active center also play an important role in the redesign of ω-TAs.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery.

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 108 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 1060 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity. A beacon of this progressive wave is Asymmetric Carbene Transfer (ACT), a burgeoning strategy that significantly boosts molecular diversity with efficient bond-formation and precise chiral control. This review focuses on the capabilities of ACT in creating pharmaceutically significant molecules, encompassing an array of natural products and bioactive compounds. Through the lens of ACT, we discern its substantial influence on drug discovery, paving the way for novel therapeutic avenues by expanding the boundaries of molecular diversity. This review will shed light on prospective methodological developments of ACT and articulate their conceivable contributions to the medicinal chemistry arena.

Total Synthesis of Lissodendoric Acid A.

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Desymmetrization of Cyclic Sulfonimidamides by Asymmetric Allylation.

Herein we report the first transition metal-catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High-throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2-substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity.

Enantioselective synthesis, characterization, molecular docking simulation and ADMET profiling of α-alkylated carbonyl compounds as antimicrobial agents.

All living organisms produce only one enantiomer, so we found that all natural compounds are presented in enantiomerically pure form. Asymmetric synthesis is highly spread in medicinal chemistry because enantiomerically pure drugs are highly applicable. This study initially demonstrated the feasibility of a good idea for the asymmetric synthesis of α-alkylated carbonyl compounds with high enantiomeric purity ranging from 91 to 94% using different quinazolinone derivatives. The structure of all compounds was confirmed via elemental analysis and different spectroscopic data and the enantioselectivity was determined via HPLC using silica gel column. The synthesized compounds' mode of action was investigated using molecular docking against the outer membrane protein A (OMPA) and exo-1,3-beta-glucanase, with interpreting their pharmacokinetics aspects. The results of the antimicrobial effectiveness of these compounds revealed that compound 6a has a broad biocidal activity and this in-vitro study was in line with the in-silico results. Overall, the formulated compound 6a can be employed as antimicrobial agent without any toxicity with high bioavailability in medical applications.

Asymmetric Synthesis of Three Alkenyl Epoxides: Crafting the Sex Pheromones of the Elm Spanworm and the Painted Apple Moth.

A concise synthesis of the sex pheromones of elm spanworm as well as painted apple moth has been achieved. The key steps were the alkylation of acetylide ion, Sharpless asymmetric epoxidation and Brown's P2-Ni reduction. This approach provided the sex pheromone of the elm spanworm (1) in 31% total yield and those of the painted apple moth (2, 3) in 26% and 32% total yields. The ee values of three final products were up to 99%. The synthesized pheromones hold promising potential for use in the management and control of these pests.

Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis.

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.

Chemoenzymatic Synthesis of ABC-Type Enantiostructured Triacylglycerols by the Use of the p-Methoxybenzyl Protective Group.

This report demonstrates the first asymmetric synthesis of enantiopure structured triacylglycerols (TAGs) of the ABC type presenting three non-identical fatty acids, two of which are unsaturated. The unsaturated fatty acids included monounsaturated oleic acid (C18:1 n-9) and polyunsaturated linoleic acid (C18:2 n-6). This was accomplished by a six-step chemoenzymatic approach starting from (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The synthesis also benefited from the use of the p-methoxybenzyl (PMB) ether protective group, which enabled the incorporation of two different unsaturated fatty acids into the glycerol skeleton. The total of six such TAGs were prepared, four constituting the unsaturated fatty acids in the sn-1 and sn-2 positions, with a saturated fatty acid in the remaining sn-3 position of the glycerol backbone. In the two remaining TAGs, the different unsaturated fatty acids accommodated the sn-1 and sn-3 end positions, with the saturated fatty acid present in the sn-2 position. Enantiopure TAGs are urgently demanded as standards for the enantiospecific analysis of intact TAGs in fats and oils.