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Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt‐catalyzed C−H activation/annulation strategy in high yield with excellent enantio‐ and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio‐ and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials. [ABSTRACT FROM AUTHOR]

The asymmetric synthesis of 3,4-dihydropyrimidin-2-(1H)-one thioacetals was achieved for the first time using a chiral imidodiphosphoric acid catalyst. The Biginelli reaction involving aromatic aldehydes, thiourea, and 1,3-cyclohexanedione as a multi-component reaction was conducted in ethyl acetate at 40 °C with a chiral imidodiphosphoric acid catalyst. Under mild conditions, a series of chiral polycyclic 3,4-dihydropyrimidin-2-(1H)-one thioacetals were obtained with high yields and excellent enantioselectivity (up to 99% ee). [ABSTRACT FROM AUTHOR]

Axially chiral biaryl δ‐amino acids possess significantly different conformational properties and chiral environment from centrally chiral amino acids, therefore, have drawn considerable attention in the fields of synthetic and medicinal chemistry. Herein, a novel chiral phenanthroline‐potassium catalyst has been developed by constructing a well‐organized axially chiral ligand composed of one 1,10‐phenanthroline unit and two axially chiral 1,1′‐bi‐2‐naphthol (BINOL) units. In the presence of this catalyst, good to excellent yields and enantioselectivities (up to 99 % yield, 98 : 2 er) have been achieved in the ring‐opening alcoholytic dynamic kinetic resolution of a variety of biaryl lactams, thereby providing an efficient protocol for catalytic asymmetric synthesis of unnatural axially chiral biaryl δ‐amino acid derivatives. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps (8 purifications) from L‐tryptophan. The main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center, involving the silica gel‐mediated cyclization of tryptamine‐ynamide and oxidation under neat conditions. [ABSTRACT FROM AUTHOR]

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94 % and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs. [ABSTRACT FROM AUTHOR]

An efficient organocatalytic cascade vinylogous Michael‐cyclization to construct the challenging full substituted cyclohexa‐1,3‐dienes has been developed. Catalyzed by the cinchona alkaloids‐derived thiourea VIII at −60 °C, the products were obtained as a single diastereomer with two contiguous stereocenters and more than four different useful functional groups in moderate to good yields and good to excellent enantioselectivities. [ABSTRACT FROM AUTHOR]

Piperazines constitute an important structural feature of many pharmaceuticals. For the discovery of new drugs, the ability to modify the lead compound's structure is crucial. Herein, we provide an efficient method for the synthesis of chiral 2,3,5-trisubstituted piperazine structures. Our route enables the synthesis of several novel chiral aryl aziridinyl ketones that could be converted into aziridine-fused bicyclic imines. The reduction of these imines and the nucleophilic ring-opening reaction of the aziridine ring allowed us to synthesize highly functionalized piperazine derivatives. [ABSTRACT FROM AUTHOR]

Chiral 1,2-bis(2,5-diphenylphospholano)ethane (Ph-BPE) is a class of optimal organic bisphosphine ligands with C2-symmetry. Ph-BPE with its excellent catalytic performance in asymmetric synthesis has attracted much attention of chemists with increasing popularity and is growing into one of the most commonly used organophosphorus ligands, especially in asymmetric catalysis. Over two hundred examples have been reported since 2012. This review presents how Ph-BPE is utilized in asymmetric synthesis and how powerful it is as a chiral ligand or even a catalyst in a wide range of reactions including applications in the total synthesis of bioactive molecules. [ABSTRACT FROM AUTHOR]

The isolation and catalytic enantioselective synthesis of configurationally stable S‐stereogenic sulfonium ylides have been significant challenges in the field of asymmetric synthesis. These reactive intermediates are crucial for a variety of synthetic transformations, yet their inherent tendency towards rapid inversion at the sulfur stereocenter has hindered their practical utilization. Conventional approaches have focused on strategies that incorporate a C=S bond‐containing cyclic framework to help mitigate this stereochemical lability. In this work, we present an alternative tactic that leverages the stabilizing influence of an adjacent N‐atom and cyclic sulfide moiety. Exploiting a copper catalyzed enantioselective intermolecular carbene transfer reaction, structurally diverse S‐stereogenic aminosulfonium ylides have been achieved in excellent yields and enantioselectivities. Experimental results indicate that the careful selection of 2‐diazo‐1,3‐diketone precursors is crucial for achieving optimal stereoinduction in this transformation. The resulting highly enantioenriched aminosulfonium ylides allow for further stereospecific elaborations to furnish aminosulfonium ylide oxides and sulfinamide. This work expands the boundaries of chiral sulfonium ylide chemistry, providing access to a broad range of previously elusive S‐stereogenic aminosulfonium ylide scaffolds. [ABSTRACT FROM AUTHOR]

Abstract Transition metal-catalyzed addition of organometallics to aryl(alkyl)alkynes has been well known to proceed with the regioselectivity in forming a carbon–carbon bond at the alkyl-substituted carbon (β-addition). Herein, the reverse regiochemistry with high selectivity in giving 1,1-diarylalkenes (α-addition) was realized in the reaction of arylboronic acids with aryl(alkyl)alkynes by use of a rhodium catalyst coordinated with a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The regioselectivity can be switched by the choice of ligands on the rhodium catalysts. This reverse regioselectivity also enabled the catalytic asymmetric synthesis of phoenix-like axially chiral alkylidene dihydroanthracenes with high enantioselectivity through an α-addition/1,4-migration/cyclization sequence.

Abstract β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds. However, their chemical or enzymatic synthesis is challenging due to the presence of two stereocenters. We design phenylalanine ammonia lyases (PAL) variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids. Based on extensive computational analyses, we unravel the enigma behind PAL’s inability to accept β-methyl cinnamic acid (β-MeCA) as substrate and achieve the synthesis of the corresponding amino acids of β-MeCA and analogs using a double (PcPAL-L256V-I460V) and a triple mutant (PcPAL-F137V-L256V-I460V). The reactions are scaled-up using an optimized E. coli based whole-cell biotransformation system to produce ten β-branched phenylalanine analogs with high diastereoselectivity (dr > 20:1) and enantioselectivity (ee > 99.5%) in yields ranging from 41-71%. Moreover, we decipher the mechanism of PcPAL-L256V-I460V for the acceptance of β-MeCA and converting it with excellent stereoselectivity by computational simulations. Thus, this study offers an efficient method for synthesizing β-branched aromatic α-amino acids.

Chiral hydroxamic acid (HA) and bis-hydroxamic acid (BHA) ligands have made significant contributions to the field of asymmetric synthesis, particularly in the synthesis of natural products. These ligands possess unique molecular structures that allow for exceptional stereochemical control, leading to their widespread use in catalytic systems. This review highlights the advancements made in asymmetric synthesis using chiral hydroxamic acid and bis-hydroxamic acid ligands and their impact on the synthesis of complex natural products. This discussion encompasses their role in enantioselective C–C bond formation, the functionalization of C–H bonds, the asymmetric transformations involving heteroatoms, and their application in the total synthesis of natural products. The versatility and efficiency of chiral hydroxamic acid ligands and bis-hydroxamic acid ligands make them invaluable tools for synthetic chemists working towards the efficient and selective synthesis of natural products. This review provides a comprehensive overview of their contributions, showcasing their potential to expand the boundaries of chemical synthesis and access the diverse array of natural product scaffolds.

A stereoselective Biginelli reaction involving a CH‐active podand, thiourea, and benzaldehyde was carried out using C2‐symmetric bis(hydroxy)proline‐containing amides as chiral inducers. The target dihydropyrimidinethione‐containing podand was obtained with an enantiomeric excess of 65–75 % and a yield of 58 % under mild conditions. It was established that in the process of asymmetric induction the value of ee depended on the presence of OH group in the proline fragment and of the linker structure in the chiral inducer molecule, in particular, on the presence of asymmetric carbon atoms and the movability of the single bond between them in the linker itself. Based on experimental data, one of the probable reaction mechanisms confirming the special role of the L‐proline or trans‐4‐hydroxyproline fragments in asymmetric induction has been proposed. The developed technique for obtaining an active tuberculostatic agent expands the possibilities for using C2‐symmetric chiral inducers in asymmetric catalysis and is of interest for the synthesis of enantiomerically pure compounds of similar structure. [ABSTRACT FROM AUTHOR]

An efficient N‐heterocyclic carbene (NHC)‐catalyzed kinetic resolution of 2‐substituted 3‐nitro‐1,2‐dihydroquinolines (DHQs) allowing the synthesis of densely functionalized enantioenriched tetrahydroquinolines through the resolution at remote stereocenter is described. The Re‐face addition of α,β‐unsaturated azolium homoenolate intermediate generated in situ from enal with the more kinetically favored (S)‐enantiomer of the racemic 2‐substituted 3‐nitro‐1,2‐dihydroquinolines (rac‐1), affording the enantiopure tetrahydroquinolines (up to >99 : 1 dr, >99 : 1 er) and the opposite (R)‐enantiomer of DHQ (ent‐1) was recovered (up to >99 : 1 er). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Five- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied. 1 Introduction 2 Catalyst-Controlled Cα –H Functionalization (Approach a) 3 Decarboxylative α-AAA Reactions (Approach b) 4 Cα –X Substitution Reactions (Approach c) 5 De Novo Synthesis from Acyclic Precursors (Approach d) 6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e) 7 Kinetic Resolution and Deracemization (Approach f) 8 Conclusions [ABSTRACT FROM AUTHOR]

This research Account describes the development of chiral organocatalysts, focusing on diphenyl-2-pyrrolidinemethanol and its derivatives as valuable tools in asymmetric transformations. The research also includes the discovery of a novel anionic Si→C alkyl migration method, which has been developed into a one-pot procedure for synthesizing (E)-chalcones from hydroxyamide and N , N -diethylcarbamates. The findings underscore the potential of sulfide and silicon as valuable reagents for organic synthesis and emphasize the importance of exploring new reaction pathways and mechanisms to discover novel synthetic methods. 1 Introduction 2 Synthesis of 2 and Sulfur Reagent as Chiral Lewis Acid 3 Sulfur/Selenium Reagent as Chiral Lewis Base 4 Anionic Si→C Alkyl Migration 5 Conclusion [ABSTRACT FROM AUTHOR]

Transaminase‐catalysed asymmetric amination is a valuable transformation for the synthesis of chiral amines. However, its use in synthetic chemistry has been curtailed by a narrow substrate scope and limited information on commercially available catalysts. In this work we have explored the substrate scope of selected commercially available transaminases, focusing on prochiral ketones bearing two bulky substituents and their application in both enzyme‐catalysed and enzyme‐triggered reactions. (R)‐ and/or (S)‐selective enzymes converted methyl‐, isopropyl‐, n‐butyl‐, and cyclohexyl‐phenone substrates to the corresponding amines in the range of 6–>99 % ee. In some cases, a stereochemical switch was detected, in which (R)‐enantioselectivity was observed with enzymes typically assigned as (S)‐selective. Upscaling of selected biotransformations provided chiral amines, in >99 % ee and up to 40 % isolated yield. Furthermore, transaminase‐triggered reactions, which were previously limited to methyl‐ and ethyl‐derivatives, were expanded to phenyl‐derivatives for the formation of a cis‐2,6‐disubstituted piperidine and 2,4‐diphenyl pyrroline, and isolated in up to 67 % yield. [ABSTRACT FROM AUTHOR]

A synthetic method for preparation of optically active trifluoromethylthio (SCF3) compounds by a copper‐catalyzed regio‐ and enantioselective hydroboration of 1‐trifluoromethylthioalkenes with H‐Bpin has been developed. The enantioselective hydrocupration of an in situ generated CuH species and subsequent boration reaction generate a chiral SCF3‐containing alkylboronate, of which Bpin moiety can be further transformed to deliver various optically active SCF3 molecules. Computational studies suggest that the SCF3 group successfully controls the regioselectivity in the reaction. [ABSTRACT FROM AUTHOR]

Atropisomers have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N−N biaryl atropisomers have drawn increasing interest due to their unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well‐developed C−C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N−N biaryl atropisomers including N−N pyrrole−pyrrole, N−N pyrrole−indole, N−N indole−indole, and N−N indole−carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N−N biaryl atropisomers synthesis is offered. [ABSTRACT FROM AUTHOR]

Spirocyclic compounds have always attracted attention due to their presence as a structural core in a wide variety of natural and bioactive molecules and to exhibit pharmaceutical properties. An asymmetric synthesis of spiro[indoline‐3,4′‐pyrano[2,3‐c]pyrazoles] via Michael addition of trifluoromethyl substituted pyrazolone to isatylidene ethyl cyanoacetate derivatives was conducted with excellent enantioselectivities up to 99 % and up to 97 % isolated yield at room temperature with using 2 mol % of bifunctional quinine derived squaramide organocatalysts. [ABSTRACT FROM AUTHOR]

The asymmetric synthesis of polyunsaturated triene C18:3 n-3 and C18:3 n-6 methoxylated ether lipids (MEL) of the 1-O-alkyl-sn-glycerol type is described as possible structural candidates for a triene C18:3 MEL of an unknown identity found in a mixture of shark and dogfish liver oil. Their C18:3 hydrocarbon chains constitute an all-cis methylene skipped n-3 or n-6 triene framework, along with a methoxyl group at the 2′-position and R-configuration of the resulting stereogenic center. The methoxylated polyenes are attached by an ether linkage to the pro-S hydroxymethyl group of the glycerol backbone. The syntheses were based on the polyacetylene approach that involves a semi-hydrogenation of the resulting triynes. Both syntheses were started from our previously described enantio- and diastereomerically pure isopropylidene-protected glyceryl glycidyl ether, a double-C3 building block that was designed as a head group synthon for the synthesis of various types of MELs. [ABSTRACT FROM AUTHOR]

Hydroxynitrile lyases (HNLs) primarily catalyze the stereoselective synthesis of cyanohydrins, but some of them also carry out asymmetric nitroaldol synthesis (Henry reaction). By virtue of the importance of asymmetric C−C bond formation, and the wide application of chiral cyanohydrins and β‐nitroalcohols, HNLs have gained significance in organic synthesis. Over the years new HNLs have been discovered and their synthetic scope are evaluated. Engineering of HNLs has contributed towards increasing not only the catalytic toolbox but also broad substrate selectivity, stereoselectivity, enzyme stability, and application of the enzymes for different transformations other than the conventional ones. This review describes the recent discoveries of diverse hydroxynitrile lyases (HNLs) and the developments to date since 2016, with respect to their biocatalytic applications in the asymmetric synthesis using both natural and promiscuous reactions. [ABSTRACT FROM AUTHOR]

Chiral trisubstituted vicinal diols are a type of important organic compounds, serving as both common structure units in bioactive natural products and chiral auxiliaries in asymmetric synthesis. Herein, by using siloxypropadienes as the precursors of allyl copper(I) species, a copper(I)‐catalyzed diastereoselective and enantioselective reductive allylation of ketones was achieved, providing both syn‐diols and anti‐diols in good to excellent enantioselectivity. DFT calculations show that cis‐γ‐siloxy‐allyl copper species are generated favorably with either 1‐TBSO‐propadiene or 1‐TIPSO‐propadiene. Moreover, the steric difference of TBS group and TIPS group distinguishes the face selectivity of acetophenone, leading to syn‐selectivity for 1‐TBSO‐propadiene and anti‐selectivity for 1‐TIPSO‐propadiene. Easy transformations of the products were performed, demonstrating the synthetic utility of the present method. Moreover, one chiral diol prepared in the above transformations was used as a suitable organocatalyst for the catalytic asymmetric reductive self‐coupling of aldimines generated in situ with B2(neo)2. [ABSTRACT FROM AUTHOR]

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future. [ABSTRACT FROM AUTHOR]

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression. [ABSTRACT FROM AUTHOR]

Benzofuran‐ and benzopyran‐fused polycyclic acetals are found in a variety of biologically active natural products. The synthetic methods toward this class of polycyclic heterocycles have fascinated one of the most intensive pursuits in total synthesis. Nevertheless, stereoselective methods towards the rapid construction of such skeletons still remain challenging for organic chemists. Significant progress has been made in this research area in recent years, however, literature on enantioselective approaches to construct these molecules has not fully reviewed. Driven by their intriguing and complex scaffolds with potential usefulness, we compose the recent advances in this review covering all the important works in this field. We hope this review will promote future research in this area. [ABSTRACT FROM AUTHOR]