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The catalytic decarboxylation of malonic acid half oxy‐ and thioesters, β‐ketocarboxylic acids, and their related compounds is a straightforward, powerful, and atom‐economical strategy for the in‐situ formation of enolates, which are important and well‐studied synthons for various functional materials and natural products. This strategy, inspired by the biosynthesis of polyketides and fatty acids, is an attractive method for synthesizing enols from carboxyl compounds with less reactive α‐hydrogen atoms under mild conditions. In addition, these reactions are environmentally friendly and are of great interest to chemists because the use of a stoichiometric amount of base can be avoided, and the only byproduct is CO2. Thus far, remarkable progress has been made, especially in the field of organocatalytic enantioselective decarboxylation reactions, allowing for the stereocontrolled formation of new C−H, C−C, C−heteroatom, and C−X bonds. This review provides a comprehensive overview of organocatalytic enantioselective decarboxylation reactions and highlights the significant progress made since 2020. In particular, it focuses on chiral catalyst systems and transition states as key parameters for decarboxylation reactions. [ABSTRACT FROM AUTHOR]

This review highlights the use of DACH as a versatile ligand in catalytic asymmetric transformations providing mechanistic rationales and relevant comments presented in chronological order for each of the 21 reaction types with references up to December 25, 2023. Intended to be as practically comprehensive as possible, this review assembles useful examples of using DACH as a ligand in organocatalytic or as metal complexes in asymmetric transformations. The resulting enantiomerically enriched, if not pure, chiral non-racemic small molecules are of great utility as value added intermediates in the total synthesis of natural products, in the design and synthesis of medicinally important compounds, and in other areas in organic and bioorganic chemistry where chirality plays a role. The graphic image depicts Spartacus with his arms folded in the same sense of chirality as (R , R)-DACH. 1 Introduction 2 DACH: A Brief Historical Narrative 3 Catalytic Asymmetric Hydrogenation of Alkenes 4 Catalytic Asymmetric Dihydroxylation of Alkenes 5 Catalytic Asymmetric Sulfoxidation and Sulfimidation 6 Catalytic Asymmetric 1,4-Conjugate Addition 6.1 Using Jacobsen's DACH Metal–salen Complexes as Catalysts 6.2 Using Takemoto's Bifunctional H-Bonding DACH Thiourea Organocatalyst 6.3 Using DACH Ni(II) Complexes as Catalysts 6.4 Using DACH H-Bonding Catalysis 7 Catalytic Asymmetric Epoxidation of Alkenes 8 Catalytic Asymmetric Claisen Rearrangement 9 Catalytic Asymmetric 1,2-Nucleophilic Addition to Carbonyl Compounds 9.1 Catalytic Asymmetric Addition of Dialkylzinc to Aldehydes and Ketones 9.2 Catalytic Asymmetric Alkynylation of Aldehydes and Ketones 9.3 Catalytic Asymmetric Addition of Cyanide to Aldehydes and Ketones 10 Catalytic Asymmetric Allylic Alkylation 11 Catalytic Asymmetric Cyclopropanation of Alkenes 12 Catalytic Asymmetric Cycloaddition Reactions 13 Catalytic Asymmetric Aziridination of Alkenes 14 Catalytic Asymmetric Hydrogenation of Prochiral Ketones and Imines 15 Catalytic Asymmetric Aldol Reactions 16 Catalytic Asymmetric Opening of Small Ring Systems 16.1 Desymmetrization of meso -Epoxides and meso -Aziridines 16.2 Kinetic Resolution of Racemic Epoxides 16.3 Enantioselective Addition of CO2 to Epoxides 16.4 Enantioselective Ring Opening of Oxetanes 17 Catalytic Asymmetric Strecker Reactions 18 Catalytic Asymmetric Mannich Reactions 19 Catalytic Asymmetric Henry and Aza-Henry Reactions 20 Catalytic Asymmetric Morita–Baylis–Hillman and Rauhut–Currier Reactions 21 Catalytic Asymmetric Petasis Reactions 22 Organocatalytic Asymmetric Cascade Reactions 23 Miscellaneous Catalytic Reactions 24 Conclusion and Outlook 25 DACH Catalysts and Ligands List [ABSTRACT FROM AUTHOR]

The asymmetric [3+2] cycloaddition of azomethine ylides generated from the corresponding imino ester-to-trans-β-nitrostyrene catalysis by chiral aziridine-containing phosphines and phosphine oxides is described. Of the sixteen stereoisomers that could be formed as a result of the title reaction, three were formed, two of which were obtained in an enantiomerically enriched or pure form, and one in a racemic form. One of the products underwent epimerization under basic reaction conditions. [ABSTRACT FROM AUTHOR]

In the quest for the more rapid and eco‐compatible preparation of complex molecules from widely available ones, borrowing hydrogen is one of the most elegant manners to directly functionalize alcohols. Such catalytic cycles reduce the synthetic cost, and avoid waste and additional steps associated with adjusting the redox state for the functionalization of carbon chains. In this field, the last ten years have seen the development of general strategies to control the absolute stereochemistry of the created molecules. This enantiocontrol can arise from the three distinct steps of the catalytic cycle, namely the initial dehydrogenation, carbonyl functionalization or final hydrogen back‐transfer. This review presents the different enantioselective approaches developed according to these principles and highlights the great potential of these transformations, the current limitations and future challenges. [ABSTRACT FROM AUTHOR]

The Lichen moth, Lyclene dharma dharma (Arctiidae, Lithosiinae), plays a significant role in forest ecosystem dynamics. A concise and novel method to synthesize the active sex pheromone components, (S)-14-methyloctadecan-2-one ((S)-1), (S)-6-methyloctadecan-2-one ((S)-2), and their enantiomers has been developed. Key steps in the synthesis include the use of Evans' chiral auxiliaries, Grignard cross-coupling reactions, hydroboration–oxidation, and Wacker oxidation. The synthesized sex pheromone components hold potential value for studies on communication mechanisms, species identification, and ecological management. [ABSTRACT FROM AUTHOR]

Chiral mono- and bis-(thio)urea supramolecular organocatalysts were studied in the enantioselective vinylogous addition reaction of 2-trimethylsilyloxyfuran (TMSOF) to carbonylic compounds; the corresponding chiral γ-hydroxymethyl-butenolides are obtained in good yields and with high enantiomeric excesses. The catalyst structure, as well as the reaction conditions, strongly influence the efficiency of the reaction. The conformational features of mono(thio)urea catalysts 2 and 3 and bis(thio)urea catalysts 7 and 8 were investigated by DFT calculations along with the structure of their complexes with benzaldehyde. Natural Bond Orbital (NBO) and Non-Covalent Interaction (NCI) calculations provided useful information concerning the activating H-bonding interactions in the complexes. [ABSTRACT FROM AUTHOR]

This research showcases a methodology for crafting highly intricate hydrocarbazole spirooxindole frameworks endowed with three consecutive stereocenters. Achieved through a trienamine‐catalyzed remote [4+2]‐annulation reaction, the method's significance is underscored by synthesizing an extensive array of library molecules (up to 27 examples). These compounds mimic natural products, exhibit good yields (up to 85 %), exceptional diastereo‐, enantiomeric ratios (up to 17 : 1 dr, 99.9 : 0.1 er). The practicality of our strategy is further exemplified by successfully synthesizing a hexahydroepoxyethanocarbazole spirooxindole scaffold via a sequential [4+2]‐annulation/‐reduction/epoxidation‐cyclization reaction, achieving a 75 % overall yield, maintaining an excellent stereoselectivity (99.5 : 0.5 er). [ABSTRACT FROM AUTHOR]

Springtails use unique compounds for their outermost epicuticular wax layer, often of terpenoid origin. We report here the structure and synthesis of socialane, the major cuticular constituent of the Collembola Hypogastrura socialis. Socialane is also the first regular nonaprenyl terpene with a cyclic head group. The saturated side chain has seven stereogenic centers, making the determination of the configuration difficult. We describe here the identification of socialane and a synthetic approach using the building blocks farnesol and phytol, enantioselective hydrogenation, and α‐alkylation of sulfones for the synthesis of various stereoisomers. NMR experiments showed the presence of an anti‐configuration of the methyl groups closest to the benzene ring and that the other methyl groups of the polyprenyl side‐chain are not uniformly configured. Furthermore, socialane is structurally different from [6+2]‐terpene viaticene of the closely related H. viatica, showing species specificity of the epicuticular lipids of this genus and hinting at a possible role of surface lipids in the communication of these gregarious arthropods. [ABSTRACT FROM AUTHOR]

Chiral mono- and bis-(thio)urea supramolecular organocatalysts were studied in the enantioselective vinylogous addition reaction of 2-trimethylsilyloxyfuran (TMSOF) to carbonylic compounds; the corresponding chiral γ-hydroxymethyl-butenolides are obtained in good yields and with high enantiomeric excesses. The catalyst structure, as well as the reaction conditions, strongly influence the efficiency of the reaction. The conformational features of mono(thio)urea catalysts 2 and 3 and bis(thio)urea catalysts 7 and 8 were investigated by DFT calculations along with the structure of their complexes with benzaldehyde. Natural Bond Orbital (NBO) and Non-Covalent Interaction (NCI) calculations provided useful information concerning the activating H-bonding interactions in the complexes.

Enantioselective synthesis, which yields one enantiomer in higher concentration or purity than the other, has transformed the production of flavonoids. Flavonoids, which are found in large quantities in nature and are known to exhibit a diverse array of physiological activities, are an ideal choice for enantioselective synthesis due to the significance of chirality in their therapeutic effects. Enantioselective synthesis is used in the medicinal, nutraceutical, and agrochemical sectors to produce flavonoids, which are useful in the development of novel therapeutics with improved effectiveness and fewer adverse reactions. The ability to obtain specific enantiomers of flavonoids facilitates the elucidation of biochemical strategies and the relationship between structure and activity, thereby providing avenues for tailored drug design and optimization. This review highlights the critical role that enantioselective synthesis plays in achieving the full potential of flavonoids for a variety of therapeutic and non‐therapeutic applications. It also discusses the challenges and prospects of enantioselective syntheses to create relevant classes of flavonoid monomers, emphasizing their applications in the field. The review focused on the synthetic methods for fabricating native flavonoids and their analogs, highlighting the critical role that enantioselective synthesis of flavonoids plays in maximizing their therapeutic potential for enhancing human health and wellbeing. [ABSTRACT FROM AUTHOR]

Trifluoro‐ and trichloroacetamides serving as pronucleophiles undergo enantioselective Lewis base catalyzed N‐allylation with Morita‐Baylis‐Hillman carbonates to produce enantioenriched β‐amino acid derivatives. The reactions proceed as a kinetic resolution to give the allylation products and the remaining carbonates in good yields and high enantioselectivity. The obtained products are amenable to diastereoselective derivatization to produce a library of spiro‐isoxazoline lactams. [ABSTRACT FROM AUTHOR]

We report herein a chiral CpXRh(III)‐catalyzed domino cyclization/C3‐arylation process using 2‐alkynylanilines and 1‐diazonaphthoquinones as viable substrates, delivering indole‐based derivatives endowed with axial chirality. The method features high enantioselectivity, broad substrate scope, and robust functional group tolerance. Subsequent functionalization of the synthesized scaffolds underlines the practicality of this approach in the design of indole‐derivated axially chiral frameworks, demonstrating its substantial promise in synthetic and medicinal chemistry applications. [ABSTRACT FROM AUTHOR]

This article explores the synthesis of (-)-Catharanthine, a compound used in the production of anticancer drugs. The authors focus on the use of enzyme catalysts in the synthesis process, highlighting the potential of biocatalysts in environmentally friendly organic syntheses. They describe a method for synthesizing a chiral isoquinuclidine using an enzyme catalyst, which could be used to produce a key intermediate for (-)-Catharanthine synthesis. The researchers successfully obtained a chiral amino alcohol with high enantioselectivity and yield, which they used to synthesize (-)-Catharanthine. Ongoing studies in the laboratory aim to develop synthetic strategies for other natural products with complex chiral ring systems. [Extracted from the article]

Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)‐catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7‐membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee). [ABSTRACT FROM AUTHOR]

(Difluoromethylated cyclopropane represents an important motif, which is widely found in bioactive and functional molecules. Despite significant progress in modern chemistry, the atom‐economic and enantioselective synthesis of difluoromethylated cyclopropanes is still challenging. Herein, an Rh2(II)‐catalyzed asymmetric enyne cycloisomerization is described to construct chiral difluoromethylated cyclopropane derivatives with up to 99% yield and 99% ee in low catalyst loading (0.2 mol%), which can be easily transformed into highly functionalized difluoromethylated cyclopropanes with vicinal all‐carbon quaternary stereocenters by ozonolysis. Mechanistic studies and the crystal structures of alkyne‐dirhodium complexes reveal that the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst may play key roles in this reaction.) [ABSTRACT FROM AUTHOR]

σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer's disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown. [ABSTRACT FROM AUTHOR]

The rational combination of two catalysts to expedite the construction of chiral complex biologically and pharmacologically relevant chiral compounds has widely gained momentum over the past decade. In particular, enamine or iminium catalysis ensuing from the activation of aldehyde or ketone by chiral amine catalysts in conjugation with other organocatalytic cycles has facilitated several asymmetric transformations to yield the enantioenriched products. Regardless of the considerable discussion on the various dual catalytic approaches, literature lacks a comprehensive review focusing on the enamine and iminium‐based dual organocatalytic systems. Thus, this review article has discussed the noteworthy achievements in the field of asymmetric catalysis and synthesis catalyzed by the enamine and iminium‐based dual organocatalytic systems. [ABSTRACT FROM AUTHOR]

Enantioselective catalysis is of crucial importance in modern chemistry and pharmaceutical science. Although various concepts have been used for the development of enantioselective catalysts to obtain highly pure chiral compounds, most of them are based on homogeneous catalytic systems. Recently, we successfully developed nanostructured metal layers imprinted with chiral information, which were applied as electrocatalysts for the enantioselective synthesis of chiral model compounds. However, so far such materials have not been employed as heterogeneous catalysts for the enantioselective synthesis of real pharmaceutical products. In this contribution, we report the asymmetric synthesis of chiral pharmaceuticals (CPs) with chiral imprinted Pt−Ir surfaces as a simple hydrogenation catalyst. By fine‐tuning the experimental parameters, a very high enantioselectivity (up to 95 % enantiomeric excess) with good catalyst stability can be achieved. The designed materials were also successfully used as catalytically active stationary phases for the continuous asymmetric flow synthesis of pharmaceutical compounds. This illustrates the possibility of producing real chiral pharmaceuticals at such nanostructured metal surfaces for the first time. [ABSTRACT FROM AUTHOR]

Enantiomerically enriched five‐ and six‐membered benzo oxygen heterocycles are privileged architectures in functional organic molecules. Over the last several years, many effective methods have been established to access these compounds. However, comprehensive documents cover updated methodologies still in highly demand. In this review, recent transition metal catalyzed transformations lead to chiral five‐ and six‐membered benzo oxygen heterocycles are presented. The mechanism and chirality transfer or control processes are also discussed in details. [ABSTRACT FROM AUTHOR]

Abstract (Difluoromethylated cyclopropane represents an important motif, which is widely found in bioactive and functional molecules. Despite significant progress in modern chemistry, the atom‐economic and enantioselective synthesis of difluoromethylated cyclopropanes is still challenging. Herein, an Rh2(II)‐catalyzed asymmetric enyne cycloisomerization is described to construct chiral difluoromethylated cyclopropane derivatives with up to 99% yield and 99% ee in low catalyst loading (0.2 mol%), which can be easily transformed into highly functionalized difluoromethylated cyclopropanes with vicinal all‐carbon quaternary stereocenters by ozonolysis. Mechanistic studies and the crystal structures of alkyne‐dirhodium complexes reveal that the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst may play key roles in this reaction.)

The asymmetric [3+2] cycloaddition of azomethine ylides generated from the corresponding imino ester-to-trans-β-nitrostyrene catalysis by chiral aziridine-containing phosphines and phosphine oxides is described. Of the sixteen stereoisomers that could be formed as a result of the title reaction, three were formed, two of which were obtained in an enantiomerically enriched or pure form, and one in a racemic form. One of the products underwent epimerization under basic reaction conditions.

The Lichen moth, Lyclene dharma dharma (Arctiidae, Lithosiinae), plays a significant role in forest ecosystem dynamics. A concise and novel method to synthesize the active sex pheromone components, (S)-14-methyloctadecan-2-one ((S)-1), (S)-6-methyloctadecan-2-one ((S)-2), and their enantiomers has been developed. Key steps in the synthesis include the use of Evans’ chiral auxiliaries, Grignard cross-coupling reactions, hydroboration–oxidation, and Wacker oxidation. The synthesized sex pheromone components hold potential value for studies on communication mechanisms, species identification, and ecological management.

Introduction of Crabtree's iridium‐based hydrogenation catalyst in 1977 marked a paradigm shift both with respect to the role of iridium in homogeneous catalysis as well as catalytic hydrogenation of olefins. In 1998, Pfaltz introduced an improved catalyst, by use of BARF− as anion, and established the first chiral variant of the Crabtree catalyst. This led to numerous practical highly enantioselective syntheses. Elucidation of mechanistic details posed great problems because of instability of the crucial intermediates. A remarkable breakthrough was achieved by Brandt, Andersson et al. in 2003, based on dft calculations. These authors replaced a previously assumed IrI/IrIII catalytic cycle by a novel IrIII/IrV cycle. The proposal was experimentally verified by Pfaltz in 2014 and corroborated by advanced quantum chemical calculations. This essay is an attempt to describe a fascinating interplay of experiments and quantum chemical calculations for an important synthetic method. [ABSTRACT FROM AUTHOR]

The review covers research published since 2017 and is focused on enantioselective synthesis using radical reactions. It describes recent approaches to the asymmetric synthesis of chiral molecules based on the application of the metal catalysis, dual metal and organocatalysis and finally, pure organocatalysis including enzyme catalysis. This review focuses on the synthetic aspects of the methodology and tries to show which compounds can be obtained in enantiomerically enriched forms. [ABSTRACT FROM AUTHOR]

Carbohydrate-based macrocycles can be enantioselective catalysts in certain reactions. Previously, it was proven that the carbohydrate moiety could affect the catalytic activity of the monoaza-15-crown-5 type macrocycles derived from sugars. According to our experiments so far, the most effective enantioselective catalysts were the d-glucose- and the d-galactose-based crown ethers. To obtain more information about the effect of the carbohydrate unit, a rare monosaccharide, d-idose was incorporated into the monoaza-15-crown-5 structure. The key intermediates were methyl 4,6-O-benzylidene-α-d-idopyranoside and methyl 4,6-O-benzylidene-β-d-idopyranoside, which were synthesized from d-galactose. The efficiency of the idopyranoside-based crown compounds synthesized was investigated in asymmetric phase transfer reactions. In liquid-liquid biphasic reactions the highest enantioselectivity was 81% ee, while in solid-liquid phase systems the highest asymmetric induction was 67% ee. It was observed that the enantiodiscrimination was strongly dependent on the configuration of the anomeric center, on the side arm of the nitrogen, and on the structure of the substrate. [ABSTRACT FROM AUTHOR]

As the monomers of proteins, amino acids are critical in chemistry and biology, playing important roles in multiple fields such as synthetic chemistry, medicinal chemistry, and materials chemistry. Unlike proteinogenic amino acids, unnatural amino acids can be difficult to obtain from living organisms and generally are synthesized chemically. Recently, a method involving the asymmetric N−H bond carbene insertion reaction with α‐diazoacetates as the carbene precursor has shown high enantioselectivity and good functional group tolerance, allowing for the facile synthesis of natural and unnatural amino acids and the introduction of new concepts in catalysis. [ABSTRACT FROM AUTHOR]

Hyperolid reed frogs are one of the few families of Anurans known to possess glands that emit volatile compounds used in chemical communication. Hyperolius cinnamomeoventris, a model species, possesses a gular gland on its vocal sac that emits chemicals, and sends visual and auditory signals during calling. Previous investigations have shown that the glandular compounds are typically macrocyclic lactones. However, in this work, we show that another major constituent of the male specific gland is (10R,1S,6R,7R,10R)-amorph-4-ene-10β-ol [(1R,4R,4aR,8aS)-4-isopropyl-1,6-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-ol]. This compound was synthesized for the first time and has the opposite configuration to amorph-4-ene-10β-ol known from plants. A short synthesis using an organocatalytic approach through a tandem Mannich/intramolecular Diels–Alder reaction led to a mixture of cadinols, which was used for the assignment of the natural cadinol structures and their stereoisomers.

Molecules stereogenic only at tetrahedral boron atoms show great promise for applications, for example as chiroptical materials, but are scarcely investigated due to their synthetic challenge. Hence, this study reports a two‐step synthesis of enantioenriched boron C,N‐chelates. First, the diastereoselective complexation of alkyl/aryl borinates with chiral aminoalcohols furnished boron stereogenic heterocycles in up to 86 % yield and d.r. >98 : 2. Treatment of these O,N‐complexes with chelate nucleophiles was surmised to transfer the stereoinformation via the ate‐complex into the C,N‐products. This chirality transfer succeeded by substitution of the O,N‐chelates with lithiated phenyl pyridine to give boron stereogenic C,N‐chelates in up to 84 % yield and e.r. up to 97 : 3. The chiral aminoalcohol ligands could be recovered after isolation of the C,N‐chelates. The chirality transfer tolerated alkyl, alkynyl and (hetero‐)aryl moieties at boron and could be further extended by post‐modification: transformations such as catalytic hydrogenations or sequential deprotonation/electrophilic trapping were feasible while maintaining the stereochemical integrity of the C,N‐chelates. Structural aspects of the boron chelates were studied by variable temperature NMR and X‐ray diffraction. [ABSTRACT FROM AUTHOR]

Chiral biscyclopropanes are an important skeleton in many bioactive molecules. However, there are few routes to synthesize these molecules with high stereoselectivity due to the nature of multiple stereocenters. Herein, we report the first example of Rh2(II)‐catalyzed enantioselective synthesis of bicyclopropanes with alkynes as dicarbene equivalents. The bicyclopropanes with 4–5 vicinal stereocenters and 2–3 all‐carbon quaternary centers were constructed in excellent stereoselectivity. This protocol features high efficiency and excellent functional group tolerance. Moreover, the protocol was also extended to the cascaded cyclopropanation/cyclopropenation with excellent stereoselectivities. In these processes, both sp‐carbons of alkyne were converted into stereogenic sp3‐carbons. Experimental and density functional theory (DFT) calculations revealed that the cooperative weak hydrogen bonds between the substrates and the dirhodium catalyst may play key roles in this reaction. [ABSTRACT FROM AUTHOR]

In this personal account, our recent developments on the asymmetric synthesis of a quaternary carbon stereogenic center by organocatalysis using a primary amino acid and its salt as a catalyst are described in three chapters: (1) conjugate addition to nitroalkenes and vinyl ketones, (2) nucleophilic addition to π‐allyl palladium complexes, and (3) nucleophilic substitution reactions with allyl and propargyl halides. By these methods, asymmetric α‐allylation of α‐branched aldehydes and ketones smoothly proceeded to give γ‐nitroaldehydes, ketoaldehydes, α‐allylated aldehydes, and α‐allylated β‐ketoesters possessing a quaternary carbon stereogenic center in good yields with high enantioselectivities. [ABSTRACT FROM AUTHOR]

Since the pioneer reports of the groups of Akiyama and Terada on Brønsted acid organocatalysis, this field never stopped growing with the development of ingenious strategies for the activation of challenging poorly reactive substrates. The development of superacidic organocatalysts is an important way to selectively functionalize reluctant electrophiles and other approaches have also emerged such as the combination of Lewis and Brønsted acids as well as the consecutive organocatalysis and superacid activation. This Concept aims to highlight these different strategies and demonstrate their complementarity. [ABSTRACT FROM AUTHOR]

2‐Pyrazolines are important five‐membered heterocycles, containing two adjacent nitrogen atoms. They can incorporate various functional groups and possess unique biological properties. Moreover, they have been used as useful building blocks. In recent years, the field of 2‐pyrazoline synthesis has experienced enormous progress. Novel strategies have been developed, and many studies reporting improvements or adaptations of existing protocols have been published, giving access to new functionalizations, unexplored structures, and/or enantioselective synthesis. This review summarizes the progress made in synthetic methodologies during the period from 2012 to 2022. The functionalization challenges and capabilities, scopes and limitations of the reactions, substitution patterns, and mechanisms of the reactions, where appropriate, will be discussed. [ABSTRACT FROM AUTHOR]

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β‐unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ‐nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β‐(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)‐rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results. [ABSTRACT FROM AUTHOR]

An improved synthesis for tryptophan-dehydrobutyrine diketopiperazine (TDD), a co-metabolite of the hybrid polyketide/non-ribosomal peptide hangtaimycin, starting from ʟ-tryptophan is presented. Comparison to TDD isolated from the hangtaimycin producer Streptomyces spectabilis confirmed its S configuration. The X-ray structure of the racemate shows an interesting dimerisation through hydrogen bridges. The results from bioactivity testings of hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given.

Chloropupukeananin is a natural product that inhibits HIV-1 replication and has antitumor activity. Its structure consists of a chlorinated tricyclo[4.3.1.03,7]decane core skeleton with an array of highly oxidized multifunctional groups. In the biosynthesis of chloropupukeananin, (+)-iso-A82775C and (−)-maldoxin are employed as biosynthetic precursors for the intermolecular Diels–Alder and carbonyl–ene reactions, followed by the migration of the p-orcellinate group. Chloropupukeanolides and chloropestolides are intermediates and isomers in biosynthesis; their unique chemical structures and biosynthetic pathways have attracted significant attention from synthetic chemists. In this review, I present the synthetic studies on chloropupukeananin and its related compounds that have been conducted thus far.

Silanols are valuable and important compounds, which have found widespread applications in the field of materials science, synthetic chemistry, and medicinal chemistry. Although a handful of approaches have been developed for the synthesis of various silanols, access to enantioenriched silicon‐stereogenic silanols remains underdeveloped. This Concept article intends to summarize and highlight recent advances in the construction of silicon‐stereogenic silanols and endeavors to encourage further research in this area. [ABSTRACT FROM AUTHOR]

The use of stereoselective phase-transfer catalysis as a reliable method for the enantioselective synthesis of optically active α-amino acid derivatives using achiral Schiff base esters has been well-developed in batch in the last 40 years. Recently, continuous flow technology has become of great interest in the academy and industry, since it offers safer process operating conditions and higher efficiency compared to a traditional batch processing. Herein, we wish to report the first example of enantioselective phase transfer benzylation of alanine Schiff base ester, under continuous flow conditions. Two different methodologies were investigated: a liquid-solid phase transfer catalytic benzylation using a packed-bed reactor and a liquid-liquid phase transfer catalytic benzylation in continuous stirred-tank reactors. Liquid-liquid phase transfer process in flow showed slightly better productivity than the batch process, while solid-liquid phase transfer benzylation proved much more advantageous in terms of productivity and space-time yield. Furthermore, continuous flow system allowed the isolation of benzylated product without any work up, with a significant simplification of the process. In both cases, phase transfer asymmetric benzylation promoted by Maruoka catalyst demonstrated high enantioselectivity of target quaternary amino ester in flow, up to 93% ee. [ABSTRACT FROM AUTHOR]

σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown.

Both enantiomers of 2-methyllinalyl diphosphate (2-Me-LPP) were synthesized enantioselectively using Sharpless epoxidation as a key step and purification of enantiomerically enriched intermediates through HPLC separation on a chiral stationary phase. Their enzymatic conversion with 2-methylisoborneol synthase (2MIBS) demonstrates that (R)-2-Me-LPP is the on-pathway intermediate, while a minor formation of 2-methylisoborneol from (S)-2-Me-LPP may be explained by isomerization to 2-Me-GPP and then to (R)-2-Me-LPP.

It was the late Professor Kenji Mori, the giant of pheromone synthesis and pioneer of pheromone stereochemistry, who laid the foundation for the practical application of insect pheromones, which play an important role in Integrated Pest Management, one of the key concepts of agriculture in the 21st century. Therefore, it would be meaningful to retrace his achievements at this time, three and a half years after his death. In this review, we would like to introduce some of his notable synthetic studies from his Pheromone Synthesis Series and reconfirm his contributions to the development of pheromone chemistry and their impacts on natural science. [ABSTRACT FROM AUTHOR]

Stereoselective synthesis has been emerging as a resourceful tool because it enables the obtaining of compounds with biological interest and high enantiomeric purity. Flavonoids are natural products with several biological activities. Owing to their biological potential and aiming to achieve enantiomerically pure forms, several methodologies of stereoselective synthesis have been implemented. Those approaches encompass stereoselective chalcone epoxidation, Sharpless asymmetric dihydroxylation, Mitsunobu reaction, and the cycloaddition of 1,4-benzoquinone. Chiral auxiliaries, organo-, organometallic, and biocatalysis, as well as the chiral pool approach were also employed with the goal of obtaining chiral bioactive flavonoids with a high enantiomeric ratio. Additionally, the employment of the Diels–Alder reaction based on the stereodivergent reaction on a racemic mixture strategy or using catalyst complexes to synthesise pure enantiomers of flavonoids was reported. Furthermore, biomimetic pathways displayed another approach as illustrated by the asymmetric coupling of 2-hydroxychalcones driven by visible light. Recently, an asymmetric transfer hydrogen-dynamic kinetic resolution was also applied to synthesise (R,R)-cis-alcohols which, in turn, would be used as building blocks for the stereoselective synthesis of flavonoids. [ABSTRACT FROM AUTHOR]

Although there is an abundance of methods for the enantioselective synthesis of 2‐isoxazolines and 2‐isoxazolin‐5‐ones, relatively few of these approaches have been reported when these heterocycles bear fully substituted stereocenters. In this review, we will detail the methods that have been used to successfully accomplish these challenging asymmetric transformations and give insights into their importance, such as allowing access to unique three‐dimensional chemical space. The limitations of the currently known reactions will be discussed, as well as highlighting the future developments needed to advance the research field. [ABSTRACT FROM AUTHOR]

Over the last decades, biocatalysis has achieved growing interest thanks to its potential to enable high efficiency, high yield, and eco‐friendly processes aimed at the production of pharmacologically relevant compounds. Particularly, biocatalysis proved an effective and potent tool in the preparation of chiral molecules, and the recent innovations of biotechnologies and nanotechnologies open up a new era of further developments in this field. Different strategies are now available for the synthesis of chiral drugs and their intermediates. Enzymes are green tools that offer several advantages, associated both to catalysis and environmentally friendly reactants. Specifically, the use of enzymes isolated from biological sources or of whole‐cell represents a valuable approach to obtain pharmaceutical products. The sustainability, the higher efficiency, and cost‐effectiveness of biocatalytic reactions result in improved performance and properties that can be translated from academia to industry. In this review, we focus on biocatalytic approaches for synthesizing chiral drugs or their intermediates. Aiming to unveil the potentialities of biocatalysis systems, we discuss different examples of innovative biocatalytic approaches and their applications in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

The enantioselective total synthesis of representative members of the eburnamine-vincamine alkaloids (+)-vincamine, (−)-eburnamonine, and (−)-criocerine has been accomplished. The synthesis took advantage of a highly stereoselective Ir-catalyzed hydrogenation/lactamization cascade reaction, which allows for the stereoselective construction of the C/D rings as well as the installation of the critical cis-C20/C21 relative stereochemistry of the eburnamine-vincamine alkaloid skeleton in one pot.

Carbohydrate-based macrocycles can be enantioselective catalysts in certain reactions. Previously, it was proven that the carbohydrate moiety could affect the catalytic activity of the monoaza-15-crown-5 type macrocycles derived from sugars. According to our experiments so far, the most effective enantioselective catalysts were the d-glucose- and the d-galactose-based crown ethers. To obtain more information about the effect of the carbohydrate unit, a rare monosaccharide, d-idose was incorporated into the monoaza-15-crown-5 structure. The key intermediates were methyl 4,6-O-benzylidene-α-d-idopyranoside and methyl 4,6-O-benzylidene-β-d-idopyranoside, which were synthesized from d-galactose. The efficiency of the idopyranoside-based crown compounds synthesized was investigated in asymmetric phase transfer reactions. In liquid-liquid biphasic reactions the highest enantioselectivity was 81% ee, while in solid-liquid phase systems the highest asymmetric induction was 67% ee. It was observed that the enantiodiscrimination was strongly dependent on the configuration of the anomeric center, on the side arm of the nitrogen, and on the structure of the substrate.

The review covers research published since 2017 and is focused on enantioselective synthesis using radical reactions. It describes recent approaches to the asymmetric synthesis of chiral molecules based on the application of the metal catalysis, dual metal and organocatalysis and finally, pure organocatalysis including enzyme catalysis. This review focuses on the synthetic aspects of the methodology and tries to show which compounds can be obtained in enantiomerically enriched forms.