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A rhodium-catalyzed protocol has been established for the enantioselective hydroamination of gem-difluoroallenes with anilines. This strategy shows complete atom-efficiency to access a variety of enantioenriched gem-difluoroallylic amines in excellent branched selectivity (>99:1 for each case), which are important backbones in many biologically active compounds. Mechanistic studies suggest the generation of a gem-difluoro π-allyl rhodium intermediate by an exclusive hydrometalation pathway, which undergoes nucleophilic substitution of amines.

The first highly efficient and practical chiral Brønsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π‐allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl‐containing aza‐heterocycles and bicyclic aza‐heterocycles. [ABSTRACT FROM AUTHOR]

A copper-catalyzed hydroamination of styrenes using piv ZPhos as ligand is reported. Enantioselectivities up to 94% are achieved under optimized conditions with aryl and heteroaryl styrenes. A variety of electrophilic O -benzoylhydroxylamines are well tolerated. [ABSTRACT FROM AUTHOR]

We report of a concise synthesis of (R)‐sitagliptin monophosphate – a drug predominantly applied in the treatment of type 2 diabetes. Utilizing our recently developed RhI‐catalyzed hydroamination of allenes for the stereoselective construction of the inherent chiral amino function, a new approach to (R)‐sitagliptin monophosphate on a 3.5 mmol scale was established. [ABSTRACT FROM AUTHOR]

The precise synthesis of chiral polymers remains a significant challenge in polymer chemistry, particularly for applications in advanced biomedical and electronic materials. The development of degradable polymers is important for eco‐friendly and advanced materials. Here, we introduce a stereo‐controlled degradable polymer via cascade enyne metathesis polymerization and enantioselective acetal synthesis through Pd‐catalyzed asymmetric hydroamination. This approach allows for the creation of chiral acetal‐based polymers with controlled stereochemistry and degradability, highlighting their potential for use in drug delivery and electronic applications. This concept article reviews the background, development, and potential applications of these stereo‐controlled degradable polymers. [ABSTRACT FROM AUTHOR]

In the present study, we report the first silver-dependent enantiodivergent gold-catalysed reaction. The asymmetric intramolecular hydroamination of alkenes catalysed by the combination of a single chiral binuclear gold(I) chloride complex and silver perchlorate can afford both enantiomers of the products by a simple solvent change from toluene to methanol. Such an enantiodivergent reaction is strictly independent of the reaction temperature or of the nature of the catalyst anion and displays the same first-order kinetic rate law with respect to substrate concentration in both solvents. Beyond a simple solvent effect the enantioinversion is controlled by gold-silver chloride adducts which occur only in methanol and allow a dual activation of the reagent. While one single gold atom activates the alkene moiety, the other gold atom forms an oxophilic gold-silver chloride adduct which is likely to interact with the carbamate function. By comparison with toluene, which affords ( S)-enantiomer, this proximal and bimetallic activation would allow an opposite stereodifferentiation of the two diastereomeric intermediates during the final protodeauration step and lead therefore to the ( R)-enantiomer. [ABSTRACT FROM AUTHOR]

Amino alcohols are important ligands for the asymmetric catalytic hydroamination of aminoallenes to form chiral pyrrolidines. Herein, we report the crystal structures of two chiral amino alcohols, D-N-(2-Adamantyl)phenylglycinol and L-N-(2-Adamantyl)diphenylphenylalinol, that function as ligands within transition metal complexes that catalyze the hydroamination of aminoallenes. Both molecules crystallize in the noncentrosymmetric orthorhombic space group P212121. Inter- and intramolecular hydrogen bonding plays an important role in stabilizing each alcohol in the solid state in the absence of a transition metal. The presence of these hydrogen bonds has been verified by single crystal X-ray diffraction and their overall strength determined by computational methods. [ABSTRACT FROM AUTHOR]

The first highly enantioselective Brønsted acid catalyzed intramolecular hydroamination of alkenes enables the efficient construction of a series of chiral (spirocyclic) pyrrolidines with an α-tetrasubstituted carbon stereocenter with excellent functional group tolerance. A unique feature of this strategy is the use of a thiourea group acting as both the activating and the directing group through cooperative multiple hydrogen bonding with a Brønsted acid and the double bond. The utility of this method is highlighted by the facile construction of chiral synthetic intermediates and important structural motifs that are widely found in organic synthesis. [ABSTRACT FROM AUTHOR]

A new class of chiral zirconium complexes supported by chiral tridentate [O−NO−]-type of ligands derived from amino acids were synthesized and structurally characterized. They catalyzed asymmetric hydroamination/cyclization of primary aminoalkenes to give five- and six-membered N-heterocyclic amines with up to 94% ee. [ABSTRACT FROM AUTHOR]

A stereocontrolled degradable polymer was synthesized via living cascade enyne metathesis polymerization. Highly stereodefined N,O‐acetal‐containing enyne monomers were prepared using the Pd‐catalyzed hydroamination of alkoxyallenes and ring‐closing metathesis. The resulting chiral polymer exhibited a narrow dispersity window. Block copolymers were prepared not only by sequentially adding nondegradable and degradable monomers but also by using enantiomerically different monomers to produce stereocontrolled blocks. Owing to the hydrolyzable N,O‐acetal moiety in the backbone structure, the resulting polymer could degrade under acidic conditions generated using various acid concentrations to control the degradation. Additionally, the aza‐Diels–Alder reaction modified the polymer without losing the stereochemistry. [ABSTRACT FROM AUTHOR]

In the background is featured Ginkakuji (Silver Pavilion), a Zen temple along Kyoto′s eastern mountains (Higashiyama) in Japan. In the foreground is featured a chemistry sketch based on the Yin and Yang symbol. As many possible dualities (such as light and dark, fire and water…) are thought of as physical manifestations of the duality symbolised by Yin and Yang, parallels can be drawn with organic chemistry and the gold(I)‐catalysed asymmetric hydroamination of alkenes. An enantiodivergent reaction is possible depending on the presence of silver. Whereas a gold‐catalysed hydroamination reaction afforded (S)‐product in toluene, the use of methanol led to an enantioinversion and the generation of (R)‐product through solvation of silver and bimetallic activation of the amino‐alkene reagent. For more information see the Full Paper by F. Agbossou‐Niedercorn, C. Michon and co‐workers on page 10777 ff. [ABSTRACT FROM AUTHOR]

Enantiomerically pure amines are crucial intermediates for a wide range of pharmaceuticals, natural products, and bioactive compounds. Asymmetric intermolecular hydroamination of alkenes is one of the most atom-economical methods for the synthesis of chiral amines. However, the direct stereoselective hydroamination of alkenes remains a significant challenge. Herein, we developed a novel fully biocatalytic system to enable the direct stereoselective hydroamination of aryl alkenes to produce chiral amines. The process involves sequential alkene asymmetric hydration catalyzed by a hydratase (HD), followed by in situ oxidation of alcohol into ketone by two enantiocomplementary alcohol dehydrogenases (ADHs), and finally, enantioselective transformation of ketone into enantiomerically pure amine by a ω-transaminase (TA). The addition of lactate dehydrogenase (LDH) facilitated the connection between alcohol oxidation and pyruvate reduction, making the cascade reaction redox self-sufficient and driving the process towards the desired target product. In vitro cascade biocatalysis for asymmetric hydroamination of 4-hydroxystyrenes 1a–f was first investigated by using the combined enzymes (HD/ADHs/LDH/TA) with trace amounts of NAD+ (0.05 mM) and pyridoxal-5′-phosphate (PLP) (0.1 mM), affording both enantiomers of amines 4a–f in 30–90% conversions and >99% ee. Furthermore, whole-cell-based cascade biocatalysis was achieved by using the constructed recombinant Escherichia coli cells co-expressing the five enzymes without additional NAD+ cofactor; (R)- and (S)-amines 4a–f could be obtained in 35–93% conversions and >99% ee. Finally, the preparative experiments were demonstrated by using the whole-cell biocatalyst E. coli (RFM-ERR-CB) and E. coli (RFC-ERR-CB) with substrate 1a, affording (S)-4a and (R)-4a in 54.8% and 59.2% yields and >99% ee. This research achievement provides a highly selective, highly atom-economical, green and sustainable method for synthesizing chiral amines from alkenes via formal alkene asymmetric hydroamination. [ABSTRACT FROM AUTHOR]

New chiral zirconium systems catalyze the asymmetric hydroamination/cyclization of primary aminoalkenes affording five- and six-membered N-heterocyclic amines with up to 94% e.e. [ABSTRACT FROM AUTHOR]

Enantioenriched pyrrolidines and derivatives are ubiquitous substructures in compounds of importance to medicinal and biological chemistry. Herein, we report an efficient cobalt-catalyzed intramolecular asymmetric hydroamination reaction that produces chiral pyrrolidines with good to excellent yield and enantiocontrol. Compared with previously reported radical-involved methodologies for enantioenriched pyrrolidines, these conditions feature two elegant versatilities, enabling (1) the use of cobalt-catalyzed hydrogen atom transfer (HAT) to generate organocobalt intermediates that bring radical reaction to organometallic chemistry, and (2) enantioselective intramolecular C–N bond forging through an SN2-like displacement involving dynamic kinetic resolution (DKR). This approach provides a new alternative and efficient methodology for enantioselective radical-involved C–N bond construction that can be used in the synthesis of both chiral pyrrolidines and homologous nitrogen heterocycles. [ABSTRACT FROM AUTHOR]

Kinetic and spectroscopic studies are performed on the enantioselective copper(I) hydride-catalyzed hydroamination of styrene. [ABSTRACT FROM AUTHOR]

The thiourea moiety in the substrates acts as both the activating and directing group through cooperative multiple hydrogen bonding with the Broensted acid and the double bond. [ABSTRACT FROM AUTHOR]

Catalytic asymmetric hydroamination of alkenes with Lewis basic amines is of great interest but remains a challenge in synthetic chemistry. Here, we developed a Co‐catalyzed asymmetric hydroamination of arylalkenes directly using commercially accessible secondary amines. This process enables the efficient access to valuable α‐chiral tertiary amines in good to excellent yields and enantioselectivities. Mechanistic studies suggest that the reaction includes a CoH‐mediated hydrogen atom transfer (MHAT) with arylalkenes, followed by a pivotal catalyst controlled SN2‐like pathway between in situ generated electrophilic cationic alkylcobalt(IV) species and free amines. This radical‐polar crossover strategy not only provides a straightforward and alternative approach for the synthesis of enantioenriched α‐tertiary amines, but also underpins the substantial opportunities in developing asymmetric radical functionalization of alkenes with various free nucleophiles in oxidative MHAT catalysis. [ABSTRACT FROM AUTHOR]

Review: overview of the most effective stereoselective methods using various catalyst ystems based on alkali, alkaline earth, and transition metals, as well as enzyma tic and organocatalytic approaches; 239 refs. [ABSTRACT FROM AUTHOR]

Review: 36 refs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel in-situ calcium-based catalyst for intramolecular amino alkene hydroamination. • Proligand synthesis by a chiral pool-based approach. • Highest Ca-based enantioselectivity of 77 % by short reaction times and low catalyst concentration. The synthesis of (2 S ,3 S)-3-methyl-2-(methyl(pyridin-2-yl-methyl)amino)-1,1-diphenylpentan-1-ol 5 and its use together with [Ca(N(SiMe 3) 2) 2 (thf) 2 ] 6 as in situ generated catalytic system in the enantioselective intramolecular hydroamination of 2,2-diphenylpent-4-en-1-amine 7 as benchmark substrate is discussed. Enantiomeric excesses of up to 77 %, the highest yet reported for calcium-based systems, as well as significantly shortened reaction times while only requiring 5 mol-% of catalyst, were achieved. [ABSTRACT FROM AUTHOR]

Enantioselective hydroamination/cyclizations of several monosubstituted and disubstituted aminoalkenes have been achieved, catalyzed by tetracoordinate anionic La(III) complexes. [ABSTRACT FROM AUTHOR]

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C–N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C–C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine–imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C–H bond forming reactions include hydrogenation of C＝N bonds and C–H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis for enantioselective intramolecular hydroamination of alkenes is a critical method in the construction of enantioenriched nitrogen-containing rings, often prevalent in biologically active compounds and natural products. Herein, we demonstrate a facile enantioselective intramolecular hydroamination of alkenes for the synthesis of chiral pyrrolidine, piperidine, and indoline moieties, using a manganese (II) chiral aprotic cyclic urea catalyst. The cyclic ligand hinders the inversion of the N atom of the urea and effectively discriminate between the enantiomers of substrates. High-resolution mass spectrometry, deuterium labeling experiments, and molecular orbital energy analysis clearly reveal the intermediates and mechanism of the transformation. As a key step, oxygen coordination by chiral aprotic urea presents a robust control over the asymmetric intra-HA reaction through the involvement of a convergent assembly of two vital intermediates (Mn-N and C-Mn-Br), providing access to chiral cyclic amine systems in high yields with excellent enantioselectivity. Nitrogen-containing rings containing chiral carbon centers are a staple of bioactive molecules and natural products of interest, and synthetic methodologies for their development are a continual focus of organic chemists. Here, the authors disclose a protocol for the synthesis of enantioenriched saturated azacycles, via intramolecular hydroamination of alkenes, using a chiral cyclic urea ligand with manganese. [ABSTRACT FROM AUTHOR]

Titanium complexes of imine diol ligands showed improved enantioselectivity up to 22 %ee relative to complexes with bidentate amino alcohol ligands. [Display omitted] • Chiral tridentate imine diol ligands were prepared in two steps. • Titanium complexes of the ligands were prepared in situ. • Hydroamination/cyclization of an aminoallene substrate in 22 %ee. • A 2:1 complex is postulated to reduce reactivity and enantioselectivity. Our laboratory has developed catalysts based on earth abundant titanium for asymmetric reactions including intramolecular hydroamination. Previously, we showed that titanium complexes of imine diol ligands showed improved enantioselectivity relative to complexes with bidentate amino alcohol ligands. As the catalyst with the highest selectivity had di- tert -butyl substitution, we sought to increase the steric protection by preparing three new ligands with diaryl substitution. These ligands were readily prepared in two steps: first, synthesis of diaryl substituted salicylaldehydes by a Suzuki coupling and second, a Schiff base condensation with a chiral amino alcohol. After characterizing the ligands, in situ hydroamination/cyclization with 6-methyl-hepta-4,5-dienylamine was carried out at temperatures ranging from 105 °C to 135 °C to give exclusively 2-(2-methyl-propenyl)-pyrrolidine with enantioselectivity up to 22 %ee. Unexpected dimerization of the catalyst resulted in reduced activity, so the reaction required a catalyst loading of 10–20%. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis enables the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates1. Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a notable challenge2,3. Here we introduce a class of Earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, such as ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number of up to 107,800. Our mechanistic studies indicate that exceptional stereoselectivity arises from the modular assembly of confined chiral catalysts and cooperative non-covalent interactions between the catalyst and the substrate.An Earth-abundant manganese catalyst that can hydrogenate imines to amines with high enantioselectivity works even for small differences in the groups on the imine, which is still a challenge for precious metal catalysts. [ABSTRACT FROM AUTHOR]

Optimizing lanthanide catalyst performance with organic ligands often encounters significant challenges, including susceptibility to water or oxygen and complex synthesis pathways. To address these issues, our research focuses on developing inorganic lanthanide clusters with enhanced stability and functionality. In this study, we introduce the [Sm6O(OH)8(H2O)24]I8(H2O)8 cluster (Sm-OC) as a sustainable and efficient catalyst for the aerobic oxidation of thiols under heating conditions. The Sm-OC catalyst demonstrated remarkable stability, outstanding recyclability, and excellent chemoselectivity across a diverse range of functional groups in 38 different tests. Notably, it enables efficient unsymmetrical disulfide synthesis and prevents the formation of over-oxidized by-products, highlighting its superior performance. This Sm-OC catalyst provides a practical and robust tool for the precise construction of versatile disulfides, thus establishing a template for the broader use of lanthanide clusters in organic synthesis. [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 possible catalytic mechanism was proposed and studied comprehensively at the M062X/6-31G(d,p) level of theory for a reported chemoselective intermolecular SN2 nucleophilic substitution of aldehydes with alkanolamine. The calculated results show that the catalytic cycle occurs through six stages, namely, the nucleophilic attack of active N-heterocyclic carbene (NHC) on the substrate, generation of the Breslow intermediate, oxidative addition of NBS and alkanolamine, SN2 nucleophilic substitution, Et3N-assisted debromination, and finally regeneration of the NHC along with the release of the product. The results show that TSs of the C–N or C–O bond formation is the key transition state that determines the chemoselectivity of the title reaction. Moreover, our results demonstrated that the N-bromoamine intermediate is more favorable both thermodynamically and kinetically than hypobromite by 14.2 kcal mol−1, which is consistent with the fact that only the N-acylation product was observed in the experiment. In addition, we found that alkanolamine not only acts as a reactant but also as a proton-shuttle and stabilizer to stabilize the structure of the favored chemoselective transition state by multiple N–H⋯N, N–H⋯O and C–H⋯Br− noncovalent interactions. Et3N firstly acts as a base to promote the formation of the active catalyst NHC, then the protonated Et3N acts as a proton-shuttle to accelerate the Breslow intermediate formation and decrease the activation barrier. The Parr functions and frontier molecular orbital analyses of key species indicate that NHC remarkably enhances the nucleophilicity of the substrate aldehyde, leading to a significant increase of the HOMO energy and a moderate increase of the LUMO energy. We hope this work could provide deeper insights into the fundamental mechanisms of the Et3N-assisted NHC-catalyzed SN2 substitution reactions. [ABSTRACT FROM AUTHOR]

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C–X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources. [ABSTRACT FROM AUTHOR]