Search

The application of biocatalysis has become essential in both academic and industrial domains for the asymmetric synthesis of chiral amines, and it serves as an alternative tool to transition‐metal catalysis and complements traditional chemical methods. It relies on the swift expansion of available processes, primarily as a result of advanced tools for enzyme discovery, combined with high‐throughput laboratory evolution techniques for optimizing biocatalysts. This concept paper explores the utilization of non‐conventional media such as ether‐type solvents, deep eutectic solvents, and micellar catalysis to enhance biocatalytic reactions for chiral amine synthesis. Each section focuses on the unique properties of these media, including their ability to stabilize enzymes, alter substrate solubility, and modulate enzyme selectivity. The paper aims to provide insights into how these innovative media can overcome traditional limitations, offering new avenues for sustainable and efficient chiral amine production through biocatalytic processes. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The 21st century has witnessed a continuous evolution in the development of boron‐stereogenic chemistry. Since the 1990s, various innovations for the synthesis of tetracoordinate boron‐stereogenic compounds, which exhibited great potential applications, have been demonstrated by synthetic chemists. This paper reviews the significant progress and recent advances towards the assembly of enantioenriched boron‐stereogenic compounds, and hopes to shed light on new perspectives and inspire further research in this emerging field. [ABSTRACT FROM AUTHOR]

Organic‐chemical literature encompasses large numbers of catalysts and reactions they can effect. Many of these examples are published merely to document the catalysts' scope but do not necessarily guarantee that a given catalyst is "optimal"—in terms of yield or enantiomeric excess—for a particular reaction. This paper describes a Machine Learning model that aims to improve such catalyst‐reaction assignments based on the carefully curated literature data. As we show here for the case of asymmetric magnesium catalysis, this model achieves relatively high accuracy and offers out of‐the‐box predictions successfully validated by experiment, e.g. in synthetically demanding asymmetric reductions or Michael additions. [ABSTRACT FROM AUTHOR]

Chiral phosphoric acid (CPA) has been established as a cornerstone in chemical synthesis reactions for over five decades, owing to its distinctive molecular structure and remarkable catalytic effect. However, in recent years, a revolutionary approach to asymmetric synthesis has emerged, utilizing photocatalytic excitation of molecules to generate free radicals, effectively surpassing the limitations of classical organic synthesis methodologies.A prominent and significant area of research has been dedicated to the investigation of chiral phosphoric acid synergistic photocatalysis for enantioselective chemical synthesis. This unique catalytic system encompasses a bifunctional hydrogen‐bonding catalyst, enabling simultaneous interactions between radical intermediates and substrates. The review paper focuses on the application and progress of this catalytic system in asymmetric synthesis throughout the past decade. [ABSTRACT FROM AUTHOR]

Based upon their exceptional reactivity as cooperative Brønsted acid‐base catalysts chiral diphosphane Pd‐aqua complexes have successfully been utilized in a broad range of asymmetric transformations. Originally discovered by Sodeoka 25 years ago, they readily form reactive chiral Pd enolates upon deprotonation of β‐dicarbonyl compounds and simultaneously, a Brønsted acid liberated from the catalyst activates the electrophile. After the initial report and some ensuing papers had been published in the early 2000s, the field lay dormant for more than a decade. In recent years, however, new developments towards the enantioselective synthesis of various heterocycles and other useful compounds have evolved which take advantage of the unique properties of chiral Pd‐aqua complexes. [ABSTRACT FROM AUTHOR]

We report herein an asymmetric Pictet–Spengler reaction of α‐ketoesters. In the presence of a catalytic amount of simple alanine‐derived squaramide and p‐nitrobenzoic acid, reaction of tryptamines with methyl 2‐oxoalkanoates afforded the corresponding 1‐alkyl‐1‐methoxycarbonyl tetrahydro‐β‐carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2‐deteurium‐labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro‐β‐carbolinium ion could be the rate‐ and enantioselectivity‐determining step. A concise enantioselective total synthesis of (+)‐alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper. [ABSTRACT FROM AUTHOR]

Cyclopropane structure has been the object of interest in multiple investigations due to its prevalence in different natural products. In addition, this structure has a particular reactivity, specifically the 1,1‐cyclopropanedicarboxylate compounds, which act as acceptor‐donor cyclopropanes. Its reactivity could be compared with that of an α,β‐unsaturated carbonyl, which undergoes conjugate addition reaction and depending on the nature of the nucleophile this can lead to a cycloaddition reaction. Therefore, cyclopropane can be transformed into several useful structures in organic synthesis. Different methods have been described to achieve cyclopropanes such as, Simmons‐Smith reaction, decomposition of diazoalkanes and Michael‐Initiated ring closure (MIRC). Due to the absence of metals, this last method has been applied to the asymmetric organocatalytic synthesis of cyclopropanes, where the substrates activation is through the imine‐enamine intermediates formation or by hydrogen bonds. The asymmetric reaction consists of a domino reaction composed of a conjugate addition reaction and a cyclization reaction via intramolecular nucleophilic substitution. In this review, different asymmetric organocatalytic syntheses of the last two decades until 2021 are presented. With the intention to facilitate the reading of the review, an example of each paper was selected with the optimal reaction conditions and with the best organocatalyst producing the best yield and high stereoselectivity. [ABSTRACT FROM AUTHOR]

Asymmetric organocatalytic synthesis is a powerful tool in organic chemistry to achieve desired stereoisomers in high purity via mild catalytic routes. The immobilization of homogeneous catalytic species onto heterogeneous phases embodies the evolution of asymmetric catalysis, since it allows the recycling of the catalyst for several runs until degradation. Previously reported non‐covalent immobilization of proline‐based catalysts for aldol reaction onto magnetic nanoparticles functionalized with β‐cyclodextrin (MNP‐β‐CB) demonstrated the viability of the methodology. This paper proposes two new catalyst recycling strategies based on Cucurbit[7]uril (CB[7]) for the aldol reaction and the Robinson annulation. These recycling methodologies are conceptually different. The former relies on the homogeneous encapsulation of the catalyst in cucurbituril, CB[7] ⋅ Cat, and its recycling in the aqueous phase by extraction of the aldol product with organic solvents. The latter relies on the heterogeneous encapsulation of the catalyst as MNP‐CB[7] ⋅ Cat2 system and its recycling by magnetic harvesting. Density functional theory (DFT) calculations have been employed to rationalize the thermodynamics of experimental results, and to suggest caveats and plausible improvements in view of a future catalytic design. [ABSTRACT FROM AUTHOR]

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper‐catalyzed enantioselective hydrosilylation of gem‐difluorocyclopropenes to provide the corresponding chiral gem‐difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me2PhSi‐Bpin accompanying sodium tert‐butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three‐membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio‐enriched gem‐difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C−C bond leading to the transient acyclic intermediates. [ABSTRACT FROM AUTHOR]

There are marine cytotoxic bromotriterpenoids, named the thyrsiferol family that are structurally characterized by some tetrahydropyran (THP) and tetrahydrofuran (THF) rings. The thyrsiferol family belongs to natural products that are often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic tetrasubstituted carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, to elucidate ambiguous stereostructures and unassigned absolute configurations of aplysiol B, laurenmariannol, and saiyacenol A, members of the thyrsiferol family, we carried out their asymmetric chemical syntheses featuring 6‐exo and 5‐exo oxacyclizations of epoxy alcohol precursors and 6‐endo bromoetherification of a bishomoallylic alcohol. In this paper, we report total assignments of their stereostructures through their asymmetric chemical syntheses and also their preliminary cytotoxic activities against some tumor cells. These results could not have been achieved without depending on asymmetric total synthesis. [ABSTRACT FROM AUTHOR]

As an important branch of the Michael addition reaction, the aza‐Michael addition cascade reaction has been developed rapidly in recent years. This is because the reaction serves as an important method for effectively constructing functionalized C−N bonds, which can be widely used in the synthesis of chiral drugs and their intermediates and natural products. Given the importance of this topic, this review highlights the recent developments of aza‐Michael addition triggered cascade reactions in asymmetric synthesis, including aza‐Michael/Michael, aza‐Michael/Aldol, aza‐Michael/Henry, aza‐Michael/hemiacetal, aza‐Michael/Mannich, aza‐Michael/alkylation, aza‐Michael/cyclization, aza‐Michael/ring‐opening, aza‐Michael‐IED/HAD, aza‐Michael/INCR, and aza‐Michael/1,6‐conjugate addition reactions. In this paper, the reaction mechanism and derivatization experiments of different reactions are timely introduced to provide a more comprehensive theoretical basis for subsequent studies. [ABSTRACT FROM AUTHOR]

Organic unsymmetrical disulfides have been extensively applied in various academic and industrial fields including intermediates in organic synthesis, agriculture, and food science, natural materials, biochemistry, pharmaceutical and medicine chemistry, polymers, material engineering, etc. They play a crucial role in the fabrication of various biological active sulfur heterocycles. Due to broad and extensive applications, many methods have been developed for the synthesis of unsymmetrical S−S and efforts have been made to improve some issues such as cost, energy efficiency, green chemistry, avoid or minimizing waste generation. Several outstanding review articles have been previously published highlighting the advances of S−S bond formation, in general, using various reagents under different conditions in the absence or presence of oxidants/catalysts. In 2020, a review paper was published by our group focusing on recent developments since 2014 in the synthesis of organic symmetrical disulfides. However, investigations on new catalytic methods are being regularly reported and new types of unsymmetrical disulfides are synthesized. The present overview has attempted to systematically summarize recent advances in the process of unsymmetrical S−S bond formation with a major focus since 2010, highlighting mechanistic considerations, substrate scope, advantages, and limitations. The patents are not studied in this overview. [ABSTRACT FROM AUTHOR]

A stereoselective synthesis of 2-acetamido-1,2-dideoxyaltronojirimycin (8) and its manno epimer 9 is described. The synthetic approach is based on key bicyclic carbamate 7, which is easily accessible with high enantiomeric purity on a multigram scale by Sharpless asymmetric epoxidation of 1,4-pentadien-3-ol or 2,4-pentadien-1-ol. This procedure completes an efficient stereodivergent approach to five isomers of 2-acetamido-1,2-dideoxyiminosugars in high overall yields starting from the same key intermediate 7. The approach described in this paper is based on control of the stereoselectivity of the sulfite ring-opening reaction to give retention of configuration through anchimeric assistance from the endocyclic amine. [ABSTRACT FROM AUTHOR]

The focus of this paper is on the intermolecular interaction active between polyaniline (PANI) and 10‐camphorsulfonic acid (10CSA). Enantiopure 10CSA, present in the electropolymerization solution, promotes chiral induction in the supramolecular polyaniline polymer (cPANI). Tight integration of experimental data (circular dichroism, CD, near edge X‐ray absorption spectra, NEXAFS, conductive probe atomic force microscopy, CP‐AFM) and theoretical [density functional theory, (DFT)] results allows to unfold the nature of the electronic interaction between PANI and 10CSA and to shed light on the physical interactions inducing the chiral character to bulk pristine non‐chiral PANI: eventually yielding cPANI. The electropolymerization follows a "wet chemistry" method: electrochemical polymerization of aniline in the co‐presence in bulk solution of enantiopure 10‐camphorsulfonic acid (10CSA). The latter is exploited as chirality inductor. The method of integration between experimental results with ab‐initio theoretical calculations, strongly suggests that the chiral induction exerted by the CSA stems from exchange interaction between CSA and PANI. [ABSTRACT FROM AUTHOR]

Homoisoflavanones, 3‐benzylchroman‐4‐ones, which are naturally occurring sappanin‐type homoisoflavonoids, possess a 16‐carbon skeleton and a single chiral center. In this paper, we present various asymmetric synthesis of homoisoflavanones that have been developed. The first approach is a lipase‐catalyzed desymmetrization of 2‐benzylpropane‐1,3‐diol and its diacetate. Three approaches for the synthesis of an optically active 3‐benzylchroman‐4‐one are asymmetric protonation of the silyl enol ether derived from a racemic homoisoflavanone, iridium‐catalyzed asymmetric hydrogenation of α‐phenoxymethylcinnamic acid, and Evans asymmetric aldol reaction. Recently, our group performed Noyori ruthenium‐catalyzed asymmetric transfer hydrogenation with dynamic kinetic resolution, followed by alcohol oxidation of 3‐benzylchroman‐4‐ol. [ABSTRACT FROM AUTHOR]

Supramolecular capsules can be used to change the activity and selectivity of a catalyst through the influence of the second coordination sphere, reminiscent of how enzymes control the selectivity of their processes. In enzymes, this approach is used to also control the enantioselectivity of reactions in which the active catalytic site is often not chiral but the second coordination sphere is. We are interested in the possibility to generate a chiral second coordination sphere around an otherwise achiral transition metal complex for asymmetric catalysis. In this paper we show that the ligand template approach can be used to generate a chiral second coordination sphere around a rhodium complex, which is used in asymmetric hydroformylation. [ABSTRACT FROM AUTHOR]

Herein, the study reports the first electrochemical nickel‐catalyzed enantioselective hydro‐arylation/alkenylation of enones in an undivided cell with low‐cost electrodes in the absence of external reductants and supporting electrolytes. Aryl bromides/iodides/triflates or alkenyl bromides are employed as electrophiles for the efficient preparation of more than 56 valuable β‐arylated/alkenylated ketones in a simple manner (up to 97% yield, 97% ee). With the advantages of electrochemistry, excellent functional group tolerance and late‐stage modification of complex natural products and pharmaceuticals made the established protocol greener and more economic. Mechanism investigation suggests that a NiI/NiIII cycle may be involved in this electro‐reductive reaction rather than metal reductant driven Ni0/NiII cycle. Overall, the efficient electrochemical activation and turnover of the nickel catalyst avoid the drawbacks posed by the employment of stoichiometric amount of sensitive metal powder reductants. [ABSTRACT FROM AUTHOR]

Interactions between lone pairs and aromatic π systems are significant across biology and self‐assembled materials. Herein, employing an achiral confinement metal–organic framework (MOF) encapsulates guest molecules, it is successfully realized that lone pair (lp)‐π interaction induces fluorescence "turn‐on" and circularly polarized luminescence for the first time. The MOFs synthesized based on naphthalenediimide show nearly non‐emissive, which can be light‐up by introducing acetone or ester guests containing lone pairs‐π interaction. Furthermore, the introduction of a series of lp‐rich chiral esters induces supramolecular chirality as well as circularly polarized luminescence in achiral MOFs, while also observing chiral adaptability. This work first demonstrates the luminescence and chiral induction via lone pair electrons‐π interactions, presenting a fresh paradigm for the advancement of chiroptical materials. [ABSTRACT FROM AUTHOR]

This paper describes the synthesis of novel N‐substituted 3‐indolylglycines (3IGs), in high yields and optical purity via three‐component Mannich reaction (3CR) of indole and free glyoxylic acid in the presence of primary and secondary aliphatic amines. By using this efficient approach, a series of racemic 3‐indolylglycines (3IGs) as well as the optically pure (S)‐3‐indolylglycine ((S)‐3IG) in multigram synthesis using (R‐1‐phenylethylamine ((R)‐α‐PEA) as chiral pool were synthetized. In parallel investigations, 3IGs were used as the starting material for the highly stereoselective synthesis of spiroindolenines bearing three controlled contiguous stereogenic centers. Despite our expectations, the N‐chloroacetyl esters of 3IGs did not provide the expected spiroindolenine derivatives but led us to the discovery of a new methodology for the preparation of 3‐indolylmaleimides (3IMs); compounds known for their broad range of important biological and fluorescence activities. [ABSTRACT FROM AUTHOR]

The enantiomeric excess of chiral starting materials is one of the important factors determining the enantiopurity of products in asymmetric synthesis. Fifty‐one commercially available chiral reagents used as building blocks, catalysts, and auxiliaries in various enantioselective syntheses were assayed for their enantiomeric purity. The test results were classified within five impurities level (ie, <0.01%, 0.01%‐0.1%, 0.1%‐1%, 1%‐10%, >10%). Previously from 1998 to 2013, several reports have been published on the enantiomeric composition of more than 300 chiral reagents. This series of papers is necessitated by the fact that new reagents are forthcoming and that the enantiomeric purity of the same reagent can vary from batch to batch and/or from supplier to supplier. This report presents chiral liquid chromatography (LC) and gas chromatography (GC) methods to separate enantiomers of chiral compounds and evaluate their enantiomeric purities. The accurate and efficient LC analysis was done using newly introduced superficially porous particle (SPP 2.7 μm) based chiral stationary phases (TeicoShell, VancoShell, LarihcShell‐P, and NicoShell). [ABSTRACT FROM AUTHOR]

The work reported within this paper describes an example of the application of bimetallic catalysts system in allylic substitution reactions. The development of new nucleophiles and the control of enantio‐ and diastereoselectivity are the main research topics in this area. An improvement in the reactivity and diastereoselectivity has been realized for the dual Ir/Cu catalyzed allylic alkylation of inactive prochiral nucleophiles, under mild reaction conditions. Furthermore, the choice of the metallacyclic iridium complex and chiral Cu‐Phox complex combination allows for access to all four stereoisomers from the same starting materials with excellent enantioselectivity and diastereoselectivity (up to >99% ee and >20:1 dr). Significantly, this method provides a stereodivergent access to 2‐amino‐3‐methylpent‐4‐acid ester, an important fragment for the synthesis of Halipeptin A. [ABSTRACT FROM AUTHOR]

An efficient bifunctional squaramide‐catalyzed Michael addition/cyclization of azadienes with malononitrile has been successfully developed, providing a facile access to chiral benzofuran‐fused 1,4‐dihydropyridines with excellent yields, wide substrate scope and up to 99% ee. Additionally, this formal [4+2] cycloaddition can be performed in gram scale without noticeable loss of yield and enantioselectivity. An efficient bifunctional squaramide‐catalyzed Michael addition/cyclization of azadienes with malononitrile has been successfully developed, providing a facile access to chiral benzofuran‐fused 1,4‐dihydropyridines with excellent yields, wide substrate scope and up to 99% ee. Additionally, this formal [4+2] cycloaddition can be performed in gram scale without noticeable loss of yield and enantioselectivity. [ABSTRACT FROM AUTHOR]

Abstract: This paper reports on the first repetitive batch selective hydroboration of terminal and internal alkynes in a series of poly(ethylene glycols) (PEGs), used as solvents and media for the immobilization of a Ru(CO)Cl(H)(PPh3)3 catalyst. The system based on 2 mol% of Ru−H complex and poly(ethylene glycol) with α‐methyl/ω‐trimethylsilyl ending groups (Mw=2000) was found to be the most efficient, and was able to carry out over 19 complete runs with the Z‐addition of pinacolborane to the phenylacetylene. With the use of one portion of the developed catalytic system, the hydroboration of five different alkynes was performed consecutively, and led to five different products being obtained with high yields and purities. The developed strategy was characterized by high TON values and it was found to be the best recyclable protocol, leading to alkenyl boronates in all reported cases. [ABSTRACT FROM AUTHOR]

Abstract: The development of silica‐supported molecular catalysts for tandem reactions is an important research direction of heterogeneous catalysis. Besides their significant merits in sustainable catalytic processes, numerous strategies have been utilized to construct silica‐supported molecular catalysts. Here, we emphasize tandem reactions and summarize the recent advances in sequential organic transformations. This paper is composed of four parts. The beginning part introduces silica as supports. The second part provides a large number of examples for the construction of non‐chiral molecular catalysts used for tandem reactions. The third part offers an outline for the construction of chiral molecular catalysts used for enantioselective tandem reactions. Finally, the perspectives for the further development of silica‐supported molecular catalysts for tandem reactions are addressed. [ABSTRACT FROM AUTHOR]

Abstract: The asymmetric Mannich reaction is a very important method for C−C bond formation, and it is the classical method for the preparation of β‐amino ketones and aldehydes. The resulting β‐amino carbonyl compounds are widely found in nature, which attests to the importance of this reaction. This Focus Review provides an overview of asymmetric Mannich reactions, the various catalysts that have been used, and its applications, for papers published since 2013. [ABSTRACT FROM AUTHOR]

The efficient synthesis of chiral 2,2‐disubstituted indolin‐3‐ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one‐step construction of enantioenriched 2,2‐disubstituted indolin‐3‐ones is presented. The reaction proceeds through a self‐sorted [3+2] heteroannulation/regioselective dehydration/1,2‐ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3‐binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine‐directed regio‐ and enantioselective ortho‐Csp2‐H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well. [ABSTRACT FROM AUTHOR]

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of β‐carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of β‐carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo‐/enantio‐selective control, and good functional group tolerance, allowing access to a variety of valuable chiral β‐carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products. [ABSTRACT FROM AUTHOR]

Asymmetric sequential hydrogenations of α‐methylene γ‐ or δ‐keto carboxylic acids are established in one‐pot using a bimetallic Ru/Ru catalyst system, achieving the stereodivergent synthesis of all four stereoisomers of both chiral γ‐ and δ‐lactones with two non‐vicinal carbon stereocenters in high yields (up to 99%) and with excellent stereoselectivities (up to >99% ee and >20:1 dr). The compatibility of the two chiral Ru catalyst systems is investigated in detail, and it is found that the basicity of the reaction system plays a key role in the sequential hydrogenation processes. The protocol can be performed on a gram‐scale with a low catalyst loading (up to 11000 S/C) and the resulting products allow for many transformations, particularly for the synthesis of several key intermediates useful for the preparation of chiral drugs and natural products. [ABSTRACT FROM AUTHOR]

In this paper, phosphine-catalyzed [3 + 3] annulation of Morita-Baylis-Hillman carbonates with C, N-cyclic azomethine imines has been achieved. The reaction worked smoothly under mild conditions to afford 4,6,7,11b-tetrahydro-1 H-pyridazino[6,1- a]isoquinoline derivatives in high yields with good to excellent diastereoselectivities. [ABSTRACT FROM AUTHOR]

Most known β2-selective proteasome inhibitors suffer from relatively poor cell permeability as the result of a net positive charge caused by the basic moiety at P1. In this paper, we describe the synthesis of oligopeptide vinyl sulfones that contain different amino acids bearing amino groups with reduced basicity at P1 and/or P3. For this, we developed the first enantioselective synthesis of lysine(4-ene) and lysine(4-yne). These amino acids, as well as histidine and diaminopropionicacid-glycine, were incorporated at the P1 and/or P3 positions of oligopeptide vinyl sulfones. All inhibitors were found to inhibit β2, but with a loss of potency compared to our most potent and selective β2 inhibitor, LU-102. These results notwithstanding, our results provide important insights for the future design of β2-selective proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Disubstituted oxindoles represent an important family of bioactive compounds and synthetic derivatives that mimic natural products. The construction of the asymmetric quaternary carbon at C-3 or C-2 is therefore a challenging problem for organic chemists. In the last years, many papers have appeared on asymmetric catalytic methods for the synthesis of these compounds, in particular about spirocyclic derivatives and this literature has been largely reviewed, as well as the literature on 3-substituted-3-hydroxyoxindoles and 3-substituted-3-aminooxindoles. On the other hand, the literature on non-spirocyclic 3,3-dialkyloxindoles as well as on 2,2-disubstituted 3-indolinones has not fully reviewed since our previous review on this topic. This review aims to fill this gap covering the literature on these topics. Abbreviations: Alloc=allyloxycarbonyl; Ant=anthracenyl; BINOL=1,1′-binaphthalene-2,2′-diol; Boc= t-butoxycarbonyl; Bz=benzoyl; Cbz=benzyloxycarbonyl; CSA=camphorsulfonic acid; Cy=cyclohexyl; DABCO=1,4-diazabicyclo[2.2.2]octane; dba=bis(dibenzylideneacetone); DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; (DHQD)2AQN=hydroquinidine (anthraquinone-1,4-diyl) diether; (DHQD)2PHAL=hydroquinidine 1,4-phthalazinediyl diether; (DHQD)2PYR=hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether; DIPEA= N, N-diisopropylethylamine; esp=α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid; HFIP=1,1,1,3,3,3-hexafluoro-2-propanol; HMDS=hexamethyldisilazane; β-ICD=β-isocupreidine; LG=leaving group; Mes=2,4,6-trimethylphenyl; Moc=methoxycarbonyl; MOM=methoxymethyl; MS=molecular sieves; MsOH=methanesulfonic acid; NHC=N-heterocyclic carbene; Npt=naphthyl; PG=protecting group; Phg=phenylglycine; Phth=phthalimidyl; Piv=2,2-dimethylpropanoyl; PMB=4-methoxybenzyl; Red-Al=sodium bis(2-methoxyethoxy)aluminium hydride; Suc=succinimidyl; TBDPS= tert-butyldiphenylsilyl; TBS= tert-butyldimethylsilyl; TES=triethylsilyl; TIPS=triisopropylsilyl; TMEDA= N, N, N′,N′-tetramethylethylenediamine; TMG=1,1,3,3-tetramethylguanidine; TMS=trimethylsilyl; Ts=4-toluenesulfonyl. [ABSTRACT FROM AUTHOR]

An efficient L‐leucinol catalysed asymmetric synthesis of 3‐substitued‐3‐hydroxyoxindoles was for the first time completed under continuous flow, providing a safer route for accelerating the reaction at higher temperatures without adversely affecting enantioselectivity. Initial batch solvent screening of the isatin‐acetone aldol reaction revealed neat acetone as the media best suited in flow as it dissolved isatin and afforded (S)‐enantiomer of the adduct in 84 % ee. Solvents with Kamlet‐Taft basicity (β)>0.6 and proticity (α)≈0 had a higher solubility of isatin but poor reaction performance while solvents with β<0.2 and α<0.6 performed excellently in the reaction albeit with poor isatin solubility. The addition of 10 equivalents of water improved the neat reaction to afford 94 % yield in 93 % ee at 20 °C after 48 h. When transferred to continuous flow, complete conversion was observed in 12 h residence time at 40 °C without loss in enantioselectivity. Further substrate studies in flow were undertaken with a 4‐fold dilution and a 60 °C reaction temperature required for some derivatives. Excellent yields and enantioselectivities were obtained in most cases. [ABSTRACT FROM AUTHOR]

The development of heterogeneous catalysts for asymmetric synthesis is one of the most challenging topics in chemistry, as it allows obtaining enantiomerically pure compounds. Recently, metal layers incorporating molecular chiral cavities, obtained by electroreduction of a metal source in the simultaneous presence of a non‐ionic surfactant and asymmetric molecules, have been proposed for a wide range of applications, including enantioselective electroanalysis and electrosynthesis, as well as chiral separation. In contrast to this previous work, solely based on electrochemical phenomena, herein we designed and employed nanostructured chiral encoded Pt−Ir alloys, supported on high surface area nickel foams, as heterogeneous catalysts for the asymmetric hydrogenation of aromatic ketones. Fine‐tuning the experimental conditions allows achieving very high enantioselectivity (>80%), combined with improved catalyst stability. [ABSTRACT FROM AUTHOR]

Chiral phosphoric acid‐catalyzed couplings of C‐alkynyl N,N′‐di‐(tert‐butoxycarbonyl)‐aminals with β‐naphthols led to chiral propargylamines in moderate to high yields with high to excellent enantioselectivity, in which the reactions underwent sequential chiral phosphoric acid‐catalyzed in situ formation of N‐(tert‐butoxycarbonyl)‐imines (N‐Boc‐imines) from the aminals, and 1,2‐addition of β‐naphthols to the N‐Boc‐imines. Chiral 1,2‐dihydronaphtho[2,1‐b]furans and naphtho[2,1‐b]furans were prepared with satisfactory results when 10 mol% AgOAc and 20 mol% 2,6‐lutidine or 1.2 equiv. of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) were added to the resulting chiral propargylamines solution, respectively. [ABSTRACT FROM AUTHOR]

The Cover Feature shows the structures of fluorinated furan lignan, namely trifluoromethylated ent‐fragransin C1 and chiral 1,4‐diarylbutanetriol, which is a key intermediate. Using an acid catalyst, chiral trifluoromethylated 1,4‐diarylbutanetriol undergoes chemoselective generation of the benzylic carbocation followed by stereoselective cyclization to provide the furan product with high stereo‐selectivity. The fireworks illustrate the reaction processes and celebrate the accomplishment of the work using "Loi Kratong" festival, one of the famous Thai traditions held in full‐moon night of November, as a background. More information can be found in the Full Paper by D. Soorukram et al. [ABSTRACT FROM AUTHOR]

The Cover Feature shows a supramolecular catalytic system, envisioned as a factory machine. The worker uses a chiral cyclohexane to control the chirality in the remote rhodium machine head which does the selective hydrogenation reaction. The transfer of chirality is achieved by stacked phenyl‐phosphine gears shown in the insides of the machine. The system has enabled distant chirality transfer, named 𠄌backdoor induction", for hydrogenation of model substrates with very high selectivity (up to 97% ee). The future goal is to apply this system to industrially relevant substrates. More information can be found in the Full Paper by S. I. Kirin et al. [ABSTRACT FROM AUTHOR]

Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines. [ABSTRACT FROM AUTHOR]

An efficient total synthesis of the sesquiterpenoid (−)‐dehydrocostus lactone is reported. Our earlier approach by a domino enediyne metathesis was extended by a domino dienyne metathesis strategy to give access to suitably functionalized hydroazulene cores. Highly stereoselective asymmetric anti aldol reactions provided the enantiopure substrates for this key step of our synthesis. Multiple hydroboration/oxidation of the resulting hydroazulenes set up three out of four stereogenic centers in a single step. First, oxidation to give a diketo‐γ‐lactone enabled an enantioselective formal synthesis of the target guaianolide. Subsequently, the final steps of this approach were improved by using a double carbonyl olefination at the stage of a masked γ‐butyrolactone, which completed the synthesis in a much more efficient way. [ABSTRACT FROM AUTHOR]

An enantioselective addition reaction for the construction of 1,3‐nonadjacent stereogenic centers is developed by means of a chiral strong Brønsted base catalyst. The chiral sodium ureate catalyst efficiently promoted the reaction of α‐thioacetamides as less acidic pronucleophiles with vinyl sulfones having a variety of α‐substituents including aryl, alkyl and halo groups, and α‐phenylacrylates, accomplishing the construction of various 1,3‐nonadjacent stereogenic centers in highly diastereo‐ and enantioselective manners. This is a rare example of the construction of 1,3‐nonadjacent stereogenic centers with less acidic pronucleophiles. In addition, the application of Michael acceptors having various types of α‐substituents in a single catalyst system is achieved for the first time, demonstrating the utility of the present catalyst system for the construction of 1,3‐nonadjacent stereogenic centers. [ABSTRACT FROM AUTHOR]

The motivation of foldamer chemistry is to identify novel building blocks that have the potential to imitate natural species. Peptides and peptide mimetics can form stable helical conformations and further self-assemble into diverse aggregates in water, where it is difficult to isolate a single helix. In contrast, most 'abiotic' foldamers may fold into helical structures in solution, but are difficult to assemble into tertiary ones. It remains a challenge to obtain 'abiotic' species similar to peptides. In this paper, a novel foldamer scaffold, in which p-phenyleneethynylene units are linked by chiral carbon atoms, was designed and prepared. In very dilute solutions, these oligomers were random coils. The hexamer and octamers could form a hexagonal lyotropic liquid crystal (LC) in CH2Cl2 when the concentrations reached the critical values. The microscopic observations indicated that they could assemble into the nanofibers in the LC. Interestingly, after some LC phases were diluted at room temperature, the nanofibers could be preserved. The good stabilities of the assemblies are possibly attributed to a more compact backbone and more rigid side chains. [ABSTRACT FROM AUTHOR]

The development of sustainable processes for the valorization of byproducts and other waste streams remains an ongoing challenge in the field of catalysis. Racemic borneol, isoborneol and camphor are currently produced from α‐pinene, a side product from the production of cellulose. The pure enantiomers of these monoterpenoids have numerous applications in cosmetics and act as reagents for asymmetric synthesis, making an enzymatic route for their separation into optically pure enantiomers a desirable goal. Known short‐chain borneol‐type dehydrogenases (BDHs) from plants and bacteria lack the required specificity, stability or activity for industrial utilization. Prompted by reports on the presence of pure (−)‐borneol and (−)‐camphor in essential oils from rosemary, we set out to investigate dehydrogenases from the genus Salvia and discovered a dehydrogenase with high specificity (E>120) and high specific activity (>0.02 U mg−1) for borneol and isoborneol. Compared to other specific dehydrogenases, the one reported here shows remarkably higher stability, which was exploited to obtain the first three‐dimensional structure of an enantiospecific borneol‐type short‐chain dehydrogenase. This, together with docking studies, led to the identification of a hydrophobic pocket in the enzyme that plays a crucial role in the stereo discrimination of bornane‐type monoterpenoids. The kinetic resolution of borneol and isoborneol can be easily integrated into the existing synthetic route from α‐pinene to camphor thereby allowing the facile synthesis of optically pure monoterpenols from an abundant renewable source. [ABSTRACT FROM AUTHOR]

This work demonstrates that a tert‐leucine‐derived 2‐phenolic anilide is the efficient organocatalyst to catalyze the asymmetric cross‐aldol reaction of glyoxylate and alkyl aldehydes in high yield and enantioselectivity at room temperature. As compared to the reported simple primary amino acids, the 2‐phenolic anilide can produce two hydrogen bonds from its phenolic hydroxy and amide groups with aldehyde moiety of ethyl glyoxylate, greatly enhancing the electrophilicity of ethyl glyoxylate and effectively increasing the asymmetric induction of the aldol reaction. Additionally, the large side group‐bearing tert‐leucine is also essential to high enantioselectivity. The reaction was successfully performed on 50 mmol scale with no decrease in the yield and enantioselectivity, showing potential for the chemical production of the pharmaceutical intermediate (R)‐pantolactone with high yield and enantiopurity in an eco‐friendly method. [ABSTRACT FROM AUTHOR]

The coenzyme A (CoA) esters of 4-methylalkanoic acids are pivotal intermediates in metabolism of alkanes by anaerobic bacteria found in O2-deprived environments. A generic method for synthesis of either (R)- or (S)-acid in high enantiomeric purity from enantiomers of methyl 3-hydroxy-2-methylpropionate is described for (R)- and (S)-4-methyloctanoic acid and (R)-4-methyldodecanoic acid. In a typical procedure silylprotection of methyl (S)-3-hydroxy-2-methylpropionate was followed by reduction of the ester to a primary alcohol, which was tosylated. Cu(I)-catalysed cross-coupling of the tosylate with propylmagnesium chloride followed by deprotection, tosylation and base-induced reaction with di-t-butyl malonate, gave di-t-butyl (R)-(2-methylhexyl)malonate. Microwave heating of the diester in 2,2,2-trifluoroethanol gave a 42% overall yield of (R)-4-methyloctanoic acid, which was shown to be the enantiomer derived by metabolism of hexane by proteobacterium Aromatoleum sp. HxN1. Deprotection of the diester with trifluoroacetic acid gave (R)-2-(2-methylhexyl)malonic acid, which is the biological precursor of (R)-4-methyloctanoic acid (via CoA esters). [ABSTRACT FROM AUTHOR]

Developing new transition metal‐catalyzed asymmetric cycloadditions for the synthesis of five‐membered carbocycles (FMCs) is a research frontier in reaction development due to the ubiquitous presence of chiral FMCs in various functional molecules. Reported here is our discovery of a highly enantioselective intramolecular [3+2] cycloaddition of yne‐alkylidenecyclopropanes (yne‐ACPs) to bicyclo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules using a cheap Co catalyst and commercially available chiral ligand (S)‐Xyl‐BINAP. This reaction avoids the use of precious Pd and Rh catalysts, which are usually the choices for [3+2] reactions with ACPs. The enantiomeric excess in the present reaction can be up to 92 %. Cationic cobalt(I) species was suggested by experiments as the catalytic species. DFT calculations showed that this [3+2] reaction starts with oxidative cyclometallation of alkyne and ACP, followed by ring opening of the cyclopropyl (CP) group and reductive elimination to form the cycloadduct. This mechanism is different from previous [3+2] reactions of ACPs, which usually start from CP cleavage, not from oxidative cyclization. [ABSTRACT FROM AUTHOR]

The stereoselective synthesis of P‐chirogenic diphosphinotriazoles using ephedrine methodology was described. The coordination behavior of these compounds as P,P‐ligands has been demonstrated by the preparation as well as the spectroscopic and X‐ray crystallographic analyses of a palladium complex. The efficiency of these new P‐chirogenic diphosphines in the palladium‐catalyzed asymmetric allylic substitution reaction was also evaluated. [ABSTRACT FROM AUTHOR]

A short, efficient, practical, and protecting-group-free diastereoselective total synthesis of (±)-6- epi-cleistenolide ( 1) has been achieved in five steps in 60 % overall yield. The use of a chemoenzymatic approach also gave (-)-6- epi-cleistenolide ( 1) (>99.9 % ee). The Achmatowicz reaction, chemoselective oxidation of a hemiacetal, diastereoselective 1,3- anti reduction of a β-hydroxy ketone, and enzymatic resolution of a 1,3-diol are the key features of this linear total synthesis. The synthetic strategy demonstrated in this paper could be extended for an asymmetric total synthesis of (-)-cleistenolide ( 1) and related biologically active natural products. [ABSTRACT FROM AUTHOR]

P‐chirogenic compounds are useful ligands and organocatalysts in asymmetric synthesis. However, the lack of preparative methods and their configurational instability have significantly hampered their development. Herein, we report a simple strategy for the preparation of enantiomerically pure P,C‐chirogenic diphosphines. Amidation of the borane adducts of rac‐phosphinobenzoic acids with enantiomerically pure trans‐1,2‐diaminocyclohexane afforded a 1:2:1 mixture of the diastereomers (C*,C*,Rp,Rp), (C*,C*,Rp,Sp), and (C*,C*,Sp,Sp), which were separated by column chromatography on silica gel. The prepared (C*,C*,Rp,Rp) and (C*,C*,Sp,Sp) stereoisomers were identical to those obtained from the enantiopure phosphines, which were synthesized by a multi‐step route using chiral auxiliaries. Hence, this simple, short and convenient route towards P,C‐chirogenic diphosphines obviates the use of chiral auxiliaries and enables the access to diphosphines with differently configured P‐stereocenters. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) is an in vivo process leading to free radical overproduction, which triggers polyunsaturated fatty acid (PUFA) peroxidation resulting in the formation of racemic non‐enzymatic oxygenated metabolites. As potential biomarkers of OS, their in vivo quantification is of great interest. However, since a large number of isomeric metabolites is formed in parallel, their quantification remains difficult without primary standards. Three new PUFA‐metabolites, namely 18‐F3t‐isoprostane (IsoP) from eicosapentaenoic acid (EPA), 20‐F4t‐neuroprostane (NeuroP) from docosahexaenoic acid (DHA) and 20‐F3t‐NeuroP from docosapentaenoic acid (DPAn‐3) were synthesized by two complementary synthetic strategies. The first one relied on a racemic approach to 18(RS)‐18‐F3t‐IsoP using an oxidative radical anion cyclization as a key step, whereas the second used an enzymatic deracemization of a bicyclo[3.3.0]octene intermediate obtained from cyclooctadiene to pursue an asymmetric synthesis. The synthesized metabolites were applied in targeted lipidomics to prove lipid peroxidation in edible oils of commercial nutraceuticals. [ABSTRACT FROM AUTHOR]

Efficient synthesis of optically active N‐fused 1,3‐oxazolidines containing quaternary and tertiary stereocenters was achieved via Pd‐catalyzed asymmetric (3+2) cycloadditions of sulfamate‐derived cyclic imines and vinylethylene carbonates. Using a chiral phosphoramidite ligand, the cycloadditions proceeded effectively providing sulfamidate‐fused 1,3‐oxazolidines in high yields (up to 96%) with stereoselectivities (up to 25:1 dr; >99% ee). Additionally, the scale‐up reaction and further transformations of the product were also achieved demonstrating the synthetic utility toward the construction of useful heterocycles such as chiral oxazoline bearing a quaternary stereocenter. [ABSTRACT FROM AUTHOR]

This work reports selective synthesis of asymmetric (‐) α–Hydroxyl Amides like N‐aryl mandelamides via asymmetric transfer hydrogenation (ATH) of α–keto Amides like N‐aryl benzoyl formamides using Ru‐Tethered TsDPEN catalyst. The electronic and steric effect at ortho position leading to high enantioselectivity for ATH of carbonyl, sandwiched between two sp2 carbon is studied. A wide range of mono and di ortho substituted α–hydroxyl amide is synthesized using this protocol with good enantioselectivity. [ABSTRACT FROM AUTHOR]