Asymmetric Addition Reactions Research Articles

Novel Stereo‐Induction Pattern in Pudovik Addition/Phospha‐Brook Rearrangement Towards Chiral Trisubstituted Allenes

AbstractDespite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide‐mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha‐Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central‐to‐axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo‐induction pattern in the Pudovik addition/phospha‐Brook rearrangement cascade reaction.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

S/CuMgAl-41 as an efficient Hybrid catalyst for asymmetric addition reaction in isopropyl alcohol solvent

In this study, a series catalysts of CuMgAl-LDHs were successfully prepared by co-precipitation method. Subsequently, the catalyst S/CuMgAl-41 was prepared by modifying CuMgAl-41 with thiourea. The physical and chemical properties of the catalyst were characterized by XRD, N2 adsorption-desorption, SEM, ICP, FT-IR, TG-DSC and XPS. The catalytic performance of the catalyst was investigated. It showed that S/CuMgAl-41 exhibited synergistic catalytic activity with better ee value due to both acidic and alkaline active sites and confined spaces with proper interlayer spacing. When isopropyl alcohol was chosen as solvent, the S/CuMgAl-41 has the best catalytic effect for asymmetric aldol addition reaction between p-nitrobenzaldehyde (p-NBD) and acetone. Additionally, the process conditions for optimizing the asymmetric addition reaction have been thoroughly studied. It was found that S/CuMgAl-41 exhibited good reusability and stability. Moreover, the asymmetric aldol addition of acetone and p-NBD catalyzed by S/CuMgAL-41 can occur due to the result of synergistic effects of various factors, including acid-base active center, hydrogen bond, confined effect and anchoring effects between hydrotalcite laminate of S/CuMgAL-41. This novel catalytic design provides a new idea for asymmetric synthesis of p-NBD and acetone.

Platinum/Copper Dual-Catalyzed Asymmetric Vinylogous Addition Reactions for the Synthesis of Functionalized Indoles.

The development of multicomponent ligands to improve catalytic reactivity and selectivity remains a significant challenge for the synthesis of chiral building blocks. Here, a modular synthesis of structurally diverse multiligated platinum complexes, characterized by X-ray crystallography, was revealed to open up a previously inaccessible reaction space. A library of more than 16 binary component-ligated platinum complexes was identified as a practical toolkit to enable faster screening. The isolated bench-stable Pt(II)(oxazoline)(phosphine) complex paired with a chiral copper complex exhibits fundamentally new cooperative reactivity. The newly designed Pt/Cu dual catalytic system contributed to the development of highly enantioselective vinylogous addition reactions between a Pt-activated electrophilic α,β-unsaturated carbene and a Cu-activated nucleophile, resulting in a reliable process for the asymmetric synthesis of valuable functionalized indoles in good yields and excellent enantioselectivities.

Platinum/Copper Dual‐Catalyzed Asymmetric Vinylogous Addition Reactions for the Synthesis of Functionalized Indoles

AbstractThe development of multicomponent ligands to improve catalytic reactivity and selectivity remains a significant challenge for the synthesis of chiral building blocks. Here, a modular synthesis of structurally diverse multiligated platinum complexes, characterized by X‐ray crystallography, was revealed to open up a previously inaccessible reaction space. A library of more than 16 binary component‐ligated platinum complexes was identified as a practical toolkit to enable faster screening. The isolated bench‐stable PtII(oxazoline)(phosphine) complex paired with a chiral copper complex exhibits fundamentally new cooperative reactivity. The newly designed Pt/Cu dual catalytic system contributed to the development of highly enantioselective vinylogous addition reactions between a Pt‐activated electrophilic α,β‐unsaturated carbene and a Cu‐activated nucleophile, resulting in a reliable process for the asymmetric synthesis of valuable functionalized indoles in good yields and excellent enantioselectivities.

Synthesis of Aminoalkyl Sclareolide Derivatives and Antifungal Activity Studies.

Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4-6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.

Progress in <italic>N</italic>,<italic>N′</italic>-dioxide/metal complex-catalyzed asymmetricreactions of ylides

<p indent="0mm">Ylides, as inner salt molecules, possess the properties of high activity and diverse reactivity. They are attractive for their convenient synthesis of compounds containing heteroatom. On the other hand, privileged Feng <italic>C</italic>₂ symmetric <italic>N</italic>,<italic>N′</italic>-dioxide ligands can coordinate with plenty of main group metals, transition metals, and rare earth metals, offering the opportunity to efficiently catalyze more than 70 types of asymmetric reactions. In this article, the<italic>N</italic>,<italic> N′</italic>-dioxide/metal complexes-promoted asymmetric reactions of sulfur ylides, nitrium ylides and iodonium ylides were reviewed, including asymmetric addition, cycloaddition, rearrangement and domino reactions, through Lewis acid catalysis, bimetallic relay catalysis, and photocatalysis. The possible reaction mechanism including transition state was emphasized. Last, the challenges and prospects of the <italic>N</italic>,<italic>N′</italic>-dioxide/metal complex-promoted asymmetric reactions of ylides were discussed.

Investigation of the Asymmetric Addition Reactions Induced by Pentacoordinated Hydrospirophosphorane Substrate.

Pentacoordinated bisaminoacyl hydrospirophosphoranes were first found to induce the asymmetric addition reactions as a novel chiral organic framework. Asymmetric addition reactions of bisaminoacyl hydrospirophosphoranes with aromatic aldehyde and in situ generated imine were investigated, and the corresponding α-hydroxyspirophosphonates and α-amino spirophosphonates were obtained. The addition reaction of hydrospirophosphoranes with ΔP configuration showed better stereoselectivity than that with ΛP configuration, not only for the addition reaction to aromatic aldehyde but also to in situ generated imine. Furthermore, the stereochemical mechanisms of asymmetric addition reactions induced by pentacoordinated hydrospirophosphorane were proposed by 31P NMR tracing experiment and X-ray diffraction analysis.

The recent advances in the contribution of chiral triarylmethanes and tetraarylmethanes with organocatalysts

Chiral triarylmethane skeleton is an important structural unit of many known compounds that are widely applied in organic functional materials and pharmaceuticals. Thus, the efficient construction of this class of compounds has attracted intensive attention from chemists. There are two main difficulties in synthesizing this type of compound: (i) the steric resistance of molecular structures would make it hard to be constructed; (ii) there are three similar aryl groups on the stereocenter, which is difficult to achieve stereo-identification. At present, the most common strategy is to introduce the third aryl group into a diarylmethane framework through the asymmetric Friedel-Crafts reaction or addition reaction of electron-rich arenes, so as to construct chiral triarylmethanes. In this review, we summarized the recent developments in the construction of various chiral triarylmethanes and chiral tetraarylmethanes from easily accessible compounds under organocatalytic conditions. This article describes based on the types of electrophilic reagents, mainly including quinone methides, indole imine methides, and azadienes. At the same time, we also emphasize the mechanism of each representative reaction, which might enlighten the future development of this field.

Solid Phase‐Mediated Asymmetric Palladium‐Catalyzed Hydroalkoxylation of Alkoxyallene

AbstractThe Pd‐catalyzed asymmetric addition reaction of solid phase‐supported alcohol with ene‐alkoxyallenes is reported. Combined with the subsequent metal catalysis, this reaction gave access to various monosaccharides with no need for isolation of the intermediates. Potential utility of the method in the oligosaccharide synthesis was demonstrated by the synthesis of (α)‐mannose disaccharide.magnified image

Diastereoselective and Enantioselective Synthesis of α-p-Methoxyphenoxy-β-Lactones: Dependence on the Stereoelectronic Properties of the β-Hydroxy-α-p-Methoxyphenoxycarboxylic Acid Precursors.

Treatment of β-hydroxy-α-p-methoxyphenoxy carboxylic acids derived from the asymmetric glycolate aldol addition reaction with p-nitrobenzenesulfonyl chloride yielded divergent results depending on the nature of the β-substituent of the carboxylic acid. Substrates bearing either alkyl substituents (R = -n-butyl, -n-octyl, -benzyl, isopropyl, -tert-butyl) or aryl systems bearing electron-withdrawing substituents (R = -p-C6H4Cl, -p-C6H4Br, -p-C6H4NO2) yielded β-lactones. In contrast, α-p-methoxyphenoxy-β-hydroxycarboxylic acids bearing electron-donating aryl groups or the sterically demanding 2-naphthyl group formed (Z)-alkenes.

Catalytic Asymmetric Synthesis of Axially Chiral 3,3'‐Bisindoles by Direct Coupling of Indole Rings

Comprehensive SummaryA new strategy for the enantioselective synthesis of axially chiral 3,3'‐bisindoles was devised by the direct coupling of two indole rings. This strategy makes use of the C3‐umpolung reactivity of 2‐indolylmethanols, which enables the catalytic asymmetric addition reaction of 2‐indolylmethanols with rationally designed 2‐substituted indoles, thus constructing axially chiral 3,3'‐bisindole scaffolds in overall excellent yields (up to 98%) with high enantioselectivities (up to 96 : 4 er). This approach not only has overcome the challenges in constructing axially chiral five‐five‐membered heterobiaryls, but also represents a new application of the C3‐umpolung reactivity of 2‐indolylmethanols in asymmetric catalysis. More importantly, this class of axially chiral 3,3'‐bisindoles can undergo a variety of post‐functionalizations to give axially chiral 3,3'‐bisindole‐based organocatalysts, which have found their preliminary applications in asymmetric catalysis.

Direct Asymmetric Addition of Heteroatom Nucleophiles to Imines

AbstractThe direct asymmetric addition of heteroatom nucleophiles to imines represents one of the most efficient tools for the formation of carbon‐heteroatom bonds and has received much interest recently. The review is devoted to the asymmetric addition reactions of non‐carbon nucleophiles to imines. The present review is divided into five main sections: reactions with N‐nucleophiles; reactions with P‐nucleophiles; reactions with O‐nucleophiles; reactions with S‐nucleophiles; reactions with Se‐nucleophiles. It has been seen that chiral catalysts such as quinines, BINOLs, chiral phosphoric acids as well as various Brønsted and Lewis acids are the source of asymmetry of the presented reactions of asymmetric addition of non‐carbon nucleophiles to imines.magnified image

Hybrid Catalysts from Copper Biosorbing Bacterial Strains and Their Recycling for Catalytic Application in the Asymmetric Addition Reaction of B2(pin)2 on α,β-Unsaturated Chalcones

The recycling of heavy metal contaminants from wastewater as a source of valuable products perfectly fits with the principles of a Circular Economy system in view of restoring pollutants back into the system endowed with new social and economic benefits. Heavy metals are often present in such a low concentration that it makes the removal efficiency difficult to realize through the conventional physicochemical methods with high selectivity. Biosorption, conversely, by EPSs (extracellular polymeric substances) produced by several bacterial cells’ strains, is gaining a great deal of attention as an economic, efficient and sustainable depolluting process of wastewater from metal cations such as copper. Metal coordination to EPS components was thus deeply investigated by 1H NMR titration experiments. The 1,10–Phenanthroline–copper complex was exploited for quantifying the ability of different strains to sequester copper by a practical UV-Vis spectrophotometric method. The obtained data distinguished Serratia plymuthica strain SC5II as the bacterial strain displaying copper-adsorbing properties higher than any other, with Stenotrophomonas sp. strain 13a resulting in the worst one. Different analytical techniques, i.e., Dynamic Light Scattering (DLS), FT-IR analysis and SEM spectroscopy were thus employed to rationalize these results. Finally, the obtained copper chelates were successfully employed as hybrid catalysts in the asymmetric boron addition to α,β-unsaturated chalcones for the synthesis of valuable pharmaceutical intermediates, thus placing waste management in a new circular perspective.

Investigation of the effect of microflow reactor diameter on condensation reactions in l-proline-immobilized polymer monoliths

Structure of porous monolith in a microflow reactor and the reactor diameter affect the residence time distribution (RTD). The effect of the RTD on the catalytic efficiency of the asymmetric aldol addition reaction was examined.

Asymmetric Addition and Cycloaddition Reactions with Ylidene‐Five‐Membered Heterocycles

AbstractFive‐membered heterocycles bearing an exocyclic double bond have been successfully used as substrates in asymmetric addition and cycloaddition reactions. Ylidene‐heterocycles are attractive substrates due to their high functionalization and the presence of an electrophilic conjugated exocyclic double bound that can participate in nucleophilic addition reactions as well as cycloaddition reactions, which may be triggered by the formation of aromatic intermediates or products in many cases. During the last decades, catalytic methodologies have been developed using ylidene‐heterocycles as substrates in order to synthesize useful optically active heterocyclic derivatives. 4‐Ylidene‐pyrazol‐5‐ones, isoxazolin‐5‐ones, 2,3‐dioxopyrrolidines, rhodanines, oxazolidindiones, Erlenmeyer‐Ploch azlactones and 5‐ylidene‐thiazolones have been successfully used as substrates in asymmetric reactions. This review collects the powerful research in asymmetric addition and cycloaddition reactions where ylidene‐five‐membered heterocycles have been used.magnified image

Unlocking Asymmetric Michael Additions in an Archetypical Class I Aldolase by Directed Evolution.

Class I aldolases catalyze asymmetric aldol addition reactions and have found extensive application in the biocatalytic synthesis of chiral β-hydroxy-carbonyl compounds. However, the usefulness of these powerful enzymes for application in other C–C bond-forming reactions remains thus far unexplored. The redesign of class I aldolases to expand their catalytic repertoire to include non-native carboligation reactions therefore continues to be a major challenge. Here, we report the successful redesign of 2-deoxy-d-ribose-5-phosphate aldolase (DERA) from Escherichia coli, an archetypical class I aldolase, to proficiently catalyze enantioselective Michael additions of nitromethane to α,β-unsaturated aldehydes to yield various pharmaceutically relevant chiral synthons. After 11 rounds of directed evolution, the redesigned DERA enzyme (DERA-MA) carried 12 amino-acid substitutions and had an impressive 190-fold enhancement in catalytic activity compared to the wildtype enzyme. The high catalytic efficiency of DERA-MA for this abiological reaction makes it a proficient “Michaelase” with potential for biocatalytic application. Crystallographic analysis provides a structural context for the evolved activity. Whereas an aldolase acts naturally by activating the enzyme-bound substrate as a nucleophile (enamine-based mechanism), DERA-MA instead acts by activating the enzyme-bound substrate as an electrophile (iminium-based mechanism). This work demonstrates the power of directed evolution to expand the reaction scope of natural aldolases to include asymmetric Michael addition reactions and presents opportunities to explore iminium catalysis with DERA-derived catalysts inspired by developments in the organocatalysis field.

Greener Approaches to Selected Asymmetric Addition Reactions Relevant to Drug Development

Asymmetric organic synthesis is of paramount importance in the development of drugs. Asymmetric addition reactions such as aldol reaction, Michael addition, and Mannich addition reactions are important carbon-carbon bond-forming reactions and have been employed in the synthesis of a broad range of biologically important molecules. Many of these reactions have been developed under solvent-free conditions or in greener solvents like water. Several reactions have been developed at room temperature or by using a non-conventional energy source such as microwave irradiation. Several greener catalysts have been developed for such reactions. The present review article discusses the application of green chemistry parameters in the development of selected asymmetric addition reactions leading to biologically important molecules during the last ten years. Asymmetric aldol reactions, asymmetric Michael reactions, and different asymmetric addition reactions involving imines such as Mannich reaction, aza-benzoin reaction, etc. in aqueous media or under solvent-free conditions have been reviewed. Application of different types of catalysts such as prolinamides, 1,2-diamines, polymer and magnetic nanoparticle-supported chiral catalysts is demonstrated.

Palladium-Catalyzed Asymmetric Decarboxylative Addition of β-Keto Acids to Heteroatom-Substituted Allenes.

The Pd-catalyzed asymmetric addition reaction of β-keto acids to heteroatom-substituted allene is reported. This reaction generates β-substituted ketones in an asymmetric manner through a branch-selective decarboxylative allylation pathway. The reaction accommodates various alkoxyallenes as well as amidoallenes.

Palladium‐Catalyzed Asymmetric Decarboxylative Addition of β‐Keto Acids to Heteroatom‐Substituted Allenes

AbstractThe Pd‐catalyzed asymmetric addition reaction of β‐keto acids to heteroatom‐substituted allene is reported. This reaction generates β‐substituted ketones in an asymmetric manner through a branch‐selective decarboxylative allylation pathway. The reaction accommodates various alkoxyallenes as well as amidoallenes.