Catalytic Enantioselective Reaction Research Articles

Synthesis of Alkene Atropisomers with Multiple Stereogenic Elements via Catalytic Asymmetric Rearrangement of 3‐Indolylmethanols

AbstractCatalytic enantioselective preparation of alkene atropisomers with multiple stereogenic elements and discovery of their applications have become significant but challenging issues in the scientific community due to the unique structures of this class of atropisomers. We herein report the first catalytic atroposelective preparation of cyclopentenyl[b]indoles, a new kind of alkene atropisomers, with stereogenic point and axial chirality via an unusual rearrangement reaction of 3‐indolylmethanols under asymmetric organocatalysis. Notably, this novel type of alkene atropisomers have promising applications in developing chiral ligands or organocatalysts, discovering antitumor drug candidates and fluorescence imaging materials. Moreover, the theoretical calculations have elucidated the possible reaction mechanism and the non‐covalent interactions to control the enantioselectivity. This approach offers a new synthetic strategy for alkene atropisomers with multiple stereogenic elements, and represents the first catalytic enantioselective rearrangement reaction of 3‐indolylmethanols, which will advance the chemistry of atropisomers and chiral indole chemistry.

Synthesis of Alkene Atropisomers with Multiple Stereogenic Elements via Catalytic Asymmetric Rearrangement of 3-Indolylmethanols.

Catalytic enantioselective preparation of alkene atropisomers with multiple stereogenic elements and discovery of their applications have become significant but challenging issues in the scientific community due to the unique structures of this class of atropisomers. We herein report the first catalytic atroposelective preparation of cyclopentenyl[b]indoles, a new kind of alkene atropisomers, with stereogenic point and axial chirality via an unusual rearrangement reaction of 3-indolylmethanols under asymmetric organocatalysis. Notably, this novel type of alkene atropisomers have promising applications in developing chiral ligands or organocatalysts, discovering antitumor drug candidates and fluorescence imaging materials. Moreover, the theoretical calculations have elucidated the possible reaction mechanism and the non-covalent interactions to control the enantioselectivity. This approach offers a new synthetic strategy for alkene atropisomers with multiple stereogenic elements, and represents the first catalytic enantioselective rearrangement reaction of 3-indolylmethanols, which will advance the chemistry of atropisomers and chiral indole chemistry.

Development of Catalytic Enantioselective Mannich Reactions Using Esters.

Catalytic enantioselective Mannich reactions of simple nonactivated esters proceeded using a chiral potassium strong base catalyst prepared from a chiral bisoxazoline and potassium hexamethyldisilazide. Alkyl acetates, alkyl propionates, and an alkyl butyrate were employed as the simple esters, and the desired reactions proceeded smoothly to afford Mannich products in good to high yields with high enantioselectivities. One of the products was successfully employed in the asymmetric total synthesis of Maraviroc.

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Tartaric acid-derived chiral carbon nanodots for catalytic enantioselective ring-opening reactions of styrene oxide.

Chiral carbon nanodots (CNDs) were fabricated through the hydrothermal processing of sulfanilic acid and chiral tartaric acid, exhibiting outstanding catalytic performance for the chiral catalysis of the ring-opening reaction. Furthermore, the catalytic mechanism was proposed to understand the link between the chiral structure and the performance of the catalyst.

Recent progress in the catalytic enantioselective reactions of 1,1-diborylalkanes.

Organoboron compounds are environmentally benign, have low toxicity and are versatile reagents that are extensively employed in organic synthesis, especially in the realm of asymmetric synthesis. The last several decades have witnessed a tremendous outburst of asymmetric reactions based on various organoboron compounds. Among them, 1,1-diborylalkanes, which contain two boryl groups at the same sp3-carbon atom, are regarded as some of the most versatile and powerful reagents for their unique structure and unusual reaction mode in organic synthesis. Moreover, owing to the stabilizing effect of the empty p-orbital of the neighboring boron atoms and the inherent good steric-hindrance, 1,1-diborylalkanes often exhibit extraordinary reactivity and stereoselectivity compared to other kinds of organoboron compounds in asymmetric synthesis. Herein, the present highlight summarizes and discusses the recent progress achieved in the catalytic enantioselective reactions of 1,1-diborylalkanes during the past decade.

The Intermolecular Pauson‐Khand Reaction: Applications, Challenges, and Opportunities

AbstractThe rapid assembly of complex organic molecules from simple and structurally diverse building blocks is a prevalent challenge in organic synthesis. The Pauson‐Khand reaction (PKR) is a method of choice for the construction of five membered rings that has historically been popularized as a late‐stage intramolecular cyclization method. The intermolecular version of the PKR, on the other hand, constitutes a powerful approach for the rapid assembly of densely functionalized cyclopentanic cores at early stages of a synthetic sequence. Despite its potential, the intermolecular PKR is much less prevalent in the organic synthesis literature due to several historical limitations, most importantly a reduced scope with respect to the alkene component of the reaction. The last decade has witnessed important developments in the area including a) experimental and theoretical studies that provide a good mechanistic understanding of the reaction and its selectivity, b) methodological developments that have broadened the scope of potential alkene partners, and c) the development of catalytic enantioselective versions that provide useful levels of enantioselectivity. In parallel, remarkable synthetic applications of the intermolecular PKR have emerged, including (enantioselective) total syntheses of complex natural products (polycyclic terpenes, alkaloids, prostanes) as well as examples of industrial relevance. A fundamental limitation of the PKR that needs to be addressed in the future is the current lack of a ligand‐accelerated version of the reaction, which would be a promising advance towards developing more efficient and general catalytic (enantioselective) reactions.

Tandem Isomerization/α,β-Site-Selective and Enantioselective Addition Reactions of N-(3-Butynoyl)-3,5-dimethylpyrazole Induced by Chiral π-Cu(II) Catalysts.

Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,β-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,β-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Cluster Preface: Modern Boron Chemistry: 60 Years of the ­Matteson Reaction

James P. Morken (left) was born in Concord, California (USA) and obtained his B.S. in chemistry in 1989 from UC Santa Barbara (USA) working with Prof. Bruce Rickborn. He obtained his Ph.D. from Boston ­College (USA) in 1995 with Prof. Amir Hoveyda and was an NSF ­Postdoctoral Fellow with Prof. Stuart Schreiber at Harvard University (USA). In 1997, he became an Assistant Professor of Chemistry at the University of North Carolina at Chapel Hill (USA). He was promoted to Associate Professor in 2002 and in 2006 joined the faculty of Boston College (USA). In 2014, he was named the Louise and James Vanderslice and Family Chaired Professor of Chemistry at Boston College. Professor Morken’s research focuses on the development of transition-metal-­catalyzed asymmetric processes and their use in complex molecule synthesis. He is particularly interested in the study and development of catalytic enantioselective reactions involving organoboron reagents. Varinder K. Aggarwal (right) studied chemistry at Cambridge University and received his Ph.D. in 1986 under the guidance of Dr. Stuart ­Warren. After postdoctoral studies under Prof. Gilbert Stork at Columbia University (1986–1988), he returned to the UK as a lecturer at Bath University. In 1991, he moved to Sheffield University, where he was promoted to professor in 1997. In 2000, he moved to Bristol University, where he holds the Chair in Synthetic Chemistry. His research interests include the development of new catalytic processes for asymmetric synthesis, the development of chiral carbenoids and their use and subsequent applications in catalysis and synthesis, and the development of new methodology and its applications in synthesis and the total synthesis of biologically important targets.

Rhodium‐Catalyzed Direct Enantioselective Alkynylation of Trifluoropyruvates with Terminal 1,3‐Diynes

AbstractA direct catalytic enantioselective alkynylation reaction of trifluoropyruvates with terminal 1,3‐diynes was achieved by using C2‐symmetric NCN pincer rhodium (III) complexes with bis(imidazolinyl)phenyl ligands. This protocol is effective for enantioselective synthesis of optically active trifluoromethylated tertiary alcohols with the diyne moiety. A variety of electronically and structurally diverse terminal 1,3‐diynes are well tolerated. Furthermore, the catalytic reaction is applicable to preparation of both enantiomers of the chiral CF3‐containing conjugated diynols with high enantioselectivity.

Enantioselective Friedel-Crafts Reaction of Heteroaromatic Compounds with Glyoxals Catalyzed by Chiral Oxazaborolidinium Ion Catalyst.

A catalytic enantioselective Friedel-Crafts reaction of various heteroaromatic compounds with glyoxals has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxyketones in high yield (up to 96%) with excellent enantioselectivity (up to >99% ee). The synthetic utility of this method was illustrated by conversion of the products to various derivatives such as 1,2-diol and β-amino alcohol.

Chiral Organocatalysts in Enantioselective CO2 Utilization Reactions

AbstractThe development of efficient CO2 utilization reactions has gained a significant amount of attention in recent years. Although transformations of CO2 to produce basic chemicals have been extensively investigated, the development of catalytic enantioselective CO2 utilization reactions for the preparation of fine chemicals remains limited at this stage. Several excellent methods for catalytic enantioselective CO2 utilization using chiral metal complex catalysts have been reported. Many researchers have also focused on developing organocatalyzed approaches to enantioselective CO2 utilization, and several excellent examples have appeared in recent years. Herein, recent advances in catalytic enantioselective CO2 utilization reactions using chiral organocatalysts are reviewed to provide a forecast for organocatalyzed enantioselective CO2 utilization research.

Enantioselective catalytic Strecker reaction on cyclic (Z)-aldimines in flow: reaction optimization and sustainability aspects

Catalytic enantioselective Strecker reactions on an achiral substrate using sub-stoichiometric amounts of a chiral catalyst represent an evolving key strategy for the effective synthesis of α-amino nitriles. We herein disclosed the set-up of a flow-based methodology for enantioselective Strecker, employing ethyl cyanoformate as a relatively safe cyanide source, a cinchona-based catalyst, and methanol as additive. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, the optimum solvent for the flow synthesis, minimum catalyst loading, additive, temperature, and residence time. The newly developed method allows straightforward reaction channeling towards the fast and complete formation of the α-amino nitrile products, thus reducing the yield drop due to indolenine degradation during long-lasting batch-wise reactions. Moreover, we herein provide preliminary hints for sustainability, by proposing a simple procedure for catalyst recycling, thus opening the way for further optimization of the proposed methodology.Graphical

Asymmetric α-Cyanation of β-Keto Esters Catalyzed by Chiral Tin Alkoxides

AbstractA catalytic enantioselective α-cyanation reaction of β-keto esters with p-toluenesulfonyl cyanide (TsCN) as a cyanating reagent was achieved using an (R)-BINOL-derived chiral tin dibromide possessing 4-tert-butylphenyl groups at the 3- and 3′-positions as a chiral precatalyst in the presence of sodium ethoxide in ethanol. Optically active α-cyano-β-keto esters having a chiral quaternary carbon were obtained in good to high yields under the influence of the chiral tin diethoxide generated in situ.

Recent Advances in Enantioselective Catalytic Electrochemical Organic Transformations

Different approaches can be undertaken to realise a stereoselective electrochemical synthesis. Significant contributions to enantioselective electrochemical organic synthesis have been reported and largely reviewed in recent years. However, the development of general strategies for the electrochemical enantiocontrol of a transformation still presents considerable challenges; in particular, relatively few contributions of highly enantioselective catalytic electrochemical reactions have been reported to date. In this review article, the most recent examples of asymmetric electrochemical catalysis are discussed. The article is organised by the three types of enantioselective catalysis: metal-based catalysis, organocatalysis and biocatalysis; in each section, the most significant and recent advances are presented and discussed.

Dirhodium(II)-catalyzed enantioselective cyclopropenation of internal alkynes with trifluoromethyl carbene

Catalytic enantioselective reactions of trifluoromethyl carbene represent a powerful method for the construction of chiral trifluoromethyl-functionalized molecules, but the utilization of less reactive internal alkynes remains a persistent challenge in this domain. Herein, we report a chiral dirhodium(II) complex-catalyzed enantioselective cyclopropenation reaction of disubstituted alkynes by using 2,2,2-trifluorodiazoethane (CF3CHN2) as the trifluoromethyl carbene precursor. Achiral axial ligation by solvent molecules proves to be a key to improve the reactivity and control the stereoselectivity of metallocarbene species. This transformation provides efficient access to a wide range of enantioenriched trifluoromethyl group-substituted cyclopropenes, cyclopropanes, fused cyclopropane derivatives, and cyclopropyl boronate. The presented methodology constitutes a practical solution to a long-standing hurdle in catalytic enantioselective cyclopropenation of trifluoromethyl carbene with internal alkynes.

Desymmetrization of Vicinal Bis(boronic) Esters by Enantioselective Suzuki-Miyaura Cross-Coupling Reaction.

The development of an enantioselective catalytic Suzuki-Miyaura reaction that applies to meso 1,2-diborylcycloalkanes is described. This reaction provides a modular route to enantiomerically enriched substituted carbocycles and heterocycles that retain a synthetically versatile boronic ester. With appropriately constructed substrates, compounds bearing additional stereogenic centers and fully substituted carbon atoms can be generated in a straightforward fashion. Preliminary mechanistic experiments suggest that substrate activation arises from the cooperative effect of vicinal boronic esters during the transmetalation step.

Asymmetric reactions involving aryne intermediates.

Although arynes are usually considered fleeting intermediates, they are highly valuable synthons because they enable the introduction of aromatic rings and the simultaneous formation of new bonds at two sites. Although catalytic reactions using transition metals are excellent method for constructing complex polycyclic aromatic molecules in a single step, the use of asymmetric catalysis for the capture of arynes remains a crucial goal for the progress of aryne chemistry. Catalytic asymmetric reactions of arenes are challenging, requiring sufficient interactions between the neutral and highly reactive short-lived aryne intermediates in a stereo-controlled fashion. In addition, spontaneous decomposition, as well as side reactions, has hindered their development and, until recently, highly enantioselective reactions using arynes had remained elusive. This Review highlights asymmetric reactions using arynes, featuring diastereoselective, enantioselective and catalytic enantioselective reactions.

Electrophotochemical Metal-Catalyzed Enantioselective Decarboxylative Cyanation.

In contrast to the rapid growth of electrophotocatalysis in recent years, enantioselective catalytic reactions powered by this unique methodology remain rare. In this work, we report an electrophotochemical metal-catalyzed protocol for direct asymmetric decarboxylative cyanation of aliphatic carboxylic acids. The synergistic merging of electrophotochemical cerium catalysis and asymmetric electrochemical copper catalysis permits mild reaction conditions for the formation and utilization of the key carbon centered radicals by combining the power of light and electrical energy. Electrophotochemical cerium catalysis enables radical decarboxylation to produce alkyl radicals, which could be effectively intercepted by asymmetric electrochemical copper catalysis for the construction of C-CN bonds in a highly stereoselective fashion. This environmentally benign method smoothly converts a diverse array of arylacetic acids into the corresponding alkyl nitriles in good yields and enantioselectivities without using chemical oxidants or pre-functionalization of the acid substrates and can be readily scaled up.