Control Of Enantioselectivity Research Articles

Rhodium-Catalyzed Asymmetric Hydrogenation of All-Carbon Aromatic Rings.

Compared with heteroarenes, homogeneous asymmetric hydrogenation of all-carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine-catalyzed asymmetric hydrogenation of all-carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central-chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron-donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Rhodium‐Catalyzed Asymmetric Hydrogenation of All‐Carbon Aromatic Rings

AbstractCompared with heteroarenes, homogeneous asymmetric hydrogenation of all‐carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine‐catalyzed asymmetric hydrogenation of all‐carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central‐chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron‐donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Enantioselective Cobalt-Catalyzed C–H Functionalization

AbstractCo-catalyzed C–H functionalization has received great attention due to the high earth abundance, low biotoxicity, and unique reactivity of cobalt; enantioselective control of these reactions has been a formidable challenge. Various efficient strategies have recently been developed for enantioselective Co-catalyzed C–H functionalization, but there is no topical review of this field. Herein, we give a detailed summary of this rapidly growing field, highlighting critical progress, current challenges, and future trends.1 Introduction2 Enantioselective C–H Functionalization via Low-Valent Co Catalysis2.1 Chiral Diphosphines for Enantioselective Control2.2 Chiral Monophosphines or N-Heterocyclic Carbenes for Enantioselective Control3 Enantioselective C–H Functionalization via High-Valent Co Catalysis3.1 Chiral Acids for Enantioselective Control3.2 Chiral Cp Ligands for Enantioselective Control4 Conclusions and Outlook

Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

Comprehensive SummaryWhile drug chirality remains one of the most important themes in medicinal chemistry and fluorine‐containing drugs have comprised large portion of global pharmaceutical market, the synthesis of fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped. Recent strategy of enantioconvergent cross‐coupling of trifluoromethylated alkyl halide has significantly updated previous toolbox that is dependent on additional functional group to achieve desired bond formation and highly enantioselective control. However, evident limitations were present in specific coupling candidate (sp2 carbon) and/or prerequisite heteroatom in trifluoroalkyl source for inducing effective stereoconvergent differentiation. Leveraging novel design of sterically hindered bisoxazoline ligand and drastic increase of molecular complexity of in situ generated sp3 coupling partner via metal‐hydride atom transfer, herein, we report a nickel‐catalyzed, highly enantioselective hydrotrifluoroalkylation of unactivated alkenes for diverse synthesis of enantioenriched aliphatic alkanes featuring trifluoromehylated stereogenic carbon. Excellent stereochemical control (mostly >95: 5 er), high catalytic reactivity, mild conditions, and broad substrate scope (40+ examples), enable convenient late‐stage asymmetric trifluoroalkylation of various biologically active complex molecules.

Strategies for total synthesis of bispyrrolidinoindoline alkaloids.

Covering up to 2021Complex cyclotryptamine alkaloids with a bispyrrolidino[2,3-b]indoline (BPI) skeleton are an intriguing family of natural products, exhibiting wide systematic occurrences, large structural diversity, and multiple biological activities. Based on their structural characteristics, BPI alkaloids can be classified into chimonanthine-type BPI alkaloids, BPI diketopiperazines, and BPI epipolythiodiketopiperazines. These intricate molecules have captivated great attention soon after their isolation and identification in the 1960s. Due to the structural complexity, the total synthesis of these cyclotryptamine alkaloids is challenging. Nevertheless, remarkable progress has been achieved in the last six decades; in particular, several methods have been successfully established for the construction of vicinal all-carbon quaternary stereocenters. In this review, the structural diversity and chemical synthesis of these BPI alkaloids were summarized. BPI alkaloids are mainly synthesized by the methods of oxidative dimerization, reductive dimerization, and alkylation of bisoxindole. The purpose of this review is to present overall strategies for assembling the BPI skeleton and efforts towards controlling the stereocenters.

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp3)-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is efficient and selective (up to 2610 total turnover number (TTN) and 96% ee) and can be performed on preparative scale.

Nickel-Catalyzed Asymmetric Synthesis of P-Stereogenic Vinyl Phosphines

AbstractAddition reaction to alkynes is an efficient strategy for constructing valuable alkenyl compounds. However, the elusive regioselectivity has been a persistent challenge. In the context of hydrophosphination reaction which could afford valuable P-stereogenic phosphines, the control of enantioselectivity as well as regioselectivity were especially tricky. Here, we highlighted our recent work on the nickel-catalyzed regio- and enantioselective hydrophosphination of unactivated alkynes with in situ generated secondary phosphines.1 Introduction2 Hydrophosphination of Alkynes3 Derivatization Reactions4 Mechanism Research5 Summary and Outlook

Catalytic Atroposelective Dynamic Kinetic Resolution of Substituted Indoles

AbstractAdvances in asymmetric catalysis have led to enormous progress in the atroposelective synthesis of axially chiral biaryls. Because of the biological importance of indoles, stereogenic axes in aryl-substituted indoles have attracted considerable research attention in recent years. Here we present a summary of recent advances in the atroposelective synthesis of aryl-substituted indoles by dynamic kinetic resolution. Although several researchers have developed enantioselective syntheses of 3-arylindoles, N-arylindoles have been much less studied. Accordingly, we have developed a Pictet–Spengler reaction with catalytic and enantioselective control of the axial chirality around the C–N bond of the product. A chiral phosphoric acid induces the cyclization smoothly and with high yields and excellent enantioselectivities. To achieve this high selectivity, an NH group at the ortho-position of the N-substituted aromatic ring that interacts favorably with the catalyst is required. Furthermore, when substituted aldehydes are used instead of paraformaldehyde, both point and axial chiralities can be controlled during the cyclization.1 Introduction2 Atropisomerism in Indoles3 Atroposelective Dynamic Kinetic Resolution of 3-Arylindoles4 Atroposelective Dynamic Kinetic Resolution of N-Arylindoles5 Conclusions

Stereodivergent Synthesis of Enantioenriched γ‐Butyrolactones Bearing Two Vicinal Stereocenters Enabled by Synergistic Copper and Iridium Catalysis

AbstractBy virtue of a fundamentally new reaction model of azomethine ylide serving as a two‐atom synthon, we present the first example of stereodivergent preparation of γ‐butyrolactones via synergistic Cu/Ir‐catalyzed asymmetric cascade allylation/lactonization, and all four stereoisomers of γ‐butyrolactones bearing two vicinal stereocenters are accessible with excellent diastereoselective and enantioselective control. The chiral IrIII‐π‐allyl intermediate was separated and characterized to understand the origin of the regio‐ and stereoselectivity of the initial C−C bond formation process. Control experiments shed some light on the catalyst/substrate and catalyst/catalyst interactions in this dual catalytic system to rationalize the related kinetic/dynamic kinetic resolution process with different catalyst combinations. The enantioenriched γ‐butyrolactone products were converted into an array of structurally complex chiral molecules and organocatalysts that were otherwise inaccessible.

Stereodivergent Synthesis of Enantioenriched γ-Butyrolactones Bearing Two Vicinal Stereocenters Enabled by Synergistic Copper and Iridium Catalysis.

By virtue of a fundamentally new reaction model of azomethine ylide serving as a two-atom synthon, we present the first example of stereodivergent preparation of γ-butyrolactones via synergistic Cu/Ir-catalyzed asymmetric cascade allylation/lactonization, and all four stereoisomers of γ-butyrolactones bearing two vicinal stereocenters are accessible with excellent diastereoselective and enantioselective control. The chiral IrIII -π-allyl intermediate was separated and characterized to understand the origin of the regio- and stereoselectivity of the initial C-C bond formation process. Control experiments shed some light on the catalyst/substrate and catalyst/catalyst interactions in this dual catalytic system to rationalize the related kinetic/dynamic kinetic resolution process with different catalyst combinations. The enantioenriched γ-butyrolactone products were converted into an array of structurally complex chiral molecules and organocatalysts that were otherwise inaccessible.

Spontaneous chiral self-assembly of CdSe@CdS nanorods

Spontaneous chiral self-assembly of CdSe@CdS nanorods

Enantiodivergent Synthesis of Chiral Tetrahydroquinoline Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-Dependent Enantioselective Control and Mechanistic Investigations

Enantiodivergent Synthesis of Chiral Tetrahydroquinoline Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-Dependent Enantioselective Control and Mechanistic Investigations

Reversal of Enantioselectivity in the Conjugate Addition Reaction of Cyclic Enones with the CuOTf/Azolium Catalytic System

Hydroxyamide-functionalized azolium salt (NHC•HI 4) was evaluated for dual enantioselective control in a Cu-catalyzed asymmetric conjugate addition (ACA) reaction. This investigation was based on our previously reported ACA reaction catalyzed using CuOTf combined with NHC•AgI complex 1. It was revealed that the stereocontrol of the catalytic ACA reaction depended on the order of the addition of the substrates. Additionally, the chiral NHC ligand precursors, substrates, the relationship between the catalyst ee (eecat) and product ee (eepro), and halogen counter anion were completely evaluated. These results suggested that the catalytic performance of the CuOTf/4 system was comparable with that of the CuOTf/1 system. Furthermore, to gain knowledge of the Cu species generated using CuOTf and NHC ligand precursor, the reaction of CuOTf with 1 was investigated. Although obtaining the corresponding NHC•CuX species failed, the corresponding NHC•AuCl complex 11 could be synthesized by allowing 1 to react with AuCl•SMe2.

Asymmetric Palladium-Catalyzed Oxycarbonylation of Terminal Alkenes: Efficient Access to β-Hydroxy Alkylcarboxylic Acids.

A novel PdII -catalyzed enantioselective oxycarbonylation of alkenes has been established. The ligand with an ethyl group at the C-6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad alkene substrate scope, excellent regio- and enantioselectivities, scalabilities and a wide array of applications, and provides a useful route for the convenient and straightforward synthesis of chiral β-hydroxy alkylcarboxylic acids/esters.

Asymmetric Palladium‐Catalyzed Oxycarbonylation of Terminal Alkenes: Efficient Access to β‐Hydroxy Alkylcarboxylic Acids

AbstractA novel PdII‐catalyzed enantioselective oxycarbonylation of alkenes has been established. The ligand with an ethyl group at the C‐6 position of Pyox plays a significant role in the intermolecular oxypalladation process, leading to high reactivity and excellent enantioselective control. Compared to the conventional methods, the reaction itself features alkenes as easily prepared starting materials, mild and operationally simple reaction conditions, and insensitivities to air and water. Moreover, this method allows for broad alkene substrate scope, excellent regio‐ and enantioselectivities, scalabilities and a wide array of applications, and provides a useful route for the convenient and straightforward synthesis of chiral β‐hydroxy alkylcarboxylic acids/esters.

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S RN 1-Debromination Approach

Catalytic Asymmetric [4+1] Spiroannulation of α-Bromo-β-Naphthols with Azoalkenes by an Electrophilic Dearomatization/S _RN 1-Debromination Approach

Catalytic and Enantioselective Control of the C-N Stereogenic Axis via the Pictet-Spengler Reaction.

An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-β-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

Catalytic and Enantioselective Control of the C–N Stereogenic Axis via the Pictet–Spengler Reaction

AbstractAn unprecedented example of a chiral phosphoric acid‐catalyzed atroposelective Pictet–Spengler reaction of N‐arylindoles is reported. Highly enantioenriched N‐aryl‐tetrahydro‐β‐carbolines with C−N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron‐withdrawing group‐substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

Hydrogen Atom Transfer-Driven Enantioselective Minisci Reaction of Amides.

Minisci-type reactions constitute one of the most powerful methods for building up complexity around basic heteroarenes. The most desirable variants involve formal oxidative coupling of a C–H bond on each partner, leading back to the simplest possible starting materials. We herein disclose a method that enables such a coupling of linear amides and heteroarenes with full control of enantioselectivity at the newly formed stereocenter as well as site selectivity on both the heteroarene and the amide. This is achieved by the use of a chiral phosphoric acid catalyst in conjunction with diacetyl as a combined hydrogen atom transfer reagent and oxidant. Diacetyl is directly photoexcitable, and thus, no extraneous photocatalyst is required: an added feature that contributes to the simplicity and practicality of the protocol.

Highly Diastereo- and Enantioselective Synthesis of Tetrahydrobenzo[b]azocines via Palladium-Catalyzed [4 + 4] Cycloaddition

The construction of N-heterocyclic eight-membered rings with good regio-, stereo-, and enantioselective control remains a formidable challenge in asymmetric catalysis. Herein, we report a palladium...