Chiral Catalysts for Pd0-Catalyzed Enantioselective C−H Activation

In the past few decades, processes that involve transition-metal catalysis have represented a major part of the synthetic chemist′s toolbox. Recently, the interest has shifted from the well-established cross-coupling reactions to C−H bond functionalization, thus making it a current frontier of transition-metal-catalyzed reactions. Constant progress in this field has led to the discovery of enantioselective methods to generate and control various types of stereogenic elements, thereby demonstrating its high value to generate scalemic chiral molecules. The present review is dedicated to enantioselective Pd⁰-catalyzed C−H activation, which may be considered as an evolution of Pd⁰-catalyzed cross-couplings, with a focus on the different chiral ligands and catalysts that enable these transformations.     

Diverse Approaches for Enantioselective C−H Functionalization Reactions Using Group 9 CpxMIII Catalysts

Transition-metal-catalyzed C−H functionalization reactions with Cp*M^III catalysts (M=Co, Rh, Ir) have found a wide variety of applications in organic synthesis. Albeit the intrinsic difficulties in achieving catalytic stereocontrol using these catalysts due to their lack of additional coordination sites for external chiral ligands and the conformational flexibility of the Cp ligand, catalytic enantioselective C−H functionalization reactions using the Group 9 metal triad with Cp-type ligands have been intensively studied since 2012. In this minireview, the progress in these reactions according to the type of the chiral catalyst used are summarized and discussed. The development of chiral Cp^x ligands the metal complexes thereof, artificial metalloenzymes, chiral carboxylate-assisted enantioselective C−H activations, enantioselective alkylations assisted by chiral carboxylic acids or chiral sulfonates, and chiral transient directing groups are discussed.     

Chiral Inductions in Excited State Reactions: Photodimerization of Alkyl 2‐Naphthoates as a Model

Enantioselectivity in organic transformations continues to be a topic major interest in organic photochemistry. In the last decade, synergistic combination of photocatalysis and organocatalysis has emerged as a powerful strategy to gain enantioselectivity in photochemical reactions, and remarkable achievements have been obtained. In this strategy, the asymmetric induction is provided in ground state. In contrast, in the conventional enantioselective photochemistry, the chiral induction is controlled in electronic excited state, and to achieve high stereoselectivity is still a formidable challenge. Because the reactions of excited states often yield strained products with unique structures in single step that are difficult to form by thermal reactions, the development of new strategies attempted to achieve enantioselectivity in excited state reactions is still highly desired. Since the short excited state lifetime and low activation energy for reaction in excited state leave little room for manipulating the chiral induction, in order to gain enantioselectivity the substrate molecule has to already reside in a chiral environment during the excitation step. Chiral auxiliaries and chiral supramolecular hosts can provide such environments. In this presentation, we summarize the studies employing chiral auxiliary and chiral microreactor approaches to achieve high asymmetric inductions in excited state reactions performed in our laboratory. We chose the photodimerization of alkyl 2‐naphthoates as a reaction model to give deeper insights into the basic factors controlling chiral induction in excited state.     

Photo‐Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

Radical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible‐light‐mediated organocatalytic strategy that exploits the excited‐state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical‐based bond‐forming events, the method converts unactivated olefins and α,β‐unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three‐component radical cascade further demonstrates the complexity‐generating power of this photochemical strategy.     

One‐pot Chemoenzymatic Synthesis of Chiral 1,3‐Diols Using an Enantioselective Aldol Reaction with Chiral Zn2+ Complex Catalysts and Enzymatic Reduction Using Oxidoreductases with Cofactor Regeneration

We previously reported on enantioselective aldol reactions of acetone and some aldehydes catalyzed by chiral Zn²⁺ complexes of L ‐prolyl‐pendant [12]aneN₄ (L ‐ZnL¹) and L ‐valyl‐pendant [12]aneN₄ (L ‐ZnL²) in aqueous solution. Here, we report on the one‐pot chemoenzymatic synthesis of chiral 1,3‐diols in an aqueous solvent system at room temperature by a combination of enantioselective aldol reactions catalyzed by Zn²⁺ complexes of L ‐ and D ‐phenylalanyl‐pendant [12]aneN₄ (L ‐ZnL³ and D ‐ZnL³) and the successive enantioselective reduction of the aldol products using oxidoreductases with the regeneration of the NADH (reduced form of nicotinamine adenine dinucleotide) cofactor. The findings indicate that all four stereoisomers of 1,3‐diols can be produced by appropriate selection of a chiral Zn²⁺‐complex and an oxidoreductase commercially available from the “Chiralscreen OH” kit.     

Enantioselective C?C and C?H Bond Formation Mediated or Catalyzed by Chiral ebthi Complexes of Titanium and Zirconium

The development of catalytic processes that effect enantioselective bond formation under mild conditions is an important and challenging task in modern chemical synthesis. In this connection, chiral C₂-symmetric ansa-metallocenes (bridged metallocenes) have found notable applications as catalysts. This article discusses the chemistry of this class of chiral metallocene complexes with regard to their utility in catalytic and enantioselective C? C and C? H bond formation reactions. In addition, where applicable, a brief comparison with other related catalytic enantioselective processes is offered. Many of the reactions effected with high levels of enantioselectivity by catalytic amounts of these complexes are of great significance to the preparation of new materials and in the synthesis of therapeutic agents. For example, zirconocene complexes readily catalyze the enantioselective addition of alkylmagnesium halides to alkenes, and cationic zirconocene complexes may promote the highly stereoregulated copolymerization of terminal alkenes. Furthermore, the related chiral titanocenes are involved in an impressive range of useful asymmetric catalytic reactions, including the enantioselective hydrogenation of olefins and reduction of imines or ketones. This review attempts to bring together the practical aspects of the use of [(ebthi)M] complexes of Group 4 transition metals (catalyst synthesis and resolution), outline the manner in which the C₂-symmetric chiral ligands are believed to initiate stereoselective bond formation, and highlight the aspects of this chemistry that are less well understood and require further research.     

Catalytic enantioselective organozinc addition toward optically active tertiary alcohol synthesis

A highly enantioselective organozinc (R₂Zn) addition to a series of aldehydes and ketones was developed based on conjugate Lewis acid–Lewis base catalysis. Optically active secondary and tertiary alcohols were obtained in high yields with high enantioselectivities without Ti(IV) compounds. Bifunctional chiral 3,3′‐diphosphoryl‐BINOL ligands were designed and prepared through a phospho‐Fries rearrangement as a key step. On the other hand, bifunctional chiral phosphoramide ligands were designed and prepared from L ‐valine. Mechanistic studies were performed by X‐ray analyses of Zn(II) cluster and chiral ligands, a ³¹P NMR experiment on Zn(II) complexes, and stoichiometric reactions with some chiral or achiral Zn(II) complexes to propose a transition state assembly that includes monomeric active intermediates. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 143–155; 2008: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20146     

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium‐labeled substrates, and control experiments revealed that nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C?O bonds at fully substituted carbon centers in the synthesis of chiral 2,2‐disubstituted benzomorpholines.     

Catalytic Enantioselective Aza-pinacol Rearrangement

The first catalytic enantioselective asymmetric aza-pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza-ortho-xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.     

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C−O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.     

Stereodivergent Anion Binding Catalysis with Molecular Motors

A photoresponsive chiral catalyst based on an oligotriazole‐functionalized unidirectional molecular motor has been developed for stereodivergent anion binding catalysis. The motor function controls the helical chirality of supramolecular assemblies with chloride anions, which by means of chirality transfer enables the enantioselective addition of a silyl ketene acetal nucleophile to oxocarbenium cations. Reversal of stereoselectivity (up to 142 % Δee) was achieved through rotation of the motor core induced by photochemical and thermal isomerization steps.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

Catalytic Enantioselective Amination of Alcohols by the Use of Borrowing Hydrogen Methodology: Cooperative Catalysis by Iridium and a Chiral Phosphoric Acid

The catalytic asymmetric reduction of ketimines has been explored extensively for the synthesis of chiral amines, with reductants ranging from Hantzsch esters, silanes, and formic acid to H₂ gas. Alternatively, the amination of alcohols by the use of borrowing hydrogen methodology has proven a highly atom economical and green method for the production of amines without an external reductant, as the alcohol substrate serves as the H₂ donor. A catalytic enantioselective variant of this process for the synthesis of chiral amines, however, was not known. We have examined various transition‐metal complexes supported by chiral ligands known for asymmetric hydrogenation reactions, in combination with chiral Brønsted acids, which proved essential for the formation of the imine intermediate and the transfer‐hydrogenation step. Our studies led to an asymmetric amination of alcohols to provide access to a wide range of chiral amines with good to excellent enantioselectivity.     

Development of Chiral Organosuperbase Catalysts Consisting of Two Different Organobase Functionalities

In the field of chiral Brønsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Brønsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich‐type reaction of α‐phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Brønsted base catalysts and significantly broaden the utility of Brønsted base catalysis in asymmetric organic synthesis.     

Catalytic Enantioselective Intramolecular Aza‐Diels–Alder Reactions

A readily available chiral Brønsted acid was identified as an efficient catalyst for intramolecular Povarov reactions. Polycyclic amines containing three contiguous stereogenic centers were obtained with excellent stereocontrol in a single step from secondary anilines and aldehydes possessing a pendent dienophile. These transformations constitute the first examples of catalytic enantioselective intramolecular aza‐Diels–Alder reactions.     

Inner-Sphere Oxygen Activation Promoting Outer-Sphere Nucleophilic Attack on Olefins

Alkoxylation and hydroxylation reactions of 1,5-cyclooctadiene (cod) in an iridium complex with alcohols and water promoted by the reduction of oxygen to hydrogen peroxide are described. The exo configuration of the OH/OR groups in the products agrees with nucleophilic attack at the external face of the olefin as the key step. The reactions also require the presence of a coordinating protic acid (such as picolinic acid (Hpic)) and involve the participation of a cationic diolefin iridium(III) complex, [Ir(cod)(pic)₂]⁺, which has been isolated. Independently, this cation is also involved in easy alkoxy group exchange reactions, which are very unusual for organic ethers. DFT studies on the mechanism of olefin alkoxylation mediated by oxygen show a low-energy proton-coupled electron-transfer step connecting a superoxide–iridium(II) complex with hydroperoxide–iridium(III) intermediates, rather than peroxide complexes. Accordingly, a more complex reaction, with up to four different products, occurred upon reacting the diolefin–peroxide iridium(III) complex with Hpic. Moreover, such hydroperoxide intermediates are the origin of the regio- and stereoselectivity of the hydroxylation/alkoxylation reactions. If this protocol is applied to the diolefin–rhodium(I) complex [Rh(pic)(cod)], free alkyl ethers ORC₈H₁₁ (R=Me, Et) resulted, and the reaction is enantioselective if a chiral amino acid, such as l -proline, is used instead of Hpic.     

Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes

Organocatalytic methods have achieved spectacular advancements for the preparation of chiral molecules in highly enantioenriched forms. The fast development of this field can mainly be attributed to the evolution of general and reliable activation modes. The discovery and identification of new activation modes are therefore highly desirable to push the boundaries of asymmetric reactions. In this Minireview, recent advances in enantioselective carbonyl catalysis, one useful subbranch of organocatalysis for the efficient activation of simple amines, will be summarized. With elegantly designed chiral aldehyde catalysts, highly enantioselective and efficient asymmetric reactions can be developed. Continued development of enantioselective carbonyl catalysis is expected in the future.     

Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan

Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions are the key reactions.     

Enantioselective Organocatalytic Diels–Alder Trapping of Photochemically Generated Hydroxy‐o‐Quinodimethanes

The photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light‐triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy‐o‐quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity‐defining event.     

Enantioselective palladium-catalyzed total synthesis of vitamin e by employing a domino Wacker-Heck reaction

An enantioselective total synthesis of vitamin E in which a novel palladium-catalyzed domino reaction was employed as the key step is described. This reaction allows the formation of the chiral chroman framework and the concurrent introduction of part of the side chain of vitamin E. The sequence comprises an enantioselective Wacker cyclization and a subsequent Heck reaction. Accordingly, reaction of alkenylphenol 12 with methyl vinyl ketone (13) in the presence of catalytic amounts of Pd(OTFA)(2) (TFA = trifluoroacetate), the enantiopure ligand (S,S)-Bn-BOXAX (8 b; Bn = benzyl, BOXAX = 2,2'-bis(oxazolyl)-1,1'-binaphthyl, and p-benzoquinone (9) as an oxidant gives access to chiral chroman 10 with an enantioselectivity of 97 % ee in 84 % yield. Chroman 10 is then converted into 24 by an aldol condensation reaction with (3R)-3,7-dimethyloctanal (11). Subsequent 1,2-addition of methyllithium, elimination of water, and hydrogenation yields vitamin E.