Direct generation of nucleophilic chiral palladium enolate from 1,3-dicarbonyl compounds: catalytic enantioselective Michael reaction with enones

Generation of chiral palladium enolates from 1,3-dicarbonyl compounds with the palladium aqua complex and its application to the highly efficient catalytic enantioselective Michael reaction with enones are described. The palladium aqua complexes are likely to supply Br?nsted base and Br?nsted acid successively during the reaction. The former activates the carbonyl compounds to give chiral palladium enolates, and the latter cooperatively activates enones. Using a catalytic amount (2-10 mol %) of the palladium complexes, the various 1,3-dicarbonyl compounds including diketones and beta-ketoesters were converted to the desired Michael adducts in good yields (69-92%) with excellent enantiomeric excesses (89-99% ee).     

Development of catalytic asymmetric reactions via chiral palladium enolates

This article describes the generation of chiral palladium enolates and their application to several kinds of catalytic asymmetric reactions. Two methods to generate chiral enolates were developed using novel cationic palladium complexes 1 and 2 . In these processes, water or a hydroxo ligand on palladium metal plays an important role as a nucleophile to promote the transmetallation or as a Brønsted base to abstract an acidic α‐proton of the carbonyl group. These enolates showed sufficient reactivity with various electrophiles. Using a chiral Pd enolate as a key intermediate, highly enantioselective reactions such as catalytic aldol reactions, Mannich‐type reactions, Michael reactions, and fluorination reactions were developed. The unique structures of the palladium enolate complexes were elucidated and reaction mechanisms are proposed. © 2004 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 4: 231–242; 2004: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20017     

Highly enantioselective fluorination reactions of β-ketoesters and β-ketophosphonates catalyzed by chiral palladium complexes

Using chiral palladium enolates as key intermediates, efficient catalytic enantioselective fluorination reactions of active methine compounds have been developed. These reactions can be conducted in alcoholic solvents without any precaution to exclude water and moisture, and various β-ketoesters and β-ketophosphonates were fluorinated in a highly enantioselective manner (up to 98% ee).     

Counterions of BINAP-Pt(II) and -Pd(II) complexes: novel catalysts for highly enantioselective Diels-Alder reaction

[formula: see text] Platinum and palladium chiral bisphosphine complexes and their counterion effects in asymmetric Diels-Alder reactions have been investigated. The reaction of cyclopentadiene and various bidentate dienophiles in the presence of a catalytic amount of Pt(II)- or Pd(II)-BINAP complex proceeds with excellent endo/exo selectivity as well as endo enantioselectivity (up to 99% ee).     

Bifunctional transition metal-based molecular catalysts for asymmetric syntheses

The discovery and development of conceptually new chiral bifunctional transition metal-based catalysts for asymmetric reactions is described. The chiral bifunctional Ru catalyst was originally developed for asymmetric transfer hydrogenation of ketones and imines and is now successfully applicable to enantioselective C-C bond formation reaction with a wide scope and high practicability. The deprotonation of 1,3-dicarbonyl compounds with the chiral amido Ru complexes leading to the amine Ru complexes bearing C- or O-bonded enolates, followed by further reactions with electrophlies gives C-C bond formation products. The present bifunctional Ru catalyst offers a great opportunity to open up new fundamentals for stereoselective molecular transformation including enantioselective C-H and C-C as well as C-O, C-N bond formation.     

Highly enantioselective conjugate addition of malonate and beta-ketoester to nitroalkenes: asymmetric C-C bond formation with new bifunctional organic catalysts based on cinchona alkaloids

The development of readily accessible bifunctional chiral catalysts is a desirable yet challenging goal in catalytic asymmetric synthesis. In this communication, we describe the development of a new class of readily accessible chiral bifunctional organic catalysts that could be derived in one or two steps in high yield from either quinidine or quinine. These catalysts have been shown to catalyze a highly enantioselective conjugate addition of methyl and ethyl malonates and beta-ketoesters to a broad range of beta-substituted nitroalkenes, an synthetically important C-C bond-forming reaction utilizing readily available starting materials. This new catalytic asymmetric reaction proceeds in 91-98% ee and 71-99% yield.     

Catalytic enantioselective synthesis of alpha-aminooxy and alpha-hydroxy ketone using nitrosobenzene

The highly enantioselective and O-selective nitroso aldol reaction of tin enolates 2 and nitrosobenzene (1) has been developed with the use of (R)-BINAP-silver complexes as a catalyst. After the various silver salts were surveyed, the AgOTf and the AgClO4 complex were found to be optimal in the O-selective nitroso aldol reaction in both asymmetric induction (up to 97% ee) and regioselection (O/N = >99/1), affording aminooxy ketone 3. The product 3 can be transformed to alpha-hydroxy ketone 5 without any loss of enantioselectivity. Thus, the method provides an efficient approach to the catalytic enantioselective introduction of oxygen alpha- to the carbonyl group.     

Amine-salt-controlled, catalytic asymmetric conjugate addition of various amines and asymmetric protonation

The combined use of chiral Pd complex 2 and amine salt enabled completely regulated release of free nucleophilic amine. Under these conditions, an efficient catalytic asymmetric conjugate addition of various amines was achieved to afford beta-amino acid derivatives in high chemical yields with up to 98% ee. Furthermore, a highly enantioselective protonation in 1,4-addition of amine was also developed. [reaction: see text]     

Palladium-catalyzed asymmetric arylation,vinylation, and allenylation of tert-cyclobutanols via enantioselective C-C bond cleavage

A novel enantioselective C-C bond cleavage has been achieved using palladium catalysts and chiral N,P-bidentate ligands in the asymmetric arylation, vinylation, and allenylation of tert-cyclobutanols. In these reactions, the enantioselective beta-carbon elimination of Pd(II) alcoholate formed in situ is the key step. Treatment of tert-cyclobutanols with arylating reagents in toluene in the presence of Pd(OAc)(2), a chiral ferrocene-containing N,P-bidentate ligand, and Cs(2)CO(3) affords optically active gamma-arylated ketones in excellent yields with high enantioselectivity (up to 95% ee). When vinylating reagents are used in place of arylating ones, the asymmetric vinylation also proceeds to afford optically active gamma-vinylated ketones in high yields with good to high enantioselectivity. When propargylic acetates are used, which are known to generate (sigma-allenyl)palladium complexes with Pd(0) species, asymmetric allenylation occurs to afford optically active gamma-allenylated ketones in moderate to good yields with moderate to high enantioselectivity.     

Chiral Pd-catalyzed enantioselective Friedel-Crafts reaction of indoles with γ,δ-unsaturated β-keto phosphonates

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with γ,δ-unsaturated β-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-Crafts alkylation adducts with excellent enantioselectivities (up to 99% ee).     

Catalytic asymmetric Mannich-type reactions of fluorinated ketoesters with N-Boc aldimines in the presence of chiral palladium complexes

The catalytic enantioselective Mannich reaction promoted by chiral palladium complexes is described. The treatment of α-fluoro-β-ketoesters with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-ketoesters with excellent enantioselectivities (up to 99% ee).     

Synthesis of chiral titanium-containing phosphinoamide ligands for enantioselective heterobimetallic catalysis

The synthesis of six chiral titanium-containing phosphinoamide ligands is discussed. These ligands assemble chiral heterobimetallic Pd–Ti complexes, enable enantioselective intramolecular allylic aminations with hindered amine nucleophiles and achieve selectivity up to 53% ee. Mechanistic studies demonstrate the reversibility of the enantio-determining C–N bond forming step, which leads to a gradual increase in the % ee of the reaction over time. These results represent a rare example of enantioselective heterobimetallic catalysis and suggest that these new ligands could find broad application in enantioselective transition metal catalysis.     

Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines

Asymmetric catalysis is a challenge for chemists: How can we design catalysts to achieve the goal of forming optically active compounds? This review provides the reader with an overview of the development of catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines. Since its discovery, the Diels-Alder reaction has undergone intensive development and is of fundamental importance for synthetic, physical, and theoretical chemists. The Diels-Alder reaction has been through different stages of development, and at the beginning of the 21st century catalytic Diels-Alder reactions are one of the main areas of focus. The preparation of numerous compounds of importance for our society is based on cycloaddition reactions to carbonyl compounds and imines. There are several parallels between the reactions of carbonyl compounds and those of imines, which, however, begin to vanish on entering the field of catalytic reactions. Why? From a mechanistic point of view some similarities can be drawn, but the synthetic development of catalytic enantioselective hetero-Diels-Alder reactions of imines are several years behind those of the carbonyl compounds. For hetero-Diels-Alder reactions of carbonyl compounds there a number of different chiral catalysts, and great progress has been achieved in developing enantioselective reactions for unactivated and activated carbonyl compounds. In contrast the development of catalytic enantioselective hetero-Diels-Alder reactions of imines is in its infancy and only few catalytic reactions have been published. This review will focus on the most important developments, and discuss the synthetic and mechanistic aspects of enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral Lewis acids. For the hetero-Diels-Alder reactions of imines, the diastereoselective reactions of optically substrates catalyzed by Lewis acids will be presented first, followed by the catalytic enantioselective reactions.     

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones for synthesis of 2,2-disubsituted pyrrolidine derivatives

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones represents a significant challenge in organic synthesis. We report herein that the synthesis of chiral 2,2-disubsituted pyrrolidines from acyclic ketones has been accomplished by using catalytic asymmetric method in the presence of Pd(dba)₂ and (R)-binap ligand. Theses reactions occur between allyl methyl carbonate and unstabilized acyclic lithium enolates to provide the products in moderate to good enantioselectivity (up to 81% ee).     

Pd(II)-catalyzed asymmetric addition of malonates to dihydroisoquinolines

We have developed a highly efficient reaction for catalytic asymmetric addition of malonates to dihydroisoquinolines using chiral Pd(II) complexes. In the reactions, substrates with various substitution patterns were available, and the reactions were complete within several hours (<3 h in most cases) under mild reaction conditions, affording various optically active C1-substituted tetrahydroisoquinoline derivatives (up to 98% yield, up to 97% ee). Furthermore, slow addition of DDQ allowed the in situ generation of the reactive intermediate from the corresponding N-Boc-protected amine, and dehydrogenative addition reaction was successfully demonstrated.     

Stereodivergent Synthesis of Allenes with α,β-Adjacent Central Chiralities Empowered by Synergistic Pd/Cu Catalysis

The stereodivergent synthesis of allene compounds bearing α,β-adjacent central chiralities has been realized via the Pd/Cu-catalyzed dynamic kinetic asymmetric alkylation of racemic allenylic esters. The matched reactivity of bimetallic catalytic system enables the challenging reaction of racemic aryl-substituted allenylic acetates with sterically crowded aldimine esters smoothly under mild reaction conditions. Various chiral non-natural amino acids bearing a terminal allenyl group are easily synthesized in high yields and with excellent diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). Importantly, all four stereoisomers of the product can be readily accessed by switching the configurations of the two chiral metal catalysts. Furthermore, the easy interconversion between the uncommon η³-butadienyl palladium intermediate featuring a weak C=C/Pd coordination bond and a stable Csp²−Pd bond is beneficial for the dynamic kinetic asymmetric transformation process (DyKAT).     

Catalytic enantioselective electrophilic α-amination of β-ketoesters catalyzed by chiral palladium complexes

The catalytic enantioselective electrophilic α-amination promoted chiral palladium complexes is described. Treatment of β-ketoesters with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corresponding α-amino β-ketoesters with excellent enantiomeric excesses (91-99% ee). Palladium complexes were immobilized in [bmim]PF₆, and their applications to catalytic α-amination of β-ketoesters were successfully demonstrated.     

Catalytic enantioselective fluorination of α-cyano acetates catalyzed by chiral palladium complexes

The catalytic enantioselective electrophilic fluorination promoted chiral palladium complexes is described. Treatment of α-cyano acetates with N-fluorobenzenesulfonimide as the fluorine source under mild reaction conditions afforded the corresponding α-cyano α-fluoro acetates in high yields with excellent enantiomeric excesses (85-99% ee).     

Oxazolidine synthesis by complementary stereospecific and stereoconvergent methods

Complementary stereospecific and stereoconvergent reactions for enantioselective synthesis of 1,3-oxazolidines are reported. In the presence of a rhodium catalyst, reaction of enantioenriched butadiene monoxide with aryl imines is stereospecific (99% ee). Alternatively, the reaction of racemic butadiene monoxide, in the presence of a chiral palladium or nickel catalyst, provides an enantioselective synthesis of 1,3-oxazolidines (up to 94% ee). Synthesis of either the cis- or trans-1,3-oxazolidines is also accomplished under catalyst control.     

A new class of versatile chiral-bridged atropisomeric diphosphine ligands: remarkably efficient ligand syntheses and their applications in highly enantioselective hydrogenation reactions

A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereoselective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to the catalytic enantioselective hydrogenations of alpha- and beta-ketoesters (C=O bond reduction), 2-(6'-methoxy-2'-naphthyl)propenoic acid, alkyl-substituted beta-dehydroamino acids (C=C bond reduction), and N-heteroaromatic compounds (C=N bond reduction). An excellent level of enantioselection (up to 99.9% ee) has been attained for the catalytic reactions. In addition, the significant ligand dihedral angle effects on the Ir-catalyzed asymmetric hydrogenation of N-heteroaromatic compounds were also revealed.