A practical asymmetric conjugate addition to cyclic enones with chiral bifunctional Ru amido catalysts

A practical asymmetric C-C bond formation to synthetically useful β-chiral cyclic ketones (>99% ee) using bifunctional chiral amido Ru catalysts under an S/C = 1000, the highest ratio achieved so far in the literature for this class of reactions, is described. The catalytic reactivity decreases in the order of Ru(Msdpen)(hmb) > Ru(Pfbsdpen)(hmb) > Ru(Tsdpen)(hmb) > Ru(PMsdpen)(hmb), where Ru(Pfbsdpen)(hmb) is a newly developed chiral bifunctional catalyst. Complex Ru(Msdpen)(hmb) was identified as the best in terms of reactivity and enantioface selectivity, whereas Ru(PMsdpen)(hmb) gave unsatisfactory results. An importance of the NH proton in the bifunctional catalyst for determining the enantioselectivity has been experimentally demonstrated. Valuable information for the reaction mechanism was accumulated.     

Bifunctional transition metal‐based molecular catalysts for asymmetric C?C and C?N bond formation

This paper describes the recent advances in the conceptually new bifunctional Ir and Ru catalysts for asymmetric catalytic reactions. These reactions include the enantioselective Michael addition of 1,3‐dicarbonyl compounds to cyclic enones and nitroalkenes, and the enantioselective direct amination of α‐cyanoacetates with diazoesters. The outcome of these reactions in terms of reactivity and selectivity was delicately influenced by the catalyst structures and the reaction conditions including the solvents used. Even with a 1 : 1 molar ratio of donors to acceptors, the reactions proceeded smoothly to give the corresponding chiral adducts with an excellent yield and enantiomeric excess (ee). Preliminary mechanistic studies showed that the key stage of the catalytic cycle is the interaction of the bifunctional catalyst with a pronucleophilic reagent that leads to stereoselective formation of C‐, O‐, or N‐bound complexes. The resulting protonated catalyst bearing metal‐bound nucleophiles readily reacts with electrophiles to provide C? C and C? N bond formation products in a highly stereoselective manner. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 106–123; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20172     

Theoretical studies on the bifunctionality of chiral thiourea-based organocatalysts: competing routes to C-C bond formation

The mechanism of enantioselective Michael addition of acetylacetone to a nitroolefin catalyzed by a thiourea-based chiral bifunctional organocatalyst is investigated using density functional theory calculations. A systematic conformational analysis is presented for the catalyst, and it is shown that both substrates coordinate preferentially via bidentate hydrogen bonds. The deprotonation of the enol form of acetylacetone by the amine of the catalyst is found to occur easily, leading to an ion pair characterized by multiple H-bonds involving the thiourea unit as well. Two distinct reaction pathways are explored toward the formation of the Michael product that differ in the mode of electrophile activation. Both reaction channels are shown to be consistent with the notion of noncovalent organocatalysis in that the transition states leading to the Michael adduct are stabilized by extensive H-bonded networks. The comparison of the obtained energetics for the two pathways allows us to propose an alternative mechanistic rationale for asymmetric C-C bond forming reactions catalyzed by bifunctional thiourea derivatives. The origin of enantioselectivity in the investigated reaction is also discussed.     

Mechanism of enantioselective C-C bond formation with bifunctional chiral ru catalysts: NMR and DFT study

The mechanism of Michael addition reactions of 1,3-dicarbonyl compounds to cyclic enones catalyzed by bifunctional Ru catalysts bearing N-sulfonylated (R,R)-DPEN ligands (DPEN = (R,R)-1,2-diphenylethylenediamine) was studied by NMR and DFT computational analyses. NMR investigation of the stoichiometric reactions of chiral amido Ru complexes, Ru(N-sulfonylated dpen)(η(6)-arene) 1a-c, with dimethyl malonate 2 and β-keto ester 3 revealed that at decreased temperatures deprotonation proceeds in a stereoselective manner to provide amine complexes. The reaction with malonic ester 2 provided exclusively C-bound amino Ru complexes 6a,c, while the reaction of β-keto ester 3 gave an equilibrium mixture of rapidly interconverting C- and O-bound complexes. The structures of C-bound Ru complex 6c and O-bound Ru complex 9c were determined by single crystal X-ray analysis. A computational study showed that the enatioselective C-C bond formation proceeds through intermediate formation of chelating ion pairs that coordinate a molecule of enone via the Ru metal center producing a highly organized environment for the C-C bond formation, yielding selectively only one enantiomer of the product. Systematic study of a series of the catalyst-substrate combinations revealed that the experimentally observed sense of enantioselection was consistently explained by computational analysis. The tendency of increasing ee with the bulk of the coordinated arene in Ru complex is reproduced computationally by changes in the difference of either ZPPE-corrected energies or Gibbs free energies for S- and R-pathways.     

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.     

Dimeric & Polymeric Chiral Schiff Base Complexes and Supported BINOL Complexes as Potential Recyclable Catalysts in Asymmetric Kinetic Resolution and C–C Bond Formation Reactions

This review is based on dimeric and polymeric chiral Schiff base metal complexes and chiral BINOL supported metal complexes as potential recyclable catalysts for kinetic resolution of racemic and meso epoxide and asymmetric C–C bond formation reactions e.g., asymmetric addition of diethylzinc to aldehydes, enantioselective addition of phenylacetylene to aldehydes, asymmetric nitro-Aldol reactions and asymmetric cyanation reaction.     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

Enantioselective total synthesis of erogorgiaene: applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones

The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs to acyclic alpha,beta-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)(2).C(6)H(6). Moreover, several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the total synthesis; these include the significance of various structural features of the amino acid-based chiral ligands and the chiral ligand's effectiveness in reactions involving achiral and chiral substrates. In addition, the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly effective catalyst for olefin cross-metathesis.     

Catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones

The catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones with good enantioselectivities and moderate to good yields is reported. A readily available BINOL derivative is used as a chiral catalyst, and the reactions are performed with ethyl iodoacetate as a nucleophile and Me2Zn as the zinc source. The presence of air was found to be crucial to achieve an effective C-C bond formation pointing to a radical mechanism.     

Recent advances and applications of iridium-catalysed asymmetric allylic substitution

Since their discovery in 1997, iridium-catalysed asymmetric allylic substitutions have been developed into a broadly applicable tool for the synthesis of chiral building blocks via C-C and C-heteroatom bond formation. The remarkable generality of these reactions and the high levels of regio- and enantioselectivity that are usually obtained in favour of the branched products have been made possible by a thorough investigation of the catalyst system and its mode of action. Therefore, today the Ir-catalysed asymmetric allylic substitution is a powerful reaction in the organic chemist's repertoire and has been used extensively for several applications. This article aims to provide an overview of the development of iridium catalysts derived from an Ir salt and a chiral phosphoramidite and their application to the enantioselective synthesis of natural products and biologically relevant compounds.     

The first catalytic asymmetric allylation of imines with the tetraallylsilane-TBAF-MeOH system, using the chiral bis-pi-allylpalladium complex

The asymmetric allylation of imines with use of catalytic transition metals with chiral ligands should be a new frontier of the enantioselective C-C bond formation. So far allyltrimethylsilane, allyltrichlorosilane, and allyltrimethoxysilane have been commonly employed with use of either silane activators or dual silane-imine activators. However, tetraallylsilane is untouched in the allylation of aldimines. The first allylation of aldimines with the tetraallylsilane-TBAF-MeOH system with use of the bis-pi-allylpalladium catalyst under catalytic, non-Lewis acid, essentially neutral and very mild reaction conditions has been achieved. The reaction is triggered by dual activation/promotion by TBAF and MeOH in which the fluoride anion activates the C-Si bond cleavage and MeOH promotes the facile protonation of intermediate palladium amide. Thus, the synthesis of chiral homoallylamines is achieved in a shorter reaction time and higher yields and enantioselectivities through an efficient, general, and reproducible allylation protocol for imines.     

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.     

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.     

New entries in Lewis acid-Lewis base bifunctional asymmetric catalyst: catalytic enantioselective Reissert reaction of pyridine derivatives

The first catalytic enantioselective Reissert reaction of pyridine derivatives that affords products with excellent regio- and enantioselectivity is described. The key for success is the development of new Lewis acid-Lewis base bifunctional asymmetric catalysts containing an aluminum as a Lewis acid and sulfoxides or phosphine sulfides as a Lewis base. These reactions are useful for the synthesis of a variety of chiral piperidine subunits, and catalytic enantioselective formal synthesis of CP-293,019, a selective D4 receptor antagonist, was achieved. Preliminary mechanistic studies indicated that both sulfoxides and phosphine sulfides can activate TMSCN as a Lewis base. In addition, the sulfoxides with appropriate stereochemistry might stabilize a highly enantioselective bimetallic complex (a presumed active catalyst) through internal coordination to aluminum.     

手性磷酸催化的有机催化不对称反应

手性磷酸是近年来发展起来的一类新型高效、高对映选择性的Brønsted酸类有机催化剂, 已成功应用于催化不对称Mannich反应、还原胺化反应、Pictet-Spengler反应、aza-Diels-Alder反应和aza-Ene反应等许多重要的有机合成反应. 手性磷酸催化剂分子内同时含有Lewis碱性位点和Brønsted酸性位点, 可同时活化亲电与亲核底物. 作为一种新型双功能有机催化剂, 手性磷酸具有较高的催化活性和对映选择性, 催化剂最低用量可达0.05 mol%. 对各类手性磷酸催化剂在有机催化不对称合成反应中的应用研究进展, 以及不对称诱导反应的机理、手性磷酸的分子结构及反应条件对其催化活性和不对称诱导活性的影响进行了评述.     

手性二茂铁类配体在钯催化不对称反应中的应用

本文综述了近10 年来手性二茂铁类配体在钯催化不对称烯丙基取代反应,包括各种不同底物的烯丙基烷基化、烯丙基胺基化和烯丙基磺酰化反应中的应用,并对其在不对称Claisen 重排、不对称Diels-Alder 反应、不对称Heck 反应、不对称羰基化、不对称氢化硅烷化和不对称碳碳键断裂等反应中的应用进行了综述,对部分反应的机理和该领域的发展前景进行了讨论。     

Allylic alcohols as synthetic enolate equivalents: isomerisation and tandem reactions catalysed by transition metal complexes

Allylic alcohols can be isomerised into carbonyl compounds by transition metal complexes. In the last few years, catalyst design and development have resulted in highly efficient isomerisations under mild reaction conditions, including enantioselective versions. In addition, the isomerisation of allylic alcohols has been combined with C-C bond forming reactions when electrophiles such as aldehydes or imines were present in the reaction mixture. Also, C-F bonds can be formed when electrophilic fluorinating reagents are used. Thus, allylic alcohols can be treated as latent enol(ate)s. In this article, we highlight the latest developments concerning the isomerisation of allylic alcohols into carbonyl compounds, focusing in particular on tandem isomerisation/C-C or C-heteroatom bond formation processes. Significant attention is given to the mechanistic aspects of the reactions.     

Ionic liquids as a medium for enantioselective catalysis

Over the last years, interest involving ionic liquids (ILs) used as reaction medium for homogeneous enantioselective catalysis has exponentially expanded. In many cases, the use of ILs provides several advantages over reactions in organic solvents in terms of activity and enantioselectivity. Even more important, the catalyst immobilization in IL can avoid its leaching and consequently favour its recycling. This review deals with recent advances in the investigation of these new solvents in asymmetric catalysis. We go over enzymes, chiral organocatalysts and metal complexes containing chiral ligands used in enantioselective processes using ionic liquids, with special emphasis on the catalyst reuse and also the separation of organic products.     

Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by N-Sulfonylated Amino Alcohols

Asymmetric C-C bond forming reactions are of prime importance in modem synthetic organic chemistry. The use of chiral amino alcohol ligands is widespread in this area.[1] Herein, we describe the synthesis of N-sulfonylated amino alcohols 1～4 and enantioselective addition of diethylzinc to aldehydes was carried out employing titanium(Ⅳ) complexes 1～4.     

Anion-binding catalyst designs for enantioselective synthesis

Select hydrogen bond donors can catalyze reactions of ion pairs through the recognition of anions. This mode of action can be exploited in enantioselective catalysis if a suitable chiral hydrogen bond donor is applied. Beyond just anionic recognition, an enantioselective anion-binding catalyst often must host numerous non-covalent interactions, including hydrogen bonding, general base, π-π, and π-cation, to achieve high levels of enantiocontrol. Anion-binding catalysts can be strategically designed to support those non-covalent interactions required to render a process highly stereoselective. Tactics applied in anion-binding catalyst development include enhancing arene substituents for improved π-stacking, linking two anion-binding units together on a single scaffold, expanding types of functional groups for anion recognition, and building frameworks with bifunctional modes of action. The intent of this digest is to highlight observations that suggest as anion-binding catalyst designs advance, their associated synthetic methodologies for complex molecule construction become increasingly impressive.