Chiral Base Research Articles

Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations.

The use of frustrated Lewis pairs is an extremely important approach to metal-free hydrogenations. In contrast to the rapid growth of catalytic reactions, asymmetric hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prepare. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asymmetric metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ preparation of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purification, which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asymmetric metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases containing hydridic and acidic hydrogen atoms, respectively, as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asymmetric induction. With chiral diene-derived boron Lewis acids as catalysts, a broad range of unsaturated compounds, such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asymmetric metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asymmetric hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asymmetric Piers-type hydrosilylations of 1,2-dicarbonyl compounds, and they give the desired products in high yields and enantioselectivities. Moreover, asymmetric transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state.

Comparison of resolution methods for racemic 8-(phenylsulfinyl)-1-naphthoic acid

Despite of the fact that resolution is an extremely important process in the pharmaceutical and agrochemical industries, the development of the separation of enantiomers is still based on trial-and-error experiments. In order to compare the different procedures, the resolution of 8-(phenylsulfinyl)-1-naphthoic acid 1 was carried out by chiral organic bases using heat facilitated diastereomeric crystallization, enantioselective liquid–liquid extraction and chiroselective transport. The results give valuable information about the interactions in the racemate/resolving agent/solvent system, which helps with the understanding and development of resolution processes. Diastereomeric crystallization with brucine as a resolving agent afforded enantiomerically pure (−)-1.

One‐Pot Vinylation of Azlactones: Fast Access to Enantioenriched α‐Vinyl Quaternary Amino Acids

We report a fast one‐pot protocol for the direct vinylation of azlactones [oxazol‐5‐(4H)‐ones] by using as a key step an aldol addition with 2‐(phenylselenenyl)acetaldehyde followed by dehydroxyselenation. The acid hydrolysis of the oxazolone ring gave the desired fully deprotected α‐vinyl quaternary α‐amino acids in almost quantitative yields. An enantioselective variant of the method was also developed by using catalytic chiral bases. The use of Sharpless ligand (DHQD)2PHAL produced the final quaternary amino acids in good overall yields (62–78 %) and with ee values up to 86 %. Scaling up the optimized protocol to gram quantities did not affect the yields and ee values. We also demonstrated that the vinyl moiety installed onto the oxazolone ring can be exploited as a handle for the attachment of aryl groups through a Heck coupling reaction.

Phosphite-Mediated Reductive Cross-Coupling of Isatins and Nitrostyrenes.

A new reductive coupling reaction between N-alkylisatins, dimethyl phosphite, and nitrostyrenes has been developed. The reaction relies on Pudovik addition, subsequent phosphonate-phosphate rearrangement, and Michael-type addition of a transient carbanion on the indolinone with β-nitrostyrenes. This protocol introduces a convenient and versatile method for the construction of polyfunctionalized tertiary phosphates under mild conditions. Chiral general bases catalyze the title reaction with promising levels of enantioselectivity.

A New Class of Low‐Loading Catalysts for Highly Enantioselective, Metal‐Free Imine Reduction of Wide General Applicability

AbstractA new class of chiral Lewis bases for the enantioselective HSiCl3‐mediated reduction of imines was developed. Through extensive catalyst structure optimization, an extremely active species was identified that was able to promote the reduction of a large variety of functionalized substrates in high yields with enantioselectivities typically above 90 % with catalyst loadings as low as 0.1–1 mol %. The simple experimental procedure, the low cost of the reagents, the mild reaction conditions, and the straightforward isolation of the product make the methodology attractive for large‐scale applications. Its synthetic potentiality was demonstrated by the preparation of advanced intermediates of important active pharmaceutical ingredients used in the treatment of Alzheimer's and Parkinson's diseases, hyperparathyroidism, neuropathic pains, and neurological disorders. The reaction was also successfully performed in flow reactors, which thus demonstrated the possibility to realize in continuo processes to yield multigram quantities of product.

Synthesis of Planar Chiral Ferrocenes via Transition-Metal-Catalyzed Direct C-H Bond Functionalization.

Ferrocenes are of great interest in the fields of materials science, organic synthesis, and biomedical research. Of particular significance is the fact that ferrocenes bearing planar chirality have been demonstrated to be highly efficient ligands or catalysts in asymmetric catalysis, some of which have been employed in the industrial synthesis of pharmaceuticals and agrochemicals. So far, the main methods for the synthesis of planar chiral ferrocenes involve diastereoselective directed ortho-metalation (DoM), enantioselective DoM, and chiral resolution. Despite the fact that these approaches are well developed and widely applied, the use of chiral auxiliaries or external stoichiometric chiral bases is required in most cases. Additionally, the practicality of these processes is hampered by the requirement of sensitive organometallic reagents, the poor compatibility with functional groups, and the low atom economy in some cases. Therefore, the development of highly efficient strategies to introduce planar chirality on the backbone of ferrocene that do not possess these limitations is highly desirable. Meanwhile, transition-metal-catalyzed asymmetric C-H bond functionalization reactions have attracted much attention over the past few years owing to their emerging potential for providing a straightforward approach for the preparation of chiral molecules. In addition to the majority of the work focusing on the installation of central chirality, methods for the catalytic asymmetric synthesis of planar chiral compounds via C-H bond functionalization have also been explored. In this Account, we summarize our recent efforts aimed at the development of novel methods to synthesize planar chiral compounds via asymmetric C-H bond functionalization and also highlight related achievements by other groups. First, we briefly introduce the precedent examples of diastereoselective and enantioselective synthesis of planar chiral ferrocenes. Subsequently, asymmetric syntheses of structurally diverse planar chiral ferrocenes via Pd [Pd(II), Pd(0)]-, Ir-, Rh-, Au-, and Pt-catalyzed C-H bond functionalization are described. These methods have impressive advantages over traditional approaches for the synthesis of functionalized planar chiral ferrocenes in terms of both step- and atom-economies. Notably, the products of these processes are easily transformed into a variety of new catalysts or ligands, which have been demonstrated to promote efficient asymmetric reactions. Moreover, DFT calculations have been conducted to explore the origin of the excellent enantioselectivity of Pd-catalyzed enantioselective C-H bond functionalization reactions. Progress made in the area of asymmetric C-H bond functionalization provides an effective platform for the design and synthesis of planar chiral ferrocenes.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

Heterogeneous enantioselective synthesis of chromans via the oxa-Michael-Michael cascade reaction synergically catalyzed by grafted chiral bases and inherent hydroxyls on mesoporous silica surface.

A heterogeneous enantioselective oxa-Michael-Michael reaction for the synthesis of chromans has been developed on a heterogeneous acid-base synergic catalyst with inherent silica as acidic sites and immobilized chiral amines as basic sites. Final products were afforded in selectivity of up to 98% and ee of 97% from 2-nitrovinyl phenol and 3-methyl-2-butenal. The heterogeneous synergistic catalytic mechanism has also been studied.

ChemInform Abstract: Asymmetric Organocatalysis: The Emerging Utility of α,β‐Unsaturated Acylammonium Salts

AbstractReview: [41 refs.

Asymmetric Organocatalysis: The Emerging Utility of α,β-Unsaturated Acylammonium Salts.

Although acylammonium salts are well-studied, chiral α,β-unsaturated acylammonium salts have received much less attention. While these intermediates are convenient synthons, which are readily available from several commodity unsaturated acids and acid chlorides, and possess three reactive sites, their application in organic synthesis has been limited because of the lack of appropriate chiral Lewis bases for their generation. In recent years, the utility of chiral, unsaturated acylammonium salts has expanded considerably, thus demonstrating the unique reactivity of this intermediate leading to the development of a diverse array of catalytic, asymmetric transformations including organocascade processes. This Minireview highlights the recent and growing interest in these intermediates which might spark further research into their untapped potential for asymmetric organocascade catalysis. A cursory comparison is made to related unsaturated iminium and acylazolium intermediates.

Stereoselective Reduction of Imines with Trichlorosilane Using Solid-Supported Chiral Picolinamides.

The stereoselective reduction of imines with trichlorosilane catalyzed by chiral Lewis bases is a well-established procedure for the synthesis of enantio-enriched amines. Five supported cinchona-based picolinamides have been prepared and their activity tested in a model reaction. The comparison of different supporting materials revealed that polystyrene gave better results than silica in terms of stereoselectivity. The applicability of the solid-supported catalyst of choice to the reduction of different imines was also demonstrated. Additionally, for the first time, a catalytic reactor containing a polymer-immobilized chiral picolinamide has been employed for the stereoselective reduction of imines with trichlorosilane under continuous flow conditions.

Synthesis of Chiral Phosphazene Bases

Air-stable and crystalline tetraaminophosphonium tetrafluoroborates possessing chiral, enantiomerically pure 1,2-diamine moiety have been synthesized by a three-step sequential one-pot approach. The tetrafluoroborate salts can be purified by recrystallization or chromatography and subsequently converted to the phosphazene bases by treatment with t-BuOK. Basicity values in tetrahydrofuran have been measured for the obtained phosphazene bases by means of spectrophotometric titration.

Organocatalytic Transfer Hydrogenation and Hydrosilylation Reactions.

The reduction of different carbon-carbon or carbon-heteroatom double bonds is a powerful tool that generates in many cases new stereogenic centers. In the last decade, the organocatalytic version of these transformations has attracted more attention, and remarkable progress has been made in this way. Organocatalysts such as chiral Brønsted acids, thioureas, chiral secondary amines or Lewis bases have been successfully used for this purpose. In this context, this chapter will cover pioneering and seminal examples using Hantzsch dihydropyridines 1 and trichlorosilane 2 as reducing agents. More recent examples will be also cited in order to cover as much as possible the complete research in this field.

Enantioselective separation of biologically active basic compounds in ultra-performance supercritical fluid chromatography

The enantioseparation of basic compounds represent a challenging task in modern SFC. Therefore this work is focused on development and optimization of fast SFC methods suitable for enantioseparation of 27 biologically active basic compounds of various structures. The influences of the co-solvent type as well as different mobile phase additives on retention, enantioselectivity and enantioresolution were investigated. Obtained results confirmed that the mobile phase additives, especially bases (or the mixture of base and acid), improve peak shape and enhance enantioresolution. The best results were achieved with isopropylamine or the mixture of isopropylamine and trifluoroacetic acid as additives. In addition, the effect of temperature and back pressure were evaluated to optimize the enantioseparation process. The immobilized amylose-based chiral stationary phase, i.e. tris(3,5-dimethylphenylcarbamate) derivative of amylose proved to be useful tool for the enantioseparation of a broad spectrum of chiral bases. The chromatographic conditions that yielded baseline enantioseparations of all tested compounds were discovered. The presented work can serve as a guide for simplifying the method development for enantioseparation of basic racemates in SFC.

Silicon marries a chiral counterion

Organic Lewis Acids Acid is among the oldest and most versatile of chemical catalysts, but its symmetrical protons can't guide reactions to favor a product over its mirror image. Chemists have resolved this shortcoming through the use of chiral conjugate bases. While the proton activates the

Cu-catalyzed asymmetric Henry reaction promoted by chiral camphor Schiff bases

Five novel chiral camphor Schiff bases have been synthesized and utilized as ligands in asymmetric Henry reaction between nitromethane and aldehydes. The diastereoisomeric Schiff bases 5a and 5a' were separated successfully and gave completely different absolute configurations in the reaction. The reactions were carried out with CuCl-Schiff base 5a complex under mild condition with good yields and enantioselectivities. This is the first time that camphor-derivated Schiff bases were used as ligands in asymmetric Henry reaction.

ChemInform Abstract: Synthesis of P‐Stereogenic Phosphoramidite and Phosphorodiamidite Ligands and Their Application in Asymmetric Catalysis.

AbstractA library of novel P‐stereogenic phosphoramidite and phosphorodiamidite ligands based on chiral Betti bases are synthesized (not shown) and applied to Rh‐catalyzed asymmetric hydrogenation as well as Pd‐catalyzed allylic amination and a Ni‐catalyzed hydrovinylation.

ChemInform Abstract: Chiral Phosphine Oxide Aziridinyl Phosphonate as a Lewis Base Catalyst for Enantioselective Allylsilane Addition to Aldehydes.

Abstract A series of chiral Lewis bases, phosphine oxide ferrocenyl aziridinyl methanol 1–4, phosphinyl aziridinyl phosphonates 5 and 6, and phosphine oxide aziridinyl phosphonates 7 and 8 were screened for allylsilane additions to aldehydes. Among the Lewis bases, 8 was found to catalyze the reaction by forming the product in up to 94% yield and with 77% ee.

Enantioselective direct aldol reactions promoted by phosphine oxide aziridinyl phosphonate organocatalysts

A series of phosphine oxide based chiral Lewis bases were screened as organocatalysts for silicon tetrachloride mediated direct asymmetric aldol reactions between cyclohexanone and various aromatic aldehydes. One of the phosphine oxide-aziridinyl phosphonate POAP-A Lewis bases formed the aldol products in up to 75% yield and with 65% ee.

Superconducting phase with the (d + id) order parameter in an ensemble of Hubbard fermions on the triangular lattice

In the framework of the t–J 1–J 2–V model, the integral equation determining the order parameter Δ(p) of the superconducting phase is derived for an ensemble of strongly correlated fermions on a triangular lattice using the diagram technique for the Hubbard operators. Taking into account the interaction between the Hubbard fermions within two coordination spheres, we demonstrate that the exact analytical solution Δ2(p) of this equation for the superconducting phase with the (\(\left( {{d_{{x^2} - {y^2}}} + i{d_{xy}}} \right)\)) symmetry can be expressed as a superposition of two chiral basis functions. This gives rise to a new set of nodal points for the complex parameter Δ2(p). Moreover, at some critical value x c of the charge carrier density, we obtain a gapless phase with six Dirac points. The passing of x through x = x c is accompanied by the topological quantum transition corresponding to the change in the topological parameter Q.