Continuous Chirality Measure in Reaction Pathways of Ruthenium‐Catalyzed Transfer Hydrogenation of Ketones

Here we report theoretical studies on the ruthenium‐catalyzed reduction of acetophenone (and 2‐hexanone) with the intent of understanding the relative roles of catalyst and substrate along the reaction path. Overall ten reaction pathways are examined. The first eight are for acetophenone: they arise from the presence of two catalysts, with the more enantioselective one labeled 1 , and the poorer one labeled 2 , multiplied by the two configurations that the metal center of the catalysts can assume, multiplied by the two approaches, Re‐ and Si‐side, of the substrate to the catalyst. Two pathways are examined for 2‐hexanone and entail the two approaches to the ketone of the more effective catalyst. Density functional theory calculations provide structures of the minima and transition states, which subsequently have been assessed with the “continuous chirality measure” model developed by Avnir and collaborators. The picture that emerges is that the asymmetric induction is due to the interplay between the organometallic system and the organic substrate. This is effective only for catalyst 1 , which can interact effectively with acetophenone along only one in four of the reaction pathways, but not for 2 for which two out of four pathways are opened. For the hydrogenation of 2‐hexanone, the same catalyst 1 cannot produce enantiomeric excesses because the conformation of the substrate in the transition state induced by the catalyst has a relative low chirality.     

A Bis(Triazolecarboxamido) Ligand for Enantio‐ and Regioselective Molybdenum‐Catalyzed Asymmetric Allylic Alkylation Reactions

A modular, enantiomerically pure bis(1H‐1,2,3‐triazole‐4‐carboxamide) has been assembled from N,N′‐[(1R,2R)‐cyclohexane‐1,2‐diyl]dipropiolamide through a copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction and evaluated as a ligand in the molybdenum‐catalyzed asymmetric allylic alkylation (MoAAA) reaction, very high regio‐ and enantioselectivities being recorded.

     

Proline‐Catalyzed Asymmetric Aldol Reaction in Guanidine‐ Derived Ionic Liquids

A remarkable improvement of both the chemical yield (from 6% to 82%) and the enantiomeric excess (up to >99%), of (S)‐proline catalyzed direct aldol reactions of a wide range of aldehydes with acetone was found when hexasubstituted or pentasubstituted guanidinium salts were added as ionic liquids. Effects of temperature, amount of proline and the type of guandidinium salts on the outcome of the reaction were investigated.     

Modular Hydroxyamide and Thioamide Pyranoside‐Based Ligand Library from the Sugar Pool: New Class of Ligands for Asymmetric Transfer Hydrogenation of Ketones

A large library of pyranoside‐based hydroxyamide and thioamide ligands has been synthesized for asymmetric transfer hydrogenation in an attempt to expand the scope of the substrates to cover a broader range of challenging heteroaromatic and aryl/fluoroalkyl ketones. These ligands have the advantage that they are prepared from commercial D ‐glucose, D ‐glucosamine and α‐amino acids, inexpensive natural chiral feedstocks. By carefully selecting the ligand components (substituents/configurations at the amide/thioamide moiety, the position of amide/thioamide group and the configuration at C‐2), we found that pyranoside‐based thioamide ligands provided excellent enantioselectivities (in the best cases, ees of >99% were achieved) in a broad range of ketones, including the less studied heteroaromatics and challenging aryl/fluoroalkyls. Note that both enantiomers of the reduction products can be obtained with excellent enantioselectivities by simply changing the absolute configuration of the thioamide substituent.

     

Polystyrene‐Supported Enantiopure 1,2‐Diamines: Development of a Most Practical Catalyst for the Asymmetric Transfer Hydrogenation of Ketones

Chlorosulfonylated polystyrene, a commodity resin, reacts with enantiopure 1,2‐diamines to afford, in a single step, high loading catalytic resins involving monosulfonylated 1,2‐diamino moieties. These functional polymers form stable (p‐cymene)ruthenium chloride [RuCl(p‐cymene)] complexes that efficiently catalyze (down to S/C=150) the asymmetric transfer hydrogenation (ATH) of alkyl aryl ketones with formic acid‐triethylamine under essentially solvent‐free (down to 0.25 mL mmol⁻¹) reaction conditions. Among these resins, the immobilized version of TsDPEN stands out as a most practical catalyst for ATH: Uniformly high enantioselectivities are achieved with its use at low catalyst loading, and the resin can be recycled with virtually no limits.     

Ruthenium‐Catalyzed Asymmetric Hydrogenation of β‐Keto‐ enamines: An Efficient Approach to Chiral γ‐Amino Alcohols

A highly efficient and enantioselective hydrogenation of unprotected β‐ketoenamines catalyzed with ruthenium(II) dichloro{(S)‐(−)‐2,2′‐bis[di(3,5‐xylyl)phosphino]‐1,1′‐binaphthyl}[(2S)‐(+)‐1,1‐bis(4‐methoxyphenyl)‐3‐methyl‐1,2‐butanediamine] {Ru[(S)‐xylbinap][(S)‐daipen]Cl₂} has been successfully developed. This methodology provides a straightforward access to free γ‐secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases.     

General Enantioselective Synthesis of Butyrolactone Natural Products via Ruthenium‐SYNPHOS®‐Catalyzed Hydrogenation Reactions

Enantioselective syntheses of several paraconic acids have been achieved using catalyzed asymmetric hydrogenation of β‐keto esters with SYNPHOS^® as a ligand. This strategy allowed the short synthesis of biologically active (−)‐methylenolactocin 1 , (−)‐protolichesterinic acid 2 , (−)‐phaseolinic acid 3 and (+)‐roccellaric acid 4 .     

Ruthenium‐Catalyzed Synthesis of Secondary Alkylamines: Selective Alkylation with Aliphatic Amines

The chemoselective N‐alkylation of tert‐alkylamines applying aliphatic amines is described for the first time. In the presence of the Shvo catalyst 1 , tert‐octylamine 4 and 1‐adamantylamine 5 are alkylated using primary, secondary, and even tertiary amines to give the corresponding monoalkylated tert‐alkylamine in moderate to very good yields and excellent selectivity. This novel reaction proceeds without an additional hydrogen source and ammonia is formed as the only by‐product.     

Axial Chirality Control by 2,4‐Pentanediol for the Alternative Synthesis of C3*‐TunePhos Chiral Diphosphine Ligands and Their Applications in Highly Enantioselective Ruthenium‐Catalyzed Hydrogenation of β‐Keto Esters

A highly efficient strategy for the synthesis of a series of C₃*‐TunePhos chiral diphosphine ligands was well established with several remarkable features. The synthetic utility of these ligands was explored for the ruthenium‐catalyzed asymmetric hydrogenation of β‐keto esters. Up to 99% ee values were achieved for the enantioselective synthesis of β‐hydroxy acid derivatives, which are very important chiral building blocks for the synthesis of a variety of natural products and biologically active molecules.     

An Ion‐Pair Immobilization Strategy in Rhodium‐Catalyzed Asymmetric Transfer Hydrogenation of Aromatic Ketones

A chiral diamine‐based homogeneous cationic rhodium catalyst was developed and two heterogeneous cationic rhodium catalysts were obtained via the encapsulation of the homogeneous cationic rhodium catalyst within Me‐SBA‐15 and Me‐SBA‐16. All these catalysts presented excellent catalytic activities and high enantioselectivities in ultrasound‐promoted asymmetric transfer hydrogenation of aromatic ketones and represent a successful use of the ion‐pair immobilization strategy. More importantly, the encapsulation of the cationic rhodium functionality within Me‐SBA‐16 had an obvious high recyclability, in which the recycled catalyst could be reused nine times without significantly affecting its enantioselectivity, showing good potential in industrial application.     

Kilogram‐Scale Asymmetric Ruthenium‐Catalyzed Hydrogenation of a Tetrasubstituted Fluoroenamide

Ruthenium‐catalyzed asymmetric homogeneous hydrogenation (AHH) is used as the key step of a multi‐kilogram scale synthesis of an enantiomeric fluoropiperidine. The AHH of a tetrasubstituted β‐fluoroenamide is carried out under mild conditions using a Ru/Josiphos catalyst with high ee (98%).     

The Synthesis of Spirobitetraline Phosphoramidite Ligands and their Application in Rhodium‐Catalyzed Asymmetric Hydrogenation

A racemic 1,1′ ‐ spirobitetralin‐8,8′‐diol (SBITOL) was conveniently synthesized from 3‐methoxybenzaldehyde in 26 % yield over 9 steps and resolved via its bis‐(S)‐camphorsulfonates. The corresponding chiral spirobitetraline monophosphoramidite ligands have been prepared and their rhodium complexes were applied in the asymmetric hydrogenation of dehydroamino esters with good to excellent enantioselectivities (up to 99.3 % ee).     

Highly Enantioselective Synthesis of 3‐Hydroxy‐2‐methylpropanoic Acid Esters through Ruthenium‐SYNPHOS®‐Catalyzed Hydrogenation: Useful Building Blocks for the Synthetic Community

Both enantiomers of 3‐hydroxy‐2‐methylpropanoic acid tert‐butyl ester were prepared with high enantioselectivity (up to 94 %) through a ruthenium‐SYNPHOS®‐promoted asymmetric hydrogenation reaction using an atom‐economic transformation from simple and inexpensive precursors.     

Evaluation of Ligands for Ketone Reduction by Asymmetric Hydride Transfer in Water by Multi‐Substrate Screening

Various ligands for the ruthenium‐catalyzed enantioselective reduction of ketones in water have been investigated. Multi‐substrate reactions have been carried out for the comparison of various proline amides and aminoalcohol ligands. Two sets of six aromatic ketones have been selected in order to evaluate the enantiomeric excesses of all the resulting alcohols by a single chromatographic analysis. The proline amide derivative prepared from (1R,2S)‐cis‐aminoindanol revealed as the best ligand for most of the ketones used in the multi‐substrate reductions. This ligand has been employed for the enantioselective reduction of a variety of other aromatic ketones and in all cases the enantiomeric excesses were improved compared to those obtained with phenylprolineamide used in our previous work.     

Threonine‐Derived Phosphinite‐Oxazoline Ligands for the Ir‐Catalyzed Enantioselective Hydrogenation

A series of chiral phosphinite‐oxazolines was synthesized in four steps starting from carboxylic acids and threonine methyl ester. In the asymmetric hydrogenation of a number of alkenes, iridium complexes of these ligands induced significantly higher enantioselectivities than the corresponding serine‐derived complexes. Enantiomeric excesses of 89 to 99% were obtained for unfunctionalized alkenes with turnover numbers of up to 5000.     

Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs Metathesis Catalysts: On the Way to a Tandem Process

Herein, we report the successful transformation of a 1^st generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1^st generation Hoveyda–Grubbs catalyst ( HG‐I ) was found to promote the enantioselective reduction of acetophenone to 1‐phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ‐generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis–ketone asymmetric transfer hydrogenation was carried out.

     

Convenient General Asymmetric Synthesis of Roche Ester Derivatives through Catalytic Asymmetric Hydrogenation: Steric and Electronic Effects of Ligands

An efficient and concise asymmetric hydrogenation of acrylate esters promoted by the cationic ruthenium monohydride complex [Ru(H)(η⁶‐cot)SYNPHOS]⁺BF₄⁻ is reported. A full investigation of the effects of catalyst precursors, solvents, temperature, hydrogen pressure, substrates as well as steric and electronic properties of ligands was carried out. The corresponding valuable Roche ester derivatives were obtained in good to excellent isolated yields and high enantioselectivities under mild conditions. The robustness and practicability of this highly enantioselective hydrogenation was demonstrated by the synthesis of the 3‐hydroxy‐2‐methylpropanoic acid tert‐butyl ester on a multigram scale, resulting in excellent yield and ee up to 94%.     

New Polymer‐Supported Catalysts for the Asymmetric Transfer Hydrogenation of Acetophenone in Water – Kinetic and Mechanistic Investigations

Heterogenization is a powerful approach for the generation of easily recyclable catalysts. In this study, a modified tethered rhodium(III)‐ p‐toluenesulfonyl‐1,2‐diphenylethylenediamine (Rh‐TsDPEN) complex immobilized on polymeric supports was applied to kinetic and up‐scaling experiments on the asymmetric transfer hydrogenation of acetophenone in water. Study of the catalyst has helped in understanding some aspects of its operating mode. The results indicate that, in the investigated range, a simple second‐order model describes the enantioselective conversion of acetophenone to phenylethanol. Optimal reaction conditions were determined, and particularly the solution pH was found to play a decisive role for the activity and reusability of the catalyst. The good performance under optimized conditions emphasizes the practical usefulness of this recyclable catalytic system for environmentally benign asymmetric transfer hydrogenation processes.     

Enantioselective Synthesis of α‐Trifluoromethyl Arylmethylamines by Ruthenium‐Catalyzed Transfer Hydrogenation Reaction

A simple combination of dichloro(para‐cymene)ruthenium(II) dimer, a chiral amino alcohol and isopropyl alcohol allowed for in‐situ generation of the bifunctional catalyst responsible for the transfer hydrogenation reaction of trifluoromethyl ketimines in excellent yields with high enantioselectivities (up to 93% ee). Herein, we describe the optimization, scope, limitations, and applications of the method.