Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.     

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 .     

Transfer Hydrogenation of α‐Branched Ketimines: Enantioselective Synthesis of Cycloalkylamines via Dynamic Kinetic Resolution

The transfer hydrogenation of 2‐substituted bicyclic and monocyclic ketimines using HCO₂H/ Et₃N as the hydrogen source and TsDPEN‐based Ru(II) and Ir(III) catalysts proceeds with dynamic kinetic resolution to afford the corresponding cis‐cycloalkylamines with moderate to excellent levels of diastero‐ and enantioselectivity. A “one‐pot” procedure starting from ketones as starting materials with in situ formation of the reacting imines has also been developed.     

Catalytic Asymmetric Hydrogenation of α‐Arylcyclohexanones and Total Synthesis of (−)‐α‐Lycorane

An efficient catalytic asymmetric hydrogenation of racemic α‐arylcyclohexanones with an ethylene ketal group at the 5‐position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α‐arylcyclohexanols with two contiguous stereocenters with up to 99% ee and >99:1 cis/trans‐selectivity. Using this highly efficient asymmetric hydrogenation reaction as a key step, (−)‐α‐lycorane was synthesized in 19.6% overall yield over 13 steps from commercially available starting material.     

Biotransformation of (+)‐ and (−)‐bornyl acetate using the plant parasitic fungus Glomerella cingulata as a biocatalyst

The microbial transformations of (+)‐ and (?)‐bornyl acetate were investigated using the plant parasitic fungus, Glomerella cingulata. As a result, (+)‐ and (?)‐bornyl acetate were converted to (+)‐ and (?)‐5‐exo‐hydroxybornyl acetate, (+)‐ and (?)‐5‐oxobornyl acetate and (+)‐ and (?)‐borneol respectively. The structures of the metabolic products were determined by spectroscopic data. © 2001 Society of Chemical Industry     

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.     

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.

     

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%).     

Bulky Achiral Triarylphosphines Mimic BINAP in Ru(II)‐ Catalyzed Asymmetric Hydrogenation of Ketones

In the present work, we report on catalysis of the enantioselective hydrogenation of ketones with Ru(II) complexes composed of cheap achiral monodentate phosphine ligands in combination with an enantiopure 1,2‐diamine, affording a variety of optically active secondary alcohols with high efficiency and enantioselectivity. The steric impact of achiral monophosphine ligands in Ru complexes was found to be a critical factor for the high enantioselectivity of the reaction. This finding throws some light on a long‐standing challenge, the high cost of chiral bisphosphine ligands, associated with an industrial application of the asymmetric hydrogenation of ketones.     

Enantioselective Synthesis of Chiral Tetrahydroisoquinolines by Iridium‐Catalyzed Asymmetric Hydrogenation of Enamines

Chiral iridium complexes based on spiro phosphoramidite ligands are demonstrated to be highly efficient catalysts for the asymmetric hydrogenation of unfunctionalized enamines with an exocyclic double bond. In combination with excess iodine or potassium iodide and under hydrogen pressure, the complex Ir/(S_a,R,R)‐ 3a provides chiral N‐alkyltetrahydroisoquinolines in high yields with up to 98% ee. The L/Ir ratio of 2:1 is crucial for obtaining a high reaction rate and enantioselectivity. A deuterium labeling experiment showed that an inverse isotope effect exists in this reaction. A possible catalytic cycle including an iridium(III) species bearing two monophosphoramidite ligands is also proposed.     

Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines by Ruthenium‐Catalyzed Asymmetric Hydrogenation in Ionic Liquid

Asymmetric hydrogenation reactions of quinolines and 3,4‐dihydroisoquinolines using the chiral cationic ruthenium complex Ru(TsDPEN) [TsDPEN=N‐(p‐toluenesulfonyl)‐1,2‐diphenylethylenediamine] as catalyst in neat imidazolium ionic liquids have been investigated. The catalytic performance was influenced by the anion of the ionic liquids for both substrate classes. A range of 2‐alkyl‐substituted 1,2,3,4‐tetrahydroquinolines and 1‐alkyl‐substituted 1,2,3,4‐tetrahydroisoquinolines was obtained in high yields with up to >99% ee. Interestingly, the hydrogenation of quinoline derivatives bearing a carbonyl group was selective for the CN (quinoline) over the CO (ketone) bonds, while such a unique chemoselectivity was not observed in methanol. Furthermore, the ruthenium catalysts could be easily recycled at least 5 times in the asymmetric hydrogenation of 3,4‐dihydroisoquinoline by solvent extraction. To further facilitate the recovery of catalyst and reduce the use of organic solvent, a thin film of ionic liquid containing Ru(TsDPEN) was supported on silica gels. This supported ionic liquid‐phase catalyst was effective in the asymmetric hydrogenation of quinoline, and could be recycled at least 6 times by simple filtration.

     

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.     

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.     

Enantioselective Synthesis of cis‐4‐Formyl‐β‐lactams via Chiral N‐Heterocyclic Carbene‐Catalyzed Kinetic Resolution

An efficient synthesis of optically pure cis‐4‐formyl‐β‐lactams (up to 99% ee) by a chiral NHC‐catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4‐formyl‐β‐lactams and succinimides containing quaternary carbon centers.     

Synthesis of Chiral 2‐Hydroxy‐1‐methylpropanoates by Rhodium‐Catalyzed Stereoselective Hydrogenation of α‐(Hydroxymethyl)‐acrylate Derivatives

The synthesis of chiral 3‐hydroxy‐2‐methylpropanoic acid esters (e.g., “Roche ester” 3a ) based on the rhodium‐catalyzed stereoselective hydrogenation of Baylis–Hillman reaction products was investigated. Full conversions and enantioselectivities of up to 99% at a substrate/catalyst ratio of up to 500/1 were achieved by application of bisphospholanes of the catASium M series as ancillary ligands. An interesting kinetic resolution was observed by the diastereoselective hydroxy‐directed hydrogenation of related racemic β‐branched precursors affording mainly anti‐isomers with up to 96%ee.     

An Efficient Approach to Chiral Ferrocene‐Based Secondary Alcohols via Asymmetric Hydrogenation of Ferrocenyl Ketones

P‐Phos‐ruthenium‐DPEN precatalysts have been found to be efficient for the asymmetric hydrogenation of various ferrocenyl ketones. The use of (R)‐xylyl‐P‐PhosRuCl₂(R,R)‐DPEN generated chiral ferrocenylethanol in 99.3% e.e. with >99% conversion in a 150‐g scale.     

Titanium‐Catalyzed Enantioselective Synthesis of α‐Ambrinol

We describe the first enantioselective synthesis of the odorant compound (−)‐α‐ambrinol (96% ee) from commercial geranylacetone. The key steps are a Jacobsen’s asymmetric epoxidation and a titanium‐catalyzed stereoselective cyclization initiated by radical epoxide opening. The oxirane ring opening proceeds with retention of configuration at the epoxide chiral center, giving a secondary alcohol which can be advantageously exploited to raise the ee provided by the synthetic sequence. We also synthesized (+)‐α‐ambrinol by a closely related procedure, showing the synthetic versatility of combining titanium‐catalyzed cyclization with Jacobsen’s epoxidation reactions.     

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.