Asymmetric Reduction of 2‐Chloro‐3‐oxo Esters by Transfer Hydrogenation

Asymmetric reduction of 2‐chloro‐3‐oxo esters was achieved by catalytic transfer hydrogenation using [RuCl₂(p‐cymene)](S,S)‐TsDPEN as the chiral catalyst and HCOOH‐Et₃N as the hydrogen source. Moderate to good yields (up to 85%) and good enantioselectivities (up to 98% ee) were obtained.     

Efficient Cluster‐Based Catalysts for Asymmetric Hydrogenation of α‐Unsaturated Carboxylic Acids

The new clusters [H₄Ru₄(CO)₁₀(μ‐1,2‐P‐P)], [H₄Ru₄(CO)₁₀(1,1‐P‐P)] and [H₄Ru₄(CO)₁₁(P‐P)] (P‐P=chiral diphosphine of the ferrocene‐based Josiphos or Walphos ligand families) have been synthesised and characterised. The crystal and molecular structures of eleven clusters reveal that the coordination modes of the diphosphine in the [H₄Ru₄(CO)₁₀(μ‐1,2‐P‐P)] clusters are different for the Josiphos and the Walphos ligands. The Josiphos ligands bridge a metal–metal bond of the ruthenium tetrahedron in the “conventional” manner, that is, with both phosphine moieties coordinated in equatorial positions relative to a triangular face of the tetrahedron, whereas the phosphine moieties of the Walphos ligands coordinate in one axial and one equatorial position. The differences in the ligand size and the coordination mode between the two types of ligands appear to be reflected in a relative propensity for isomerisation; in solution, the [H₄Ru₄(CO)₁₀(1,1‐Walphos)] clusters isomerise to the corresponding [H₄Ru₄(CO)₁₀(μ‐1,2‐Walphos)] clusters, whereas the Josiphos‐containing clusters show no tendency to isomerisation in solution. The clusters have been tested as catalysts for asymmetric hydrogenation of four prochiral α‐unsaturated carboxylic acids and the prochiral methyl ester (E)‐methyl 2‐methylbut‐2‐enoate. High conversion rates (>94 %) and selectivities of product formation were observed for almost all catalysts/catalyst precursors. The observed enantioselectivities were low or nonexistent for the Josiphos‐containing clusters and catalyst (cluster) recovery was low, suggesting that cluster fragmentation takes place. On the other hand, excellent conversion rates (99–100 %), product selectivities (99–100 % in most cases) and good enantioselectivities, reaching 90 % enantiomeric excess (ee) in certain cases, were observed for the Walphos‐containing clusters, and the clusters could be recovered in good yield after completed catalysis. Results from high‐pressure NMR and IR studies, catalyst poisoning tests and comparison of catalytic properties of two [H₄Ru₄(CO)₁₀(μ‐1,2‐P‐P)] clusters (P‐P=Walphos ligands) with the analogous mononuclear catalysts [Ru(P‐P)(carboxylato)₂] suggest that these clusters may be the active catalytic species, or direct precursors of an active catalytic cluster species.     

Asymmetric Hydrogenation of α-Hydroxy Ketones: A Reaction Sensitive toward Electronic Effect of Substrates

以[RuCl2(benzene)]2 和 SunPhos为原料现场制备的催化剂,催化不对称氢化α-羟基酮类化合物可获得手性1, 2-二醇类化合物,ee值最高达99%。     

Asymmetric Hydrogenation of α,β‐Unsaturated Carboxylic Esters with Chiral Iridium N,P Ligand Complexes

Enantioselective conjugate reduction of a wide range of α,β‐unsaturated carboxylic esters was achieved using chiral Ir N,P complexes as hydrogenation catalysts. Depending on the substitution pattern of the substrate, different ligands perform best. α,β‐Unsaturated carboxylic esters substituted at the α position are less problematic substrates than originally anticipated and in some cases α‐substituted substrates actually reacted with higher enantioselectivity than their β‐substituted analogues. The resulting saturated esters with a stereogenic center in the α or β position were obtained in high enantiomeric purity.     

Asymmetric Hydrogenation of Azaindoles: Chemo‐ and Enantioselective Reduction of Fused Aromatic Ring Systems Consisting of Two Heteroarenes

High enantioselectivity was achieved for the hydrogenation of azaindoles by using the chiral catalyst, which was prepared from [Ru(η³‐methallyl)₂(cod)] and a trans‐chelating bis(phosphine) ligand (PhTRAP). The dearomative reaction exclusively occurred on the five‐membered ring, thus giving the corresponding azaindolines with up to 97:3 enantiomer ratio.     

Asymmetric Ruthenium‐Catalyzed Hydrogenation of 2,6‐Disubstituted 1,5‐Naphthyridines: Access to Chiral 1,5‐Diaza‐cis‐Decalins

The first asymmetric hydrogenation (AH) of 2,6‐disubstituted and 2,3,6‐trisubstituted 1,5‐naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5‐naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4‐tetrahydro‐1,5‐naphthyridines with up to 99 % ee and full conversions. This facile and green protocol is applicable to the scaled‐up synthesis of optically pure 1,5‐diaza‐cis‐decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis.     

Highly Enantioselective Iridium‐Catalyzed Hydrogenation of α,β‐Unsaturated Esters

α,β‐Unsaturated esters have been employed as substrates in iridium‐catalyzed asymmetric hydrogenation. Full conversions and good to excellent enantioselectivities (up to 99 % ee) were obtained for a broad range of substrates with both aromatic‐ and aliphatic substituents on the prochiral carbon. The hydrogenated products are highly useful as building blocks in the synthesis of a variety of natural products and pharmaceuticals.     

Asymmetric Hydrogenation of 3‐Substituted Pyridinium Salts

The use of an equivalent amount of an organic base leads to high enantiomeric excess in the asymmetric hydrogenation of N‐benzylated 3‐substituted pyridinium salts into the corresponding piperidines. Indeed, in the presence of Et₃N, a Rh‐JosiPhos catalyst reduced a range of pyridinium salts with ee values up to 90 %. The role of the base was elucidated with a mechanistic study involving the isolation of the various reaction intermediates and isotopic labeling experiments. Additionally, this study provided some evidence for an enantiodetermining step involving a dihydropyridine intermediate.     

Stereoarrayed CF3‐Substituted 1,3‐Diols by Dynamic Kinetic Resolution: Ruthenium(II)‐Catalyzed Asymmetric Transfer Hydrogenation

CF₃‐substituted 1,3‐diols were stereoselectively prepared in excellent enantiopurity and high yield from CF₃‐substituted diketones by using an ansa‐ruthenium(II)‐catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono‐reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF₃C(O)‐substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction.     

Ruthenium‐Catalyzed Asymmetric Hydrogenation of 3‐Oxoglutaric Acid Derivatives: A Study of Unconventional Solvent and Substituent Effects

A series of 3‐oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)‐SunPhos]Cl (SunPhos=(2,2,2′,2′‐tetramethyl‐[4,4′‐bibenzo[d][1,3]dioxole]‐5,5′‐diyl)bis(diphenylphosphine)). Unlike simple β‐keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH₂Cl₂, acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5‐tricarbonyl substrates in the tested solvents. The C‐2 and C‐4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20 % in EtOH or THF to 90 % in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent.     

Development of Chiral Spiro P‐N‐S Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation of β‐Alkyl‐β‐Ketoesters

The chiral tridentate spiro P‐N‐S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3‐dithiane moiety into the ligand resulted in a highly efficient chiral iridium catalyst for asymmetric hydrogenation of β‐alkyl‐β‐ketoesters, producing chiral β‐alkyl‐β‐hydroxyesters with excellent enantioselectivities (95–99.9 % ee) and turnover numbers of up to 355 000.     

Chiral η6‐Arene/N‐Tosylethylenediamine–Ruthenium(II) Complexes: Solution Behavior and Catalytic Activity for Asymmetric Hydrogenation

Aromatic ketones are enantioseletively hydrogenated in alcohols containing [RuX{(S,S)‐Tsdpen}(η⁶‐p‐cymene)] (Tsdpen=TsNCH(C₆H₅)CH(C₆H₅)NH₂; X=TfO, Cl) as precatalysts. The corresponding Ru hydride (X=H) acts as a reducing species. The solution structures and complete spectral assignment of these complexes have been determined using 2D NMR (¹H‐¹H DQF‐COSY, ¹H‐¹³C HMQC, ¹H‐¹⁵N HSQC, and ¹H‐¹⁹F HOESY). Depending on the nature of the solvents and conditions, the precatalysts exist as a covalently bound complex, tight ion pair of [Ru⁺(Tsdpen)(cymene)] and X^?, solvent‐separated ion pair, or discrete free ions. Solvent effects on the NH₂ chemical shifts of the Ru complexes and the hydrodynamic radius and volume of the Ru⁺ and TfO^? ions elucidate the process of precatalyst activation for hydrogenation. Most notably, the Ru triflate possessing a high ionizability, substantiated by cyclic voltammetry, exists in alcoholic solvents largely as a solvent‐separated ion pair and/or free ions. Accordingly, its diffusion‐derived data in CD₃OD reflect the independent motion of [Ru⁺(Tsdpen)(cymene)] and TfO^?. In CDCl₃, the complex largely retains the covalent structure showing similar diffusion data for the cation and anion. The Ru triflate and chloride show similar but distinct solution behavior in various solvents. Conductivity measurements and catalytic behavior demonstrate that both complexes ionize in CH₃OH to generate a common [Ru⁺(Tsdpen)(cymene)] and X^?, although the extent is significantly greater for X=TfO^?. The activation of [RuX(Tsdpen)(cymene)] during catalytic hydrogenation in alcoholic solvent occurs by simple ionization to generate [Ru⁺(Tsdpen)(cymene)]. The catalytic activity is thus significantly influenced by the reaction conditions.     

Enantioselective Synthesis of anti‐β‐Hydroxy‐α‐Amido Esters by Asymmetric Transfer Hydrogenation in Emulsions

Herein, we present two methods for an asymmetric transfer hydrogenation through the dynamic kinetic resolution of α‐amido‐β‐ketoesters. These procedures yield the corresponding anti‐β‐hydroxy‐α‐amido esters in good yields and with good diastereo‐ and enantioselectivities. First, the scope of the reduction of α‐amido‐β‐ketoesters by using triethylammonium formate azeotrope is examined. Then, an emulsion technology with sodium formate is explored, which allows for broader substrate scope, faster reaction times, and lower catalyst loading. Furthermore, these reactions are operationally simple and can be set up in air.