Iridium‐Catalyzed Asymmetric Hydrogenation of Unfunctionalized Enamines

Optically active tertiary amines are readily prepared by iridium‐catalyzed asymmetric hydrogenation of unfunctionalized enamines (see scheme). The best enantioselectivities with >90 % ee were obtained with N‐aryl‐ and N‐benzyl‐substituted enamines with a terminal double bond. The hydrogenation of enamines derived from cyclic ketones, which has not been reported yet with other catalysts, gave enantiomeric excesses of up to 87 %.

     

Iridium‐Catalyzed Asymmetric Hydrogenation of Imines

We have evaluated a wide range of iridium complexes derived from chiral oxazoline‐based N,P ligands for the asymmetric hydrogenation of imines and identified three efficient catalysts. These catalysts are readily synthesized by straightforward convenient routes and are air and moisture stable. In the reduction of acetophenone N‐arylimines and related acyclic substrates, excellent enantioselectivities (up to 96 % ee) were obtained by using 0.1–0.5 mol % of catalyst at ?20 °C and 5–50 bar hydrogen pressure.     

Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst

The iridium catalyst [IrCl(cod)]₂–phosphine–I₂ (cod=1,5‐cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H₂. The iridium‐catalyzed hydrogenation proceeded in high‐to‐good enantioselectivity when an optically active phosphine–oxazoline ligand was used. The 3‐substituted 5‐arylisoxazolium salts were transformed into 4‐isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis‐isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5‐position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3‐isoxazoline intermediate. Meanwhile, in the selective formation of 4‐isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5‐aryl substituent.     

Adaptative Biaryl Phosphite–Oxazole and Phosphite–Thiazole Ligands for Asymmetric Ir‐Catalyzed Hydrogenation of Alkenes

A library of readily available phosphite–oxazole/thiazole ligands ( L1 a – g – L7 a – g ) was applied in the Ir‐catalyzed asymmetric hydrogenation of several largely unfunctionalized E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The ability of the catalysts to transfer chiral information to the product could be tuned by choosing suitable ligand components (bridge length, the substituents in the heterocyclic ring and the alkyl backbone chain, the configuration of the ligand backbone, and the substituents/configurations in the biaryl phosphite moiety), so that enantioselectivities could be maximized for each substrate as required. Enantioselectivities were therefore excellent (enantiomeric excess (ee) values up to >99 %) for a wide range of E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The biaryl phosphite moiety was a very advantageous ligand component in terms of substrate versatility.     

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.     

Synthesis of Novel Monodentate Phosphoramidites and Their Application in Iridium‐Catalyzed Asymmetric Hydrogenations

New monodentate H₈‐binaphthol based phosphoramidites 6 b–i have been prepared. Starting from (S)‐3,3′‐dibromo‐5,5′,6,6′,7,7′,8,8′‐octahydro‐1,1′‐binaphthyl‐2,2′‐diol 3 , a general protocol for the synthesis of ligands 6 is presented. A small ligand library bearing aryl substituents in the 3,3′‐position of the binaphthol core was synthesized and successfully tested in the iridium‐catalyzed asymmetric hydrogenation of 2‐amidocinnamates to obtain different α‐amino acid derivatives in up to 99 % ee.     

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.     

Palladium‐Catalyzed Asymmetric [4+2] Cycloaddition of 2‐Methylidenetrimethylene Carbonate with Alkenes: Access to Chiral Tetrahydropyran‐Fused Spirocyclic Scaffolds

A palladium‐catalyzed asymmetric [4+2] cycloaddition of 2‐methylidenetrimethylene carbonate with alkenes derived from pyrazolones, indandione, or barbiturate has been successfully developed, affording pharmacologically interesting chiral tetrahydropyran‐fused spirocyclic scaffolds. The target compounds were generated in good to excellent yields and with high enantioselectivity (up to 99 % ee). Furthermore, this cycloaddition reaction could be efficiently scaled up, and several synthetic transformations were accomplished for the construction of other useful chiral spiropyrazolone and spiroindandione derivatives.     

Catalytic Asymmetric Hydrogenation of Pyrimidines

The asymmetric hydrogenation of pyrimidines proceeded with high enantioselectivity (up to 99 % ee) using an iridium catalyst composed of [IrCl(cod)]₂, a ferrocene‐containing chiral diphosphine ligand (Josiphos), iodine, and Yb(OTf)₃ (cod=1,5‐cyclooctadiene). The chiral catalyst converted various 4‐substituted pyrimidines into chiral 1,4,5,6‐tetrahydropyrimidines in high yield. The lanthanide triflate is crucial for achieving the high enantioselectivity as well as for activating the heteroarene substrate.