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.     

Ir-catalyzed asymmetric hydrogenation of simple ketones with chiral ferrocenyl P,N,N-ligands

The Ir-catalyzed asymmetric hydrogenation of simple aromatic ketones with chiral ferrocenyl P,N,N-ligands has been developed. Under the optimized conditions, a wide range of ketones were hydrogenated to afford the corresponding chiral alcohols in good to excellent enantioselectivities (up to 98%?ee).     

Asymmetric Hydrogenation of α,β‐Unsaturated Nitriles with Base‐Activated Iridium N,P Ligand Complexes

Although many chiral catalysts are known that allow highly enantioselective hydrogenation of a wide range of olefins, no suitable catalysts for the asymmetric hydrogenation of α,β‐unsaturated nitriles have been reported so far. We have found that Ir N,P ligand complexes, which under normal conditions do not show any reactivity towards α,β‐unsaturated nitriles, become highly active catalysts upon addition of N,N‐diisopropylethylamine. The base‐activated catalysts enable conjugate reduction of α,β‐unsaturated nitriles with H₂ at low catalyst loadings, affording the corresponding saturated nitriles with high conversion and excellent enantioselectivity. In contrast, alkenes lacking a conjugated cyano group do not react under these conditions, making it possible to selectively reduce the conjugated C?C bond of an α,β‐unsaturated nitrile, while leaving other types of C?C bonds in the molecule intact.     

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.     

Spiro[4,4]‐1,6‐nonadiene‐Based Phosphine–Oxazoline Ligands for Iridium‐Catalyzed Enantioselective Hydrogenation of Ketimines

From imines to amines through catalysis by Ir^I complexes of a new type of P,N ligand (see scheme): This reaction affords the corresponding optically active amines with up to 98 % ee and has also been used with perfect stereoselectivity in the asymmetric synthesis of sertraline ( 1 ), an important antidepressant chiral drug.

     

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.     

Chiral P,N‐ligands for the highly enantioselective addition of diethylzinc to aromatic aldehydes

A new sterically hindered chiral P,N‐ligand was synthesized and successfully applied to copper catalyzed asymmetric addition of diethylzinc to aromatic aldehydes. Various aromatic aldehydes can react smoothly to give the corresponding addition products with good to excellent enantioselectivities, which provides a readily accessible method for the preparation of chiral secondary alcohols.     

Ir‐SpinPHOX Catalyzed Enantioselective Hydrogenation of 3‐Ylidenephthalides

The first asymmetric hydrogenation of 3‐ylidenephthalides has been developed using the Ir^I complex of a spiro[4,4]‐1,6‐nonadiene‐based phosphine‐oxazoline ligand (SpinPHOX) as the catalyst, affording a wide variety of chiral 3‐substituted phthalides in excellent enantiomeric excesses (up to 98 % ee). The utility of the protocol has been demonstrated in the asymmetric synthesis of chiral drugs NBP and BZP precursor, as well as the natural products chuangxinol and typhaphthalide.     

Optimized Scalable Synthesis of Chiral Iridium Pyridyl-Phosphinite (Pyridophos) Catalysts

Iridium catalysts with chiral P,N ligands have greatly enhanced the scope of asymmetric olefin hydrogenation because they do not require a coordinating group near the C=C bond like Rh and Ru catalysts. Pyridophos ligands, possessing a conformationally restricted annulated pyridine framework linked to a phosphinite group, proved to be particularly effective, inducing high enantioselectivities in the hydrogenation of a remarkably broad range of substrates. Here we report the development of an efficient scalable synthesis for the two most versatile Ir-pyridophos catalysts, derived from 2-phenyl-8-hydroxy-5,6,7,8-tetrahydroquinoline or the analogue with a five-membered carbocyclic ring, respectively, by modification and optimization of the original synthetic route. The optimized route renders both catalysts readily accessible in multi-gram quantities in analytically pure form in overall yields of 26–37 %, starting from acetophenone and cyclopentanone or cyclohexanone, respectively. A major advantage of the new synthesis is the efficient and practical kinetic resolution of the late-stage pyridyl alcohol intermediates with commercial immobilized Candida antarctica lipase B, giving access to both enantiomers of these catalysts as essentially enantiopure compounds. The catalysts are obtained as crystalline solids, which are air-stable and can be stored for years at −20 °C without notable decomposition.