Jian-Bo Xie

An Additional Coordination Group Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric Hydrogenation of Ketones

The production of enantiopure chiral compounds is important for pharmaceutical and agrochemical industries because enantiomers can exhibit distinct biological activities. Therefore, processes that directly produce the desired enantiomer are desirable. First reported by Knowles, Horner et al. in 1968, catalytic asymmetric hydrogenation of unsaturated compounds such as olefins, ketones, and imines is one of the most commonly used methods for producing enantiopure chiral compounds. Great progress has been made in this field, and many chiral catalysts are developed for a wide range of unsaturated substrates. It is noteworthy that some of these synthetic chiral catalysts, which are much smaller and simpler than enzymes, exhibit activities and selectivities comparable to those of enzymes: in some cases, one molecule of catalyst can produce millions of new molecules enantioselectively. For example, the diphosphine/diamine ruthenium catalyst reported by Noyori et al. and the iridium ferrocenyl catalyst Ir-(R,S)Xyliphos developed by a team from Novartis (Scheme 1)

Chiral Iridium Catalysts Bearing Spiro Pyridine‐Aminophosphine Ligands Enable Highly Efficient Asymmetric Hydrogenation of β‐Aryl β‐Ketoesters

Optically active b-hydroxy acids and their derivatives are versatile chiral building blocks for many useful molecules, including pharmaceuticals and natural products. Catalytic asymmetric hydrogenation of b-ketoesters is an efficient and economically feasible method for preparing these important chiral compounds. Pioneered by Noyori and co-workers, the chiral ruthenium diphosphine complexes [RuX2(diphosphine)] (X = Cl or Br) and their analogues have become by far the most popular catalysts for this transformation. Many of them show excellent enantioselectivity [> 99% enantiomeric excess (ee)] and extraordinarily high activity (turnover number (TON) of up to 100000) for the hydrogenation of b-alkyl b-ketoesters. However, only a few of these complexes exhibit high enantioselectivity for the hydrogenation of b-aryl b-ketoesters. Zhang et al. reported that the ruthenium catalysts bearing the ligands xylyl-obinapo (3,3’-bis(3,5-dimethylphenyl)-2,2’-bis(diphenylphosphinoxy)-1,1’-binaphthyl) and C3*-TunePhos [6] give up to 99% ee for the hydrogenation of b-aryl b-ketoesters. Using ruthenium complexes of 4,4’-substituted binap ligands (binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), Lin et al. obtained up to 99.8 % ee for the hydrogenation of a range of b-aryl b-ketoesters. The highest TON (10000) was achieved by Saito and co-workers in the asymmetric hydrogenation of methyl 3-oxo-3-phenylpropanoate. Note that chiral rhodium or iridium complexes, which efficiently catalyze olefin and imine hydrogenation, are seldom used for the asymmetric hydrogenation of b-ketoesters. Furthermore, chiral [RuCl2(diphosphine)(diamine)] complexes, which catalyze the hydrogenation of simple ketones extremely efficiently, are also inert for the hydrogenation of b-ketoesters. The major reason for the inertness may be that the strong base, such as KOtBu, that is required for activation of the [RuCl2(diphosphine)(diamine)] catalysts enolizes the b-ketoester substrates instead of activating the catalysts. Recently, we developed chiral iridium catalysts containing a chiral SpiroPAP ligand, and these catalysts show excellent enantioselectivity (up to 99.9% ee) and an extremely high TON (as high as 4550 000) for the hydrogenation of simple ketones. These Ir/SpiroPAP catalysts are likely to have a “metal–ligand bifunctional catalysis” mechanism, similar to the [RuCl2(diphosphine)(diamine)] catalysts. [12] The aromatic N H of the Ir/SpiroPAP catalysts is more acidic than the aliphatic N H of [RuCl2(diphosphine)(diamine)] catalysts (the proton resonances of the NH or NH2 group of the catalysts are as follows: Ir[IrH2((R)-1a)Cl]: d = 5.3 ppm (CDCl3), [RuCl2((R)-Tol-binap)((R,R)-dpen)] (dpen = 1,2diphenylethylenediamine): d = 3.3 and 3.5 ppm (C6D6) ), thus indicating that the Ir/SpiroPAP catalysts may be more easily activated with a relatively weak base such as the enolate salt of a b-ketoester. To confirm this possibility, we tested Ir/SpiroPAP catalysts for the hydrogenation of bketoesters and found that the catalysts were extremely efficient for hydrogenation of b-aryl b-ketoesters. Herein, we report that the Ir/SpiroPAP-catalyzed asymmetric hydrogenation of b-aryl b-ketoesters 2 provide the chiral b-hydroxy esters 3 with excellent enantioselectivity (up to 99.8% ee) and extremely high TONs (as high as 1230 000) under mild reaction conditions (8 atm H2 at room temperature; Scheme 1). The reaction conditions were optimized for the hydrogenation of ethyl 3-oxo-3-phenylpropanoate (2a). When the reaction was carried out at room temperature under 8 atm of

Highly Enantioselective Hydrogenation of α-Arylmethylene Cycloalkanones Catalyzed by Iridium Complexes of Chiral Spiro Aminophosphine Ligands

The highly efficient asymmetric hydrogenation of alpha-arylmethylene cycloalkanones catalyzed by Ir-complexes of chiral spiro aminophosphine ligands was developed, providing chiral exo-cyclic allylic alcohols at high yields with excellent enantioselectivities (up to 97% ee) and high turnover numbers (S/C up to 10,000). This new reaction provided an efficient method for the synthesis of the key intermediate of the active form of the anti-inflammatory loxoprofen.

Chiral Iridium Spiro Aminophosphine Complexes: Asymmetric Hydrogenation of Simple Ketones, Structure, and Plausible Mechanism

The iridium complexes of chiral spiro aminophophine ligands, especially the ligand with 3,5-di-tert-butylphenyl groups on the P atom (1c) were demonstrated to be highly efficient catalysts for the asymmetric hydrogenation of alkyl aryl ketones. In the presence of KOtBu as a base and under mild reaction conditions, a series of chiral alcohols were synthesized in up to 97% ee with high turnover number (TON up to 10,000) and high turnover frequency (TOF up to 3.7×10(4)  h(-1)). Investigation on the structures of the iridium complexes of ligands (R)-1a and 1c by X-ray analyses disclosed that the 3,5-di-tert-butyl groups on the P-phenyl rings of the ligand are the key factor for achieving high activity and enantioselectivity of the catalyst. Study of the catalysts generated from the Ir-(R)-1c complex and H(2) by means of ESI-MS and NMR spectroscopy indicated that the early formed iridium dihydride complex with one (R)-1c ligand was the active species, which was slowly transformed into an inactive iridium dihydride complex with two (R)-1c ligands. A plausible mechanism for the reaction was also suggested to explain the observations of the hydrogenation reactions.

Iridium-Catalyzed Asymmetric Hydrogenation of α-Substituted α,β-Unsaturated Acyclic Ketones: Enantioselective Total Synthesis of (−)-Mesembrine

A highly efficient asymmetric hydrogenation of α-substituted α,β-unsaturated acyclic ketones catalyzed by chiral spiro iridium complexes for the preparation of chiral 2-substituted allylic alcohols has been developed (ee up to 99.7%). This method provides a concise route to (-)-mesembrine (34% yield, 12 steps).