Chiral proline-based ligands for iridium-catalyzed asymmetric hydrogenation

Iridium complexes with chiral P,N ligands are highly efficient catalysts for the asymmetric hydrogenation of a broad range of substrates. Since the highest enantioselectivities achieved vary strongly depending on the substrate type, it is important to developed new ligands, which have various features, even if many catalysts have already been designed. Herein are presented various proline-based ligands, which coordinate to iridium in a bidentate fashion involving two different coordinating atoms. First are described proline-based P,O ligands followed by two types of proline-based P,N ligands.
In chapter 2, proline-based P,O ligands were investigated as ligands for the iridium-catalyzed asymmetric hydrogenation. These ligands were clearly identified to coordinate in a bidentate fashion to iridium, forming a seven-membered metallacycle upon binding of both the carbonyl oxygen atom and the phosphorus atom. L-Proline proved to be a convenient enantiopure modular scaffold and allowed to prepare in a few steps a broad library of chiral compounds in good yields, possessing a wide range of steric and electronic properties. Three subclasses of these ligands were developed and investigated: carbamatophosphines, amidophosphines and ureaphosphines.
These P,O ligand/iridium complexes were evaluated in the asymmetric hydrogenation of a series of substrates spanning a range of coordinating properties. Especially trisubstituted functionalized and unfunctionalized alkenes were reduced with good enantioselectivities within short reaction times. Depending on both the structure of the coordinating carbonyl substituent and the phosphine substituents, moderate to high enantioselectivities were achieved. The catalysts, which were identified to allow for the highest enantioselectivities in the asymmetric hydrogenation of routinely tested substrates (e.g. (E)-1,2-diphenyl-1-propene, (E)-ethyl 3-phenylbut-2-enoate, (E)-2-methyl-3-phenylprop-2-en-1-ol) were also tested in the asymmetric hydrogenation of more challenging prochiral trisubstituted alkenes, such as α,β-unsaturated carboxylic esters and ketones. Excellent conversions and enantiomeric excesses up to 95% were obtained when amidophosphines or ureaphosphines were employed as ligands in the iridium-catalyzed asymmetric hydrogenation of trisubstituted α,β-unsaturated, α-substituted carboxylic esters. Even more impressive is the level of enantioselectivity obtained for α,β-unsaturated ketones, which were reduced with several catalysts that afforded enantioselectivities much higher than previously reported P,N-based systems.
Inspired by the structure of these P,O ligands, analogous proline-based P,N ligands were investigated. It was thought to combine two features: the well known chelation of P,N ligands to iridium and the proline-based structure. Also these P,N ligands were easily prepared and steric and electronic properties were studied by varying the substituents at the phosphorus atom and the pyrrolidine nitrogen. These P,N ligands form a seven-membered metallacycle when bound to iridium. Previous reports suggest that the size of the metallacycle strongly influences the enantioselectivity of the asymmetric reduction, therefore these ligands were investigated. These novel complexes showed excellent activities in the asymmetric reduction of unfunctionalized and functionalized trisubstituted standard substrates, albeit with slightly lower enantioselectivities than those achieved with P,O ligand/iridium complexes.
Furthermore, a second type of proline-based P,N ligand was investigated. This scaffold involves a hydrazone moiety in combination with a phosphorus donor and forms a six-membered metallacycle, upon binding to iridium. The synthesis of these ligands proved to be more difficult. Only aldhydrazones could be synthesized efficiently and complexed to iridium. These complexes were tested as catalysts for the hydrogenation of alkenes and proved to be quite unstable. Nevertheless, these complexes reduced some substrates with full conversions, but fluctuating enantioselectivities.
Finally, in chapter 5, the proline-based P,O ligands presented in chapter 1 were investigated as chiral ligands for the palladium-catalyzed allylic alkylation reaction. Good activities were achieved but the enantioselectivities were low and can not compete with previously reported ligands for this transformation.