Abstract:Chiral phosphoramidites have been identified as excellent ligands for various metal-catalyzed enantioselective transformations. Taking advantage of their easy preparation and modular nature, we designed a fully automated protocol for the parallel preparation of a library of 32 phosphoramidites and its screening in asymmetric hydrogenation of amino acid precursors. This initial study led to the discovery of a new ligand for the preparation of an enantiopure beta(3)-homoalanine precursor. [structure--see text]
“…Their good accessibility and modular nature makes these ligands particularly suitable for combinatorial applications. [27] Phosphoramidites are essentially built up from two fragments, both of which can be varied to a large extent. In a common synthetic procedure, a (non-)chiral diol is converted into the corresponding chlorophosphite by refluxing in an excess of PCl 3 .…”
Abstract:The rhodium-catalyzed asymmetric hydrogenation of several b-substituted itaconic acid monoesters, using a library of monodentate phosphoramidite and phosphite ligands is described. Two b-alkylsubstituted substrates were readily hydrogenated by the rhodium complex RhA C H T U N G T R E N N U N G (COD) 2 BF 4 in combination with (S)-PipPhos as a ligand resulting in ees of 99%. In contrast, the corresponding more hindered b-arylsubstituted substrates did not exhibit acceptable enantioselectivities under these conditions. However, the use of a 48-membered ligand library led to the identification of several suitable ligands for these substrates, resulting in ees of 89-99 %. The resulting optically active succinic acid derivatives are potentially useful building blocks for more elaborate compounds, because of the ability to differentiate between the carboxylic acid and the ester groups on either side of the molecule.
“…Their good accessibility and modular nature makes these ligands particularly suitable for combinatorial applications. [27] Phosphoramidites are essentially built up from two fragments, both of which can be varied to a large extent. In a common synthetic procedure, a (non-)chiral diol is converted into the corresponding chlorophosphite by refluxing in an excess of PCl 3 .…”
Abstract:The rhodium-catalyzed asymmetric hydrogenation of several b-substituted itaconic acid monoesters, using a library of monodentate phosphoramidite and phosphite ligands is described. Two b-alkylsubstituted substrates were readily hydrogenated by the rhodium complex RhA C H T U N G T R E N N U N G (COD) 2 BF 4 in combination with (S)-PipPhos as a ligand resulting in ees of 99%. In contrast, the corresponding more hindered b-arylsubstituted substrates did not exhibit acceptable enantioselectivities under these conditions. However, the use of a 48-membered ligand library led to the identification of several suitable ligands for these substrates, resulting in ees of 89-99 %. The resulting optically active succinic acid derivatives are potentially useful building blocks for more elaborate compounds, because of the ability to differentiate between the carboxylic acid and the ester groups on either side of the molecule.
“…We have tested this protocol initially on a series of 32 ligands, which were subsequently screened in the Rh-catalysed asymmetric hydrogenation of two model substrates (see Figure 3). [25] In Figure 4, we show the result of this library of 32 phosphoramidites in the asymmetric hydrogenation at 6 bar H 2 of methyl 2-acetamido-cinnamate and methyl Z-3-acetamido-2-butenoate. For the first substrate, almost all of the members of the library led to full conversions, indicating that most of the ligands were formed with an acceptable degree of purity.…”
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“…Despite considerable progress in organometallic chemistry in the last few decades, it is often not possible to rationally design ligands and thus the development of new catalysts, especially in industry, often relies on trial-and-error [9][10][11]. This in turn necessitates the fast synthesis and screening of large families of ligands [11][12][13][14][15][16][17]. Systems based on bidentate phosphorus ligands have been shown to be highly successful in asymmetric transition-metal catalysis [18,19], but efficient combinatorial methodologies to facilitate the synthesis and screening of vast libraries of these type of ligands are still lacking.…”
An efficient modular method towards the synthesis of a library of polystyrene supported diphosphine ligands by combining solid-phase synthesis with rational ligand design has been developed. These supported ligands, obtained in quantitative yield, were efficiently and effectively screened in Rh-catalysed asymmetric hydrogenation of several benchmark substrates.
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