Instant Ligand Libraries. Parallel Synthesis of Monodentate Phosphoramidites and in Situ Screening in Asymmetric Hydrogenation

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]

Synthesis of Versatile Building Blocks through Asymmetric Hydrogenation of Functionalized Itaconic Acid Mono‐Esters

“…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 .…”

The Combinatorial Approach to Asymmetric Hydrogenation: Phosphoramidite Libraries, Ruthenacycles, and Artificial Enzymes

“…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.…”

Solid-Phase Synthesis and Catalytic Screening of Polystyrene Supported Diphosphines

“…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.…”