Abstract
A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C 2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.
Highlights
A general and powerful method for the stereocontrolled Pd-catalyzed N-allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge
Modeling studies suggested that compounds of type 1 would represent promising building blocks for a new generation of EVH1 inhibitors, due to an enhanced flexibility of the C-terminus in combination
Building blocks of type 3 in turn could be prepared by stereo-controlled Pdcatalyzed N-allylation of an amino acid ester 5 by using a racemic carbonate of type rac-4 (Scheme 1)
Summary
A general and powerful method for the stereocontrolled Pd-catalyzed N-allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Building blocks of type 3 in turn could be prepared by stereo-controlled Pdcatalyzed N-allylation of an amino acid ester 5 by using a racemic carbonate of type rac-4 (Scheme 1). Under optimized conditions by using only 1 mol % of [PdCl(allyl)]2 as a pre-catalyst and 2.4 mol % of ligand L6, the reaction proceeded smoothly at À10 8C within only 2.5 hours to afford (S)-3 a with high enantiomeric purity (98:2 e.r.) in 83 % isolated yield (entry 17).
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