Optimising a metal catalysed asymmetric reaction typically involves multiple ligand screening to achieve suitable levels of enantioselctivity. This approach is frequently relatively random with respect to the identity of the ligands examined, is time consuming, and is often unsuccessful. A potentially more systematic approach to improving enantioselectivity is through the addition of an element of chirality to an existing chiral non-racemic ligand (the parent ligand). One of the two resulting diastereomeric offspring ligands will result in a matched stereochemical relationship potentially leading to an increase in ee, with a converse decrease in ee for the mismatched alternative. This approach was applied to a variety of metal catalysed reactions starting with three ligands widely used in asymmetric catalysis: PPFA (1), Josiphos (2) and Phosferrox (3). In all cases a phosphorus based stereogenic centre was introduced to give both possible isomers diastereomerically pure. Methodology developed previously for the synthesis of (R,Sp,Sphos)/(R,Sp,Rphos) derivatives of PPFA (1) was applied successfully to Phosferrox (3), and (R,Sp,Sphos)/(R,Sp,Rphos) derivatives of Josiphos (2) were synthesised from the corresponding PPFA compound by stereospecific substitution.

Catalyst optimisation for asymmetric synthesis by ligand chirality element addition

2019 Spring National Meeting

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