Synthesis of new phosphino-oxazoline ligands for asymmetric catalysis

Abstract

Borabox ligands proved to be efficient ligands for controlling the enantioselectivity of various metal-catalyzed reactions. Therefore modification of an existing borabox backbone was implemented and new borabox ligands modified on C(5) position of the oxazoline ring were prepared and tested in the copper-catalyzed asymmetric cyclopropanation. In this study high stereocontrol of the reaction was observed. However the presence of sterically demanding groups at position C(5) did not improve the results compared to the C(5) non-substituted analogs. The synthesis of analogous boron-bridged phosphino-oxazolines was attempted via several synthetic approaches in order to prepare new zwitterionic N,P-ligands. The simple stepwise substitution by subsequent addition of lithiated oxazoline and phosphine was not possible. It either led to borabox ligands or to undesired dimeric species, which were inert towards reaction with other nucleophiles. We decided to tune the electronic properties of the boron compound by variation of the substituents in order to avoid multiple substitution or undesired dimer formation. Therefore aminochloroborates were examined due to their lower reactivity compared to chloroboranes or chloroborates. A derivative with a phosphine-aminoborate backbone was prepared but unfortunately the decreased reactivity of the nitrogen-substituted boron center did not allow another nucleophilic addition of the oxazoline moiety. In order to avoid dimer formation the reactivity of potassium diaryldifluoroborates was investigated. These tetrasubstituted boron compounds reacted with lithium oxazolines and provided products of nucleophilic substitution at the boron center. The resulting oxazoline-substituted fluoroborates could be isolated as zwitterions after protonation of the oxazoline nitrogen atom. However, the second intended substitution with the phosphine moiety was not possible. In addition, quantum chemistry calculations were carried out to support the experimental studies. The synthesis of new NeoPHOX ligands derived from inexpensive chiral aminoacids L-serine and L-threonine was developed. These chiral ligands were tested in the iridium-catalyzed asymmetric hydrogenation and palladium-catalyzed allylic substitution. In both reactions the enantioselectivities achieved were excellent for most of the substrates tested. In the iridium catalyzed hydrogenation it was found that presence of an acid-stable protecting group of tertiary alcohol (R2) is necessary in order to achieve full conversions. The enantioselectivities obtained in the catalytic asymmetric hydrogenation and allylic substitution with the L-serine and L-threonine derived ligands were almost identical to those reported for tert-butyl- substituted NeoPHOX ligands, which are derived from very expensive amino acid tert- leucine. The use of Ir catalysts for the diastereoselective hydrogenation of Diels-Alder products was investigated. The best results were obtained with a pyridine-phosphinite complex that afforded the saturated cyclohexane derivatives with diastereoselectivities of up to 98:2 and full conversion. The reaction is strongly catalyst-controlled, so it is possible to obtain each of the two diastereomeric products with high selectivity using either (R)- or (S)-catalyst.