Enantioselective Hydrogenation Catalysis Aided by a σ-Bonded Calix[4]arene to aP-Chirogenic Aminophosphane Phosphinite Rhodium Complex

Abstract

The first P-chirogenic aminophosphane-phosphinite (AMP*P) ligand (4a) supported on the upper rim of a calix [4]arene moiety was synthesized in two steps using the ephedrine methodology. Ligand 4a was used for the preparation of the corresponding rhodium complex [Rh(COD)-(AMP*P)]BF 4 (5a) (COD=1,8-cyclooctadienyl), which was tested for asymmetric catalyzed hydrogenation of various substrates. The structures of the AMP*P ligand as diborane and rhodium complexes 3a and 5a were established by X-ray analysis. The asymmetric hydrogenation catalyzed with the Rh complex 5a exhibits excellent enantioselectivities up to 98%. Investigation of modified P-chirogenic aminophosphane-phosphinite ligands 4b,c, bearing an isoelectronic or a sterically similar substituent on the P-chirogenic aminophosphane unit, demonstrates that the calix[4]arene substituent of the aminophosphane moiety plays a major role in the better asymmetric induction. The enantioselectivity of the catalyzed hydrogenation was weakly influenced by the hydrogen pressure, which is in good agreement with a stereodetermining step involving the substrate-rhodium complexes. Computer modeling indicated the presence of two conformers for the active AMP*P rhodium species, according to whether the rhodium metal is outside or inside the calix[4]arene cavity (called outer and inner). It is obvious that the complexation of the substrate with the active rhodium species forces this complex to adopt fully the outer conformation and hence explains why the calixarene fragment plays a key role in the stereodetermining step. † This paper is dedicated to Prof. H. Kagan for his 80th birthday.

Enantioselective Access to Chiral Drugs by using Asymmetric Hydrogenation Catalyzed by Rh(POP) Complexes

“…The antiseizure agent levetiracetam22 (Scheme 4, see later) can be straightforwardly obtained from P9 (Scheme ) by treatment with NH 3 22b. Alkene S9 has recently proven to be a challenging substrate in Rh‐mediated asymmetric hydrogenation as only moderate enantioselectivities were achieved even under optimized conditions 23. Lastly, the hydrogenation product P11 (Scheme ) represents an advanced intermediate used in the total synthesis of the antiepileptic drug lacosamide24 (Scheme , see later).…”

The Synthesis of Chiral Phosphorus Ligands for use in Homogeneous Metal Catalysis

“…JugØ extended his well-established ephedrine based protocol [98] for the synthesis of P-chiral aminophosphine phosphinites (AMPPs), [99] which are linked to a calix [4]arene backbone (Scheme 46). [100] In comparison to isoelectronic AMPPs that have less bulky substituents, the calixarene based ligand induced much higher enantioselectivities in the Rh-catalyzed asymmetric hydrogenation of standard substrates, which gives evidence that the calixarene unit contributes significantly to the stereoface discriminating ability of the chiral ligand.…”

Cavity-shaped ligands for asymmetric metal catalysis

“…In 2010, Jugé and Harvey [25] managed to graft a single P-chirogenic aminophosphanephosphinite chelating unit onto a calix [4]arene upper rim. The ligand 5 was tested in the rhodium-catalyzed hydrogenation of various prochiral olefins and ee values as high as 98%…”