Diastereoselective and Reversible Metallacycle Formation by Attack of a Pt-PR₂OH Group on a Coordinated Nitrile in Pt-Catalyzed Hydration

Abstract

Kinetic resolution of the racemic nitrile CH(Et)-(CN)(cyclo-N(CH 2 ) 3 C(O)−) by catalytic asymmetric hydration to form the amide CH(Et)(C(O)NH 2 )(cyclo-N(CH 2 ) 3 C(O)−) (Levetiracetam, Keppra) is an industrial biocatalytic process. To develop analogous procedures using chiral metal complexes as catalyst precursors, we investigated the mechanism and selectivity of the individual steps. Treatment of Pt(diphos)Cl 2 with AgOTf and secondary phosphine oxides (SPOs) gave the cations [Pt(diphos)(PR' 2 OH)(Cl)][OTf] 1−6 containing either a chiral diphos ((R,R)-FerroLANE derivatives or (S,S)-Et-FerroTANE) or a chiral SPO tautomer ((R)-DMB-SPOPine). A second equiv of AgOTf yielded dicationic [Pt(diphos)(PR' 2 OH)][OTf] 2 (9−12 and 14), with Fe−Pt interactions, or [Pt((S,S)-Et-FerroTANE)-(PMe 2 OH)(OTf)][OTf] (13). Pt complexes 9 and 11−14 catalyzed hydration of the Keppra nitrile to the amide under mild conditions, with increased activity for smaller FerroLANE substituents. With water as the limiting reagent and an excess of racemic nitrile, no enantioselectivity in kinetic resolution by catalytic nitrile hydration was observed. Reaction of [Pt(R,R)-Me-FerroLANE)(PMe 2 OH)][OTf] 2 (9) with enantiomerically enriched or racemic Keppra nitrile resulted in diastereoselective and reversible metallacycle formation to give [Pt((R,R)-Me-FerroLANE)(PMe 2 OC(R*)�NH][OTf] 2 (15, R* = CH(Et)(cyclo-N(CH 2 ) 3 C(O)−)). Similar processes occurred with dications 10−11 and 13−14 with rac-Keppra nitrile, or with 9 and rac-PhCH(R)(CN) (R = Me, Et, i-Pr, Cy) or with racemic cyclo-Ph 2 CCH 2 CH(CN) to generate metallacycles 16−24. Metallacycle 15 reacted with water by attack at the PMe 2 O group, demonstrated by 18 O-labeling studies, to yield the Keppra amide via an intermediate iminol complex [Pt((R,R)-Me-FerroLANE)(PMe 2 OH)(NH�C(R*)(OH))][OTf] 2 (25).