posted on 2024-01-23, 19:33authored byJorge
A. Garduño, Andrew J. Sasser, Hannah J. Sexton, Russell P. Hughes, David S. Glueck, Arnold L. Rheingold
Kinetic resolution of the racemic
nitrile CH(Et)(CN)(cyclo-N(CH2)3C(O)–) by catalytic
asymmetric
hydration to form the amide CH(Et)(C(O)NH2)(cyclo-N(CH2)3C(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)Cl2 with AgOTf and secondary phosphine oxides
(SPOs) gave the cations [Pt(diphos)(PR'2OH)(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'2OH)][OTf]2 (9–12 and 14), with Fe–Pt interactions, or [Pt((S,S)-Et-FerroTANE)(PMe2OH)(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)(PMe2OH)][OTf]2 (9) with enantiomerically enriched or racemic
Keppra nitrile resulted in diastereoselective and reversible metallacycle
formation to give [Pt((R,R)-Me-FerroLANE)(PMe2OC(R*)NH][OTf]2 (15, R* =
CH(Et)(cyclo-N(CH2)3C(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-Ph2CCH2CH(CN) to generate metallacycles 16–24. Metallacycle 15 reacted with water
by attack at the PMe2O group, demonstrated by 18O-labeling studies, to yield the Keppra amide via an intermediate
iminol complex [Pt((R,R)-Me-FerroLANE)(PMe2OH)(NHC(R*)(OH))][OTf]2 (25).