Kinetic resolution of esters via metal catalyzed methanolysis reactions

Abstract

Some chiral lanthanide complexes of the Schiff base adducts of: a) bis(2-pyridylcarboxaldehyde) and (1R),(2R)-trans-1,2-diaminocyclohexane (Pyr-R,R′-chxn: 3); b) 6-methyl-2-pyridylcarboxaldehyde and (1R),(2R)-trans 1,2-diaminocyclohexane (MePyr-chxn, 4); and c) 2,6-pyridyldicarboxaldehyde and (1R),(2R)-trans-1,2-diaminocyclohexane ((Pyr-R,R′-chxn)2, 5) have been screened for their utility to promote kinetic resolution via metal catalyzed alcoholyses of the p-nitrophenyl esters of chiral d- and l-Boc-protected glutamine and phenylalanine. Solvents were varied to optimize the kinetic selectivity values, defined as k 2L/k2D or k2D/k2L, for the methanolysis and in some cases, ethanolysis of these substrates. At ambient temperature the greatest selectivity was found for the ethanolysis of Boc-Gln-OPNP, catalyzed by 3:Yb 3+:(-OEt) (k2L/k2D = 7.2). The greatest selectivity for Boc-Phe-OPNP is k 2D/k2L = 3.9 for its methanolysis promoted by 5:La3+:(-OMe). A kinetic method is introduced for the determination of both d and l rate constants for catalyzed alcoholysis from a single kinetic experiment. The activation parameters ΔH ‡ and ΔS‡ were determined for the metal catalyzed methanolysis and ethanolysis of the Boc-Gln-OPNP substrates, and selectivity factors were found to increase at lower temperatures. A low temperature time course for the ethanolysis of racemic Boc-Gln-OPNP catalyzed by 3:Yb3+:(-OEt) at -15 °C indicated that after 3 hours 60% residual d-enantiomer was observed having an enantiomeric excess of >95% ee. The activation parameters for the ethanolysis of the same substrate catalyzed by (Pyr-R,R′-chxn)2:La3+:(-OEt) predict a k2D/k2L = 40.4 at -40 °C with a large ee of >99% with ∼80% of l isomer remaining at that temperature which has been experimentally confirmed. © The Royal Society of Chemistry.