Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands

Abstract

Attempts to perform the OsO₄-catalyzed enantioselective base-free aminohydroxylation of β,β-disubstituted enoates are described. Low yields and racemic products were obtained in the presence of standard chiral ligands, suggesting the occurrence of a "Second Cycle" process due to slow hydrolysis of the amino alcohol product from the Os metal center. Support for this hypothesis was provided by the slightly improved enantioselectivity (60:40 er) obtained with an amino alcohol ligand. Based on density functional theory calculations, it is proposed that the lack of significant enantioselectivity is due to a low-energy (3 + 2) oxo/imido cycloaddition transition state without the chiral ligand in the Second Cycle that outcompetes protonolysis in the First Cycle.

Keywords: Aminohydroxylation; Density functional theory; Enantioselective reaction; Osmium tetroxide; β-Hydroxy amino acids.

Fig. 1.

Yaku’amide A (1), with β-hydroxy amino acids shown in red.

Fig. 2.

Transition-state structures for protonolysis and cycloaddition pathways from intermediate C-1.

Scheme 1.

First and Second Cycles of the SAA reaction.

Scheme 2.

Transition-state structures and free energies comparing water proton transfer pathways and (3 + 2) cycloaddition pathways from intermediate C-1. (kcal/mol)