Synthesis of N-propionylated (S)-(−)-2-(pyrrolidin-2-yl)propan-2-ol and its use as a chiral auxiliary and selectivity marker in asymmetric aldol reactions

Abstract

The N-propionylated pyrrolidine derivative and chiral auxiliary, (S)-(−)-2-(pyrrolidin-2-yl)propan-2-ol, was synthesised and used in stereoselective aldol reactions with benzaldehyde. Differences in stereoselectivity were investigated as a function of temperature, solvent, chelating agent and the amount of the chelating agent used by monitoring the ¹H NMR spectra of the aldol adducts that were obtained. Among the additives that were investigated, Cp₂ZrCl₂ induced higher anti-selectivity, while SnCl₂ induced higher syn-selectivity respectively. TMSCl was found to induce high selectivity for one syn- and one anti-diastereomer. Varying the ligand sets on titanium additives was found to induce differences in selectivity, with (i-PrO)₃TiCl exhibiting syn-selectivity and Cp₂TiCl₂ exhibiting anti-selectivity. Differences in reactivity and stereoselectivity were also found to depend upon the amount of Lewis acid that was added. Methods for removal of the auxiliary were also investigated. Acidic hydrolysis was used successfully to obtain the desired 3-hydroxy-2-methyl-3-phenylpropionic acids, but was found to give low yields and resulted in a large amount of epimerisation. Furthermore, the ethyl esters of these hydroxy acids are easy to separate into pure syn- and anti-diastereomers by LC.