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

The N-propionylated pyrrolidine derivative and chiral auxiliary, (S)-(-)-2- (pyrrolidin-2-yl)propan-2-ol, was synthesised and used in stereoselective a ldol reactions with benzaldehyde. Differences in stereoselectivity were inv estigated as a function of temperature, solvent, chelating agent and the am ount of the chelating agent used by monitoring the H-1 NMR spectra of the a ldol 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 on e syn- and one anti-diastereomer. Varying the ligand sets on titanium addit ives was found to induce differences in selectivity, with (i-PrO)(3)TiCl ex hibiting syn-selectivity and Cp2TiCl2 exhibiting anti-selectivity. Differen ces in reactivity and stereoselectivity were also found to depend upon the amount of Lewis acid that was added. Methods for removal of the auxiliary w ere also investigated. Acidic hydrolysis was used successfully to obtain th e desired 3-hydroxy-2-methyl-3-phenylpropionic acids, but was found to give low yields and resulted in a large amount of epimerisation. Furthermore, t he ethyl esters of these hydroxy acids are easy to separate into pure syn- and anti-diastereomers by LC.