Approaches to the synthesis of (2R,3S)-2-hydroxymethylpyrrolidin-3-ol (CYB-3) and its C(3) epimer: a cautionary tale

Abstract

The syntheses of (2R,3S)-2-tert-butyldiphenylsilyloxymethylpyrrolidin-3-ol (TBDPS-protected CYB-3) (21) and its C(3) epimer (25) have been achieved in 9 and 8 steps respectively from D-serine. However, chiral HPLC analysis of the key β-hydroxy ester intermediates in these syntheses (17 and 18) revealed that appreciable levels of racemisation had occurred in the aldol and Claisen condensation reactions used in this synthetic sequence.