Preparation and characterization of [5-13C]-(2S,4R)-leucine and [4-13C]-(2S,3S)-valine -: Establishing synthetic schemes to prepare any site-directed isotopomer of L-leucine, L-isoleucine and L-valine

In this paper a chemo-enzymatic method has been developed that gives access to any isotopomer of the essential amino acids isoleucine and valine. The method gives the correct introduction of the second chiral center in (2S,3S)-isoleucine and allows for discrimination between the two prochiral methyl groups in valine as shown by the preparation of (2S,3S)-[4-C-13] valine. For the preparation of (2S)-leucine in any isotopomeric form, the O' Donnell method to prepare optically active amino acids has been used. The protected glycine scaffold used in this method has been prepared by a strategy that allows access to any isotopomeric form. The preparation of [5-C-13]-(2S,4R)-leucine shows that the O' Donnell method in combination with the Evans method to obtain chiral 2-methylpropyl iodide leads to a good discrimination between the two prochiral methyl groups. The O' Donnell strategy for the preparation of alpha-amino acids is preferred over other methods since the reaction conditions are mild, the chiral auxiliary can be easily recovered and the optically active product can be easily separated. For the preparation of isotopically enriched valine and isoleucine the O' Donnell method is not suitable, because the alkyl substituents involved have a secondary halide substituent which is sterically too hindered to give an effective reaction with the protected glycine. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).