Combining synthetic and analytical strategies for preparative HPLC enantioseparation of monastrol racemic mixture

Large-scale resolution of racemic monastrol has been carried out by normal-phase mode HPLC on an amylose-based chiral stationary phase. Because monastrol solubility, in media of proper compositions for normal-mode HPLC separations (in terms of retention factors and selectivity), was significantly low and impractical for preparative scopes, racemic monastrol was transformed into the corresponding O-tert-butyldimethylsilyl derivative. The tert-butyldimethylsilyl group was chosen as a suitable derivatizing agent because it induced approximatively a six-times higher solubility and allowed for an almost quantitative recovery of pure monastrol from the derivatization-deprotection sequence. The competitive isotherms of the O-tert-butyldimethylsilyl compounds, measured through frontal analysis, were fitted to competitive Langmuir and four-parameter bi-Langmuir models. The equilibrium dispersive model of chromatography was used for modeling the nonlinear separation of the racemate and to optimize the experimental conditions for collection of highly concentrated fractions of pure (R,S)-O-tert-butyldimethylsilyl compounds, from which significant amounts of the corresponding enantiomers of monastrol (about 100 mg of each enantiomer with 30 runs on an analytical-scale column) were obtained by quantitative back-derivatization.