Solid-state NMR investigation of effect of fluorination and methylation on prednisolone conformation

Abstract

Prednisolone (Prd) is a polymorphous synthetic corticosteroid that has three crystalline forms mediated by different solvents. In this study, we have demonstrated that solid-state {1H}13C cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy is able to resolve the effects of methylation and fluorination on the conformation of the steroidal rings in Prd. Two compounds were chosen for the study, 6-α-methylprednisolone (Prd-6M) and 6-α-fluoroprednisolone (Prd-6F). The 13C signals of Prd-6F showed primarily doublet patterns, with splittings of 40-380 Hz, indicating multiple ring conformations, whereas the 13C signals of Prd and Prd-6M exhibited a singlet pattern, indicating a unique conformation. Using evidence from chemical shift deviation and anisotropy analysis, we have demonstrated by solid-state NMR that Prd-6F adopts two different steroidal ring conformations that are different from that of Prd-6M, and less similar to that of unsubstituted Prd.