Resolution of Planar-Chiral Ferrocenylborane Lewis Acids: The Impact of Steric Effects on the Stereoselective Binding of Ephedrine Derivatives

Resolution of the planar-chiral bidentate Lewis acid Fc[B(Cl)Mel[SnMe2Cl] (Fc = 1,2-ferrocenediyl) (1) by complexation with pseudoephedrine derivatives was studied. Compound 1 was first converted to the methoxy derivative Fc[B(OMe)Me][SnMe2Cl] (2) by treatment with Me3SiOMe. The latter was fully characterized by multinuclear NMR and single-crystal X-ray diffraction analysis, both of which suggest a significant interaction between the oxygen of the B(OMe)Me substituent and the neighboring tin center. Complexation with (1S,2S)-pseudoephedrine under release of MeOH complexes, even when a deficiency proceeded smoothly at RT, but gave a 1:1 mixture of the R-p and S-p of the pseudoephedrine was used. The complexes were separated by fractional crystallization and analyzed by multinuclear NMR, 2D NOESY, and X-ray crystallography. In contrast, with the sterically more demanding ligand N-methylpseudoephedrine (MPE) highly stereoselective complexation was achieved. Reaction of 2 with 0.5 equiv of the (1S,2S)-derivative gave a complex with S-p-2, leaving behind the uncomplexed isomer R-p-2, while treatment with 0.5 equiv of the (1R,2R)-derivative furnished the isomeric complex of R-p-2 and uncomplexed S-p-2. The complex between (1S,2S)-MPE and S-p-2 was fully characterized, and the structure was examined by 2D NOESY and single crystal X-ray analysis. In all cases the central chirality at boron was found to correlate with the chirality of the pseudoephedrine derivative; that is, with (1S,2S)-pseudoephedrine or (IS,2S)N-methylpseudoephedrine the S-B isomer was formed, while (1R,2R)-pseudoephedrine led to R-B chirality at boron. Finally, a sample of enantiomerically pure R-p-2 was reacted with (1S,2S)-MPE to answer the question why complexation is less favorable for this combination. Two species were detected in solution, corresponding to a mixture of the S-B and R-B isomers, which were found to be in fast equilibrium on the NMR time scale at RT. An X-ray diffraction analysis showed that in the solid state only the S-B isomer was present. The crystal structure revealed a very unfavorable steric interaction between the NMe2 group and the free Cp ring of ferrocene, leading to major distortions in the structure.