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)Me][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 proceeded smoothly at RT, but gave a 1:1 mixture of the Rp and Sp complexes, even when a deficiency 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 Sp-2, leaving behind the uncomplexed isomer Rp-2, while treatment with 0.5 equiv of the (1R,2R)-derivative furnished the isomeric complex of Rp-2 and uncomplexed Sp-2. The complex between (1S,2S)-MPE and Sp-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 (1S,2S)-N-methylpseudoephedrine the SB isomer was formed, while (1R,2R)-pseudoephedrine led to RB chirality at boron. Finally, a sample of enantiomerically pure Rp-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 SB and RB 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 SB 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.