Conformational preference in aromatic amides bearing chiral ortho substituents: its origin and application to relayed stereocontrol.

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.

Lithium-sulfoxide-lithium exchange for the asymmetric synthesis of atropisomers under thermodynamic control.

Ortholithiation and reaction with (-)-menthyl p-toluenesulfinate introduces a sulfoxide substituent ortho to the stereogenic Ar-CO axis of an aromatic amide. The sulfoxide exerts a powerful conformational bias on the axis, such that after rapid equilibration at ambient temperature essentially only one of two diastereoisomeric Ar-CO atropisomers is populated. Sulfoxide-lithium exchange by treatment with t-BuLi regenerates the ortholithiated amide in an enantiomerically pure and conformationally stable form. Rapid electrophilic trapping of the organolithium therefore generates highly enantiomerically enriched atropisomeric tertiary aromatic amides. The overall process, involving temporary substitution of lithium to sulfoxide to lithium, amounts to a dynamic resolution under thermodynamic control.