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.
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.
The double ortholithiation and electrophilic quench of N,N,N'N'-tetraisopropylbiphenyl-2,2'-dicarboxamide 1 is diastereoselective, giving the chiral, C(2)-symmetric atropisomers of the 3,3'-disubstituted products 3. These chiral atropisomers can be converted with moderate to good stereoselectivity to their achiral, centrosymmetric epimers by heating. The stereoselectivity of the double lithiation-quench reaction is determined by the stereochemistry of the intermediate doubly lithiated species 2, either diastereoisomer of which may be formed stereospecfically from the corresponding atropisomeric dibromo compounds.[reaction: see text]
Aromatic amides 4 (3-aroyl-2,2,4,4-tetramethyloxazolidines or TMO amides) derived by acylation of 2,2,4,4-tetramethyloxazolidine 6 undergo ortho-and lateral lithiation reactions. Given sufficient steric hindrance to bond rotation, they exhibit atropisomerism about the Ar-CO bond and the Ar-CO axis is able to control the atroposelective formation of new stereogenic centres. Unlike amides derived from hindered secondary amines such as diisopropylamine, the 3-aroyl-2,2,4,4-tetramethyloxazolidines are acid-sensitive, and treatment with methanesulfonic acid gives lactones or lactams by cyclisation onto the amide group.
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