(−)-Ephedrine as an auxiliary for the asymmetric synthesis of atropisomeric amides by dynamic resolution under thermodynamic control

Artificial Molecular Rotors

“…395 The CdO group then lies more or less perpendicular to the plane of the aromatic ring, 396,397 and the barrier to rotation can be high enough (∆G q between 25 and 40 kcal mol -1 ) that enantiomers can be resolved [398][399][400][401][402][403] and the barriers to rotation of the amide unit can be measured. 404, 405 Clayden and co-workers have used their experience in making chiral aromatic amides, [406][407][408] for use in stereocontrolled reactions, [409][410][411][412][413][414][415][416] toward the creation of "geared" molecular systems ( Figure 28). 417,418 Using a sterically hindered 2-methyl-1-naphthamide system bearing a chiral pyrrolidine (53a), they found that aryl-CO bond rotation (∆G 306 q ) 26 kcal mol -1 ) was correlated with C-N bond rotation (∆G 306 q ) 24 kcal mol -1 ).…”

Asymmetric synthesis of biaryl atropisomers by dynamic resolution on condensation of biaryl aldehydes with (−)-ephedrine or a proline-derived diamine

“…Previous success with stereocontrol employing ephedrine-derived oxazolidines [ 15 , 26 – 27 34 – 35 ] and proline-derived imidazolidines [ 25 , 27 ] prompted us to investigate the thermal stability and conformational preferences of similar products arising from condensation reactions of 2-formylbiaryls. A family of starting aldehydes 6a – f was made by the method of Meyers [ 36 ].…”

“…In connection with our work on non-biaryl atropisomers such as amides [ 12 – 16 ], ethers [ 17 ] and ureas [ 18 – 20 ], we have explored the opportunities offered by dynamic kinetic [ 21 – 23 ] and dynamic thermodynamic [ 24 ] resolution [ 11 , 16 , 25 – 30 ]. We reported methods for the latter based on resolving “auxiliaries” which include silylethyl groups [ 28 ], proline-derived imidazolidines [ 25 , 27 ], ephedrine-derived oxazolidines [ 26 – 27 ], and, most extensively, sulfoxides [ 16 , 29 – 31 ]. These perform well when a powerful electronic or steric bias is evident about the atropisomeric bond over which control is applied [ 32 ], and in the case of atropisomeric amides have offered levels of conformational control up to 200:1 [ 33 ].…”

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

“…We hoped that hydrolysis under mild conditions would allow us to remove the ephedrine "auxiliary" and permit isolation of the 2,6-disubstituted amides in enantiomerically enriched form. 14, 25 The sequence of reactions starting with 22 or 23 and culminating in such a deprotection would amount to a dynamic thermodynamic resolution. 59 The problem with the strategy is that, as noted previously, 14 while ephedrine-derived oxazolidines are rather stable to hydrolysis, the aldehyde products are relatively configurationally unstable at the Ar-CO bond.…”