Asymmetric Acylation of sec-Alcohols with Twisted Amides Possessing Axial Chirality Induced by the Adjacent Asymmetric Center

This paper reports that axially chiral twisted amides serve as asymmetric acylating agents for sec -alcohols under neutral conditions. Kinetic resolution of various racemic sec- alcohols and desymmetrization of 1,2-, 1,3-, and 1,4- meso- diols were performed by using the twisted amides. The utility of this desymmetrization method was shown by the preparation of the synthetic intermediate 28 for macrolide antibiotic nodusmicin and 18-deoxynargenicin. The stereoselectivity of the acylation reactions is significantly dependent on the bulkiness of both the acyl group and the C-4 substituent of the chiral auxiliary. When an amide possessing an imidazolyl group at C-4 was employed, the stereoselectivity was reversed to give R esters. A possible working model of the acylation reaction is also described on the basis of the structural studies of the twisted amides by IR and 1 H and 13 C NMR spectroscopies and AM1 calculations. These studies suggested that rotamer II is thermodynamically more stable than the others. The rotamer II has an axial chirality about its C(O)−N linkage that is induced by the adjacent chiral center. This would enable discrimination of the two enantiomeric hydroxy groups of the racemic alcohols or meso -diols.