CHIRAL COOPERATIVITY - THE EFFECT OF DISTANT CHIRAL CENTERS IN FERROCENYLAMINE LIGANDS UPON ENANTIOSELECTIVITY IN THE GOLD(I)-CATALYZED ALDOL REACTION

Long-range chiral cooperativity in enantiomerically pure ferrocenylamine ligands containing both planar and multiple centers of chirality (multiple stereogenic C-atoms) was demonstrated in the Au(I)-catalyzed reaction of aldehydes and isocyanoesters. Synthetic methodology was developed for the synthesis of ferrocenylamine ligands with two and three chiral centers of known absolute configuration in the C-side chain in addition to the planar chirality of the molecule. The diastereo- and enantioselectivity of the Au(I)-catalyzed formation of the trans- and (cis-dihydrooxazoles 5 and 6, respectively, from benzaldehyde (1) and methyl isocyanoacetate (2) depend upon the sequence of chirality (absolute configuration of the chiral centers) in the side chain of the ferrocenylamine ligands. Particularly significant effects were observed upon the enantioselectivity for the minor cis-dihydrooxazole 6, for which, in certain cases, resulted in a change in the enantiomeric dihydrooxazole 6 produced in excess with a change in the absolute configuration of a distant chiral center. Significant effects upon diastereo- and enantioselectivity were observed when chiral ferrocenylamine ligands containing free OH groups were utilized. Using ligands containing a free OH group gave 6 with an absolute configuration opposite to that produced by the corresponding ester and carbamate derivatives. The possible mechanisms for the transmission of chiral information in the proposed stereoselective transition state (TS) was discussed, including both the formation of a stereogenic N-atom and steric effects based upon Newman's rule of six.