Selective synthesis of the 2-hydroxyferrocene-aldimine enantiomers—extended planar chiral analogues of the “flat” salicylaldimineligand family

Abstract

Efficient selective synthetic pathways to the O-(tert-butyl)diphenylsilyl-protected 2-hydroxyferrocene carbaldehyde enantiomers [(p-S)-12 and (p-R)-12, each >99.5% ee] are described. The general synthesis starts from Kagan's ferrocene carbaldehyde acetal [(S,S)-6], bearing the (2S,4S)-[4-(methoxymethyl)-1,3-dioxan-2-yl] chiral auxiliary. The synthetic route to (p-S)-12 involves a sequence of directed ortho-lithiation/iodination, followed by acetoxylation (Cu₂O/acetic acid), saponification and protection by the TBDPS silyl-protective group. Acid-catalyzed hydrolysis of the chiral acetal then gave the O-TBDPS-protected (p-S)-configurated hydroxyferrocene carbaldehyde enantiomer in an overall yield of 76% over 4 steps. The (p-R)-12 enantiomer was prepared by a similar route starting from (S,S)-6 using the –SiMe₃group as a reversible blocking group to direct the required functionalization to the (p-R)-series. A total of six steps furnished (p-R)-12 in a combined yield of 27%. The aldehyde enantiomers of 12 were used for the synthesis of the corresponding N-2,6-diisopropylphenyl-imines. Subsequent deprotection gave the new “ferrocene-salimine” ligands 2-hydroxy-[N-(2,6-diisopropylphenyl)iminomethyl]-ferrocene (p-S)-2a and (p-R)-2a, respectively. We also synthesized the (p-S)-enantiomers of the corresponding N-mesityl and N-pentafluorophenyl aldimine derivatives [(p-S)-2b, (p-S)-2c].