Design And Syntheses Of Chiral Ferrocenophanes And Their Application In Asymmetric Catalysis

Ferrocenophane which combined the advantages of ferrocene and cyclophane, including flexibility, redox activity and being easily modified were expected to become the distinctive chiral ligands for the the asymmetric reactions. However, due to its highly rigid structure, big challenge exited in the synthesis of ferrocenophane. Its applications were limited especially in the asymmetric catalysis. Therefore, a variety of ferrocenophanes were synthesized and applied to catalyze the asymmetric reactions, including the asymmetric aldol reaction, the asymmetric Michael reaction, the asymmetric coupling reaction of naphthol and the asymmetric oxidative cross-dehydrogenative coupling reaction. The main results were obtained as follows:1) Synthesis of ferrocenophanes(Scheme 1)A. The N-Boc protected ferrocenophane was given from the condensation of 1,1′-ferrocenedicarboxaldehyde with corresponding chiral amines under high dilution condition and subsequent reduction with Na BH(OAc)3. Moderate yield was obtained. Ferrocenophane L1 and L6 were obtained upon Boc-deprotection.B. The N-Boc protected ferrocenophane was efficiently synthesized from the nucleophilic substitution of 1,1’-ferrocene-bis(methylenepyridinium) with N-Boc-(S, S)-diaminocyclohexane in 85% yield Correspondingly, ferrocenophane L7 was obtained in 93% yield upon Boc-deprotection.2) Application of ferrocenophane in asymmetric aldol reactionsThe ferrocenium was served as Lewis acid and large steric hindrance in the reaction, the stereoselectivity and reactivity was greatly improved. For comparison, H-bonding as stereocontrolling unit was used to control stereoselectivity in traditional organocatalysis. Two strategies of redox tuning aldol reaction were employed.(1) Chemical oxidation. Using 10 mol% L7 as catalyst and 15 mol% [Fe Cp2]+BF4 as oxidant, excellent yields and stereoselectivity were obtained(up to 94% yield, 95:5 dr, 94% ee). The catalyst L7 could be reused for five recycles without much loss of its activity. A plausible mechanism was outlined according to the EPR spectrum and the control experiment(Scheme 2).(2) Electrochemical oxidation. A novel approach of electrochemical tuning asymmetric reaction was developed. The 10 mol% L7, 5 mol% ferrocene, 0.1 M p-Ts ONa, 0.2 M EMIMBF4 in CH3 OH and CH3 CN were electrolyzed for the stated time, the aromatic aldehydes and ketones were added. Moderate yields and excellent stereoselectivities were obtained(up to 65% yield, 13:1 dr, 92% ee), which further confirmed the role of ferrocenium in oxidized L7(Scheme 3).3) Application of ferrocenophane in asymmetric Michael addition reaction Ferrocenophanes catalyzed efficiently the asymmetric Michael addition reaction of ketones with a variety of nitroalkenes. Using 10 mol% L1 as catalyst and 10 mol% Ph COOH as additive, up to 94% yield, 90:10 dr and 85% ee were obtained. The scopes of substrates were broad. A plausible mechanism was proposed(Scheme4) Application of ferrocenophanes in Cu(I)-catalyzed asymmetric oxidative coupling reaction of 2-naphthol derivativesUsing 10 mol% L1 as chiral ligand and 10 mol% Cu Cl as catalyst, up to 79% yield and 92% ee were obtained. A plausible mechanism was proposed(Scheme 5).5) Application of ferrocenophanes in transition-metal catalyzed the asymmetric cross-dehydrogenative coupling reactionThe novel strategy combined organocatalysis and transition metal-catalyzed cross-dehydrogenative coupling reaction. Using 10 mol% L7 as aminocatalyst and 5 mol% Cu(OTf)2 as catalyst, various chiral tetrahydroisoquinoline derivatives were obtained with up to 58% yield, 5:1 dr, 91% ee(Scheme 6). A plausible mechanism was proposed(Scheme 7).