Synthesis Of Inherently Chiral Calix[4]arenes Substituted On The Lower Rim And Their Applications In Asymmetric Henry Reaction

Objectives:Inherently chiral calixarenes, whose chiralities originate from the asymmetric array of achiral residues on their skeletons, have attracted much attention for their unique structures and potential applications in chiral recognition and asymmetric catalysis. Recently, the study on synthesis and properties of inherently chiral calix[4]arenes have been frequently reported. However, those applied to asymmetric catalytic reactions are mostly substituted on the upper rim. Moreover, their catalytic properties(ee%) are comparably low. Thus, one task of our research is to synthesize new inherently chiral calix[4]arenes substituted on the lower rim and prepare for the study of their asymmetric catalysis properties. Now a variety of chiral drugs, such as(-)-Denopamine and(-)-Norepinephrine, comprise a structural unit of 2-amino-1-aryl ethanol and Henry reaction is one of their efficient synthesis methods. Untill now, their chiral catalysts in asymmetric Henry reaction are almost chiral metal complexes. Taking the superiorities of chiral organocatalyst into account, another task of our research is to apply inherently chiral calix[4]arenes substituted on the lower rim to asymmetric Henry reaction to check their asymmetric catalysis properties. Moreover, a more economic and greener synthesis route could be expectedly obtained for chiral 2-amino-1-aryl ethanol drugs in the process.Methods:Based on the reported resolution of p-tert-butyl calix[4]atene, we firstly synthesized a pair of diastereoisomers of inherently chiral calix[4]atene substituted on the lower rim, then synthesized several pairs of enantiomers of inherently chiral calix[4]arenes after etherification, hydrolysis, amidation, reduction and so on. Then, inherently chiral calix[4]arenes were applied to the asymmetric catalysis of Henry reactions. Firstly, we chose nitrobenzene formaldehyde and nitromethane as substrates for a model Henry reaction. Then the best catalytic condition was obtained after comparison of catalytic results of the model reaction in different reaction conditions such as temperature, solvent, catalyst and so on. Secondly, the best catalytic condition was popularized to Henry reactions of other aldehydes and nitromethane.Results: Three kinds of inherently chiral calix[4]arenes substituted on the lower rim have been synthesized. The first one, 2-5a and 2-5b, contains amide and hydroxyl group. The second one, 2-6a and 2-6b, contains amine and hydroxyl group. The third one, 2-7b, contains amide and pyridinyl group. Then, inherently chiral calix[4]arenestreated as bifunctional organocatalysts were applied to asymmetric Henry reaction. The asymmetric catalysis results of Henry reactions show they have somewhat asymmetric catalysis capability, in which 2-6a and 2-6b have the highest asymmetric catalytic abilityConclusions: From inherently chiral calix[4]arene diastereomer reported, three kinds of bifunctional inherently chiral calix[4]arenes substituted on the lower rim have been synthesized with hydroxy, amino, amide or pyridiyl groups. Henry reaction is an efficient synthesis method of chiral drug intermediates with 2-amino-1-aryl alcohol unit. Thus the reaction was selected as the catalytic reaction to check their asymmetric catalysis properties. The catalysis results show that inherently chiral calix[4]arenes with bifunctional groups reproduce comparable yield and somewhat enantioselectivity in Henry reactions of different aldehydes and nitromethane. The experimental results provided some guidance for further design and modification of inherently chiral calix[4]arenes.