Resolution And Application Of Bridging Chiral Calix[4]arenes

Objectives : Calixarene as a new generation of supramolecular host has some advantages such as many modified sites, flexible conformations and a size-adjustable cavity. Based on the above advantages, the calixarene derivatives have been widely used in chiral recognition, chiral catalysts, artificial enzyme and chemical sensors. In recent years, the research of inherently chiral calixarenes has been frequently reported and their synthesis become highly efficient and applicable. However, their applications in asymmetric catalysis are unsatisfactory since the stereo selectivities in asymmetric catalysis are comparably low. Compared to inherently chiral calix[4]arenes, the representative characteristics of bridging chiral calix[4]arenes is that bridging point chirality exists on their asymmetrically substituted bridging methylenes, which can be modified through not only changing the calix[4]arene substituents but also changing the calix[4]arene conformation. Now, the research of bridging chiral calix[4]arenes are in a preliminary stage. There are two purposes in this research. Firstly, the optically pure bridging chiral calix[4]arenes were prepared through conjugation of bridging chiral calix[4]arene racemates with chiral auxiliary,separation of the resulted diastereomers on conventional column chromatography, and subsequent removal of chiral auxiliary. Secondly, the optical pure bridging chiral calix[4]arenes were modified into chiral organocatalysts for chiral drug synthesis.Asymmetric Henry reactions of aromatic aldehyde have extensive applications in the synthesis of a variety of chiral drugs such as 2-amino-1-aryl alcohols. In this research,asymmetric Henry reaction was selected as a model reaction to test the chiral catalysis efficiency of the synthesized bridging chiral calix[4]arenes. It was expected that some efficient organocatalysts for asymmetric Henry reaction can be obtained.Methods : In the research, the bridging chiral calix[4]arene diastereomers were prepared from conjugation of bridging chiral calix[4]arene racemate and expected to show so obviously different that the racemate can be resolved through their separation.Starting from bridging chiral calix[4]arene 2-13, three routes were designed to prepare enantiopure bridging chiral calix[4]arenes. The route 1 was to reduce the nitro group into amino group, and couple the amino group with a chiral auxiliary. The route2 was to firstly hydrolyze the amide bonds of bridging chiral calix[4]arene 2-13 to produce carboxylic acids and then couple the carboxylic acids with a chiral auxiliary.The route 3 was to directly couple the hydroxyl groups of 2-13 with a chiral auxiliary.The optically pure bridging chiral calix[4]arenes were reduced into bridging chiral calix[4]arene aminoalcohol, which were treated as chiral organocatalysts for asymmetric Henry reaction. The preliminary chiral catalysis results provided some guidance for the modification of bridging chiral calix[4]arene organocatalysts.Results : The research attempted to separate the bridging chiral calix[4]arene racemates through two amino acids,(S)-2-bromine-N-(1-phenyl) acetamide and(S)–naphthol. The first two kinds of chiral auxiliaries were failed since the resulted diastereomers can't be separated. As a result, a pair of enantiopure bridging chiral calix[4]arene carboxylic acids monobridge-substituted with an equatorial N,N'-dimethylformamidyl group(2-20 a and 2-20b) have been facilely prepared by the optical resolution their racemate with a chiral auxiliary(S)-Binol. Moreover, the absolute configurations of the enantiomers were determined by X-ray crystallographic analysis. Correspondingly, the absolute configuration of bridging point chirality in 2-20 a and 2-20 b could be further assigned to be S and R,respectively. Catalysts 3-1 was produced from the reduction of 2-20 a. However, the catalytic efficiency of 2-20 a is undesirable. Then the further structural modification of bridging chiral calix[4]arene organocatalysts were executed to prepare 3-2 and 3-3.Conclusions : Bridging chiral calix[4]arenes 2-19 a and 2-19 b were efficiently separated with chiral auxiliary(S)- binaphthol. Their absolute configuration were deduced as S and R, respectively. Bridging chiral calix[4]arene 3-1 was prepared from bridging chiral calix[4]arene 2-20 a, and used as oganocatalyst in asymmetric Henry reaction. The catalytic yield is high while the chiral catalytic efficiency is undesirable,which may be attributed to the unfavorable rigidity and low alkaline. Nevertheless,the preliminary catalytic results of Henry reaction provided some guidance for the further structural modification of bridging chiral calix[4]arenes.