Synthesis of New Chiral Crown Ethers Incorporating Two Different Chiral Units and 'Matched/Mismatched' Effect of the Two Chiral Units on the Chiral Recognition

Abstract

Chiral crown ethers have been widely applied as chiral selectors in differentiating the two enantiomers of racemic compounds containing a primary amino group. Especially chiral crown ethers have been quite useful as chiral selectors of liquid chromatographic chiral stationary phases (CSPs) for the recognition of the two enantiomers of racemic primary amino compounds. Among a large number of chiral crown ethers, two types have been most successfully utilized as liquid chromatographic CSPs. The first type is chiral crown ethers incorporating chiral 1,1'-binaphthyl unit, which were first developed by Cram. Especially, chiral crown ethers such as bis-(1,1'-binaphthyl)-22-crown-6 immobilized on silica gel or polystyrene were used as CSPs in separating the enantiomers of racemic α-amino acids and their derivatives in the late 1970s by Cram and coworkers. Afterward, chiral crown ethers related to (3,3'-diphenyl-1,1'binaphthyl)-20-crown-6 (1, Fig. 1) dynamically coated on octadecyl silica gel or covalently bonded to silica gel were developed as liquid chromatographic CSPs and successfully utilized in the resolution of racemic α-amino acids and other racemic compounds containing a primary amino group. The second type of chiral crown ether successfully utilized as a chiral selector of CSPs is the one incorporating two tartaric acid units, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2, Fig. 1), which was first synthesized by Lehn and coworkers. Initially, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was utilized as a chiral selector for the chiral separation by capillary electrophoresis. The use of (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was then extended as a chiral selector of liquid chromatographic CSPs. Liquid chromatographic CSPs based on (+)-(18crown-6)-2,3,11,12-tetracarboxylic acid (2) were very successful in the resolution of various racemic primary amino compounds or racemic non-primary amino compounds. In addition, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was utilized as an NMR chiral solvating agent. However, chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit have never been known to the best of our knowledge. Chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'binaphthyl and tartaric acid unit are expected to show characteristics somewhat different from chiral crown ether 1 or 2 in the chiral recognition. In this study, we wish to report the synthesis of novel chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit and their applications as chiral selectors of liquid chromatographic CSPs. We prepared actually two diastereomeric chiral crown ethers, (R,R,R)-3 and (R,S,S)-3 (Fig. 2), incorporating both (R)-3,3'-diphenyl-1,1'-binaphthyl and (R,R)or (S,S)-tartaric acid unit as chiral barriers. Combination of the two different chiral units as chiral barriers is expected to endow the two diastereomeric chiral crown ethers with characteristic chiral recognition ability according to the stereochemistry of the two chiral units. Synthesis of the two diastereomeric chiral crown ethers was successfully performed as shown in Scheme 1. Diols (R,R)-4 and (S,S)-4 prepared from commercially available (R,R)and (S,S)-N,N,N',N'-tetramethyltartaramide respectively via the known procedure were converted into their tosyl derivatives, (R,R)-5 and (S,S)-5. Tosylation of (R,R)-4 or (S,S)-4 was most successful when a small amount of 4(dimethylamino)pyridine (DMAP) was added to the reaction mixture. The cyclization of tosyl derivative (R,R)-5 or (S,S)-