Binaphthyl-20-crown-6 derivatives

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

Just as selective oxidation can be carried out on these systems, reduction also occurs with considerable selectively. Hydrogenation of binaphthol (Pd catalyst) in glacial acetic acid at room temperature for seven days affords the octahydro (bis-tetrahydro) derivative in 92% yield with no apparent loss of optical activity when the reaction is conducted on optically pure material. The binaphthol may then be converted into the bis-binaphthyl crown in the usual fashion. 

ISEs based on decylidene bis(4 -benzo-15-crown-5) 60 showed a moderate Rb+ selectivity over K+ and Cs+ <1997MIJ348>, while those derived from binaphthyl crown ethers 61a-c, incorporating anthraquinone, benzoqui-none, and 1,4-dimethoxybenzene, respectively, showed a better Rb+ selectivity over NH4+, alkali, and alkali earth metal ions <2004ELA1785>. 

Toda procedure for obtaining enantiomeri-cally pure compounds will find broad application very soon. This development could make preparative HPLC with chiral columns obsolete and be applied to distillable amino acid derivatives as well. After all, analytical resolution of amino acids was quite successful by host/guest complexation chromatography with reversed-phase packings loaded with Cram s chiral 1,1 -binaphthyl crown ethers (similar to 1). [20]... 

Before synthetic chiral stationary phases were developed, attempts were made to use naturally occurring chiral materials for the stationary phase. Quartz, wool, lactose and starch were inadequate but triacetylated cellulose has met with some success. The synthetic stationary phases introduced by Pirkle are able to interact with solute enantiomers in three ways, one of which is stereochemically dependent. Typically these interactions are based on hydrogen bonding, charge transfer (rc-donoi -acceptor based) and steric repulsive types. An independent chiral stationary phase therefore consists of chiral molecules each with three sites of interaction bound to a silica (or other) support. Early work in this area demonstrated that 5-arginine bound to Sephadex would resolve 3,4-dihydroxy-phenylalanine, and that direct resolution of chiral helicenes could be accomplished with columns packed with 2-(2,4,5,7-tetranitro-9-fluorenylideneaminoxy)-propionamide or tri-P-naphthol-diphosphate amide. Amino acid esters have also been resolved with a silica bound chiral binaphthyl crown ether, but better separations are achieved with A-acylated amino acid derivatives with amino-acid derived chiral stationary phases. 

The monobenzhydiyl derivative of (S)-binaphthol has played an important role, not only in the synthesis of chiral bisbinaphthyl crown ether derivatives, for example, (55)-124, containing two different bridges between the two binaphthyl units, but also in the provision of an entry into the constimtionally isomeric derivative (5S)-125. Rational stepwise syntheses of macrocyles containing three binaphthyl units have been devised and applied to the synthesis of (SSS)-126 and (RSS)-127. Cleariy, in all these procedures, the C2 symmetry of the chiral building block restricts the number of products (to one ) and defines the symmetries of the macrocycles formed. 

Prelog and co-workers (160, 161) chose 9,9 -spirobifluorene as a starting material for synthesizing chiral crown ethers since (i) it has a more rigid carbon skeleton than the 1,1 -binaphthyl unit, and (ii) it can be substituted easily in the 2 and 2 positions by electrophilic reagents. Thus, the 2,2 -diacetyl derivative (Figure 19) obtained after a Friedel-Crafts on 9,9 -spirobifluoiene can be con-... 

Although a large number of biscrown ethers based on the binaphthyl nucleus have been synthesized (157) many of these have only been isolated and characterized as their racemic modifications. An exception is provided (157) by (SS)-152, obtained from the chiral bisbinaphthyl-22-crown-6 derivative in which one of the binaphthyl units carries chloromethyl groups (in the 3 and 3 positions) capable of reacting, in the presence of base, with tetraethylene glycol. 

The 22-crown-6 derivative (SS)-129 [incorporating (5)-binaphthyl units] with the (/ )-PhCH(C02Me)NH3 cation (210). 

Crown ether binaphthyl derivatives 128-131 (Scheme 71) were synthesized and investigated by Akagi [139], Compounds 128-131 were used to induce chiral nematic phases (N ) in liquid crystals. It was found that the helical twisting power increased with decreasing ring size. Helical polyacetylenes were synthesized in the N phases. It was found that the interdistance between the fibril bundles of the helical polyacetylene was equal to the half-helical pitch of the N liquid... 

Scheme 71 Axial chiral crown-like binaphthyl derivatives 128-131...

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

Pioneering studies by Cram and co-workers employed crown ether arrays 35a-c incorporating a 2,2 -dihydroxy-l,l -binaphthyl unit as the chiral barrier <1975PAC327>. Enhancements in the chiral recognition of amino acids were obtained by placing large substituents, at the 3,3 -positions of the binaphthyl moiety, so as to raise its steric barrier. 3,3 -Diphenyl derivative 35c is often the benchmark to which other chiral crown ethers are compared <1981JOC393>. 

Chiral crown-ethers were originally developed to be used as chiral carriers in enantios-elective liquid-liquid extraction and/or as chiral phase transfer catalysts. The principle of stereoselective host-guest complexation with a chiral crown-ether type host and its application to LC has been first described in 1978 by Cram and co-workers [ 12. Currently, crown-ether type CSPs. which incorporate atropisomeric binaphthyl derivatives as chiral units incorporated in a 18-crown-6 type backbone with substituents that enforce discrimination between enantiomers are commercially available as Crownpak CR (-I-) and (—) (Daicel Chemical Ind.) (see Fig. 9.23a). 

The well known chiral carbon skeleton designated as binaphthyl hinge has been introduced into asymmetric synthesis and resolution of racemates in the form of the derivatives of 2,2 -dihydroxy-l,r-binaphthyl (84, binaphthol). The application of chiral crown compounds containing this binaphthyl tmit for the separation of amino acids and amino acid esters by use of liquid/liquid chromatography has been described particularly by Cram et al. in detail... 

Primary ammonium ions can bind to crown ethers, especially I8-crown-A derivatives, via formation of three H-bonds as shown in 5. In seminal work by Cram and coworkers, this interaction was exploited in a series of chiral receptors based on the twisted 1,1 -binaphthyl and 1,1-ditetralyI units. A key example is receptor 6, containing two binaphthyl units, of which one carries methyl substituents. This compound was capable of extracting protonated methyl d- and L-phenylglycinates and... 

Ma, Y. et al., Poly(binaphthyl-20-crown-6) as receptor based molecular selective po-tentiometric electrodes for catecholamines and other 1,2-dihydroxybenzene derivatives,... 

Figure 5 Chiral crowns (a) a binaphthyl 18-crown-6 derivative (b) an 18-crown-6 derivative prepared from maleic acid (c) an 18-crown-6 DOTA derivative. ...

The crown ethers described so far are able to bind simple metal cations and, in the case of 18-crown-6, the ammonium cation. The latter observation led one of Pedersen s fellow Nobel Laureates, Donald Cram, to consider if crown ethers could be used to resolve racemic mixmres of amino acids. None of the crown ethers prepared by Pedersen was chiral however, the Cram group was able to synthesize 18-crown-6 derivatives that incorporated one, two, or three binaphthyl groups. These crown ethers could be separated into their enantiomers and attached to a silica support. The modified silica was subsequently used to separate racemic mixtures of amino acids by chromatography. Early experiments gave separation factors for racemic mixtures of simple amino acid methyl esters in the region of 1.5-3.5. 

Chiral crown ethers are synthetic macrocyclic polyethers and were first introduced as CSPs for LC by Cram and co-workers in the late 1970s. In their pioneer works, bis-(l,r-binaphthyl)-22-crown-6 was immobilized on silica gel [126] or polystyrene [127] to resolve a-amino acids and their derivatives. Since then, different chiral crown ether CSPs have been developed and successfully applied in the HPLC separation of enantiomers containing primary amine and secondary amine groups [20, 128-139]. Both dynamically coated [128, 129] and covalently bonded [130-132] chiral crown ether CSPs are commercially available. 

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