Binaphthol separation

Fig. 5.13. Atypical chromatogram forthe binaphthol separation problem if a nonracemic feed pulse is injected to a clean bed.

The incorporation of two nonidentical chiral residues, each supporting C2 symmetry, into a mactocyclic poly ether affords a chiral crown compound with C2 symmetry provided its structure is constitutionally symmetrical. Thus, base-promoted reaction of the half-crown diol prepared from (5)-birraphthol with the half-crown ditosylate d-72 synthesized tom diacetone-manrritol affords (144) the 20-crown-6 derivative (S)-d-113 with C2 symmetry. When d-72 is condensed in like fashion with (/ 5)-binaphthol, then the diastereoisomeric 20-crown-6 derivative (/ )-d-114 can be separated chromatogiaphically tom (S)-d-113. In this matmer, (/ 5)-binaphthol is resolved by the carbohydrate unit during the synthesis. 

In contrast, the phosphoramidites comprising (R) -binaphthol or (S) -binaphthol moieties (1) are obtained as a diastereomeric mixture and can be separated. The separation of the diastereomers has been achieved for many derivatives exploiting the different solubility profiles of the two diastereomers. Alternatively, the separation could be accomplished by column chromatography. These methodologies need to be optimized for each diastereomeric pair, thus representing currently the synthetic bottleneck for the rapid generation of different QUINAPHOS derivatives. 

The geometrical isomers and enantiomers of the overcrowded alkenes 15-18 can readily be separated using chiral HPLC. Recently, an asymmetric synthesis of overcrowded alkenes has been developed, involving chirality transfer from an axial single bond to an axial double bond (Scheme 8).32 This methodology is particularly attractive for preparation of larger quantities of enantiomerically pure chiral switches based on overcrowded alkenes. The orientation of the two xanthylidene moieties is dictated by a binaphthol template. After a coupling step and separation of the diastereomers, the bi-xanthylidene is obtained with 96 % e.e. after removal of the template. 

Finally, a multireaction system will also be considered. The example is related to the separation of binaphthol enantiomers, and was reported by Morbidelli, Mazzotti and co-workers in some detail [1]. Separation of the enantiomers is even possible with an achiral stationary phase due to dimerization reactions taking place in the fluid phase. 

In this section, the application of equilibrium theory is illustrated for a fairly complex multireaction system. The problem to be considered is that of the separation of binaphthol enantiomers through using achiral chromatography. This problem was studied by Baciocchi et al. [1] among others, who in particular made the following experimental observations. When a pulse with a racemic composition of enantiomers was injected on to the column, no separation occurred. However in all cases... 

R. Baciocchi, G. Zenoni, M. Mazzotti, et al., Separation of binaphthol enantiomers through achiral chromatography. J. Chromatogr. 

Racemic mixture and meso form, 19 separation of meso form racemate by chromatography, 223 irradiation converts the meso form to the racemate (R)-W enantiomer does not form a 19 complex with (5)-binaphthol,... 

Purify the residue by flash chromatography on silica, eluting first with diethyl ether [110 mL to separate (S)-binaphthol 53] then diethyl ether THF (1 1) to yield (/ )-4-(5,5-dimethyl-2-oxo-2x5-[1,3,2]dioxaphosphinan-2-yl)-2,2,5,5-tetramethyl-3-thiazolidine, 57 (87 mg, 99%, 99% e.e.), as a solid. 

Racemic binaphthol was first converted to binaphthodithiol by Cram [71 ]. In order to obtain enantiopure BINAS. Modena prepared the racemic thioether and then resolved it via diasteromeric separation of the corresponding sulfoxides [72]. 

Preparative Methods this reagent is an intermediate for the preparation of optically pure ethylenebis(tetrahydro-l-ind-enyl)zirconium dichloride. That is, according to the procedure described for the kinetic resolution of ethylenebis(tetrahydro-1 -indenyl)titanium dichloride with (/ ,/ )- or (S. Sf-binaphtholate, 1 equiv of racemic ethylenebis(tetrahydro- l-indenyl)zirconium dichloride can be resolved with 0.5 equiv of (/ ,7 )-binaphthol in the presence of sodium metal in toluene to yield the optically active (5, 5)-ethylenebis(tetrahydro-l-indenyl)zirconium dichloride and the (—)-[ethylenebis(tetrahydro-l(7 )-indenyl]-zirconium (/ )-binaphtholate. The separated optically pure (—)- [ethy lenebis( tetrahydro-1 (7 )-indenyl]zirconium (7 )-bi-... 

Also, it is expected that the micellar size is controlled easier than with a conventional low-molecular-mass surfactant (EMMS). The first report on enantiomer separation by MEKC using a chiral HMMS appeared in 1994, where poly(sodium A-undecylenyl-L-valinate) [poly(L-SUV)] was used as a chiral micelle and binaphthol and laudanosine were enantioseparated. The optical resolution of 3,5-dinitrobenzoylated amino acid isopropyl esters by MEKC with poly(sodium (10-undecenoyl)-L-valinate) as well as with SDVal, SDAla, and SDThr was also reported. 

Fig. 7.12 En antiomer separation of racemic analytes achieved on silica-supported poly(frons-l, 2-diaminocyclohexane-diacryl-amide)-type CSPs prepared by surface-initiated graft polymerization. (A) temazepam, n-hexane/ethanol (50/50 v/v) (B) binaphthol, dichloromethane/methanol (97/3 v/v) ...

The binaphthol host 10b was found to be very effective for enantiomeric separation of some sulfoxides. When a solution of 10b and two molar equivalents of rac-me-thyl m-methylphenyl sulfoxide (85c) in benzene-hexane was kept at room temperature for 12 h, a 1 1 complex of 10b and (-i-)-85c was obtained, after one recrystallization from benzene, as colorless prisms in 77% yield. Chromatography of the complex on sihca gel gave (-i-)-85c of 100% ee in 77% yield [32]. By the same procedure, rac-85d was separated by 10b to give (-i-)-85d of 100% ee in good yield. However, rac-85a was poorly separated with 10b, giving approximately 5% ee enantiomer, while 85b and 85e did not form complexes with 10b. In order to establish why the chirality of the m-substituted derivatives 85c and 85d is so precisely recognized by 10b, the crystal structure of the complex of 10b and (-i-)-85c was studied by X-ray analysis [33]. 

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... 

To a solution of (S,S)-552 (0.30 g, 0.506 mmol) in dry diethyl ether (40 ml) was added lithium aluminum hydride (0.20 g, 5.27 mmol, 10 eq.) and the mixture was refluxed with stiring for 4 h. The reaction mixture was quenched with cautious addition of ethyl acetate and then water. The water (20 ml) was added and organic layer was separated. Aqueous layer was extracted with diethyl ether (3 10 ml). Combined organic extracts were washed with water, dried over Na2S04, filtered and evaporated to dryness. Preparative TLC on silica gel with chloroform / ethyl acetate (4 1) afforded 80 mg (50.3 %) of pure (S)-554, [a]54g -61.1° (c = 0.973, acetone), and 127 mg of recovered (5)-binaphthol (4), [a]D " -35.0° (c = 1.06, THF) [14]. 

Camphorsulfonyl chloride can be used as a resolving reagent for chiral amines, alcohols, and binaphthols. Derivatives of camphor-sulfonates and camphorsulfonamides are generally crystalline compounds and frequently form crystals suitable for X-ray analysis. For example, racemic 3,3,3-trifluoroalanine derivative 22 was resolved into optically pure sulfonamides 23a and 23b by deriva-tization with (15)-camphorsulfonyl chloride followed by HPLC separation (eq 11). Upon recrystallization from ethyl acetate-hexane (1 5), isomer 23a forms white needles and X-ray analysis established its configuration as R,S). 

This binaphthol compound, by virtue of restricted rotation about the single bond joining the two naphthalene groups, is a chiral compound. That is, the molecule cannot readily exist in a planar form because of the steric interference of the bulky —OH substituents, and, in fact, the two enantiomers have been separated. Such enantiomeric compounds contain no stereocenter, but rather have an axis of chirality, or a chiral axis, which in this case contains the bond joining the two napthalene rings (see Fig. lO.SW) ... 

Binaphthol, 1,1 -binaphthyl-2,2-dicarboxylic acid and l,l -binaphthyl-2,2 -dihydrogen phosphate Various phosphate buffers with different concentrations and pHs, containing a-, fi-and y-CDs separately UV, 214 mn 31... 

There are many chiral molecules for which enantiomeric forms can be interconverted by a rotation about a single bond. The enantiomeric conformations of gauche butane provide an example, where rapid rotation interconverts the two under most conditions. If the rotation that interconverts a pair of such enantiomers is slow at ambient temperature, however, the two enantiomers can be separated and used. Recall from our first introduction of isomer terminology (Section 6.1) that stereoisomers that can be interconverted by rotation about single bonds, and for which the barrier to rotation about the bond is so large that the stereoisomers do not interconvert readily at room temperature and can be separated, are called atropisomers. One example is the binaphthol derivative shown in the margin. It is a more sterically crowded derivative of the biphenyl compound discussed previously as an example of a chiral molecule with no "chiral center". A second example is frans-cyclooctene, where the hydrocarbon chain must loop over either face of the double bond (Eq. 6.4). This creates a chiral structure, and the enantiomers interconvert by moving the loop to the other side of the double bond. 

A similar situation arises when three different oxy groups are linked to the phosphorus. As a consequence, it becomes stereogenic. In combination with atropi-somerism, diastereomers are formed as found with acylphosphite phosphites 1 [44]. Attempts to separate them in order to elucidate their individual contribution to rhodium-catalyzed hydroformylation were unsuccessful. However, the different effects of diastereomers on catalyst formation and hydroformylation results could be evidenced by individual synthesis of all three configurationally stable tris(binaphthol) phosphites 2 [108]. 

Lepri et al. investigated the chromatographic behavior of racemic dinitropyridyl, dinitrophenyl, dinitrobenzoyl, 9-fluorenylmethoxycarbonyl amino acids, tryptophanamides, lactic acid derivatives, and unusual enantiomers such as binaphthols on reversed phase TLC plates developed with aqueous-organic mobile phase containing bovine serum albumin (BSA) as chiral agent. More than 75 racemates has been separated in these experiments with planar chromatography using BSA in mobile phase. BSA showed enantioselectivity towards racemates with structures completely different from amino acids, their derivatives, and similar compounds such as hydroxy acids. 

HPLC is one of the most universal methods for determining the enantiomeric composition of substances and mixtures in a short time frame. Its application is not restricted to molecules in which chirality is based on a quaternary carbon atom with four different substituents it can also be employed for compounds containing a chiral silicon, nitrogen, sulfur, or phosphorus atom. Likewise, asymmetric sulfoxides or aziridines, the chirality of which is based on a lone electron pair, can be separated. Chirality can also be traced back to helical structures, as in the case of polymers and proteins to the existence of atropiso-merism, the hindered rotation about a single bond, as observed, for example, in the case of binaphthol, or to spiro compounds. 

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