Inclusion complexation, optical

Fig. 4. Chiroselective inclusion formation of racemic l-phenylethylammonium salt ((R/S)-14) using optically active crown compound ((i, 5)-13) [53955-48-9]. The diastereomeric inclusion complex (R)-(14) is more stable than (3, 3)-(13)-(3)-(14) (top views, dotted lines represent hydrogen...

Immobilization. The abiUty of cyclodextrins to form inclusion complexes selectively with a wide variety of guest molecules or ions is well known (1,2) (see INCLUSION COMPOUNDS). Cyclodextrins immobilized on appropriate supports are used in high performance Hquid chromatography (hplc) to separate optical isomers. Immobilization of cyclodextrin on a soHd support offers several advantages over use as a mobile-phase modifier. For example, as a mobile-phase additive, P-cyclodextrin has a relatively low solubiUty. The cost of y- or a-cyclodextrin is high. Furthermore, when employed in thin-layer chromatography (tic) and hplc, cyclodextrin mobile phases usually produce relatively poor efficiencies. 

Chiral Chromatography. Chiral chromatography is used for the analysis of enantiomers, most useful for separations of pharmaceuticals and biochemical compounds (see Biopolymers, analytical techniques). There are several types of chiral stationary phases those that use attractive interactions, metal ligands, inclusion complexes, and protein complexes. The separation of optical isomers has important ramifications, especially in biochemistry and pharmaceutical chemistry, where one form of a compound may be bioactive and the other inactive, inhibitory, or toxic. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

A regio- and stereoselective Beckmann rearrangement utilized diastereose-lective host guest interactions of the inclusion complexes 225 and 228 in a solid state reaction. Initially, a 1 1 mixture of the chiral host 223 and the racemic oximes 224 and 227, respectively, was treated with ultra sound in the solid state to induce the optical resolution. Then H2SO4 was added to start the Beckmann rearrangement, the corresponding c-caprolactams 226 and 229 were isolated in 68 % and 64 % yields and ee of about 80 % and 69 % (determined by HPLC analysis on chiracel OC) (Scheme 43) [46]. 

Cycloamylose forms inclusion complexes stereoselectively with the enantiomers of isopropyl methylphosphinate (124) from which it was possible to isolate one enantiomer with an optical purity of 66%. The absolute configuration of menthyl methylphosphinate has been revised to the opposite of that previously assigned. 

Enantioselective bromination of cyclohexene (11) in an inclusion complex with the optically active host compound, (i, i )-(-)-trans-4,5-bis(hydroxy-diphenylmethyl)-2,2-dimethyl-l,3-dioxacyclopentane (10a) was accomplished. 

Some solid-solid reactions were shown to proceed efficiently in a water suspension medium in Sect. 2.1. When this reaction, which gives a racemic product, is combined with an enantioselective inclusion complexation with a chiral host in a water suspension medium, a unique one-pot preparative method of optically active product in a water medium can be constructed. Some such successful examples are described. 

The enantioselective inclusion complexation of the reaction product with lOa-c in aqueous medium is more efficient than that by the recrystallization method. For example, inclusion complexation of rac-65e with 10a,b did not occur by recrystallization from an organic solvent however, enantioselective complexation occurred efficiently in aqueous medium to give finally optically active 65e [12]. 

When a mixture of methyl phenyl sulfide (69a) (1 g, 8.1 mmol), 30% H2O2 (1.84 g, 16.2 mmol), and water (10 ml) was stirred at room temperature for 24 h, rac-lOa was produced (Scheme 11). To the water suspension medium of rac-70a was added 10c (2 g, 4 mmol), and the mixture was stirred for 15 h to give a 1 1 inclusion complex of 10c with (+)-70a. Heating the filtered complex in vacuo gave (+)-70a of 57% ee (0.45 g, 82% yield). From the filtrate left after separation of the inclusion complex, (-)-70a of 54% ee (0.4 g, 73% yield) was obtained by extraction with ether. By the same procedure, optically active 70b-d were also prepared (Table 11). In the case of (+)-70b and (-)-70c,the efficiency of the enantiomeric resolution was very high. 

Since the optically active host remaining after separation of the optically active guest from its inclusion complex by distillation can be used again and again, this one-pot method in water is an ecological and economical method [12]. 

Enantioselective Br2 addition to cyclohexene (11) was accomplished by the solid-state reaction of a 2 1 inclusion complex of 10b and 11 with 7, although the optical yield was low (Sect. 2.1). However, some successful enantioselective solid-state reactions have been reported. For example, reaction of a 1 1 complex of 68 and acetophenone (64a) with borane-ethylenediamine complex (130) in the solid state gave the (i )-(+)-2-hydroxyethylbenzene (65a) of 44% ee in 96%... 

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

Optically active Diels-Alder adducts were also prepared by using a one-pot preparative method and enantioselective formation of inclusion complex with optically active hosts in a water suspension medium.68 For example, A-ethylmaleimide reacts with 2-methyl-1,3-butadiene in water to give the racemic adduct 1. Racemic 1 and the optically active host 2 form enantioselectively a 1 1 inclusion complex of 2 with (+)-l in a water suspension. The inclusion complex can be filtered and heated to release (+)-l with 94% ee (Eq. 12.23). 

When guest molecules are arranged together in the channel of a host-guest inclusion complex, intermolecular reactions of the guest compound may proceed stereoselec-tively and efficiently. An enantioselective reaction is expected when optically active host compounds are used. 

An enantioselective photoreaction of a guest compound is expected when an inclusion complex of the guest with an optically active host compound is irradiated in the solid state. 

The 1 1 inclusion complexes 68 composed of 2a and nitrones 67 were prepared by keeping a solution of 2a and an equimolar amount of 67 in benzene-hexane (1 1) at room temperature for 12 h 40). Melting points of the complexes 68 are shown in Table 8. Irradiation of 68 in the solid state gave optically active oxaziridines 69. Irradiation time, yields and optical purity of the products are summarized in Table 8 40). Enantioselectivity in the formation of 67d, 67f, and 67g is high, but that of 69b, 69 c, and 69 e is low. This suggests a distinct influence coming from the substituents. 

In the case of 67g which has a chiral alkyl group, optically pure 67g was included at the complexation process with 2a, and (—)-67g of 100% ee [[a]D —66.8° (c 0.22, CHClj)] was obtained. Irradiation of the 1 1 inclusion complex of 2a and (—)-67g of 100% ee gave 69g of 100% ee which has three optically pure chiral centers 40). This is not the result of a chiral induction by the optically active alkyl group, since irradiation of 67g of 100% ee in benzene gave 69g of only 12% de (diastereomeric excess). 

The optically resolved host compounds 6 b and 7 b also forms 1 1 inclusion complexes with 676 (mp 132 to 134 °C) and 67c (mp 178 to 180 °C), respectively. However, both complexes are photostable13). 

Harada et al. started from preparing inclusion complexes by adding an aqueous solution of PEG bisamine (PEG-BA) to a saturated aqueous solution of a-CD at room temperature and then allowing the complexes formed to react with an excess of 2,4-dinitrofluorobenzene. They examined the product by column chromatography on Sephadex G-50, with DMSO as the solvent, and obtained the elution diagram shown in Fig. 46. They identified the first, second, and third fraction, respectively, as the desired product, i.e., a polyrotaxane, dinitrophenyl derivatives of PEG, and uncomplexed a-CD, by measurement of both optical rotation and UV absorbance at 360 nm for the first, UV absorbance at 360 nm for the second, and optical rotation for the third. 

The polymerization of trans-1,3-pentadiene, 149, in a chiral channel inclusion complex with enantiomerically pure perhydrotriphenylene affords an optically active polymer, 150 (236). Asymmetric polymerization of this monomer guest occurs also in deoxycholic acid inclusion complexes (237). 

Even less expected, perhaps, are the reactions involving gas-solid addition of HBr, Cl2, and Br2 to a, 3-unsaturated acid guest species in a- and P-cyclodextrin inclusion complexes (242). Although the chemical yields are not high, the optical yields in some cases are extraordinary. Thus, chlorine addition to methacrylic acid in a-cyclodextrin yields (- )-2,3-dichloro-2-methylpropanoic acid in nearly quantitative optical yield. The 3-cyclodextrin methacrylic acid clathrate undergoes chlorine addition to yield preferentially the enantiomeric (+ )-product, with an e.e. of 80%. 

An attempt to directly resolve alkyl alkanesulfmates via 0-cyclodextrin inclusion complexes was only partly successful (35,106). In the majority of cases, the optical purity of the isolated esters was in the 5 to 10% range. In the case of isopropyl methanesulfinate, however, inclusion was highly stereospecific and afforded the ester with 68% optical purity. 

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