Cyclodextrins chiral induction

Tabushi, I., (1986) Chiral selection and chiral induction by the use of regiospecifically di-(or poly Substituted cyclodextrins Pure Appl. Chem. 58, 1529-1534. 

Of particular interest are the gas-solid bromination, chlorination and hydrobromina-tion of unsaturated acids complexed with cyclodextrins, which proceed with a high degree of chiral induction. For example, in the gas/solid chlorination of methacrylic acid complexed with a-cyclodextrin1032, (-)-2,3-dichloro-2-methylpropanoic acid is obtained in a 100% optical yield. 

In our first study we attached a pyridoxamine unit to a primary carbon of jS-cyclodextrin (structure 12). We saw that pyridoxamine alone is able to transaminate pyruvic acid to form alanine, phenylpyruvic acid to form phenylalanine, and indolepyruvic acid to form tryptophan, all with equal reactivity by competition experiments. However, when the cyclodextrin was attached to the pyridoxamine there was a 200-fold preference for the indolepyruvate over pyruvate in one-to-one competition, forming greater than 98% of tryptophan, and in the competition with phenylpynivate and pyruvate the phenyManine was formed in greater than 98% as well. Thus the ability of the substrates to bind into the cyclodextrin cavity led to striking selectivities. In addition there was some chiral induction in these processes, since )3-cyclodextrin is itself chiral, but the magnitudes of the induction were quite modest. 

We also set about to see whether we could get good chiral induction in the product amino acids, not by the simple accident of the chirality of the cyclodextrin but by basic groups that could direct the proton transfer involved in transamination so as to give a preference for one enantiomer of the product amino acid. We described some of this work, " and in it also referred to work reported by Tabushi in which the same general principle was applied. In our work only relatively modest selectivities were seen the largest optical ratio (L/D) in the product was only 6.8. 

Chiral Induction, p. 245 Crown Ethers, p. 326 Cryptophanes, p. 340 Cyclodextrins, p. 398 Cyclodextrins, Applications, p. 405 Cyclophanes Eizdoacidic, Endohasic, and Endolipophilic Cavities, p. 424... 

As one of the enzymic reactions, asymmetric synthesis catalyzed by cyclodextrins has been studied in the past, but gave all the products in a low optical yield. We have already found a strong chiral induction for the chlorination of methacrylic acid in the crystalline cyclodextrin complexes. 100 % enantiomeric excess (e.e.) of (-)-2,3-dichloro-2-methyl-propionic acid and 88 % e.e. of its enantiomer were isolated in a- and 3-cyclodextrins, respectively. This paper describes asymmetric addition of gaseous halogens and hydrogen halides in the crystalline complexes comprising trans-cinnamic acid as a reactant and a- or 3-cyclodextrin as chiral matrix. Asymmetric bromination of menthyl cinnamate and of salts from the acid and several chiral amines have been reported, but gave low chiral inductions up to 2 16 % e.e.. 

ABSTRACT The gas-solid halogenation and hydrohalogenation using micro-crystalline cyclodextrin complexes are found to be efficient for production of the optical active halides of ethyl trans-cinnamate in moderate optical yields On exposure to HBr at 2QOC for 15-20 hr, the cinnamate in solid a- and S-cyclodextrin complexes yields ethyl R-(+)-3-bromo-3-phenylpropanoate in 46% e.e., and S-(-)-enantiomer in 31% e.e., respectively. No addition nor substitution products are obtained with HCl vapor at 0-50°C for 15-65 hr. Bromination of the B-cyclodextrin complex results in the formation of optical active ethyl erz/t/zrc>-2,3-dibromo-3-phenylpropanoate, while chlorination gives the optical active mixture of trans and cis addition products, ethyl erythro- and threo-2,3-di-chloro-3-phenylpropanoates in 60-80% yields. Mechanism of chiral induction in the present gas-solid reaction has been proposed on the basis of the crystal structure of the complex. 

Reactions in cyclodextrins can show chiral inductions because of the chirality of the glucose units. As one example, we have been examining the reaction of certain nitrophenyl esters, bound into the cyctodextrin cavity, with the hydroxyl groups of... 

Being formed of D-glucose units, cyclodextrins are chiral and chiral induction on substrates have been observed with cyclodextrin reactions (173). 

Seebach and Oei [446,447] reported the asymmetric hydrodimerization of acetophenone (a maximum asymmetric yield of 6.4%) in a chiral cosolvent. The use of small amounts of chiral crown ethers was attempted however, no significant asymmetric induction was observed [443]. It is interesting that in the presence of /5-cyclodextrin, head-to-tail coupling of acetophenone leads to optically active dimeric monoalcohol (ca. 24% ee), whereas the head to head coupling gives optically inactive pinacols [448,449]. 

This particular property allows an application of the cyclodextrins as chiral material for chromatographic racemate resolution or as substrates for the asymmetric induction leading to bond closure or bond cleavage (enzyme modelling). Apart from the topological (static) conditions, the dynamic processes of complex formation and complex dissociation here also play a part in the host/guest interactions and are therefore important for the efficiency of the separation effect. 

We have used chiral y-cyclodextrin GC columns under isothermal GC-MS conditions (column temperature 9 120 ) and found that enantiomers of /ran -zwiebelane (9a, Figure 2) and the thiosulfinates MeS(0)SMe, MeS(0)SPr-/i, and MeSS(0)Pr-/i (Figure 3) can be resolved and that individual enantiomers are stable under the analytical conditions (25). However, analysis of an onion extract on the chiral column showed that all of these con unds were present as racemic mixtures, su esting that asymmetric induction is not involved in their formation from achiral sulfenic acid ... 

Hydrobromination of the same substrate in the a-cyclodextrin complex gave the monobromide with the opposite configuration at 46 % e.e.. This clearly shows that ethyl trans-cinnamate forms complexes with a- and 3-cyclodextrins such that the anti-addition of hydrogen bromide occurs with high but different enantioselectivities in the two cases to yield monobromide derivatives of opposite chiralities. A detailed mechanism, however, could not be described at the present time for the observed asymmetric induction in the hydrobromination and bromination of the a-cyclodextrin complex, because no crystalline or molecular structures were determined for the ester included in a-cyclodextrin. 

The approach using cyclodextrin as a binding site has also been developed. Cyclodextrins are widely utilized in biomimetic chemistry as simple models for an enzyme because they have the ability to form inclusion complexes with a variety of molecules and because they have catalytic activity toward some reactions. Kojima et al. (1980, 1981) reported the acceleration in the reduction of ninhydrin and some dyes by a 1,4-dihydronicotinamide attached to 3 Cyclodextrin. Saturation kinetics similar to enzymatic reactions were observed here, which indicates that the reduction proceeds through a complex. Since the cavity of the cyclodextrin molecule has a chiral environment due to the asymmetry of D-glucose units, these chiralities are expected to be effective for the induction of asymmetry into the substrate. Asymmetric reduction with NAD(P)H models of this type, however, has not been reported. Asymmetric reduction by a 1,4-dihydronicotinamide derivative took place in an aqueous solution of cyclodextrin (Baba et al. 1978), although the optical yield from the reduction was quite low. Trifluoromethyl aryl ketones were reduced by PNAH in 1.1 to 5.8 % e.e. in the presence of 3-cyclodextrin. Sodium borohydride works as well (Table 18). In addition to cyclodextrin, Baba et al. also found that the asymmetric reductions can be accomplished in the presence of bovine serum albumin (BSA) which is a carrier protein in plasma. 

As shown in Table 18, trifluoromethyl aryl ketones were reduced in 22.3-46.6 % e.e. by PNAH and 15.6-38.8 % e.e. by sodium borohydride in 1.5-1.7 mM solution of BSA. The degree of asymmetric induction was rather high in comparison with those from the reactions with cyclodextrin, which suggests the possibility that such a simple protein as BSA can provide a chiral reaction field, as an enzyme does. As already mentioned some proteins have a similar (or sometimes greater) affinity toward a molecule in the ground state in comparison with an enzyme. The difference between these two proteins in different classes is the affinity toward a transition state. The enzyme has to bind the transition state more strongly than the ground state. 

In the larger cavity of -cyclodextrin it is possible to bind both the diene and the dienophile of certain Diets-Alder reactions. The result of this binding is to catalyze the reaction, and this catalysis is quite selective [24]. Only pairs of reagents which can both fit into the cavity are catalyzed, while other Diets-Alder reactions may be inhibited by the same cyctodextrin if one of the components is bound but the second cannot also fit in. Furthermore, the cyclodextrin-catalyzed reactions in general give a different product distribution from that obtained in the absence of the catalyst, because the geometry in the mixed complex helps to determine the orientation of the two components. There is even a small but real induction of optical activity in the Diels-Alder products, since they are being formed in a chiral environment. 

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