Chiral development

Three examples of novel sources of chirality developed by researchers at Osaka University are worthy of special mention in the context of chiral crown ethers. 

The idea that the vacuum represents an achiral interface that separates two space-time segments of opposite chirality developed from the notion that mass-dependent quantum effects arise from a field in the vacuum which affects the smallest of objects most prominently. The original argument (Boeyens, 1992) was that quantum behaviour results from feeble interactions through the interface, which create the impression of random wave-like perturbations imposed on the regular motion of small particles. 

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

In other approaches, chirahty descriptors were developed with the intention not of measuring chirality but of describing chirality in a way that correlations could be established with observable properties. These descriptors have different values for opposite enantiomers, in order that chirality-dependent properties can be predicted from them. They are usually multidimensional. 

One example of a quantitative measure of molecular chirality is the continuous chirality measure (CCM) [39, 40]. It was developed in the broader context of continuous symmetry measures. A chital object can be defined as an object that lacks improper elements of symmetry (mirror plane, center of inversion, or improper rotation axes). The farther it is from a situation in which it would have an improper element of symmetry, the higher its continuous chirality measure. 

In order to calculate S, one has to find the nearest configuration of Pi points that is G-symmetric. In the majority of cases, S is the distance of a chiral object from a reflection mirror. The fblding/unfolding procedure was developed for finding that configuration. 

In most common chiral molecules, chirality arises from chiral tetravalent atoms. A conformation-independent chirality code (CICC) was developed that encodes the molecular chirality originating from a chiral tetravalent atom [42], For more generality, a conformation-dependent chirality code (CDCC) is used [43]. CDCC ti cats a molecule as a rigid set of points (atoms) linked by bonds, and it accounts for chirality generated by chirality centers, chirality axes, or chirality planes. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

We 11 continue with the three dimensional details of chemical reactions later m this chapter First though we need to develop some additional stereochemical principles con cernmg structures with more than one chirality center... 

This method is widely used for the resolution of chiral amines and carboxylic acids Analogous methods based on the formation and separation of diastereomers have been developed for other functional groups the precise approach depends on the kind of chem ical reactivity associated with the functional groups present m the molecule... 

High yields of the enantiomerically pure alcohol and enantiomerically pure ester are reg ularly achieved The growing interest m chiral drugs (see the boxed essay on this topic p 296) has stimulated the development of large scale enzymatic resolution as a com mercial process... 

For developing osmium catalyzed oxidation methods for preparing chiral com pounds of high optical pu rity Professor K Barry Sharpless (Scripps Research Institute) shared the 2001 Nobel Prize in chemistry... 

Techniques for determining the absolute configuration of chiral molecules were not developed until the 1950s and so it was not possible for Eischer and his contemporaries to relate the sign of rotation of any substance to its absolute configuration A system evolved based on the arbitrary assumption later shown to be correct that the enantiomers... 

Two mechanisms for chiral separations using chiral mobile-phase additives, analogous to models developed for ion-pair chromatography, have been... 

Limitations with the chiral selectivity of the native cyclodextrins fostered the development of various functionalized cyclodextrin-based chiral stationary phases, including acetylated (82,83), sulfated (84), 2-hydroxypropyl (85), 3,5-dimethylphenylcarbamoylated (86) and... 

Astemi2ole (10) has further been modified into a series of 4-phenylcyclohexylamine compounds, resulting in the synthesis of cabastine, for example. Cabastine is a highly active compound and its geometric isomers are also active, demonstrating the stereoselectivity of histamine receptors toward chiral ligands. The > S, 4 R-levo antipode of cabastine was the most active, and therefore this isomer, levocabastine (13), has been chosen for further development. Because of high potency, levocabastine has been developed for topical appHcation such as eye drops and nasal spray. 

One of the newer and more fmitful developments in this area is asymmetric hydroboration giving chiral organoboranes, which can be transformed into chiral carbon compounds of high optical purity. Other new directions focus on catalytic hydroboration, asymmetric aHylboration, cross-coupling reactions, and appHcations in biomedical research. This article gives an account of the most important aspects of the hydroboration reaction and transformations of its products. For more detail, monographs and reviews are available (1—13). 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

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