Agent with chiral activity

The number of pharmacologically active agents now known to be present in various old remedies is large [7] and many of these compounds are based on chiral molecules. Information about some of the earliest herbal remedies that contain chiral active ingredients goes back nearly 5000 years. A few examples of old therapies with chiral active ingredients are presented below. 

There are two basic procedures that have been successfully used for the separation of isomers. The first is to add a chiral agent to the mobile phase such that it is adsorbed, for example, on the surface of a reverse phase, producing a chirally active surface. This approach has been discussed on page (38) in chapter 2. The alternative is to employ a stationary phase that has been produced with chiral groups bonded to the surface. 

A very convenient asymmetric synthesis of cyclopropane or epoxide systems developed by Johnson (184) is based on the use of chiral sulfur ylides as the agents that induce optical activity. Generally, this method consists of the asymmetric addition of a chiral sulfur ylide to the C=C or C=0 bond and subsequent cyclization of the addition product to form a chiral cyclopropane or epoxide system together with chiral sulfinamide. A wide range of chiral... 

Kinetic resolution.l33 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on p. 102. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,134 since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as 45 with one enantiomer of a chiral epoxidizing agent (see 5-36).135 In the case of 45 the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor)... 

To solve this problem, Pericas and co-workers have introduced a dual catalytic system consisting of a chiral amino alcohol 2, to control the enantioselectivity of the addition process, and a bulky silylating agent, to further activate the inline substrate (Scheme 1) [7]. When the 2/TIPSC1 system was used to promote the addition to imines derived from aromatic aldehydes, the addition reactions took place with good yield (63-75%) and high enantioselectivities (72-91%). Even in this case, a substoichiometric amount of chiral amino alcohol is required for a satisfactory result. 

Optically active diisopinocamphenylborane can be used to resolve racemic olefins. The reagent adds to one enantiomer, and the other is unchanged. Optical purities on the order of 37-65% are possible. Chiral ally lie alcohols can be resolved with chiral epoxidizing agents derived from tartrate complexes of titanium. One enantiomer is epoxidized and the other is not. Thus, die two alcohol enantiomers can be separated, one as the unsaturated alcohol and one as the epoxy alcohol. Use of die other tartrate isomer reverses die stereoselectivity. Selectivities on die order of >100 are possible with this method. As in any kinetic resolution, however, only one enantiomer can be recovered. The other is converted to a different chiral product. 

In particular, reduction of unsymmetric ketones to alcohols has become one of the more useful reactions. To achieve the selective preparation of one enantiomer of the alcohol, chemists first modified the classical reagents with optically active ligands this led to modified hydrides. The second method consisted of reaction of the ketone with a classical reducing agent in the presence of a chiral catalyst. The aim of this chapter is to highlight one of the best practical methods that could be used on an industrial scale the oxazaborolidine catalyzed reduction.1 1 This chapter gives an introductory overview of oxazaborolidine reductions and covers those of proline derivatives in-depth. For the oxazaborolidine derivatives of l-amino-2-indanol for ketone reductions see Chapter 17. 

Enantioselective fluorination is commonly conducted with chiral agents such as quinine-based [N-F]+ compounds, and these have been successfully utilised in ionic liquids.115,161 Very good yields and selectivities have been obtained in the enantioselective fluorination of /Nkctoesters catalysed by the chiral palladium complex 57, see Scheme 9.2. l l Depending on the substrate employed, substantial acceleration of the reaction rate relative to that in ethanol was observed with yields and selectivities comparable to those obtained in water or ethanol. The reaction rate was found to depend on both the length of the alkyl substituent of the imidazolium cation as, well as on the type of anion present, whereas the selectivity was not affected by such variations. The products were extracted from the ionic liquid phase with diethyl ether, and in that manner catalytic activity was maintained for up to ten cycles. 

Several optically active polymers of acrylates and methacrylates have been obtained by enantioselective polymerization of a racemic monomer initiated by a Grignard compound complexed with chiral reagent. Complexing agents for the polymerization of (K,S)-a-methylbenzyl methacrylate include chiral alcohols, such as quinine and cinchonine [63], (— )-sparteine and its derivatives [64-67], and other axially disymmetric biphenyl compounds [68,69]. Other racemic monomers used include (/ ,S)-a-methylbenzyl acrylate [70], (K,S)-l-phenylethyl acrylate, methacrylate and a-ethylacrylate [71], and 1,2-diphenylethylmethacrylate [72]. 

A chiral substituent on nitrogen can direct the predominant attack of an oxidizing agent to one dia-stereotopic face of an imine. Ratios as high as 97 3 were observed in a series of imines derived from a-methylbenzylamine (equation 43). The oxidation of achiral imines with optically active peroxy acids, most notably monoperoxycamphoric acid [(+)-MPCA], do afford optically active oxaziridines, but not generally in synthetically useful optical ratios, but ratios as high as 80 20 have been reported. ... 

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