Enantiospecific analyses

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

Hayball, P.J. Nation, R.L. Bochner, R Le Leu, R.K. Enantiospecific analysis of ketoprofen in plasma by high-performance liquid chromatography. J.Chromatogr., 1991, 570, 446—452... 

There will be a continued need for enantiospecific methods of preparation and analysis, not only to ensure the quality of the final drug substance and reference materials, but also to control starting materials used for their manufacture, and key intermediates during synthesis. Likewise, specific and sensitive bioanalytical methods will be required to follow the fate of individual enantiomers after their administration. 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

Statistical analysis is important and relatively easy. Suppose we have a fully atactic polymer which we analyse for the triad content for isotactic polymer. Only three methyl resonances due to triads are observed, and the statistical ratio of mm, rr, and mr is 1 1 2. Thus even in the atactic polymer our isotactic content is 25% Pentad analysis, however, would give only 8% mmmm isotactic content Especially for catalysts with low enantiospecificity it is worthwhile keeping this in mind. 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

The structure of 5-isothiocyanatopupukeanane (257), a sesquiterpene isothiocyanate from an Axinyssa species from Guam, was determined by X-ray analysis [260]. Two isomeric sesquiterpene thiocyanates, 2-thiocyanatoneopupukeanane (258) and 4-thiocyanatoneopupukeanane (259) were isolated from an unidentified sponge from Pohnpei and from Phycopsis terpnis from Okinawa [261]. A sample of Axinyssa (= Trachyopsis) aplysinoides from Palau yielded a rare thiocyanate, 2-thiocyanatopupukeanane (260), while two specimens from Pohnpei yielded 13-isothiocyanatocubebane (261), 1-isothiocyanatoaromadendrane (262) and 2-thiocyanatoneopupukeanane (258) [262]. This last compound had previously been assigned different stereochemistry at C2 [261]. (-)-4-Thiocyanatoneopupukeanane has been synthesised in an enantiospecific manner (259) [263]. Both enantiomers of 2-thiocyanatoneopupukeanane (258) have been synthesised from (7 )-carvone [264]. 

Irradiation of 1 1 host-guest crystals of coumarin 85a with (/ ,/ )-(— )-6a derived from tartaric acid gave the (— )-antvdtedd-to-head dimer 86a of 96% ee [88]. Enantiospecific photodimerization of thiocoumarin 85b gave optically pure (+ )-anti-head-to-head dimer 86b when the 1 1 complex with R,R)- — )-6b was used. X-ray structure analysis revealed that the distance between the two ethylenic double bonds was short enough (3.59 and 3.42 A for 85a and 3.73 and 3.41 A for 85b) for addition to occur and topochemically [89]. Further, both reactions were found to proceed via a single crystal-to-single crystal transformation. 

Menthyl chloroformate, [17], is commercially available and has been used in several applications. For example, Seeman et al. (72) carried out the preparative chromatographic resolution of nornicotine using [17] as a CDA. The diastereomeric carbamates formed via the reaction of racemic nornicotine with [17] were separated by preparative silica gel LC, and the pure enantiomers of nornicotine were liberated by acid-catalyzed hydrolysis of the carbamates (72). Several reports have described the use of [17] in the enantiospecific determination of drug concentrations in biological fluids thus, the reagent has been used in the analysis of encainide and some of its metabolites (73), flecainide (74), and propranolol (75), and other drugs (76). 

Insertion of propene into alkylzirconium model compounds derived from isospecific bis-indenyl catalysts may lead to low enantiospecificity [65]. Thus, site control alone does not lead to high stereoregularities. Molecular mechanics calculations [66] and a thorough analysis of the substituent effect on the statistical distribution of microstructure defects indicate that, firstly, the polymer chain assumes the energetically most favourable position with respect to the (asymmetric) site. According to Corradini, the indenyl ligand or the chlorine atoms of the lattice will direct the pol)rmer chain. The polymer chain occupies the "free space" near the site. In Fig. 6.21 we have schematically drawn this for the TiCls... 

As an example of an enantiospecific acylation in organic solvent with the irreversible acyl donor vinyl laurate (see Fig. 3), only the (R)-enantiomer is acylated, while the (S)-2-octanol is obtained directly in 69% yield, a purity >99% and with an excellent enantiomeric ratio S R>99.5 0.5 (as determined by chiral GC-analysis). The selectivity of the forward reaction, catalyzed by a lipase in MTBE, is thereby maximized, because the use of the enolester precludes the reverse reaction. Batches of about 70 kg are produced routinely and the technology can be easily transferred to larger sizes. 

Specificity is a property of monocomponent systems and it occurs when the method is free of interference. Selectivity is related to the complexity of the matrix and it occurs when not more than one ion (molecule) interferes in determination. Enantioselectivity is a relatively new term introduced for the assay of enantiomers.257258 An analytical method is enantioselective when it can discriminate between enantiomers. Enantiospecificity is an extreme case of enantioselectivity. It is possible to create the conditions for a highly enantioselective analysis, and in this case enantiospecificity can also occur. For example, a maltodextrin with dextrose equivalence (DE) of 4.0 to 7.0 was used in capillary zone electrophoresis as a stationary phase for the separation of the enantiomers,259 and also in the design of a potentiometric, enantioselective membrane electrode.260 The method for capillary zone electrophoresis is enantioselective, as it is for the potentiometric method. 

Sallustio, B.C. Abas, A. Hayball, P.J. Purdie, Y.J. Meffin, P.J. Enantiospecific high-performance liquid chromatographic analysis of 2-phenylpropionic acid, ketoprofen and fenoprofen. J.Chromatogr., 1986, 374, 329-337... 

Enantioselective GC analysis, 3242 Enantioseparation, 1032 Enantiospecific, 2446 Endarachne binghamiae (Petalonia binghamiae), 2900 Endocaimabinoids (EC), 3417,... 

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