Chirality impact

M. Hamende, E. Cavoy, Book ofAbstracts of the Symposium on Chirality Impact on Drug Design and Development, Braine-LAlleud (Belgium), November 26,... 

J. R. Brown, Drug Chirality Impact on Pharmaceutical Regulation, Legal Studies and Services Limited, Healthcare and Regulatory Affairs Division, London Press Centre, London, 1990. 

When ofloxacin was first introduced it was made available as the racemate. Later the optical isomers were prepared and it was found that the (3)-enantiomer, DR 3355 (6b), was substantially more active (8—128-fold) than the (R)-isomer against a broad range of bacteria (47—50). This chiral preference is not unique to ofloxacin and has been demonstrated in other quinolones as well (51,52). This significant finding has already had an impact on the design of new quinolone antibacterials still in development (53). 

A general phenomenon observed with chiral stationary phases having hydrophobic pockets is that a decrease of flow rate results in an increase in resolution. This change has significant impact mostly in reversed-phase mode (see Fig. 2-10). 

The availability of a new class of efficient separations technology for chiral drugs can have an impact on other business issues now at the forefront of the pharmaceutical industry. For example, the strategy of better drug life cycle management can be... 

Changes in pressure typically have a greater impact on retention than on selectivity. Most studies of CSPs have indicated little effect of pressure on stereoselectivity [28, 31]. However, Bargmann-Leyder et al. reported pressure-related changes in selectivity for an amylose-based CSP, though the magnitude of the pressure effect was not the same for all the compounds studied [58]. Pressures in the range of 15-20 MPa are common for chiral SFC. 

Some internationally harmonized guidelines regarding specifications and tests, impurities and validation of analytical methods have particular relevance to the development of chiral drugs and are discussed below. In addition, the impact of work on the common technical document is considered. 

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

Several reaction types and functional group transformations will be outlined in the following sections with a major emphasis on those biocatalytic processes of major impact on enantioselective synthesis and chiral product preparation. 

At a fundamental level, it has been shown that PECD stems from interference between electric dipole operator matrix elements of adjacent continuum f values, and that consequently the chiral parameters depend on the sine rather than the cosine of the relative scattering phases. Generally, this provides a unique probe of the photoionization dynamics in chiral species. More than that, this sine dependence invests the hj parameter with a greatly enhanced response to small changes in scattering phase, and it is believed that this accounts for an extraordinary sensitivity to small conformational changes, or indeed to molecular substitutions, that have only a minimal impact on the other photoionization parameters. 

Chirality at surfaces can be manifested in a number of forms including the intrinsic chirality of the surface structure and even the induction of chirality via the adsorption of achiral molecules onto achiral surfaces. The ability of STM to probe surfaces on a local scale with atomic/molecular resolution has revolutionized the understanding of these phenomena. Surfaces that are globally chiral either due to their intrinsic structure or due to the adsorption of chiral molecules have been shown by STM to establish control over the adsorption behavior of prochiral species. This could have profound consequences for the understanding of the origin of homochirality in life on Earth and in the development of new generations of heterogeneous chiral catalysts that may, finally, make a substantial impact on the pharmaceutical industry. 

Chiral dendrimers are a class of compounds which offer the possibility to investigate the impact of chirality in macromolecular systems. Their specific properties are based on their well defined highly ordered structures with nano-scopic dimension (in this report we refer to dendrimers if the molecule has a core with at least three branches attached and a defined structure otherwise we will use the term dendritic compound). 

Early work in the field of asymmetric hydroboration employed norbornene as a simple unsaturated substrate. A range of chiral-chelating phosphine ligands were probed (DIOP (5), 2,2 -bis(diphenyl-phosphino)-l,l -binaphthyl (BINAP) (6), 2,3-bis(diphenylphosphino)butane (CHIRAPHOS) (7), 2,4-bis(diphenylphosphino)pentane (BDPP) (8), and l,2-(bis(o-methoxyphenyl)(phenyl)phos-phino)ethane) (DIPAMP) (9)) in combination with [Rh(COD)Cl]2 and catecholborane at room temperature (Scheme 8).45 General observations were that enantioselectivities increased as the temperature was lowered below ambient, but that variations of solvent (THF, benzene, or toluene) had little impact. 

Enantiomers of the same compound may have differing threshold values. This property was observed for a new, strong and high impact, flavor compound, 3-thio-2-methylpentan-l-ol, first detected in thermally processed materials but that is actually present in raw onions.54 First of all, there is a marked concentration effect at 1 ppm in 5% saltwater, the odor is described as sulfuric, burnt gum, sweaty, onion and at 0.5 ppb as meat broth, sweaty, onion, leek . Since there are two chiral centers (both dependent on carbon) there are four stereoisomers, all of which have been prepared 18a, 18b, 19a, 19b (Scheme 7). For this compound, enantiomers have the following marked differences in odor thresholds (but apparently all have the same general odor). 

The development of chiral phosphorus ligands has made undoubtedly significant impact on the asymmetric hydrogenation. Transition metal catalysts with efficient chiral phosphorus ligands have enabled the synthesis of a variety of chiral products from prochiral olefins, ketones, and imines in a very efficient manner, and many practical hydrogenation processes have been exploited in industry for the synthesis of chiral drugs and fine chemicals. 

Perhaps the most compelling research objective in this area will involve the development of a chiral metathesis catalyst that effects C-C bond formation efficiently and with excellent levels of enantioselectivity [41 ]. In such a case, all the reactions discussed herein, in addition to those expertly developed in other laboratories [40], will become subject to asymmetric catalysis. Such a development should prove to have an enormous impact on the field of inorganic, organome-tallic and synthetic organic chemistry. 

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