Chiral Environmental Pollutants

In the old kingdoms of upper and lower Egypt, in many examples of burial chambers mural paintings depicting significant events, inscribed stelae or tablets have been excavated that show an astonishing proximity to our modern approach to chirality. In Fig. 1.1, an example is given of a stele that exhibits hieroglyphs carved out of stone such that they are mirrored on both sides of the so-called “ankh cross”. This ankh cross plays an important role in Egyptian mythology — it is the symbol for life. The pharaohs firmly believed in life after death, and, accordingly, they wanted to link the symbol for life with their coffins as well as with the mural paintings and stelae of the burial chamber. In addition, the hieroglyphs closely related to the ankh cross appear twice, i.e., in the form of their two mirror images. This ancient interpretation of chirality/life/death is well in line with the modern assumption that life processes, for example, enzymatic transformation processes, are highly enantioselective, but that dead organic matter may also be transformed and in part mineralised by very enantioselective processes.

Enantioselective separations by chromatographic methods can be achieved using two different experimental approaches [1]. Firstly, diastereomeric derivatives are formed by reaction of a chiral compound with a chiral reagent. They may be separated on a stationary phase, which needs not necessarily be chiral. The advantage of this procedure is that a separation is possible with any chromatographic system as long as the required selectivity is available. The presence of at least one functional group as a site of reaction with an optically pure reagent is mandatory if the substrate is to be separated. One of the main drawbacks is the need to use optically pure reagents in order to avoid a systematic error. Another error may be introduced by the generation of energetically different (diastereomeric) transition states in the reaction of a mixture of enantiomers with a chiral reagent. Unless the reaction proceeds to completion, the different rates of these reactions may cause kinetic resolution and result in erroneous proportions of the product.

The authors of the present monograph would like to leave it to the reader’s judgment as to whether the rapid development of the enantioselective analytical approaches and the results that have thus become accessible during the last decade, as summarised in the subsequent chapters, still justify the critical remarks cited above.

Over the last two decades interest in the pharmacodynamic and pharmacokinetic properties of the enantiomers of racemic chiral drugs has increased considerably and has become an issue of concern to both the pharmaceutical industry and the regulatory authorities [1]. This current interest has been stimulated not only in part by the “Thalidomide case” (marketed under the trade name Contergan® in Germany), but also by the recent advances in stereoselective synthesis and stereospecific analysis, particularly in the area of chromatography. As a result of the technological advances in the latter areas it is likely that new drug development will concentrate on single stereoisomers and the development of racemic mixtures will require scientific justification. In the current regulatory climate there appears to be a continuing requirement for enantiospecific analysis and thus modern drug development presents a considerable challenge for the pharmaceutical analyst and separation scientist [1]. As a consequence, enantiospecific analytical methodologies are required throughout the drug discovery/development process. However, in the present volume, we cannot cover this rapidly developing field. The reader interested in these aspects should refer to [2–5]. Herein, we confine ourselves to enantioselective toxic and ecotoxic effects as observed for chiral drugs. This aspect appears to be of increasing concern because, as shown by the recent investigations by Weigel, drugs are being found in the aquatic environment in larger concentrations than previously expected [6].

In 1990, Brown [1] described the present situation as follows: “Lack of appreciation (but not of knowledge) of the facts that stereoisomers are different compounds and that enantiomers often exert different biological effects has been one factor leading to failure to recognise the significance of chirality in assuring safety, quality and efficacy for medicinal products”. Public concern about chiral environmental pollutants can be stated at least since the “Thalidomide/Contergan® case” (see Sect. 4.1). However, adequate regulatory steps have only been taken so far for chiral drugs, while the application of chiral pesticides still needs corresponding regulations both at national and international levels. This lack of regulation seems to be world-wide and results in case-by-case judgments. A survey of the legal implications of chirality is given in several review papers and monographs [1–5]. With regard to the registration of chiral drugs, Witte et al. attempted an overview of the situation in three of the world’s most important pharmaceutical areas [4], the most important issues of which are as dealt with in the following sections.