Separation of Enantiomers
Separation of Enantiomers
Introduction: A Survey of How and Why to Separate Enantiomers
This book is about the separation of enantiomers by synthetic methods, which is to say methods involving some chemical transformation as part of the separation process. We do not in this book cover chromatographic methods for the separation of enantiomers . Nor do we focus on methods based on crystallizations as these have been amply reviewed elsewhere (see below). We are concerned mainly therefore with resolutions that involve a synthetic component, so mostly with the various flavours of kinetic resolutions through to more modern methods such as divergent reactions of a racemic mixture (DRRM). This introduction briefly clarifies the scope of the book.
The reasons such methods are of continued importance are threefold:
Society: the need for enantiopure compounds . New molecules as single enantiomers are important to our continued well-being because they are the feedstocks of new medicines, agrochemicals, fragrances and other features of modern society in a chiral world. Of the 205 new molecular entities approved as drugs between 2001 and 2010, 63% were single enantiomers . Nature provides an abundance of enantiopure compounds, but we seek, and need, to exceed this by obtaining useful unnatural molecules as single enantiomers, and we may reasonably want to access both enantiomers of some compounds.
Academia: the basic science involved in the behaviour of chiral compounds . If we seek the state of the art in our discipline, we cannot help but think that rapid and selective chemical distinction between enantiomers, which results in their facile separation, is something beautiful in itself. There have been many successful methods developed for the synthetic separation of enantiomers, as we shall see, and these are both de facto interesting and instructive to consider for the design of future examples of such processes. The relationship between kinetic resolution and asymmetric catalysis is strong, and one can inform the design of the other. It is hoped that the diverse examples described in this book stimulate thoughts in the reader of what is possible next.
Industry: the need for new methods . There remain many classes of compounds that still cannot be resolved, or where efficiencies are too low for widespread adoption. It is still the case that classical resolution techniques are overwhelmingly used over other more complex methods. Of the 128 drug candidate molecules assessed in a recent industry survey, half were being developed as single enantiomers, and the sources of the stereocentres were mainly the chiral pool (55%) with resolution (28%) and asymmetric synthesis (10%) responsible for fewer examples . This is, predictably, a feature of economics as much as science and one must not be too quick to judge new fields like asymmetric catalysis versus older ones like classical resolution. Pasteur added something enantiopure to a racemate in 1853 , whereas the catalytic prowess of a metal centre surrounded by chiral ligands was first demonstrated only in 1968 . In addition, many chiral acids and bases have proven to be useful in classical resolutions, while Nature does not seem to be so generous in its supply of molecules that can effect catalytic, asymmetric transformations. The great progress made in synthetic chemistry has not (yet) brought us to the position that allows us to make any enantiopure substance in quantity given that resources are always limited. That leaves us with the synthesis of a racemate from which we pick one enantiomer out. Such a process can be remarkably efficient and cost-effective, if such tools are available, but the great successes described in this book should not hide the fact that we require better separation methods with wide applicability if we are to avoid an overreliance on jus