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  • Review Article
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Asymmetry on large scale: the roadmap to stereoselective processes

Nature Reviews Drug Discovery volume 4, pages 685–697 (2005)Cite this article

Key Points

  • Asymmetric processes have become increasingly popular in the synthesis of pharmaceutical compounds in recent years, for reasons including the growing prevalence of more complicated molecular architectures featuring one or several stereocentres in pharmaceutical compounds and the desire to reduce wastage resulting from the production of unwanted enantiomers.

  • When assessing whether an asymmetric process is appropriate in a given case, two questions are particularly important:

  • First, does the overall cost-of-goods requirement for the final product favour a stereoselective transformation in the synthetic sequence as opposed to a racemic one in which the separation of antipodes is achieved by other means (notably diastereomer resolution via crystallization)?

  • Second, what is the likelihood of succeeding in developing an efficient and reliable asymmetric step, both from a conceptual point of view (are there literature or patent precedents available or not) and within the given timeframe?

  • This article, after providing some historical perspective on the field, discusses such questions, and reviews progress in developing industrial scale asymmetric syntheses.

Abstract

In recent years there has been a movement in drug discovery and development away from chemical processes that produce racemic compounds towards those that produce stereochemically defined products. Asymmetric reactions are an attractive way to produce such products. Here, I discuss the factors that are important in deciding whether using an asymmetric reaction is the most appropriate approach for the large-scale synthesis of a stereochemically defined pharmaceutical compound, and highlight progress in the development of large-scale stereoselective processes.

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Figure 1: Classification of the main types of asymmetric transformations and resolutions.
Figure 2: Examples of industrial asymmetric processes: part 1.
Figure 3: Examples of industrial asymmetric processes: part 2.
Figure 4: Examples of industrial asymmetric processes: part 3.
Figure 5: Examples of industrial asymmetric processes: part 4.
Figure 6: Examples of diastereomer resolution.
Figure 7: Asymmetric catalysis applied to the construction of carbon–carbon bonds.

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  1. Global Process R&D, AstraZeneca, Södertälje, 151 85, Sweden

    Hans-Jürgen Federsel

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DATABASES

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Glossary

HETEROGENEOUS CATALYST

When the catalyst is applied in an aggregation form different to that of the reaction medium, the system is heterogeneous. For the vast majority of cases, the former is solid whereas the latter can be either liquid or gaseous.

HOMOGENEOUS SYSTEMS

In a homogeneous system, all participating species (catalyst, reagent and substrate) are in the same aggregation form, which most frequently means in a state of dissolution in a suitable solvent.

RESOLVING AGENT

An enantiomerically pure auxiliary molecule of defined stereochemistry that is used to form a precipitating salt with preferably one of the enantiomers in a racemate. From the precipitate, the desired antipode can be isolated and the auxiliary recycled.

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Federsel, HJ. Asymmetry on large scale: the roadmap to stereoselective processes. Nat Rev Drug Discov 4, 685–697 (2005). https://doi.org/10.1038/nrd1798

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