Molecular blueprints: the art of synthetic planning

This is article no. 1 in a two-part series on retrosynthesis. Next article: Synthesis of ibuprofen.

Introduction

Science is often seen as rigid, driven solely by facts and logic. Yet, in the world of chemical synthesis, molecular design and retrosynthetic analysis can be considered an art form. Synthetic creativity can be measured by the number of steps, environmental considerations, or the clever assembly of chemical building blocks. Widely used in the pharmaceutical industry and responsible for many Nobel Prize‑winning discoveries, retrosynthetic planning is central to modern synthetic chemistry.

1. Disconnection Strategy

Retrosynthesis begins with deconstructing a target molecule into simpler starting materials known as synthons. A synthon is hypothetical but represents a fragment that could react to form a target molecule. Chemists then match synthons to real‑life equivalents (R.L.E.) which can be used in the lab.

For example, if a target molecule contains an ester group, cleaving the oxygen–carbonyl bond produces four possible synthons (Figure 1). Of these synthons, the positively charged oxygen has no R.L.E., so pairing the negatively charged oxygen with a carbonyl‑containing R.L.E., such as a carboxylic acid or acid chloride, and an alcohol will effectively synthesise the desired ester.

2. Functional Group Interconversion (FGI)

FGIs are exploited by chemists when a functional group is difficult to manipulate directly. In these cases, the target functional group is converted to another functional group which is easier to work with.

For instance, this strategy is commonly used to synthesise alkene and carboxylic acid fragments. As alkenes mainly participate in addition reactions, forming C–C bonds can prove difficult; therefore, converting the alkene to an alkyne can make this simpler.

As an alkyne‑to‑alkene transformation is relatively simple, using either Lindlar’s catalyst (Z‑alkene) or Na/NH₃ (E‑alkene), alkynes can be used to build up the carbon chain before a final reduction. This is done by simple nucleophilic substitutions promoted by base deprotonation (NaNH₂) of the alkyne.

The same idea is used for installing carboxylic acids, as a common FGI is to use a nitrile group (CN). These can be easily transformed back to the target carboxylic acid using acid in aqueous conditions.

3. Synthesis of Aspirin

Retrosynthetic analysis can be used to design synthetic routes to common pharmaceuticals. For aspirin, a good disconnection strategy would be to break the ester bond and derive R.L.E. as shown above. To install the carboxylic acid, an FGI can be used. In Figure 3, two possible syntheses are highlighted utilising these strategies.

While the synthetic methods presented previously will produce aspirin in high yields, they often create large amounts of waste and use harsh acidic conditions. Bhuyan et al. have proposed a more sustainable synthesis using blue LED light to catalyse the reaction under an O₂ atmosphere (Figure 4).

Conclusion

In conclusion, retrosynthesis and synthetic planning are essential tools for designing complex molecules. While the disconnection strategy and FGIs are relatively simple concepts, their application is used routinely in both industry and academia, regardless of the complexity of the target molecule. While one strategy may be used routinely, there are often many more ways to synthesise a particular compound more efficiently or with more flair.

Stay tuned for Part 2, where the techniques discussed here are applied to the synthesis of ibuprofen.

Written by Antony Lee