Regioselectivity in action

We finish with an exampie that illustrates several aspects of chemoselectivity as well as introducing the subjects of the next two chapters. The first synthetic sweetener was saccharin but newer ones such as the BASF compound thiophenesaccharin are much in demand. The sodium salt is the active sweetener but the neutral compound has to be made via the simpler intermediate thiophene. 

The synthesis started with a conjugate addition of a thiol to an unsaturated ester. The thiol is obviously the nucleophile and regioselectively chooses conjugate addition rather than attack on either ester group. 

In the next step the diester is treated with base and a carbonyl condensation reaction occurs of the type you will meet in Chapter 26. There is a real question of regioselectivity here an enolate could form next to either ester (as shown by the orange circles) and would then attack the other ester as a nucleophile. There is little to choose between these alternatives but the first was wanted and was selected by careful experimentation, although only in 50% yield. This was acceptable on a large scale as the product could be separated by crystallization, the most practical of all methods. 

Reactions such as this—the attack of enolates on carbon electrophiles—form the subject of the next two chapters, where we will discuss in detail the mechanism of this type of reaction. 

There is a basic introduction in S. Warren and P. Wyatt, Organic Synthesis the Disconnection Approach, Wiley, Chichester, 2008, chapter 3. 

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