The β-agonsist that are clinically used are all substituted β-phenethylamine (see figure 5) and they have three kinds of phenyl rings shown in figure 4. They are called resorcinol ring, salicyl alcohol ring or N-formamide ring. The alcohol substituents in the phenyl ring are reactive and complicate the synthesis of the β-agonists. A protection step is needed while the N-residue is added in position R1 (figure 5). Another thing that complicates the synthesis is obtaining optically pure R (-) enantiomer of the compound. The stereochemistry is very important for activity because only the R (-) enantiomer is able to form the hydrogen bonds necessary to fit in the binding site and activate the β-receptor.
Salbutamol is usually inhaled in racemic mixtures (for example Ventolin). By treating asthma with optically pure (R)-salbutamol the risk of side effects, such as nervous system stimulatory effects and cardiac arrythmia, can be minimized. There are several routes for enantioselective synthesis, as well as methods for synthesis of the racemic mixture followed by chiral resolution.
Stereoselective synthesis of tributalin and salbutamol acetal can be done from O-protected-(R)-cyanohydrins. F. Effenberg, et al. describe a way for the synthesis. The main complications are to perform the deprotection step without racemization and to form a pure salt. A Ritter reaction can be used for an N-tertiary butylation. In this experiment deacetylation of (R)-salbutamol acetal was unsuccessful so it can not be used to obtain pure (R)-salbutamol. Figure 6 shows the main steps in the synthesis of salmeterol and tributalin.