Steps towards chemo-enzymatic synthesis of enantiomerically pure Levosalbutamol

• Main Author: Tveit, Erik Våland
• Other Authors: Jacobsen, Elisabeth Egholm
• Format: Master Thesis
• Language: English
• Published: NTNU 2015
• Subjects: Kjemi; Organisk kjemi; Saba; Antarc*; Antarctica
• Online Access: http://hdl.handle.net/11250/2351985

Asthma is one of the most common non-communicable diseases in the world, affecting almost 4 % of the world's population. The cause behind asthma is not understood, but it is believed to be a combination of genetic predisposition and environmental factors. This is a condition that is affecting more and more people, especially in developing countries, where medication is less available. There are many different treatments to manage this chronic inflammation of the airways; β2 adrenergic receptor agonists, corticosteroids or synthetic antibodies, but during an acute asthma attack the short-acting β2 adrenergic receptor agonists (SABAs) are the most effective. The most commonly used SABA is marketed under the name Ventoline, with the active compound being a racemic mixture of salbutamol. It is commonly known that salbuta-mol has one active enantiomer and one inactive enantiomer, but it has been debated whether the medicine with the pure active enantiomer is worth its increase in cost. This thesis focuses on exploring the possibilities for a biocatalytic approach in the synthesis of the clinically active enantiomer, levosalbutamol, in an attempt to reduce the waste and cost of the industrial synthesis. This topic has been approached previously by Camilla Skjærpe in her master thesis, on which this thesis is based. Using her work as a foundation, the synthetic route from salicylaldehyde to levosalbutamol was evaluated, and the biocatalytic use of Baker's yeast (Saccharomyces cerevisiae) and Candida antarctica lipase A (CALA) was in-corporated. The first reaction, a Friedel-Crafts acylation, gave a decent yield (34.9 %) and high purity. The second step was a reduction, where both LiAlH4 and S. cerevisiae was at-tempted. The chemical reduction had a lot of room for improvement and the yeast reduction was promising, but the complete workup was missing. Using LiAlH4 required enzymatic reso-lution with CALA, which yielded very poor results. The next and last step would be amination with t-butyl amine, but this step was not done due to time constraints combined with difficulties in the workup of the preceding step.