Chemo-enzymatic cascades for the synthesis of chiral high-value chemicals

Time: Mon 2019-09-30 10.00

Location: Kollegiesalen, Brinellvägen 8, Stockholm (English)

Doctoral student: Lisa Marx , Industriell bioteknologi, Enzyme technology

Opponent: Sabine Flitsch, University of Manchester

Supervisor: Professor Per Berglund, Industriell bioteknologi, Biokemi och biokemisk teknologi, Bioteknologi, Kemi

Abstract

Chiral amines are frequent in today´s top selling pharmaceuticals. Classical organic synthesis of pharmaceuticals is often work intensive involving many synthesis steps, the use of protection group chemistry, heavy metal catalysts and chiral crystallization techniques. In recent years biocatalysts have proven their outstanding ability to synthesize chiral compounds. In this work the possibility of employing biocatalysts as alternative catalysts for API (active pharmaceutical ingredient) synthesis was explored. Three compounds currently on the market were selected as viable case studies: Cinacalcet (a hyperparathyroidism drug), Vyvanse (an ADHD-drug) and Sertraline (an antidepressant). Two enzyme classes were investigated to directly provide the chiral amines - transaminases and imine reductases. Ketoreductases were also investigated to provide the chiral amine via the chiral alcohol. Laccases and hydrolases were employed to complete the synthesis pathways to the final API. In the case of Vyvanse a true one-pot, two-step enzymatic cascade was achieved by a transaminase and hydrolase. For Cinacalcet a chemo-enzymatic cascade could be demonstrated. Both transaminase and ketoreductase gave excellent enantioselectivities and high yield for the key intermediates, which could then be chemically converted into the final API with good yield. For Sertraline the best yield of one diastereomer precursor could be achieved by a ketoreductase, followed by further enzymatic and chemical steps to the final API. Transaminases and imine reductases both have potential in synthesizing the key amine precursors or the APIs themselves. But to date selectivity and yield are insufficient for industrial application in a lot of cases. This work demonstrates the potential of enzymes to serve as viable alternatives to organo-metallic synthesis. Furthermore enzymes have the potential to simplify work-up because of their excellent enantioselectivity. Finally, a scale-up of a one-step transamination to the key chiral precursor of Cinacalcet demonstrated the enzyme´s applicability in larger volume and at higher substrate concentration.

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Last changed: Sep 05, 2019