Biocatalysis at Work: Applications in the Development of Sagopilone. Issue 7 (28th May 2015)

• Record Type: Journal Article
• Authors: Gottfried, Kathrin; Klar, Ulrich; Platzek, Johannes; Zorn, Ludwig
• Is Part Of: ChemMedChem. Volume 10:Issue 7(2015:Jul.)
• Page Start: 1240
• Page End: 1248
• Publication Date: 2015-05-28
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500138
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>For the antitumour agent sagopilone, an epothilone analogue, a large‐scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical trials, exploring enzymatic and microbial methods to produce chiral building blocks on a multi‐kilogram scale. The three building blocks were identified as key intermediates in the synthesis and needed to be produced with high optical purity in yields higher than those previously published. The improved syntheses of two of these building blocks are detailed herein. For building block A, the chemical research synthesis was abandoned, and a novel chemical route was developed leading to building block A via an enzymatic hydrolysis process. For building blocks C, replacement of a chemical catalytic procedure by a microbial process meant that the development of a new starting material could be avoided, thereby accelerating the development process. For the clinical development process, a human metabolite of sagopilone was required as a reference. To accelerate the synthesis of the metabolite, no chemical synthesis was investigated; rather, we relied solely on oxidoreductases. The human metabolite of sagopilone was synthesised on a multi‐gram scale in a single‐step process using genetically engineered <italic>E. coli</italic> expressing human cytochrome P450 enzyme 2C19. The integration of enzymatic and microbial processes provided tools that enable the synthesis of highly functionalised intermediates and metabolites.</p> </abstract>