(S)-Pramipexole is the most prescribed dopamine agonist endowed in the anti-Parkinson therapy, while the (R)-isomer (dexpramipexole) is currently in clinical development for the treatment of amyotrophic lateral sclerosis (ALS). The recently published asymmetric reduction of the prochiral ketone is the key step for the preparation of enantiomerically pure pramipexole and biocatalytic approach represents the smartest strategy as alternate method to the traditional fractional crystallization. The stereoselective potential of different yeasts was investigated in order to afford optically pure secondary alcohols. Saccharomyces cerevisiae ability to reduce the suitable ketone to the corresponding (R)-alcohol, the precursor of (S)-pramipexole, was proved with an e.e. > 98%. Twenty marine yeast strains were screened for ketoreductase activity with the aim of reducing the ketone with a stereochemical outcome opposite than S.cerevisiae, affording (S)-alcohol. In particular, Rhodotorula mucillaginosa strains gave (S)-alcohol with an e.e. ranging from 38% to 64%. Recombinant enzymes were also employed and interesting results were achieved by the application of a novel benzil reductase from Pichia glucozyma. Thanks to co-factor recycling system, the isolated enzyme was demonstrated to be able to produce (S)-alcohol with e.e. 84% . Moreover, an optimized system that employs biocatalytic potential of most promising yeast strains is under development in order to set up a continuous reaction based on Flow Chemistry technique.
The biocatalytic approach to the preparation of Pramipexole / B. Guidi, P. Ferraboschi, S. Ciceri, M.L. Contente, V. De Vitis, F. Molinari. ((Intervento presentato al convegno Biotrans tenutosi a Vienna nel 2015.
The biocatalytic approach to the preparation of Pramipexole
B. Guidi
;P. FerraboschiSecondo
;S. Ciceri;M.L. Contente;V. De VitisPenultimo
;F. Molinari
2015
Abstract
(S)-Pramipexole is the most prescribed dopamine agonist endowed in the anti-Parkinson therapy, while the (R)-isomer (dexpramipexole) is currently in clinical development for the treatment of amyotrophic lateral sclerosis (ALS). The recently published asymmetric reduction of the prochiral ketone is the key step for the preparation of enantiomerically pure pramipexole and biocatalytic approach represents the smartest strategy as alternate method to the traditional fractional crystallization. The stereoselective potential of different yeasts was investigated in order to afford optically pure secondary alcohols. Saccharomyces cerevisiae ability to reduce the suitable ketone to the corresponding (R)-alcohol, the precursor of (S)-pramipexole, was proved with an e.e. > 98%. Twenty marine yeast strains were screened for ketoreductase activity with the aim of reducing the ketone with a stereochemical outcome opposite than S.cerevisiae, affording (S)-alcohol. In particular, Rhodotorula mucillaginosa strains gave (S)-alcohol with an e.e. ranging from 38% to 64%. Recombinant enzymes were also employed and interesting results were achieved by the application of a novel benzil reductase from Pichia glucozyma. Thanks to co-factor recycling system, the isolated enzyme was demonstrated to be able to produce (S)-alcohol with e.e. 84% . Moreover, an optimized system that employs biocatalytic potential of most promising yeast strains is under development in order to set up a continuous reaction based on Flow Chemistry technique.File | Dimensione | Formato | |
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