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Asymmetric synthesis of dihydropinidine enabled by concurrent multienzyme catalysis and a biocatalytic alternative to krapcho dealkoxycarbonylation

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  • Natalia Alvarenga, Universidade de Sao Paulo, University of Graz
  • ,
  • Stefan E. Payer, University of Graz
  • ,
  • Philipp Petermeier
  • Christoph Kohlfuerst, University of Graz
  • ,
  • Andre Luiz Meleiro Porto, Universidade de Sao Paulo
  • ,
  • Joerg H. Schrittwieser, University of Graz
  • ,
  • Wolfgang Kroutil, University of Graz
Dihydropinidine is a piperidine alkaloid found in spruce needles that has shown promising antifeedant activity against the large pine weevil, a widespread and economically relevant pest of coniferous tree plantations. Chemo-enzymatic approaches have previously been shown to enable a step-economic access to both enantiomers of this alkaloid, but the scalability of these syntheses is limited. Herein, we report a chemo-enzymatic route to dihydropinidine that is dominated by biocatalytic steps and affords the target alkaloid in excellent stereoisomeric purity (>99% ee and de) and high yield (57% overall) on multigram scale. Our synthesis makes use of a solvent-free, Lewis acid-catalyzed Michael addition and a biocatalytic alternative to Krapcho dealkoxycarbonylation, achieved by pig liver esterase (PLE)-catalyzed ester hydrolysis and acidification, and specifically developed for this purpose, to access a key intermediate, nonane-2,6-dione. This diketone is then converted into dihydropinidine by a concurrent one-pot (cascade) biotransformation catalyzed by a transaminase, an imine reductase, and an alcohol dehydrogenase. High yields and excellent regio- and stereoselectivities of the individual transformations render chromatographic purification of intermediates unnecessary and make it possible to carry out the entire sequence with a final hydrochloride precipitation of the target alkaloid as the sole purification step
Original languageEnglish
JournalA C S Catalysis
Pages (from-to)1607-1620
Number of pages14
Publication statusPublished - Jan 2020
Externally publishedYes

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