Abstract
Substituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and ‘chiral pool’ strategies. Herein, we report multi-enzymatic and chemo-enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee >99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N-heterocycles using either platinum(0)-catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one-pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr ≥98:2) and isolated yields of up to 73%. Lead-likeness analysis of five representative products using an open-source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.
Original language | English |
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Pages (from-to) | 2188-2202 |
Number of pages | 15 |
Journal | Advanced Synthesis and Catalysis |
Volume | 365 |
Issue number | 13 |
DOIs | |
Publication status | Published - 4 Jul 2023 |
Keywords
- Asymmetric Synthesis
- Flow Hydrogenation
- Imine Reductase
- Piperidine
- Transaminase
ASJC Scopus subject areas
- Catalysis
- Organic Chemistry
Cooperations
- BioTechMed-Graz