A concise dearomative approach to the synthesis of quinolizidine natural products

Project Summary/Abstract Whereas the piperidine motif is ubiquitous in pharmaceuticals, higher-order N-heterocycles such as quinolizidines and indolizidines are more challenging to prepare. This can limit their incorporation into drug development, despite their prevalence in important biologically active natural products. Dearomatization reactions offer a unique entry into these natural products, rapidly building complexity from accessible aromatic starting materials. Pairing this powerful strategy with stereodefined cyclization cascade reactions enables an orchestrated assembly of the oxidized fused ring structures present in many alkaloid targets. This proposal describes the development of an enantioselective dearomative cyclization to synthesize quinolizidines in one step from pyridine, grounded in the hypothesis that palladium can be used to kinetically trap a reversibly forming acyl chloride to synthesize enantioenriched quinolizidines through a dynamic kinetic resolution. To accelerate the development of this strategy, modern data science techniques will be applied to high-throughput datasets, enabling rapid traversal of the multidimensional and potentially complex optimization landscape. These studies are expected to provide a workflow for the future development of reaction cascades through machine learning, enabling practitioners to develop kinetically complex reaction landscapes that might otherwise seem intractable but provide opportunities to dramatically build molecular and synthetic complexity. This approach will be showcased in an asymmetric synthesis of lycopodine and lycoposerramine H, natural product inhibitors of acetylcholinesterase—a property that is therapeutically relevant for the treatment of neurodegenerative disorders. We expect that the flexible synthetic approach proposed could apply to future diversity-oriented synthesis campaigns around this natural product family towards the development of small molecule neuroprotective drugs, as well as more broadly to the synthesis of stereodefined, bioactive alkaloid skeletons.