The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (–)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3 + 2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.

The discovery of illisimonin A in 2017 extended the structural repertoire of the Illicium sesquiterpenoidsa class of natural products known for their high oxidation levels and neurotrophic propertieswith a new carbon backbone combining the strained trans-pentalene and norbornane substructures. We report an asymmetric total synthesis of (−)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.2.1.01,5]decanes via radical cyclization was explored. This approach was applied in a two-stage strategy consisting of Ti(III)-mediated cyclization and semipinacol rearrangement to access the natural product’s carbon backbone. These key steps were combined with carefully orchestrated C–H oxidations to establish the dense oxidation pattern.

A tandem Nazarov/ene reaction in trienones was found to be initiated by tris(pentafluorophenyl)borane (TPPB) and resulted in spiro compounds as single diastereoisomers. The reaction was applied to a set of substrates with different chain lengths and functionalities, and investigations on the mechanism were conducted. This novel diastereoselective reaction extends the application of interrupted Nazarov cyclizations as tools for the synthesis of natural products. More information can be found in the Communication by M. Kalesse et al. (DOI: 10.1002/chem.202101041).