Stereodivergent Diversity‐Oriented Synthesis: Exploiting the Versatility of 2‐Piperidine Ethanol

Abstract

A sequence of seven reactions (stereocontrolled allylation, Mitsunobu reaction, ring closing metathesis, and amino/amido intramolecular nucleophilic addition) efficiently convert the inexpensive starting 2‐piperidine ethanol into a small library of enatiomerically pure nitrogen containing compounds characterized by three new scaffolds that present a relevant diversity. This simple approach encroaches the further exploration of the chemical space.

Total Synthesis of (–)-Anaferine: A Further Ramification in a Diversity-Oriented Approach

“…DMP is a less toxic reagent, easier to handle and that gave, after a basic work-up, the desired product 17 in quantitative yield and without need of further purification. Finally, the cleavage of the two Boc protecting groups in acid environment, led to the desired (-)-anaferine dihydrochloride (18), whose identity was confirmed comparing analytical and spectroscopic properties with data reported in literature. The whole synthetic route is depicted in Scheme 2.…”

“…Acylation with the commercially available acryloyl chloride, followed by a ring closing metathesis, led to the formation of the desired α,β-unsaturated lactam 12. As reported in our previous studies, Umicore M73 SIMes catalyst proved to be the most efficient to favour the ring enclosure [18,26]. In this way, the fundamental (-)-anaferine carbon skeleton, characterised by two nitrogen-containing hexacycles, connected by the 2-hydroxypropane linker and maintaining the (R,R)-configuration of the two key stereocenters, was secured.…”

“…The synthesis of 3, starting from 2-piperidine ethanol is summarized in Scheme 1A, and involves as key step the conversion of 1 into the homoallylic alcohol 2a. Notably, 2a was recently exploited also for the synthesis of an α,β-unsaturated lactam (compound 5), as appreciable again in Scheme 1A [18]. Therefore, comparing the two synthetic routes, it's possible to deduce the genesis of our synthetic plan.…”

“…To this extent, two asymmetric Brown allylations were considered. The proposed synthetic strategy started from the homoallylic alcohol 2a, previously obtained in our research group from 1 in three steps, involving the protection of the piperidinic nitrogen, oxidation of the alcohol to aldehyde and its asymmetric allylation under Brown's conditions, leading to two diastereomeric alcohols 2a and 2b [18] (Scheme 1A). The relative anti-configuration of 2a was established by X-ray analysis, while the desired absolute (R,S)-configuration resulted from the use of the proper allylating agent enantiomer (in this case the (-)-B-allyl diisopinocampheylborane).…”

“…In this project, the ideal starting point to achieve structural diversification proved to be the 2-piperidine ethanol (1), a cheap and commercially available racemic product that incorporates the fundamental highlighted 2-substituted-piperidine moiety. Our library is composed by natural products (such as aloperine, coniine, boehmeriasin A and sedum alkaloids [11][12][13][14]), and synthetic derivatives [15][16][17][18], as depicted in Figure 2. We are currently trying to further enrich our library with new scaffolds.…”