Stereocontrolled and time-honored access to piperidine- and pyrrolidine-fused 3-methylenetetrahydropyrans using lactam-tethered alkenols.

Polycyclic oxygen-heterocycles bearing the 3-methylenetetrahydropyran (, 3-MeTHP) motif are resident in bioactive molecules such as hodgsonox and iridoid. Meanwhile, the δ- and γ-lactam topologies as well as their reduced variants (, piperidines and pyrrolidines) are at the core of several pharmaceuticals and fragrances. A stereocontrolled, time-honored, and cost-effective strategy that merges a 3-MeTHP motif with the aforementioned azaheterocyclic scaffolds could exponentially expand the 3D-structural space for the discovery of new small molecules with medicinal value. In these studies, readily affordable lactam-tethered alkenols have been interrogated in two complementary cascade approaches, leading to the regioselective and stereocontrolled synthesis of lactam-fused 3-MeTHPs. The first approach hinges on regioselective 6- bromoetherification of the alkenols and concomitant elimination to arrive at the desired 3-MeTHPs. The methylene portion of the 3-MeTHP is unveiled at a late stage, which is noteworthy since all existing approaches to 3-MeTHPs rely on early-stage introduction of the methylene group. The second strategy involves transition metal-catalyzed alkoxylation of the tethered alkenol followed by base-induced double bond isomerization. The lactam-fused 3-MeTHPs are obtained in high site- and diastereo-selectivities. Post-modification of the bicycles has led to the construction of 3-MeTHP-fused saturated piperidines and pyrrolidines as well as 3-MeTHPs bearing four contiguous stereocenters.