Development of ligands targeting the sigma-2 receptor and the molecular identification of the sigma-2 receptor as TMEM97, the total synthesis of (±)-alstoscholarisine E, and progress toward the total synthesis of pierisketolide A.
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Our laboratory has shown that ligands constructed using an appropriately substituted norbenzomorphan-derived scaffold exhibit high affinity and selectivity for the sigma-2 receptor (σ2R) and that several of these analogs display promising activity in models of neurodegenerative and neurological conditions. Herein, we report the development of a novel set of ligands that target the σ2R using a scaffold simplification strategy for modification of the norbenzomorphan motif to a tetralin scaffold. Systematic evaluation of structure-activity relationships (SAR) was conducted in four regions of the scaffold and across a range of substitution patterns. This effort resulted in the identification of critical pharmacophore elements and the development of several potent and selective σ2R ligands. One of these, JVW-1601, displayed promising anti-inflammatory properties in the 5XFAD mouse model of Alzheimer’s disease. In addition, unique structural features of the simplified scaffold and critical insight from the SAR investigation were leveraged to enable the molecular identification and cloning of the long sought-after σ2R. The total synthesis of (±)-alstoscholarisine E, a pentacyclic indole alkaloid, was completed in a longest linear sequence of seven steps from commercially available reagents and 15.2% overall yield, the shortest and most high-yielding synthesis reported to date. The approach features a unique variant of the vinylogous Mannich reaction and tandem intramolecular hetero Diels–Alder reaction to quickly access the core. Diastereoselective reduction of the cyclic vinyl ether moiety was accomplished via a stereoselective acyloxyacetal formation/reduction. A mild procedure to form the bridging aminal ring was discovered that occurs via iridium–catalyzed hydrosilylation of the lactam and spontaneous cyclization of the intermediate hemi-aminal with the indole nitrogen atom, thereby completing the total synthesis of (±)-alstoscholarisine E. Pierisketolide A is a rearranged ent-kaurene diterpene that possesses a bicyclo[3.2.1]octane ring with a fused 5,7-membered ring and a spirotetronate moiety. Enantioselective access to the bridged core structure was achieved using a unique Pauson-Khand reaction with a highly substituted cyclopentane that was prepared from (–)-linalool in five steps. Efforts to optimize this preliminary discovery are ongoing, and further elaboration of the tricyclic core is anticipated to complete the total synthesis of pierisketolide A.