Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of , a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD.

11-Step Total Synthesis of (-)-Maoecrystal V.

An expedient, practical, and enantioselective route to the highly congested ent-kaurane diterpene maoecrystal V is presented. This route, which has been several years in the making, is loosely modeled after a key pinacol shift in the proposed biosynthesis. Only 11 steps, many of which are strategic in that they build key skeletal bonds and incorporate critical functionalities, are required to access (-)-maoecrystal V.

Phase-transfer-catalysed synthesis of pyrroloindolines and pyridoindolines by a hydrogen-bond-assisted isocyanide cyclization cascade.

A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. This transformation proceeds at room temperature in the presence of a quaternary ammonium catalyst and base to generate functionalized products containing an all-carbon quaternary stereocentre. Quantum chemical calculations demonstrated that intramolecular general acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo dig cyclization, rather than an anionic 6π electrocyclization.