Diastereoselective Synthesis of a Medicinally Significant Cis −1,1,3‐Trisubstituted Cyclopentane Derivative through Epoxide Ring Opening

We report the synthesis of a pharmaceutically relevant cis ‐1,1,3‐trisubstituted cyclopentane derivative through the evolution of a racemic route into a robust diastereoselective scale‐up process and, ultimately, an asymmetric synthesis. The optimized strategy features a sequence of stereoselective transformations, including a Michael addition, Corey–Chaykovsky epoxide formation, and controlled epoxide ring opening. Emphasis is placed on the diastereoselective ring opening of a key spiro‐epoxide intermediate, which was investigated experimentally and rationalized by density functional theory calculations. The diastereoselective route proved reliable on multi‐hundred‐gram scale, consistently delivering high yields, while the asymmetric variant enabled access to the desired cis ‐diastereomer with excellent enantio and diastereocontrol on a milligram‐scale. This work provides a practical and scalable approach to a synthetically challenging cyclopentane motif of medicinal relevance.