Carbene-Catalyzed Intramolecular Cyclization to Access Inherently Chiral Saddle-Shaped Lactones: Achiral Bases Alternate Product Chirality

Abstract

Enantiodivergent synthesis using a single catalyst or catalysts with the same chiral scaffold has evolved as a particularly attractive tool to access both enantiomers of chiral molecules. Progress in this field mainly comes from the enantiodivergent construction of central chirality as well as axial chirality. We report herein a carbene-catalyzed base-controlled enantiodivergent synthesis of saddle-shaped eight-membered lactones with inherent chirality. With the use of the same carbene catalyst or the carbene catalysts with the same chiral scaffold, both enantiomers of the inherently chiral eight-membered lactones could be obtained under different base conditions in high yields with good to excellent enantioselectivities. The resulting inherently chiral eight-membered lactones allow further stereospecific derivatizations and exhibit notable antibacterial activity. Preliminary DFT calculations unraveled the origins of this base-controlled enantiodivergent process.