Chemoenzymatic Approaches to Izidine Alkaloids: An Efficient Total Synthesis of (+)-Absouline and Laburnamine

Abstract

Izidines are widespread structural motifs among alkaloid natural products and are also important building blocks commonly found in pharmaceuticals. Here, we report a concise and scalable chemoenzymatic synthetic route for the highly efficient asymmetric synthesis of 1-aminopyrrolizidine alkaloids, including (+)-absouline and laburnamine. The key stereoselective transformation is based on a biocatalytic cascade involving two biosynthetic enzymes from the loline biosynthetic pathway, a Mannich cyclase LolT and a decarboxylase LolD. We also demonstrate the generality of this chemoenzymatic approach for rapid access of diverse enantiopure amino-izidine motifs. Our work demonstrated the synthetic prowess of LolT and LolD, and it has paved the way for future study on the structure–activity relationship of amino-izidine analogues.