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

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.