A Catalytic Asymmetric Pictet–Spengler Platform as a Biomimetic Diversification Strategy toward Naturally Occurring Alkaloids

Abstract

Tetrahydroisoquinoline (THIQ) alkaloids constitute a large and diverse class of bioactive natural products, with the parent compounds and related downstream biosynthetic secondary metabolites spanning thousands of isolated structures. Chemoenzymatic synthetic approaches toward the relevant THIQs rely on Pictet–Spenglerases such as norcoclaurine synthase (NCS), the scope of which is strictly limited to dopamine-related phenolic substrates. To overcome these limitations in the context of chemical synthesis, we herein report asymmetric Pictet–Spengler reactions of N-carbamoyl-β-arylethylamines with diverse aldehydes toward enantioenriched THIQs. The obtained products proved to be competent intermediates in the synthesis of THIQ, aporphine, tetrahydroberberine, morphinan, and androcymbine natural products. Novel catalyst design with regard to the stabilization of cationic intermediates was crucial to accomplish high reactivity while simultaneously achieving unprecedented stereoselectivity for the reaction of biologically relevant substrates.