Enantioselective Organocatalytic Construction of N-Bridged Tricyclic Normorphan Skeleton: Application to the Total Synthesis of (+)-Peduncularine.

Abstract

The normorphan framework is a compact, sp3-rich N-bridged scaffold found in biologically active natural products and increasingly valued as a three-dimensional platform for medicinal chemistry. Despite its synthetic and biological relevance, direct catalytic asymmetric access to functionalized normorphan-related architectures remains limited. Here, we describe an enantioselective organocatalytic method for constructing an N-bridged tricyclic scaffold bearing a normorphan skeleton using a bifunctional cinchona alkaloid-derived squaramide catalyst. The reaction between 3-hydroxy-2-pyridones and α,β-unsaturated aldehydes results in the formation of a [4 + 2] cycloaddition adduct as an intermediate, which subsequently undergoes skeletal rearrangement. Mechanistic studies and DFT calculations are consistent with a bifunctional hydrogen-bond donor/base activation mode in which the catalyst organizes the initial cycloaddition step and facilitates the rearrangement process. This methodology provides access to a series of bridged normorphan skeletons that exhibit excellent enantio- and diastereoselectivities (up to 99% ee and dr >20:1). The protocol is scalable to gram quantities and was successfully applied to the asymmetric total synthesis of (+)-peduncularine and the preparation of related analogues, demonstrating the synthetic utility of the enantioenriched tricyclic platform.