The Enantioselective Total Synthesis of Exochomine

Molecules that possess fully substituted chiral centers are often challenging to construct, particularly if those centers connect two seemingly different halves or include a nitrogen atom. Herein, we describe an efficient approach to a molecule that combines both challenges in a single center in the form of exochomine. Failures in direct coupling led to a design fueled by highly specific reaction conditions for several steps and the development of an improved protocol for 1,4‐reduction in a hindered context where numerous side reactions were possible. These chemoselective solutions should have value to other problems. Challenges in obtaining matching spectral data for the synthesized natural product are also discussed. Challenging chirality: Use of a distinct synthetic strategy to address the challenges in merging two different halves bearing a chiral center at their merger point has enabled access to the alkaloid exochomine in 16 steps. Key operations include the functionalization of a hindered iminium precursor, a unique aldol‐based coupling cascade, and a robust protocol for 1,4‐reduction in a hindered context where numerous side‐reactions can occur.