A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (-)-lysine via the intermediacy of the unstable cyclic imine Delta 1-piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Delta 1-piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, isomatrine is synthesized in four steps from inexpensive commercially available chemicals. Isomatrine then serves as the precursor to additional lupin alkaloids, including matrine, allomatrine, isosophoridine, and sophoridine.

Automated summary

(+)-Matrine and (+)-isomatrine, tetracyclic alkaloids derived from Sophora flavescens, are synthesized through a biosynthetic pathway involving (-)-lysine and the intermediacy of Delta 1-piperidine. A new dearomative annulation reaction using pyridine as a stable surrogate for Delta 1-piperidine allows for the efficient synthesis of matrine alkaloids. Isomatrine, synthesized in four steps from inexpensive commercially available chemicals, serves as the precursor to other lupin alkaloids.