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 Δ1-piperidine. Inspired by the biosynthesis, a new dearomative annulation
reaction has been developed that leverages pyridine as a stable surrogate
for Δ1-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.