Emulating the Logic of Monoterpenoid Alkaloid Biogenesis to Access a Skeletally Diverse Chemical Library

We
have developed a synthetic strategy that mimics the diversity-generating
power of monoterpenoid indole alkaloid biosynthesis. Our general approach
goes beyond diversification of a single natural product-like substructure
and enables production of a highly diverse collection of small molecules.
The reaction sequence begins with rapid and highly modular assembly
of the tetracyclic indoloquinolizidine core, which can be chemoselectively
processed into several additional skeletally diverse structural frameworks.
The general utility of this approach was demonstrated by parallel
synthesis of two representative chemical libraries containing 847
compounds with favorable physicochemical properties to enable its
subsequent broad pharmacological evaluation.