Synthesis of Complex Polycyclic Scaffolds Incorporating α-Amino Esters

In order to keep up with the high demand for
biologically active molecules, chemists devised
several synthetic strategies to access novel chemical
spaces. The two main strategies to construct new
scaffolds are to revisit underexploited or forgotten
reactions or to devise new transformations. We are
exploring a unique and underexploited reaction, the
Himbert–Henn cycloaddition, to produce complex
molecular scaffolds in a single step (strategy 1). In a
second novel approach, we are modifying the
Hantzsch 4-component reaction (4CR) by
incorporating an α-amino ester residue to construct
new molecules (strategy 2). Both of these reactions
have great potential to synthesize novel and chiral
molecules from proteinogenic α-amino esters. These
unprecedented and complex polycyclic molecules
have potential application in medicinal chemistry and
natural product synthesis. 4-aza-podophyllotoxins
obtained by the Hantzsch-4CR have been proven to
be potent as anti-leukemia, anti-colon cancer, and
vascular disrupting agents (with nanomolar activity).