Mechanistic investigation and implications of a sacrificial aniline for the tandem cascade synthesis of 4-aza-podophyllotoxin analogues

Mechanistic investigations were pursued to determine a plausible mechanism in the cascade reaction involving tetronic acid with aldehydes and anilines to generate the 4-aza-2,3-dehydropodophyllotoxin core structure. The mechanistic driven hypothesis paved the way for a new reaction design using for the first time a sacrificial electron deficient aniline leading to an optimized cascade protocol (up to threefold yield improvement) for the synthesis of novel 4-aza-2,3-dehydropodophyllotoxin analogues.