Synthesis of Azabenzisochromanquinone Antibiotics, I. Hetero Diels‐Alder Reactions of Isochromanquinones with 1‐Aza‐1,3‐dienes

The total synthesis of a novel type of benzisochromanquinone antibiotics 2 containing nitrogen in the aromatic ring A is described. Three different isochromanquinone building blocks (6, 10, and 14) were subjected to cycloaddition reactions with five diverse 1‐aza‐1,3‐butadienes 15–17, 19 yielding three groups of structurally modified 6‐ and 9‐aza compounds: azaeleutherins 21–24, azaepinanaomycins 26–31, and 1‐methylazakalafungins 32–39. The regioselectivity of the reaction depends on the substituents at the diene and the structural symmetry of the quinone. The strategy provides a convenient access to a broad palette of structural variants. Particularly some azakalafungins show remarkable antibacterial and antitumor activities.