Two-Step Macrocycle Synthesis by Classical Ugi Reaction

The direct nonpeptidic
macrocycle synthesis of α-isocyano-ω-amines
via the classical Ugi four-component reaction (U-4CR) is introduced.
Herein an efficient and flexible two-step procedure to complex macrocycles
is reported. In the first step, the reaction between unprotected diamines
and isocyanocarboxylic acids gives high diversity of unprecedented
building blocks in high yield. In the next step, the α-isocyano-ω-amines
undergo a U-4CR with high diversity of aldehydes and carboxylic acids
in a one-pot procedure. This synthetic approach is short and efficient
and leads to a wide range of macrocycles with different ring sizes.