The homo-PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α-Oxo- or α-Hydroxy-γ-acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is -oxo-gamma-acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1)an asymmetric organocatalytic Mannich reaction, 2)a Passerini multicomponent reaction, 3)an amine deprotectionacyl migration protocol, and 4)a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo-Passeriniamine deprotectionacyl migration (PADAM) strategy. Highly stereoselective reduction of the -oxo--acylaminoamides afforded -hydroxy--acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.