Organocatalyzed Addition to Activated Double Bonds: from proof-of-concept to the preparation of pharmaceutical and biologically relevant molecules

Organocatalytic reactions are especially attractive since they do not require anhydrous conditions and expensive catalysts.[1-9] Most of all, waste management is significant easier with respect to the processes employing transition metals, which present issues with the disposal of residual and the phenomena of “metal leaking” into the products. The most known organocatalytic process, the Hajos–Parrish–Eder–Sauer–Wiechert reaction[10-12] is actually a domino transformation which has found significant industrial application. Despite this key result, this field has surprisingly been forgotten for nearly thirty years before its renaissance at the beginning of the millennium. In particular, organocatalytic domino reactions are appealing transformations. The mild operational conditions required allow that in the same reaction vessel several processes can operate consecutively. This situation would be more complex when the several transformations composing a domino reaction had to be run in significantly different conditions. The purpose of this chapter is to highlight and critically discuss some selected examples of organocatalytic domino reactions, not to write a comprehensive treaty on the subject. It will describe the first ground-breaking examples of organocatalytic domino reactions, (paragraph 1.1), then more specific applications from the chemistry of oxindoles (paragraph 2.1) and finally large-scale transformations, specifically the synthesis of (-)-Oseltamivir, and ABT-341 (paragraph 3.1) and the industrial scale process for the synthesis of chiral diene ligands (paragraph 4.1).