The Catalytic, Enantioselective Michael Reaction

Reyes, E.; Uria, U.; Vicario, J. L.; Vicario, L.


The catalytic enantioselective Michael reaction is the conjugate addition of a resonance-stabilized carbanion to an electron-poor olefin (an αβ-unsaturated carbonyl compound or a related derivative) mediated by substoichiometric amounts of a chiral catalyst that enables stereocontrol in the newly generated stereocenter(s). This reaction allows the direct enantioselective construction of substituted 1,5-dicarbonyl compounds or related architectures through the appropriate selection of the enolizable carbonyl compound employed as pronucleophile and the Michael acceptor. A variety of catalyst architectures have been described that make it possible to carry out this reaction with superior levels of chemical efficiency and high enantio- and stereocontrol, and also under conditions that tolerate a wide variety of functional groups. Both transition metal catalysis and organocatalysis have been employed as methodological approaches for carrying out this reaction in an enantioselective manner.

This chapter describes different catalytic systems and methods developed for achieving enantioselective Michael reactions through the end of 2012, including a detailed mechanistic explanation of the different generic modes of substrate activation operating with each type of catalyst and their associated stereochemical aspects. The intention is to provide researchers interested in applying this methodology to their own synthetic strategies with a suitable starting point for identifying an efficient synthetic approach. In addition, the preparation of selected catalysts that are excellent for a particular pairing of substrates in this reaction, together with practical experimental protocols are described and some examples in which these methodologies have been applied to total synthesis have been included. This chapter is limited exclusively to those examples in which the final Michael addition product is obtained after protonation of the conjugate addition intermediate and therefore, tandem, domino, or cascade processes initiated by Michael reactions lie outside the scope of this work.

Supplemental references are provided for articles published after the 2012 cut-off date through the first half of 2015.