Multifunctional chiral phosphine organocatalysts in catalytic asymmetric Morita-Baylis-Hillman and related reactions.Acc Chem Res. 2010 Jul 20; 43(7):1005-18.AC
Catalytic asymmetric synthesis has received considerable attention over the past few decades, becoming a highly dynamic area of chemical research with significant contributions to the field of organic synthesis. In the development of new catalysts, the concept of multifunctional catalysis described by Shibasaki and co-workers, namely, the combination of more than one functional group within a single molecule to activate the transformation, has proved a powerful strategy in the design of efficient transition metal-containing catalysts. A variety of reactions have since been addressed with multifunctional organocatalysts. One example is the Morita-Baylis-Hillman (MBH) reaction, in which a carbon-carbon bond is created between the alpha-position of an activated double-bond compound and a carbon electrophile. The seminal report on this reaction in 1972 described the prototypical couplings of (i) ethyl acrylate with acetaldehyde and (ii) acrylonitrile with acetaldehyde; the reaction is promoted by the conjugate addition of a nucleophilic catalyst to the alpha,beta-unsaturated aldehyde. Many variations of the MBH reaction have been reported, such as the aza-MBH reaction, in which an N-tosyl imine stands in for acetaldehyde. Recent innovations include the development of chiral molecules that catalyze the production of asymmetric products. In this Account, we describe the refinement of catalysts for the MBH and related reactions, highlighting a series of multifunctional chiral phosphines that we have developed and synthesized over the past decade. We also review similar catalysts developed by other groups. These multifunctional chiral phosphines, which contain Lewis basic and Brønsted acidic sites within one molecule, provide good-to-excellent reactivities and stereoselectivities in the asymmetric aza-MBH reaction, the MBH reaction, and other related reactions. We demonstrate that the reactivities and enantioselectivies of these multifunctional chiral phosphines can be adjusted by enhancing the reactive center's nucleophilicity, which can be finely tuned by varying nearby hydrogen-bonding donors. Artificial catalysts now provide highly economic access to many desirable compounds, but the general adaptability and reactivity of these platforms remain problematic, particularly in comparison to nature's catalysts, enzymes. The multifunctional organocatalysts described in this Account represent another positive step in the synthetic chemist's efforts to profitably mimic nature's catalytic platform, helping develop small-molecule catalysts with enzyme-like reactivities and selectivities.