chiral phase transfer catalysis, such as quaternary ammonium salts derived from the Cinchona alkaloids; or organocatalysis, which is activated by enamine or iminium with chiral secondary amines, usually derived from proline. In the reaction between cyclohexanone and β-nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such as p-toluenesulfonic acid: Syn addition is favored with 99% ee. In the transition state believed to be responsible for this selectivity, the enamine (formed between the proline nitrogen and the cycloketone) and β-nitrostyrene are co-facial with the nitro group hydrogen bonded to the protonated amine in the proline side group. A well-known Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944: Several asymmetric versions of this reaction exist using chiral catalysts. Examples Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor) and diethyl fumarate (Michael acceptor), that of diethyl malonate and mesityl oxide, that of diethyl malonate and methyl crotonate, that of 2-nitropropane and methyl acrylate, that of ethyl phenylcyanoacetate and acrylonitrile and that of nitropropane and methyl vinyl ketone. A classic tandem sequence of Michael and aldol additions is the Robinson annulation. Mukaiyama-Michael addition In the Mukaiyama–Michael addition, the nucleophile is a silyl enol ether and the catalyst is usually titanium tetrachloride: 1,6-Michael reaction The 1,6-Michael reaction proceeds via nucleophilic attack on the 𝛿 carbon of an α,β-,𝛿-diunsaturated Michael acceptor. The 1,6-addition mechanism is similar to the 1,4-addition, with one exception being the nucleophilic attack occurring at the 𝛿 carbon of the Michael acceptor. However, research shows that organocatalysis often favours the 1,4-addition. In many syntheses where 1,6-addition was favoured, the substrate contained certain structural features. Research has shown that catalysts can also influence the regioselectivity and enantioselectivity of a 1,6-addition reaction. For example, the image below shows the addition of ethylmagnesium bromide to ethyl sorbate 1 using a copper catalyst with a reversed josiphos (R,S)-(–)-3 ligand. This reaction produced the 1,6-addition product 2 in 0% yield, the 1,6-addition product 3 in approximately 99% yield, and the 1,4-addition product 4 in less than 2% yield. This particular catalyst and set of reaction conditions led to the mostly regioselective and enantioselective 1,6-Michael addition of ethyl sorbate 1 to product 3. Applications Pharmaceuticals A Michael reaction is used as a mechanistic step by many covalent inhibitor drugs. Cancer drugs such as ibrutinib, osimertinib, and