Mannich Reaction - Asymmetric Mannich Reactions

Asymmetric Mannich Reactions

Progress has been made towards asymmetric Mannich reactions. When properly functionalized the newly formed ethylene bridge in the Mannich adduct has two prochiral centers giving rise to two diastereomeric pairs of enantiomers. The first asymmetric Mannich reaction with an unmodified aldehyde was carried with (S)-proline as a naturally occurring chiral catalyst.

The reaction taking place is between a simple aldehyde such as propionaldehyde and an imine derived from ethyl glyoxylate and p-methoxyaniline (PMP = paramethoxphenyl) catalyzed by (S)-proline in dioxane at room temperature. The reaction product is diastereoselective with a preference for the syn-Mannich reaction 3:1 when the alkyl substituent on the aldehyde is a methyl group or 19:1 when the alkyl group the much larger pentyl group. Of the two possible syn adducts (S,S) or (R,R) the reaction is also enantioselective with a preference for the (S,S) adduct with enantiomeric excess larger than 99%. This stereoselectivity is explained in the scheme below.

Proline enters a catalytic cycle by reacting with the aldehyde to form an enamine. The two reactants (imine and enamine) line up for the Mannich reaction with Si facial attack of the imine by the Si-face of the enamine-aldehyde. Relief of steric strain dictates that the alkyl residue R of the enamine and the imine group are antiperiplanar on approach which locks in the syn mode of addition. The enantioselectivity is further controlled by hydrogen bonding between the proline carboxylic acid group and the imine. The transition state for the addition is a nine-membered ring with chair conformation with partial single bonds and double bonds. The proline group is converted back to the aldehyde and a single S,S isomer is formed.

By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts.

An additional methyl group attached to proline forces a specific enamine approach and the transition state now is a 10-membered ring with addition in anti-mode. The diastereoselectivity is at least anti:syn 95:5 regardless of alkyl group size and the S,R enantiomer is preferred with at least 97% ee.

Read more about this topic:  Mannich Reaction

Famous quotes containing the word reactions:

    Prolonged, indiscriminate reviewing of books is a quite exceptionally thankless, irritating and exhausting job. It not only involves praising trash but constantly inventing reactions towards books about which one has no spontaneous feeling whatever.
    George Orwell (1903–1950)