ANTIBODY CATALYSIS OF MULTISTEP REACTIONS - AN ALDOL ADDITION FOLLOWED BY A DISFAVORED ELIMINATION

The intramolecular aldol condensation of keto-aldehyde 1 yields a subs tituted 2-benzyl-3-hydroxy-cyclohexanone 2 and subsequently 2-benzyl-2 -cyclohexenone (3). The sequence involves four individual reaction ste ps, Three of these steps can be accelerated using general acid-base ca talysis to effect proton transfer at or near the alpha-carbon of the k etone involved in the condensation, which is at the homobenzylic posit ion relative to the aromatic group of the substrate (Ar). An antibody to the corresponding N-benzyl-N-methylpiperidinium hapten 5 was found to catalyze the entire reaction sequence. This antibody seems to act p urely as a general base and does not catalyze the carbon-carbon bond f orming step. Catalysis of the aldol elimination is selective for the d isfavored trans-elimination with a single enantiomer of stereoisomer 2 a. Catalysis is suppressed by incubating the antibody with a carboxyl- specific reagent, suggesting that a carboxyl group acts as a general b ase to catalyze the sequence. The antibody is approximately 2.0 x 10(5 ) times more reactive than acetate for catalysis of the sequence. Thes e experiments demonstrate that catalysis of reactions with several con secutive transition states is possible using catalytic antibodies.