Design and synthesis of chiral and racemic phosphonate-based haptens for the induction of aldolase catalytic antibodies

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A novel strategy for the generation of aldolase catalytic antibodies, based on the use of antibody-catalyzed enol ester hydrolysis as a 'trigger' to generate a reactive enolate intermediate, is described. A model system to test this strategy was developed and substrate 8 was synthesized. However, the targeted bifunctional haptens 11 and 33 were synthetically inaccessible, and therefore the alternative phosphonate hapten 39 was prepared. The key step in the synthesis of 39 was the direct generation of an unprotected phosphonate precursor via coupling of the secondary alcohol 37 with CH3P(O)Cl2. The chiral counterpart of hapten 39 was also synthesized from alcohol 46, prepared by Corey's asymmetric reduction method. One polyclonal antibody preparation generated from 39 appeared to catalyze the hydrolysis of the secondary acetate 49, but not the desired aldol cyclization of 8. Possible rationales for this finding are discussed.