Synthesis of sterically constrained tricyclic pyrrolidinyl alcohol ligands for the enantioselective ethylation of aryl aldehydes: assessment of the influence of ring strain and N-alkyl chain length on asymmetric induction

A series of chiral sterically constrained tricyclic pyrrolidinyl alcohol ligands were synthesized from the appropriate amino acids, and a comparative study of the activity and selectivity of the ligands for the enantioselective ethylation of aromatic aldehydes was carried out. The results obtained were compared with those previously reported for related monocyclic analogues; it was found that the bicyclo[2.2.2]octane backbone fused to pyrrolidine and the groups attached to the carbinol centre, as well as the chain length of the β-amino alcohol, had a marked effect on the enantioselectivity. The enantioselective addition of dialkylzincs to aryl aldehydes in the presence of ligands with diethyl substituents on the carbinol carbon afforded (R)-sec-alcohols in up to 99% enantiomeric excess (ee).