Chiral ligands derived from abrine. Part 6: Importance of a bulky N-alkyl group in indole-containing chiral β- tertiary amino alcohols for controlling enantioselectivity in addition of diethylzinc toward aldehydes

Abstract

A number of chiral β-amino alcohols possessing a 3-indolylmethyl group have been synthesized from the alkaloid, ( S)-abrine and elucidated for potency in the catalytic enantioselective ethylation of PhCHO with Et 2Zn. In general, the secondary amines 15a– d bearing a dialkylhydroxymethyl group induced ( R)-1-phenyl-1-propanol, whereas 15e– g and 18 bearing a diarylhydroxymethyl group favored the ( S) -enantiomer. In contrast, the β- tertiary amino alcohols 20b– d and 21 produced ( R)-1-phenyl-1-propanol, regardless of the substituents at the carbon bearing the hydroxy group. Enantiomeric excess of 87.5% was obtained for ( R)-1-phenyl-1-propanol using ligand 21 as the promoter. Eleven substituted benzaldehydes and naphthaldehydes were examined for enantioselective ethylation by using 21 and the chiral alcohols were obtained in 93–97% ee, except for o-BrC 6H 4CHO and p-Me 2NC 6H 4CHO. Excellent enantioselectivity was also observed in the ethylation of cyclohexanecarboxaldehyde (94.8% ee) and 2-thiophenecarboxaldehyde (94.9% ee) by using catalytic 21. The anti 5/4/4-fused tricyclic TS I was proposed to rationalize the asymmetric induction. The diethylhydroxymethyl and N-2- t-butylethyl groups are believed to enforce the preference for the anti-TS( R) I and it results in high enantioselectivity.