Evaluation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol for catalytic asymmetric addition of organozinc reagents to aldehydes

[GRAPHICS] A facile and practical approach to preparation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was developed from cheap and easily available L-(+)-methionine. Synthetic highlights include the three-step, one-pot construction of the chiral azetidine ring and the development of an improved one-step procedure for the synthesis of the key intermediate L-2-amino-4-bromobutanoic acid. Enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was evaluated for catalytic asymmetric addition of organozinc reagents to aldehydes. The asymmetric ethylation, methylation, arylation, and alkynylation of aldehydes achieved enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84.6% ee, respectively, in the presence of a catalytic amount of chiral N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol. Our results demonstrated further that the four-membered heterocycle-based backbone was a good potential chiral unit for the catalytic asymmetric induction reaction, and the hindrance of the bulky ferrocenyl group, compared to a phenyl group, played an important role in the enantioselectivities. A possible transition for the catalytic asymmetric addition has been proposed on the basis of the crystal structure of the chiral ligand 3b including two HOAc molecules and previous studies.