title: Asymmetric reductive Mannich reaction to ketimines catalyzed by a Cu(I) complex.
abstract: A highly diastereoselective reductive Mannich coupling of ketimines and alpha,beta-unsaturated esters was developed using CuOAc-PPh(3) or CuOAc-MePPh(2) complex as a catalyst (5 mol %) and pinacolborane as a reducing reagent. The reaction was easily conducted at room temperature, and the substrate generality was broad. This platform methodology was extended to the first catalytic asymmetric reductive Mannich reaction of ketimines using CuOAc-DIFLUORPHOS as the catalyst (10 mol %). Switching the reducing reagent from pinacolborane to (EtO)(3)SiH was key to inducing the high enantioselectivity (82-93% ee). High diastereoselectivity was also maintained (3:1 approximately 30:1). Thus, products containing contiguous tetra- and trisubstituted carbons were catalytically synthesized with high stereoselectivities. Products were converted to alpha,beta,beta-trisubstituted (beta(2,3,3)) amino acid derivatives without any racemization and epimerization through simple treatment under acidic conditions. This method is the first entry of the catalytic asymmetric synthesis of beta(2,3,3)-amino acid derivatives, which constitute important chiral building blocks of biologically significant molecules.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo113-0033, Japan.
authors.forename: Yao
authors.initials: Y
authors.lastname: Du
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Xu
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Oisaki
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D007097:Imines / Q000737:chemistry*; D008352:Mannich Bases / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D007097:Imines; D008352:Mannich Bases; D003300:Copper