[Asymmetric reactions based on activation and structure control of molecule--asymmetric reaction of lithiated nucleophiles].
The methodology we developed relies on an external chiral coordinating reagent that forms a deaggregated chelate complex with organolithium reagents. Under the positive control of a chiral dimethyl ether of stilbenediol 4, an asymmetric conjugate addition reaction of organolithium reagents with unsaturated imines and esters proceeded successfully to yield the corresponding addition products with reasonably high stereoselectivity. The sense of stereochemistry is predictable based on a coordination model. The methodology has been extended to a catalytic asymmetric 1,2-addition reaction of organolithium reagents with imines. An enantiotopic group differentiating the opening of cyclohexene oxide with organolithium was also mediated by a chiral ligand. The asymmetric Horner-Wadsworth-Emmons reaction of phosphonates and Peterson reaction of alpha-silylester with 4-substituted cyclohexanone were another successful extension of the methodology. A three-component reagent of lithium ester enolate, lithium amide, and chiral diether reacts with imines to afford beta-lactam with reasonably high enantioselectivity. Tridentate aminoether ligands were also shown to affect the catalytic asymmetric addition of lithium ester enoaltes to imines, giving beta-lactams with high enantioselectivity. Asymmetric conjugate addition of lithium amide to enoates was mediated by a chiral diether ligand to give the beta-aminoester with high yield and enatioselectivity. The methodology has been successfully applied to an asymmetric synthesis of biologically potent compounds. Dihydrexidine, a promising anti-Parkinsonism candidate, and salsolidine, a representative isoquinoline alkaloid, have been synthesized using asymmetric addition reactions of organolithium reagents as the key steps.
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. tomioka@pharm.kyoto-u.ac.jp
Kiyoshi
K
Tomioka
D000978:Antiparkinson Agents / Q000138:chemical synthesis; D002625:Chemistry, Organic / Q000379:methods*; D007202:Indicators and Reagents; D008094:Lithium / Q000737:chemistry*; D018020:Lithium Compounds / Q000737:chemistry*; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis; D012490:Salsoline Alkaloids / Q000138:chemical synthesis; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis
D000978:Antiparkinson Agents; D007202:Indicators and Reagents; D018020:Lithium Compounds; D010617:Phenanthridines; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C061532:dihydrexidine; D008094:Lithium; C059665:salsolidine