title: Chiral N,O-Ligand/[Cu(OAc)2 ]-Catalyzed Asymmetric Construction of 4-Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with α-Phthalimidoacrylates.
abstract: A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3-dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both β-substituted and β-unsubstituted α-phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4-aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P.R. China).
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P.R. China). xxyu@ecust.edu.cn.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94158 (USA).
authors.forename: Bo-Xue
authors.initials: BX
authors.lastname: Tian
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT (UK).
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Payne
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P.R. China).
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P.R. China).
authors.forename: Yang-Zi
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT (UK).
authors.forename: John S
authors.initials: JS
authors.lastname: Fossey
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237 (P.R. China). weiping_deng@ecust.edu.cn.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Deng
keywords: asymmetric synthesis; copper; cycloaddition; density functional calculations; ligands