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 |
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| Authors: | Dr. Xingxin Yu Dr. Bo‐Xue Tian Daniel T. Payne Wu‐Lin Yang Yang‐Zi Liu Dr. John S. Fossey Prof. Dr. Wei‐Ping Deng |
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| Affiliation: | 1. 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)Both authors contributed equally to this work.;2. Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94158 (USA);3. School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT (UK);4. 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) |
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| 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. |
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| Keywords: | asymmetric synthesis copper cycloaddition density functional calculations ligands |
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