Asymmetric organocatalytic direct Mannich reaction of acetylacetone and isatin derived ketimines: Low catalyst loading in chiral cinchona- squaramides Duygu _ Is ßibol a , Seda Karahan a , Cihangir Tanyeli a,⇑ a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey article info Article history: Received 6 December 2017 Accepted 29 December 2017 Available online 30 December 2017 Keywords: Asymmetric organocatalysis Mannich reaction 3-Amino-2-oxindole Isatin ketimine Bifunctional squaramide abstract A highly enantioselective synthesis of 3-amino-2-oxindoles by direct Mannich reaction between acety- lacetone and N-carbamoyl isatin ketimine has been described herein. Corresponding chiral adducts were obtained in high yields (up to 98%) and with excellent enantioselectivities (up to >99% ee) by very low (1 mol%) catalyst loading of 2-adamantyl substituted bifunctional cinchona-squaramide. Ó 2017 Elsevier Ltd. All rights reserved. Introduction Structure-based approach in medicinal chemistry and chemical biology focuses on classification of bioactive compounds and their structural relationships to determine the smallest chemical probes that may serve as drug candidates. 1 Within a vast majority of drug precursors, chiral a-tertiary amines are privileged structures for being in the skeleton of many natural products and biologically active compounds. 2 Specifically, 3-aminooxindole moiety has been encountered as the core entity of many architecturally complex natural products and pharmaceuticals such as AG-041R gastrin/ CCK-B receptor agonist, 3a CRTH2 antagonist as anti-bacterial agent and an anti-tuberculosis agent, 3b vasopressin V 1b receptor antago- nist SSR-149,415 which is used in treatment of anxiety and depres- sion, 3c an anti-malarial agent NITD609, 3d HIV-1 protease inhibitor 3e and an anti-mycobacterial against M. tuberculosis H37Rv 3f (Fig. 1). Hence various stereoselective approaches for the construction of 3-amino-2-oxindole derivatives bearing a tetra- substituted stereocenter have been developed. 4 To the best of our knowledge, these synthetic strategies include asymmetric addition to isatin imines, 5 intramolecular a-arylation of amides, 6 alkylation of 3-aminooxindole, 7 amination of 3-substituted oxin- doles, 8 and multicomponent reaction. 9 Specifically, direct Mannich reaction in which an enolizable carbonyl compound reacts with isatin ketimine is one of direct methods to obtain 2-oxindole derived tertiary amines. 5d,10,11 Initially, Yan et al. 5d reported a study in which quinine-thiourea organocatalyst afforded https://doi.org/10.1016/j.tetlet.2017.12.081 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: tanyeli@metu.edu.tr (C. Tanyeli). Fig. 1. Representative examples of biologically active compounds containing 3- amino-2-oxindole skeleton. Tetrahedron Letters 59 (2018) 541–545 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet