Enantioselective organocatalytic cycloaddition reactions between enolisable anhydrides and imines Trinity College Dublin A thesis submitted to the University of Dublin for the degree of Doctor of Philosophy by Aarón Gutiérrez Collar, Under the supervision of Prof. Stephen Connon February 2019 Declaration I declare that this thesis has not been submitted as an exercise for a degree at this or any other university and it is entirely my own work. Due ackowledegments and references are given to the work of others I agree to deposit this thesis in the University’s open access institutional repository or allow the library to do so on my behalf, subject to Irish Copyright Legislation and Trinity College Library conditions of use and acknowledgement. Aarón Gutiérrez Collar S. A. Cronin, A. Gutiérrez Collar, S. Gundala, C. Cornaggia, E. Torrente, F. Manoni, A. Botte, B. Twamley and S. J. Connon, Org. Biomol. Chem., 2016, 14, 6955. A. Gutiérrez Collar, C. Trujillo and S. J. Connon, Chem. Eur. J., Accepted Introduction ..................................................................................................................... 1 1.1 Lactams ............................................................................................................... 1 1.1.1 Biological and medicinal relevance ...................................................................... 1 1.1.2 Principal methods of synthesis and associated challenges .................................... 2 1.1.2.1 Beckmann rearrangement .................................................................................... 3 1.1.2.2 Schmidt reaction with cyclic ketones ................................................................... 4 1.1.2.3 Staudinger synthesis ............................................................................................ 5 1.1.2.4 Halolactamisation ................................................................................................ 6 1.1.2.5 Ring-closing metathesis (RCM) ........................................................................... 7 1.1.2.6 Cycloaddition reactions between imines and enolisable anhydrides...................... 7 1.2 Mannich reaction ................................................................................................. 8 1.2.1 Asymmetric Mannich additions employing transition metals ............................... 8 1.2.2 Organocatalyatic asymmetric Mannich additions ............................................... 11 1.3 Cycloaddition reactions involving enolisable anhydrides ................................... 13 1.3.1 Reaction of enolisable anhydrides with aldehydes .............................................. 13 1.3.1.1 Perkin reaction ................................................................................................... 13 1.3.1.2 Pinder reaction ................................................................................................... 14 1.3.1.3 Asymmetric organocatalytic processes ............................................................... 15 1.3.2 Reaction of anhydrides with imines ................................................................... 17 1.3.2.1 Succinic anhydrides ........................................................................................... 17 1.3.2.2 Glutaric anhydrides ............................................................................................ 18 1.3.2.3 Homophthalic anhydrides .................................................................................. 19 1.3.2.4 Mechanistic proposals ........................................................................................ 21 1.3.2.4.1 Castagnoli’s proposal ......................................................................................... 21 1.3.2.4.2 Cushman’s proposal........................................................................................... 21 1.3.2.4.3 Shaw’s and Cheong’s proposal .......................................................................... 24 1.3.2.5 Applications of the cycloaddition reactions of imines with enolisable anhydrides ...........................................................................................................................25 1.3.2.6 Current advances in the organocatalytic asymmetric version ..............................27 1.3.3 Reaction with alkenes/alkynes: the Tamura cycloaddition ..................................28 1.3.3.1 Double-activated alkenes/alkynes .......................................................................28 1.3.3.1.1 Mechanistic considerations .................................................................................29 1.3.3.1.2 Application of the cycloaddition to the synthesis of biological active molecules .31 1.3.3.1.3 Asymmetric organocatalytic processes ...............................................................35 1.3.3.2 Mono-activated alkenes ......................................................................................37 1.3.3.2.1 Organocatalytic processes...................................................................................37 1.3.3.2.2 Reaction of homophthalic anhydride with ,-unsaturated imines ......................38 1.4 Objectives ..........................................................................................................41 Results and discussion ....................................................................................................42 2 Cycloaddition reactions between homophthalic anhydride and N- sulfonylimines catalysed by cinchona alkaloids ..............................................42 2.1 Preliminary results within our group ...................................................................42 2.2 Scope of the reaction ..........................................................................................45 2.2.1 Epimerisation problem and development of a new esterification protocol ...........45 2.2.2 Synthesis of catalysts and evaluation ..................................................................48 2.2.3 Expansion of the scope with respect to the electrophilic component: screening of imines.................................................................................................................53 2.3 A new substrate: cycloaddition reaction employing a cyclic imine ......................55 2.3.1 Catalyst screen ...................................................................................................61 2.3.2 Design of a new sulfonamide-based catalyst .......................................................67 2.4 Conclusions ........................................................................................................71 3 Asymmetric catalytic Tamura cycloaddition reaction between enolisable anhydrides and ,-unsaturated imines. .........................................................72 3.1 Preliminary results ..............................................................................................73 3.2 Screening of the catalytic conditions for the reaction ......................................... 74 3.2.1 Catalyst design and evaluation ........................................................................... 75 3.3 Expanding the scope of the reaction: the anhydride component .......................... 86 3.4 Expanding the scope of the reaction: the imine component ................................ 87 3.5 Rationalisation of the stereochemistry outcome ................................................. 91 3.6 Functionalisation of the catalytic product ........................................................... 94 3.7 Conclusions ....................................................................................................... 95 4 Cycloaddition reactions between succinic anhydrides and imines................. 96 4.1 Development of the catalytic process ................................................................. 96 4.2 Expanding the scope: the imine component........................................................ 99 4.3 Expanding the scope of the reaction: the anhydride component ........................ 102 4.4 Conclusions ..................................................................................................... 106 5 Experimental procedure and data ................................................................ 107 5.1 General information ...................................................................................... 107 5.2 Experimental data for Chapter 2 .................................................................. 108 5.2.1 General procedures .......................................................................................... 108 5.2.2 Synthesis of catalysts ....................................................................................... 109 5.2.3 Synthesis of anhydrides ................................................................................... 121 5.2.4 Synthesis of imines .......................................................................................... 124 5.2.5 Catalytic cycloaddition reactions between enolisable anhydrides and imines .... 128 5.3 Experimental data for Chapter 3 .................................................................. 142 5.3.1 General procedures .......................................................................................... 142 5.3.2 Synthesis of catalysts ....................................................................................... 144 5.3.3 Synthesis of anhydrides ..................................................................................