MIAMI UNIVERSITY The Graduate School Certificate for Approving the Dissertation We hereby approve the Dissertation of Yongming Deng Candidate for the Degree: Doctor of Philosophy Hong Wang, Advisor Michael Novak, Committee Chair Scott Hartley, Reader Shouzhong Zou, Reader Annette Bollmann, Graduate School Representative ABSTRACT ASYMMETRIC CYCLIZATION REACTIONS THROUGH AN ENAMINE/ACID COOPERATIVE APPROACH. SYNTHESIS OF UNSYMMETRICALLY FUNCTIONALIZED BENZOPORPHYRINS by Yongming Deng The combination of enamine catalysis with metal catalysis, aiming to achieve organic transformations that cannot be accessed by enamine catalysis or metal catalysis independently, promises huge potential. The major obstacle in the development of enamine/metal Lewis acid combining catalysis is the incompatibility of the catalysts. The goal of this research is to solve this long lasting challenge and develop powerful asymmetric catalysts. Chapter one will provide a brief introduction to asymmetric catalysis and combing catalysis of enamine catalysis with transition metal catalysis. In Chapter two, the first application of arylamines in enamine catalysis is presented. The incompatibility of enamine catalysts and metal Lewis acid is solved by applying arylamines/acids cooperative catalysis. Through combination with either a metal Lewis acid or a chiral phosphoric acid, arylamines successfully catalyzed the asymmetric aldol reaction of cyclohexanone with both isatin and enones. Additionally, a highly chemo- and enantioselective three-component aza-Diels-Alder reaction was developed by combining arylamines with metal Lewis acids. In Chapter three, we devise a new type of chiral Lewis-acid-assisted Lewis acid catalyst formed from a metal Lewis acid and a chiral metal phosphate (MLA/M[P]3-LLA). A highly chemo- and enantioselective three-component aza-Diels-Alder reaction of cylic ketones (5, 6, and 7 membered) was successfully achieved by in situ prepared MLA/M[P]3-LLA. Preliminary structural studies have revealed that these LLA catalysts have a bimetallic center with bridging phosphate ligands. The Lewis acidity and stereoselectivity of the MLA/M[P]3-LLA catalysts can be easily tuned by changing either the Lewis acid co-catalyst or the chiral metal phosphate component, forming either homobimetallic or heterobimetallic catalysts. In Chapter four, a trio catalysis system involving arylamines, BINOL-phosphoric acids, and metal Lewis acids is first disclosed. By using this trio catalyst, a series of optically active functionalized dihydropyridines was successfully synthesized through a highly chemo- and enantioselective three-component aza-Diels-Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine. In Chapter five, a series of unsymmetrically functionalized benzoporphyrins was successfully synthesized. ASYMMETRIC CYCLIZATION REACTIONS THROUGH AN ENAMINE/ ACID COOPERATIVE APPROACH. SYNTHESIS OF UNSYMMETRICALLY FUNCTIONALIZED BENZOPORPHYRINS A DISSERTATION Submitted to the Faculty of Miami University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry and Biochemistry by Yongming Deng Miami University Oxford, Ohio 2014 Dissertation Director: Hong Wang Table of Contents Chapter 1: Introduction ....................................................................................................... 1 1.1 Synthetic Approaches to Enantiopure Compounds .................................................. 1 1.1.1 Resolution .......................................................................................................... 2 1.1.2 Chiral Pool ......................................................................................................... 2 1.1.3 Chiral Auxiliary ................................................................................................. 3 1.1.4 Asymmetric Catalysis ........................................................................................ 3 1.1.4.1 Biocatalysis in Asymmetric Catalysis ........................................................ 4 1.1.4.2 Metallic Catalysis in Asymmetric Catalysis ............................................... 4 1.1.4.3 Organocatalysis ........................................................................................... 5 1.2 Cooperative Enamine-Transition Metal Catalysis .................................................. 10 1.2.1 Combination of an Aliphatic Amine with a Soft Metal: Soft/Hard Approach 11 1.2.1.1 Combination of an Aliphatic Amine with Pd(0 or II) ............................... 11 1.2.1.2 Combination of an Aliphatic Amine with Au(I) ....................................... 13 1.2.1.3 Combination of an Aliphatic Amine with Cu( I) ...................................... 14 1.2.1.4 Combination of an Aliphatic Amine with Ir( II) ....................................... 15 1.2.2 Bifunctional Amine/Metal Lewis Acid Catalysts ............................................ 16 1.3 Summary ................................................................................................................. 18 Acknowledgement: ....................................................................................................... 19 Reference: ..................................................................................................................... 19 Chapter 2: Arylamines Catalyze Enamine Formation: A New Tool for Cooperative Organo-Aminocatalysis and Acid Catalysis ..................................................................... 22 Acknowledgement: ....................................................................................................... 22 2.1 Introduction ............................................................................................................. 23 ii 2.2 Concept Design ....................................................................................................... 24 2.3 Results and Discussion ........................................................................................... 24 2.3.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction ................................ 24 2.3.1.1 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Isatin and Cyclohexanone ...................................................................................................... 24 2.3.1.2 Arylamine/Acid Catalyzed Asymmetric Aldol Reaction of Enone and Cyclic Ketones ...................................................................................................... 27 2.3.2 Three-Component Aza-Diels-Alder Reaction (ADAR) of Enones, Cyclic Ketones, and Arylamines .......................................................................................... 30 2.3.2.1 Racemic Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines ............................................................................................................ 32 2.3.2.2 Asymmetric Three-Component ADAR of Enones, Cyclic Ketones, and Arylamines ............................................................................................................ 33 2.3.2.3 Study of Catalytic Role of Arylamine ...................................................... 40 2.4 Conclusion .............................................................................................................. 41 2.5 Experiment Section ................................................................................................. 42 2.5.1 Reaction Set Up ............................................................................................... 42 2.5.2 Characterization Data and HPLC Conditions .................................................. 45 Copyright Permission.................................................................................................... 58 Reference: ..................................................................................................................... 59 Chapter 3: Enantioselective Lewis-Acid-Assisted Lewis Acid Catalysts Derived from Chiral Metal Phosphates: Three-Component Asymmetric ADARs of Cyclic Ketones ... 61 3.1 Introduction to Lewis Acid Assisted Lewis Aicd ................................................... 62 3.2 Results and Discussion ........................................................................................... 63 3.2.1 Development of Metal Lewis Acid-Assisted Metal Lewis Acid Catalysts (MCl3/M[P]3-LLA) ................................................................................................... 64 iii 3.2.2 M(OTf)3/M[P]3-LLA: Asymmetric Three-Component ADARs of Cyclopentanone and Cycloheptanone. ...................................................................... 69 3.2.3 Further Investigation of Metal Lewis Acid/Chiral Metal Phosphate LLA. ..... 74 3.2.3.1 The Effects of Metal Phosphate and Y2BINOL3 on Bimetallic LLA Catalytic System. .................................................................................................. 74 1 31 3.2.3.2 H and P NMR Spectroscopic Analysis of Y(OTf)3/Y[P]3-LLA Catalyst. ............................................................................................................................... 76 3.2.3.3 Preliminary Crystal Structure and MALDI-TOF Spectrometry of Y(OTf)3/Y[P]3-LLA. ............................................................................................. 80 3.3 Conclusion .............................................................................................................. 81 3.4 Experiment Section ................................................................................................