The Pennsylvania State University The Graduate School Department of Chemistry DESIGN AND SYNTHESIS OF CHIRAL LIGANDS AND THEIR APPLICATIONS IN TRANSITION METAL-CATALYZED ASYMMETRIC REACTIONS A Dissertation in Chemistry by Wei Li 2012 Wei Li Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2012 The dissertation of Wei Li was reviewed and approved* by the following: Gong Chen Assistant Professor of Chemistry Dissertation Advisor Chair of Committee Tom Mallouk Evan Pugh Professor of Material Chemistry and Physics Alex Radosevich Assistant Professor of Chemistry Qing Wang Associate Professor of Material Science and Engineering Xumu Zhang Professor of Chemistry Special Member Barbara J. Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry *Signatures are on file in the Graduate School iii ABSTRACT Transition metal catalyzed reactions are among the most powerful and direct approaches for the synthesis of organic molecules. During the past several decades, phosphorous-containing ligands have been extensively studied in transition metal - catalyzed transformations particularly asymmetric hydrogenations. Development of new chiral ligands and efficient catalyst systems for various prochiral unsaturated substrates in asymmetric hydrogenations are the focus of this dissertation. An important family of atropisomeric biaryl bisphosphine ligands, C3*-TunePhos and related bisaminophosphines have been designed and synthesized. The Ru catalysts of the highly modular C3*-TunePhos have been proved to be highly efficient (up to 99.8% ee, up to 1,000,000 TON) for practical asymmetric hydrogenations of a wide range of unfunctionalized ketones as well as α-, β- keto esters and N-2-substituted allylphthalimides. The synthetic utility of bisaminophosphine ligands was studied for rhodium-catalyzed asymmetric hydrogenations of α-dehydroamino acid esters, affording up to 98% ee’s. A new chiral tridentate NNN-type indan-Ambox ligand was designed and synthesized targeting the direct hydrogenation of unfunctionalized aryl and alkyl ketones. Successful examples of unfunctionalized ketone reduction in a enantioselective catalytic pathway display the potential of tridentate ligands in asymmetric catalysis. Another rational design and synthesis of PNP-type bulky chiral tridentate ligand was also fulfilled, yet it failed to provide superior enantioselectivity. To solve the problems of asymmetric hydrogenation of imines and heteroaromatics, a series of Ir- or Pd-based catalyst systems have been developed. Highly enantioselective and highly efficient hydrogenation of N- iv aryl imine, N-H imines, β-enamine esters, quinoline derivatives and unprotected indole derivatives have been successfully achieved respectively, with up to 98% ee and 10,000 TON. Catalyst systems containing strongly electron-donating and sterically hindered bisphosphine ligand have displayed significant advantages and will lead to more updated breakthroughs. Other examples of transition metal-catalyzed reactions such as Cu- catalyzed conjugate reduction of cyclic α,β-unsaturated ketones and Ru-catalyzed dynamic kinetic resolution of α-substituted cyclic ketones have also been investigated. Some preliminary results were discussed accordingly. v TABLE OF CONTENTS LIST OF FIGURES ..................................................................................................... vii LIST OF SCHEMES.................................................................................................... ix LIST OF TABLES ....................................................................................................... xi ACKNOWLEDGEMENTS ......................................................................................... xiii Chapter 1 Introduction and Background .................................................................... 1 1.1 Introduction ..................................................................................................... 1 1.2 Chiral Ligands for Asymmetric Hydrogenation ............................................. 2 1.3 Conclusion ...................................................................................................... 13 References and Notes ........................................................................................... 16 Chapter 2 Synthesis of C3*-TunePhos Chiral Diphosphine Ligands and Their Applications in Asymmetric Hydrogenation of Unfunctionalized Ketones and Ketoesters ............................................................................................................. 24 2.1 Introduction and Background ......................................................................... 24 2.1.1 Synthesis of BINAP and Its Derivatives .............................................. 25 2.1.2 Synthesis of Atropisomeric Biaryl Ligands ......................................... 27 2.1.3 General Strategies of Synthesizing of Atropisomeric Biaryl Ligands ................................................................................................... 29 2.2 Results and Discussion ................................................................................... 30 2.2.1 TunePhos and C3*-TunePhos Ligand Synthesis .................................. 30 2.2.2 Alternative Efficient Synthesis of C3*-TunePhos and Related Bisaminophosphine Ligands .................................................................. 37 2.2.3 Ru-C3*-TunePhos Catalyzed Asymmetric Hydrogenations ................ 39 2.2.4 Rh-Bisaminophosphine Catalyzed Asymmetric Hydrogenations ........ 47 2.3 Conclusion ...................................................................................................... 50 Experimental Section ............................................................................................ 51 References and Notes ........................................................................................... 68 Chapter 3 Synthesis of Chiral Tridentate Ligands and Their Application in Enantioselective Hydrogenation Unfunctionalized Ketones ................................ 74 3.1 Introduction and Background ......................................................................... 74 3.2 Results and Discussion ................................................................................... 77 3.2.1 Development of Indan-Ambox Ligand and Its Application in the Hydrogenation of Unfunctionalized Ketone .......................................... 77 vi 3.2.2 Synthesis of PNP-Type Ligand and Its Application in the Hydrogenation of Unfunctionalized Ketone .......................................... 86 3.3 Conclusion ...................................................................................................... 90 Experimental Section ............................................................................................ 90 References and Notes ........................................................................................... 104 Chapter 4 Ir-Catalyzed Asymmetric Hydrogenation of Imines, Enamine Esters and Heteroaromatics ............................................................................................. 109 4.1 Introduction and Background ......................................................................... 109 4.2 Results and Discussion ................................................................................... 111 4.2.1 Ir-Catalyzed Asymmetric Hydrogenation of N-Aryl Imines ................ 111 4.2.2 Ir-Catalyzed Asymmetric Hydrogenation of N-H Imines .................... 121 4.2.3 Ir-Catalyzed Asymmetric Hydrogenation of Unprotected β- Enamine Esters ....................................................................................... 129 4.2.4 Ir-Catalyzed Asymmetric Hydrogenation of Quinoline Derivatives .... 136 4.2.5 Pd-Catalyzed Asymmetric Hydrogenation of 2-Indole Derivatives .... 141 4.3 Conclusion ...................................................................................................... 144 Experimental Section ............................................................................................ 145 References and Notes ........................................................................................... 180 Chapter 5 Metal-Catalyzed Asymmetric Conjugate Reduction and Dynamic Kinetic Resolution ................................................................................................ 192 5.1 Introduction and Background ......................................................................... 192 5.1.1 Cu-Catalyzed Asymmetric Conjugate Reduction ................................ 192 5.1.2 Ru-Catalyzed Dynamic Kinetic Resolution ......................................... 195 5.2 Results and Discussion ................................................................................... 196 5.2.1 Cu-Catalyzed Asymmetric Conjugate Reduction ................................ 196 5.2.2 Structural Modification and Modified Ligand Synthesis ..................... 202 5.2.3 Ru-Catalyzed Dynamic Kinetic Resolution ......................................... 205 5.3 Conclusion ...................................................................................................... 208 Experimental Section ............................................................................................ 209 References and Notes ........................................................................................... 217 vii LIST OF FIGURES Figure 1-1: Early Development in Chiral Phosphorus Ligands. .................................